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Colorectal cancer (CRC) is one of the most common solid tumors worldwide. Recent evidence suggests that a population of cancer cells, called cancer stem cells (CSCs), is responsible for tumor heterogeneity, invasion, metastasis, therapeutic resistance, and recurrence of CRC. The isolation and characterization of CSCs using cell surface markers have been reported previously with varying results. In this study, we investigated a panel of four putative CSC markers, CD44, CD24, CD166, and EpCAM, to define CRC-CSC. Paraffin embedded tissue samples from different grades of primary, untreated CRC were analyzed for the expression of four CSC markers CD44, CD326, CD24, and CD166, using immunohistochemistry. Flow cytometric analysis of CRC-CSC from HT29 (low grade) and HCT116 (high grade) human colorectal cancer cell lines was done. Marker-based isolation of CSC and non-CSC-bulk-tumor cells from HT29 was done using FACS, and tumor sphere assay was performed. There was a statistically significant difference (p < 0.05) in the expression of CD44, CD326, and CD166 between cases and controls. A novel cutoff distribution of CD44 and CD166 was suggested to help for better immunohistochemical analysis of CRC. Higher prevalence of CSC was seen in high-grade CRC as compared to low-grade CRC. Sorted and cultured CD44 + CD166+ cells formed tumor spheres, suggesting that these cells, having properties of self renewal and anchorage independent proliferation, were in fact CSC. Hence, CD44 and CD166 may serve as good CRC-CSC markers when used together with novel cutoff immunohistochemistry (IHC) expression levels.

Quantitative gait analysis enables clinicians to evaluate patient mobility and to diagnose neuromuscular disorders. The clinical application of gait analysis is currently limited by the high operating costs of gait laboratories. The use of instrumented footwear that performs out of the lab measurements on subjects' walking patterns is a promising way to overcome this limitation. Besides serving as assessment tools, such devices can also act as retraining tools that help regulate a patient's gait with acoustic or vibrotactile stimuli.

The design of cable-driven manipulators is complicated by the unidirectional nature of the cables, which results in extra actuators and limited workspaces. Furthermore, the particular arrangement of the cables and the geometry of the robot pose have a significant effect on the cable tension required to effect a desired joint torque. For a sufficiently complex robot, the identification of a satisfactory cable architecture can be difficult and can result in multiply redundant actuators and performance limitations based on workspace size and cable tensions. This work leverages previous research into the workspace analysis of cable systems combined with stochastic optimization to develop a generalized methodology for designing optimized cable routings for a given robot and desired task. A cable-driven robot leg performing a walking-gait motion is used as a motivating example to illustrate the methodology application. The components of the methodology are described, and the process is applied to the example problem. An optimal cable routing is identified, which provides the necessary controllable workspace to perform the desired task and enables the robot to perform that task with minimal cable tensions. A robot leg is constructed according to this routing and used to validate the theoretical model and to demonstrate the effectiveness of the resulting cable architecture.

In this paper, we develop an intervention to apply external gait synchronized forces on the pelvis to reduce the user's effort during walking. A cable-driven robot was used to apply the external forces and an adaptive frequency oscillator scheme was developed to adapt the timing of force actuation to the gait frequency during walking. The external forces were directed in the sagittal plane to assist the trailing leg during the forward propulsion and vertical deceleration of the pelvis during the gait cycle. A pilot experiment with five healthy subjects was conducted. The results showed that the subjects applied lower ground reaction forces in the vertical and anterior-posterior directions during the late stance phase. In summary, the current work provides a novel approach to study the role of external pelvic forces in altering the walking effort. These studies can provide better understanding for designing exoskeletons and prosthetic devices to reduce the overall walking effort.

Objective: To study stress in fathers of preterm infants admitted in a neonatal intensive care unit., Methods: Questionnaire-based study. Questionnaire included domains on infants health, maternal illness, staff behavior, parental role, home affairs and finances. Eligible fathers were repeatedly interviewed on day 7 (n=80), day 17 (n=59) and day 27 (n=28). Raw and standardized stress scores were calculated., Results: Financial burden was the main stressor at all times. Stress related to staff behavior and altered parental role reduced with time. Birthweight and fathers age, occupation and education independently predicted stress., Conclusion: Fathers of preterm infants admitted in hospital are stressed, primarily due to financial burden.

Background: Osteoradionecrosis (ORN) of the temporal bone is a complication of radiation therapy that is extremely challenging to manage., Methods: We report the case of a patient treated at our institution and present a review of the literature., Results: A 52-year-old woman presented with ORN of the temporal bone 20 years after radiation therapy for an ipsilateral parotid tumor. She failed conservative management, including serial debridements, oral and topical antibiotics/antifungals, and aural lavage. As an alternative to hyperbaric oxygen (HBO) and/or temporal bone resection, treatment with pentoxifylline-tocopherol-clodronate combination (PENTOCLO) was pursued and her condition improved dramatically., Conclusion: This is the first document use of PENTOCLO to treat ORN of the temporal bone. PENTOCLO may represent an effective nonsurgical management option for ORN of the temporal bone., (© 2015 Wiley Periodicals, Inc.)

Background: Protein levels in cerebrospinal fluid (CSF) are commonly thought to be related to sterile shunt malfunction., Objective: To investigate the relationship between protein concentration and flow through CSF shunt tubing and a shunt valve., Methods: New and explanted shunt catheters were tested with and without a shunt valve attached at various protein concentrations. The protein concentrations used were 0.5, 2, 5, and 10 g/L. A flask with artificial CSF attached to the proximal end provided flow. The flow was allowed to stabilize over 1 hour, and then the change in pressure between the proximal and distal end of the catheter was measured and recorded. The resistance to flow was calculated for new and explanted catheters for adult shunt systems, as well as with the addition of a programmable siphon control valve. The resistance was examined after the addition of various protein concentrations to a normal CSF solution., Results: Both new and explanted catheters exhibited a decrease in the resistance to flow with higher concentrations of protein., Conclusion: In our laboratory setting, there was decreased resistance of adult CSF shunt catheters with and without a valve as the concentration of protein in the CSF increased. The decrease in the resistance of CSF shunt catheters with the addition of protein to the CSF may be related to the lowering of surface tension. This is the first study to examine the effects of varying protein concentrations across different lengths of shunt tubing for both new and explanted catheters.

This paper presents a method of stride identification, extraction, and analysis of data sets of time-series contact force data for ambulating subjects both with and without Parkinson's disease (PD). This method has been made robust with the use of seeded K-Means clustering, fast Fourier transformation (FFT) spectral analysis, and minimum window size rejection. These methods combine to produce well selected strides of active walking data. We are able to calculate quality of walking measures of stride duration, stance duration (as percent of gait cycle - %GC), swing duration (%GC), time to maximum heel force (%GC), time to maximum toe force (%GC), time spent in heel contact (%GC), and time spent in toe contact (%GC).

A novel robot-aided assist-as-needed gait training paradigm has been developed recently. This paradigm encourages subjects' active participation during training. Previous pilot studies demonstrated that assist-as-needed robot-aided gait training (RAGT) improves treadmill walking performance post-stroke. However, it is not known if there is an over-ground transfer of the training effects from RAGT on treadmill or long-term retention of the effects. The purpose of the current study was to examine the effects of assist-as-needed RAGT on over-ground walking pattern post-stroke. Nine stroke subjects received RAGT with visual feedback of each subject's instantaneous ankle malleolus position relative to a target template for 15 40-minute sessions. Clinical evaluations and gait analyses were performed before, immediately after, and 6 months post-training. Stroke subjects demonstrated significant improvements and some long-term retention of the improvements in their self-selected over-ground walking speed, Dynamic Gait Index, Timed Up and Go, peak knee flexion angle during swing phase and total hip joint excursion over the whole gait cycle for their affected leg . These preliminary results demonstrate that subjects improved their over-ground walking pattern and some clinical gait measures post-training suggesting that assist-as-needed RAGT including visual feedback may be an effective approach to improve over-ground walking pattern post-stroke.

Background: Myringotomy with tube insertion can be challenging for junior Otolaryngology residents as it is one of the first microscopic procedures they encounter. The Western myringotomy simulator was developed to allow trainees to practice microscope positioning, myringotomy, and tube placement. This virtual-reality simulator is viewed in stereoscopic 3D, and a haptic device is used to manipulate the digital ear model and surgical tools., Objective: To assess the face and content validity of the Western myringotomy simulator., Methods: The myringotomy simulator was integrated with new modules to allow speculum placement, manipulation of an operative microscope, and insertion of the ventilation tube through a deformable tympanic membrane. A questionnaire was developed in consultation with instructing surgeons. Fourteen face validity questions focused on the anatomy of the ear, simulation of the operative microscope, appearance and movement of the surgical instruments, deformation and cutting of the eardrum, and myringotomy tube insertion. Six content validity questions focused on training potential on surgical tasks such as speculum placement, microscope positioning, tool navigation, ear anatomy, myringotomy creation and tube insertion. A total of 12 participants from the Department of Otolaryngology-Head and Neck Surgery were recruited for the study. Prior to completing the questionnaire, participants were oriented to the simulator and given unlimited time to practice until they were comfortable with all of its aspects., Results: Responses to 12 of the 14 questions on face validity were predominantly positive. One issue of concern was with contact modeling related to tube insertion into the eardrum, and the second was with the movement of the blade and forceps. The former could be resolved by using a higher resolution digital model for the eardrum to improve contact localization. The latter could be resolved by using a higher fidelity haptic device. With regard to content validity, 64% of the responses were positive, 21% were neutral, and 15% were negative., Conclusions: The Western myringotomy simulator appears to have sufficient face and content validity. Further development with automated metrics and skills transference testing is planned.

Background: Despite the fact that otoscopy is a widely used and taught diagnostic tool during medical training, errors in diagnosis are common. Physical otoscopy simulators have high fidelity, but they can be expensive and only a limited number of students can use them at a given time., Objectives: 1) To develop a purely web-based otoscopy simulator that can easily be distributed to students over the internet. 2) To assess face and content validity of the simulator by surveying experts in otoscopy., Methods: An otoscopy simulator, OtoTrain™, was developed at Western University using web-based programming and Unity 3D. Eleven experts from academic institutions in North America were recruited to test the simulator and respond to an online questionnaire. A 7-point Likert scale was used to answer questions related to face validity (realism of the simulator), content validity (expert evaluation of subject matter and test items), and applicability to medical training., Results: The mean responses for the face validity, content validity, and applicability to medical training portions of the questionnaire were all ≤3, falling between the "Agree", "Mostly Agree", and "Strongly Agree" categories. The responses suggest good face and content validity of the simulator. Open-ended questions revealed that the primary drawbacks of the simulator were the lack of a haptic arm for force feedback, a need for increased focus on pneumatic otoscopy, and few rare disorders shown on otoscopy., Conclusion: OtoTrain™ is a novel, web-based otoscopy simulator that can be easily distributed and used by students on a variety of platforms. Initial face and content validity was encouraging, and a skills transference study is planned following further modifications and improvements to the simulator.

The success of locomotion training with robotic exoskeletons requires identifying control algorithms that effectively retrain gait patterns in neurologically impaired individuals. Here we report how the two training paradigms, performance-based error-augmentation versus error-reduction, modified walking patterns in four chronic post-stroke individuals as a proof-of-concept for future locomotion training following stroke. Stroke subjects were instructed to match a prescribed walking pattern template derived from neurologically intact individuals. Target templates based on the spatial paths of lateral ankle malleolus positions during walking were created for each subject. Robotic forces were applied that either decreased (error-reduction) or increased (error-augmentation) the deviation between subjects' instantaneous malleolus positions and their target template. Subjects' performance was quantified by the amount of deviation between their actual and target malleolus paths. After the error-reduction training, S1 showed a malleolus path with reduced deviation from the target template by 16%. In contrast, S4 had a malleolus path further away from the template with increased deviation by 12%. After the error-augmentation training, S2 had a malleolus path greatly approximating the template with reduced deviation by 58% whereas S3 walked with higher steps than his baseline with increased deviation by 37%. These findings suggest that an error-reduction force field has minimal effects on modifying subject's gait patterns whereas an error-augmentation force field may promote a malleolus path either approximating or exceeding the target walking template. Future investigation will need to evaluate the long-term training effects on over-ground walking and functional capacity.

In recent years, the authors have proposed lightweight exoskeleton designs for upper arm rehabilitation using multi-stage cable-driven parallel mechanism. Previously, the authors have demonstrated via experiments that it is possible to apply "assist-as-needed" forces in all directions at the end-effector with such an exoskeleton acting on an anthropomorphic machine arm. A human-exoskeleton interface was also presented to show the feasibility of CAREX on human subjects. The goals of this paper are to 1) further address issues when CAREX is mounted on human subjects, e.g., generation of continuous cable tension trajectories 2) demonstrate the feasibility and effectiveness of CAREX on movement training of healthy human subjects and a stroke patient. In this research, CAREX is rigidly attached to an arm orthosis worn by human subjects. The cable routing points are optimized to achieve a relatively large "tensioned" static workspace. A new cable tension planner based on quadratic programming is used to generate continuous cable tension trajectory for smooth motion. Experiments were carried out on eight healthy subjects. The experimental results show that CAREX can help the subjects move closer to a prescribed circular path using the force fields generated by the exoskeleton. The subjects also adapt to the path shortly after training. CAREX was also evaluated on a stroke patient to test the feasibility of its use on patients with neural impairment. The results show that the patient was able to move closer to a prescribed straight line path with the "assist-as-needed" force field.

Fasudil (HA-1077), a specific Rho kinase II (ROCKII) inhibitor, is in clinical trials for recovery from spinal cord injury (SCI). The primary role of Fasudil is in axonal regeneration, as it inhibits ROCKII, the key signaling molecule involved in collapse of axon growth cone. Astrogliosis, due to the activation of astrocytes is an indicator of CNS injury. In early stages of injury, GFAP expression increases, helping to restore the integrity of the CNS. An increase in GFAP expression is also a marker of astrogliosis. Thus, reducing GFAP and hence astrogliosis at later stages of SCI is important for neuroregeneration and functional recovery. CoCl2 was used to induce hypoxic injury in astrocytic cell lines A172 (24h) and in spinal cord dorsal column white matter (8h). Several different techniques were used to study the changes in GFAP expression such as real-time PCR, western blotting and immunofluorescence staining with confocal microscopy. Hypoxia increased the expression of GFAP in A172 cells and in the spinal cord dorsal column after CoCl2 (100μM) treatment for 24h and 8h, respectively. We observed 11 folds increase in protein expression in A172 cells (24h) and 4.5 folds in spinal cord dorsal column (8h). The RNA expression was increased 3 folds in A172 cells after 24h of treatment and 4 folds in spinal cord dorsal column after 8h of treatment with 100μM CoCl2. Treatment with fasudil (20μM) significantly reduces the expression of GFAP in A172 cells and in spinal cord dorsal column. Fasudil also decreased activation of NF-κB in A172 cells after hypoxic injury. In the present study, we observed that fasudil reduces the expression of GFAP (consequently, astrogliosis) after hypoxic injury to A172 cells and spinal cord dorsal column. Our studies demonstrate that fasudil also plays a role in GFAP expression by reducing NF-κB activation at the injury site which could further help in axonal regeneration., (Published by Elsevier Ireland Ltd.)

Self-initiated mobility is a causal factor in children's development. Previous studies have demonstrated the effectiveness of our training methods in learning directional driving and navigation. The ultimate goal of mobility training is to enable children to be social, that is, to interact with their peers. A powered mobility device was developed that can localize itself, map the environment, plan an obstacle-free path to a goal, and ensure safety of a human driver. Combined with a positioning system, this system is able to apply a force field using a modular haptic feedback approach to train subjects to drive towards an object, a caregiver, a peer, or a group of peers. System feasibility was tested by designing a 'ball chasing' game. Results show that the system is promising in promoting socialization in children.

In the past few years, the authors have proposed several prototypes of a C able-driven upper AR m EX oskeleton ( CAREX ) for arm rehabilitation. One of the assumptions of CAREX was that the glenohumeral joint rotation center (GH-c) remains stationary in the inertial frame during motion, which leads to inaccuracy in the kinematic model and may hamper training performance. In this paper, we propose a novel approach to estimate GH-c using measurements of shoulder joint angles and cable lengths. This helps in locating the GH-c center appropriately within the kinematic model. As a result, more accurate kinematic model can be used to improve the training of human users. An estimation algorithm is presented to compute the GH-c in real-time. The algorithm was implemented on the latest prototype of CAREX. Simulations and preliminary experimental results are presented to validate the proposed GH-c estimation method.

Now-a-days robotic exoskeletons are often used to help in gait training of stroke patients. However, such robotic systems have so far yielded only mixed results in benefiting the clinical population. Therefore, there is a need to investigate how gait learning and de-learning get characterised in brain signals and thus determine neural substrate to focus attention on, possibly, through an appropriate brain-computer interface (BCI). To this end, this paper reports the analysis of EEG data acquired from six healthy individuals undergoing robot-assisted gait training of a new gait pattern. Time-domain partial Granger causality (PGC) method was applied to estimate directed neural connectivity among relevant brain regions. To validate the results, a power spectral density (PSD) analysis was also performed. Results showed a strong causal interaction between lateral motor cortical areas. A frontoparietal connection was found in all robot-assisted training sessions. Following training, a causal "top-down" cognitive control was evidenced, which may indicate plasticity in the connectivity in the respective brain regions.

In this paper, we study the human locomotor adaptation to the action of a powered exoskeleton providing assistive torque at the user's hip during walking. To this end, we propose a controller that provides the user's hip with a fraction of the nominal torque profile, adapted to the specific gait features of the user from Winter's reference data . The assistive controller has been implemented on the ALEX II exoskeleton and tested on ten healthy subjects. Experimental results show that when assisted by the exoskeleton, users can reduce the muscle effort compared to free walking. Despite providing assistance only to the hip joint, both hip and ankle muscles significantly reduced their activation, indicating a clear tradeoff between hip and ankle strategy to propel walking.

The application of external constraints and/or applied forces during movement can lead to reactive as well as adaptive changes in human motion. Previous research has shown adaptation in walking kinematics when external forces were applied to a leg. This work aims to study adaptation in human walking when externally applied forces were present on the pelvis during the swing and stance phases of both legs. A novel tethered pelvic assist device (TPAD) was used to passively apply symmetric downward forces on the human pelvis while walking. During the experiment, eight healthy subjects walked on a treadmill at a constant speed while their kinematics and foot pressure data were recorded.

Previous work has shown that training with the "assist-as-needed" method using a force-feedback joystick can improve the driving performance of children and adults. This paper is the first study to evaluate training with a repelling force versus an assisting force for learning of a line following task in a wheelchair through a force-feedback joystick. We designed a robotic training wheelchair, that can accurately localize itself in the training environment, and implemented assisting and repelling force fields on the force-feedback joystick. The training protocol included three groups. The control (CT) group received no force feedback. The assisting force (AF) group was trained using the "assist-as-needed" paradigm. The repelling force (RF) group was trained with the repelling force field. We observed that both the AF and RF groups improved their driving skills. The error reductions of both groups were not statistically different under the current setting. We believe that this pilot study could provide a promising foundation regarding the effects of a robotic wheelchair training algorithm on motor learning.

Identifying noninvasive treatments to alleviate the symptoms of Parkinson's disease (PD) is important to improving the quality of life for those with PD. Several studies have explored the effects of visual, auditory, and vibratory cueing to improve gait in PD patients. Here, we present a wireless vibratory feedback system, called the PDShoe, and an associated intervention study with four subjects. The PDShoe was used on two control subjects, one subject with PD who experienced freezing of gait (FOG), and one subject with PD with an implanted deep brain stimulator (DBS). This short intervention study showed statistically significant improvements in peak heel pressure timing, peak toe pressure timing, time on the heel sensor, and stance to swing ratio after just one week of twice-daily therapy. Thus, step-synchronized vibration applied to the feet of patients with PD may be an effective way to improve gait in those subjects.

This study investigates how complementary auditory feedback may affect short-term gait modifications induced by four training sessions with a robotic exoskeleton. Healthy subjects walked on a treadmill and were instructed to match a modified gait pattern derived from their natural one, while receiving assistance by the robot (kinetic guidance). The main question we wanted to answer is whether the most commonly used combination of feedback (i.e., haptic and visual) could be either enhanced by adding auditory feedback or successfully substituted with a combination of kinetic guidance and auditory feedback. Participants were randomly assigned to one of four groups, all of which received kinetic guidance. The control group received additional visual feedback, while the three experimental groups were each provided with a different modality of auditory feedback. The third experimental group also received the same visual feedback as the control group. Differences among the training modalities in gait kinematics, timing and symmetry were assessed in three post-training sessions.

Background: Early treatment of spinal cord white matter injury has been found beneficial. H2S, a neurotransmitter is neuroprotective at lower doses., Purpose: In the present study the effect of NaHS after clip compression injury of spinal cord white matter in vivo was studied., Methods: The injury was induced in 8-10 weeks old Wistar rats by exposing the spinal cord at T8-T10 level by laminectomy and applying 35 g clip for 1 min. A dose of 50 µM NaHS was given intraperitoneally after 1h of injury. 0.5mm Spinal cord tissues were collected 8h after injury from both sides including epicenter and dorsal column was microdissected and used for further study., Results: NaHS treatment decreases nitric oxide (NO) by 27% and lipid peroxide (LPO) by 18% as compared to injury, which are hallmark of attenuation in oxidative stress. Western blots shows significant changes in Myeloperoxidase (MPO) level went down by 10%. GSH contents increased 44% in treated group as compared to the injury group. NaHS treatment increased Nrf-2 expression 1.8 times. We found NaHS treatment reduced the GFAP expression 8%, there was no significant changes in NF-200 after treatment and no evident morphological changes with H and E staining., Conclusions: With the above data we conclude that NaHS at 50 µM dose at 1h after injury reduces the NO, LPO, GFAP and MPO level at injury site by increasing the expression of Nrf-2. We expect that a decrease in these parameters during acute phase of spinal cord injury would be helpful in neuroprotection and regeneration., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Damage from oxidative stress plays a critical role in spinal cord injury. Nuclear factor erythroid 2-related factor (Nrf-2) signaling pathway can be activated by cellular oxidative stress. Resveratrol, a plant-derived polyphenolic compound found in red wine, has antioxidant properties. In the present study, we have examined the neuroprotective effect of resveratrol and the role of Nrf-2 in spinal cord hypoxic injury. The spinal cord was removed from adult male Wistar rats from T2-T10 and the dorsal column was used to induce hypoxic injury in vitro with and without treatment with resveratrol (50μM). Significant changes were found in the compound action potential (CAP) of spinal cord dorsal column, and hematoxyline and eosin (H&E) staining showed that resveratrol significantly improved neuronal injury. The biochemical assays showed significant changes in lipid peroxidase (LPO), reduced glutathione (GSH), superoxide dismutase (SOD), protein carbonyl (PC), mitochondrial ATP content, and mitochondrial Ca(++). Furthermore, using immunohistochemistry and Western blot, we found that after resveratrol treatment during hypoxic injury there was a significant activation of NrF-2 and down regulation of the glial fibrillary acidic protein (GFAP) content. The results show that resveratrol treatment has neuroprotective effects on CAP, Ca(++) loading, and biochemical parameters after hypoxic injury. The neuroprotective effect is likely to be exerted by increased activation of transcription factor Nrf-2 by resveratrol along with its direct antioxidant effect to ameliorate the oxidative damage and preserve mitochondrial function., (Published by Elsevier Ltd.)

Adipocytes play a vital role in glucose metabolism. 3T3 L1 pre adipocytes after differentiation to adipocytes serve as excellent in vitro models and are useful tools in understanding the glucose metabolism. The traditional approaches adopted in pre adipocyte differentiation are lengthy exercises involving the usage of IBMX and Dexamethasone. Any effort to shorten the time of differentiation and quality expression of functional differentiation in 3T3 L1 cells in terms of enhanced Insulin sensitivity has an advantage in the drug discovery process. Thus, there is a need to develop a new effective method of differentiating the pre adipocytes to adipocytes and to use such methods for developing efficacious therapeutic molecules. We observed that a combination of Dexamethasone and Troglitazone generated differentiated adipocytes over fewer days as compared to the combination of IBMX and Dexamethasone which constitutes the standard protocol followed in our laboratory. The experiments conducted to compare the quality of differentiation yielded by various differentiating agents indicated that the lipid droplet accumulation increased by 112 % and the GLUT4 mediated glucose uptake by 137 % in cells differentiated with Troglitazone and Dexamethasone than in cells differentiated traditionally. The comparative studies conducted for evaluating efficient measurable glucose uptake by GOPOD assay, radioactive (3)H-2-deoxy-D-glucose assay and by non-radioactive 6-NBDG (fluorescent analog of glucose) indicated that the non-radioactive method using 6-NBDG showed a higher signal to noise ratio than the conventional indirect glucose uptake method (GOPOD assay) and the radioactive (3)H-2-deoxy-D-glucose uptake method. Differentiated 3T3 L1 cells when triggered with 2.5 ng/mL of Insulin showed 3.3 fold more glucose uptake in non-radioactive method over the radioactive (3)H-2-deoxy-D-glucose uptake method. The results of this study have suggested that a combination of Dexamethasone and Troglitazone for 3T3 L1 cell differentiation helps in better quality differentiation over a short period of time with increased sensitivity to Insulin. The application of these findings for developing new methods of screening novel Insulin mimetics and for evaluating the immunological responses has been discussed.

Human nervous system is capable of modifying motor commands in response to alterations in walking conditions. Previous research has shown that external perturbations that induce gait asymmetry can lead to adaptation in gait parameters. Such strategies have also been shown to temporarily restore gait symmetry in subjects with post stroke hemiparesis. This work aims to develop an experimental paradigm to induce gait asymmetry in human subjects by applying external asymmetric forces on the pelvis through the Tethered Pelvic Assist Device (TPAD). These external forces on the pelvis have the potential to influence the swing and the stance phases of both legs. Eight healthy subjects participated in the experiment where a higher resistive force was applied on the pelvis during the swing phase of the left leg as compared to the right leg. We hypothesized that such asymmetrically applied forces on the pelvis will lead to asymmetric adaptation in the human walking.

Self-initiated mobility is a causal factor in children's development. Previous studies have demonstrated the effectiveness of our training methods in learning directional driving and navigation. The ultimate goal of mobility training is to enable children to be social, that is, to interact with peers. A powered mobility device was developed that can localize itself, map the environment, plan an obstacle-free path to a goal, and ensure safety of a human driver. Combined with a positioning system, this system is able to apply a force field to train subjects to drive towards an object, a caregiver, a peer, or a group of peers. System feasibility was tested by designing a 'ball chasing' game. Results show that the system is promising in promoting socialization in children.

Most of the control strategies embedded in recent robotic exoskeletons for rehabilitation and assistance are specific implementations of the well-known "assistance as needed" paradigm. A key point in the design of these systems is the requirement for the robot to exert negligible interaction forces to the wearer if he/she is performing well. Optimizing transparency of a device is a challenging task: various strategies have been proposed to achieve this goal, involving both the mechanical structure of the robot and the control algorithms. In this work, we propose a simple yet effective approach that requires minimal redesign efforts in the robotic structure and in the controller to be implemented on existing devices. We experimentally validate the method by comparing kinematic, kinetic and electromyo-graphic data collected from 3 healthy subjects as they walked in three different conditions: free treadmill walking, walking in a robotic trainer with a traditional zero-impedance configuration and walking in the same robot with the new zero-impedance configuration. Results show that the novel configuration was capable of effectively reducing the interaction forces and, as a consequence, it affected subjects' natural gait less than the traditional one did.

The quasi-static Young's modulus of the eardrum's pars tensa is an important modeling parameter in computer simulations. Recent developments in indentation testing and inverse modeling allow estimation of this parameter with the eardrum in situ. These approaches are challenging because of the curved shape of the pars tensa which requires special care during experimentation to keep the indenter perpendicular to the local surface at the point of contact. Moreover, they involve complicated contact modeling. An alternative computer-based method is presented here in which pressurization is used instead of indentation. The Young's modulus of a thin-shell model of the eardrum with subject-specific geometry is numerically optimized such that simulated pressurized shapes match measured counterparts. The technique was evaluated on six healthy rat eardrums, resulting in a Young's modulus estimate of 22.8±1.5MPa. This is comparable to values estimated using indentation testing. The new pressurization-based approach is simpler to use than the indentation-based method for the two reasons noted above., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Designing an upper extremity exoskeleton for people with arm weakness requires knowledge of the joint torques due to gravity and joint stiffness, as well as, active residual force capabilities of users. The objective of this research paper is to describe the characteristics of the upper limb of children with upper limb impairment. This paper describes the experimental measurements of the torque on the upper limb due to gravity and joint stiffness of three groups of subjects: able-bodied adults, able-bodied children, and children with neuromuscular disabilities. The experiment involves moving the arm to various positions in the sagittal plane and measuring the resultant force at the forearm. This force is then converted to torques at the elbow and shoulder. These data are compared to a two-link lumped mass model based on anthropomorphic data. Results show that the torques based on anthropometry deviate from experimentally measured torques as the arm goes through the range. Subjects with disabilities also maximally pushed and pulled against the force sensor to measure maximum strength as a function of arm orientation. For all subjects, the maximum voluntary applied torque at the shoulder and elbow in the sagittal plane was found to be lower than gravity torques throughout the disabled subjects' range of motion. This experiment informs designers of upper limb orthoses on the contribution of passive human joint torques due to gravity and joint stiffness and the strength capability of targeted users.

Objective: To determine the feasibility of measuring tympanic membrane (TM) vibrations at multiple locations on the TM to differentiate normal eardrums from those with associated ossicular pathologies., Design: Cadaveric human temporal bone study., Setting: Basic science laboratory., Methods: A mastoidectomy and facial recess approach was performed on four cadaveric temporal bones to obtain access to the ossicles without disrupting the TM. Ossicles were palpated to ensure normal mobility and an intact ossicular chain. Laser Doppler Vibrometry (LDV) measurements were then taken on all four TMs. LDV measurements were repeated on each TM following stapes footplate fixation, incudo-stapedial joint dislocation, and malleus head fixation., Main Outcome Measures: LDV measurements of TM vibration at the umbo, the lateral process of the malleus, and in each of the four quadrants of the TM., Results: The best signal-to-noise ratios were found between 2 and 4 kHz, at the umbo, the anterior superior quadrant, the anterior inferior quadrant, and the posterior inferior quadrant. Since our goal was to assess the ossicular chain, we selected the TM locations closest to the ossicular chain (the umbo and lateral process of the malleus) for further analysis. Differences could be seen between normals and the simulated ossicular pathologies, but values were not statistically significant., Conclusions: LDV measurements are technically challenging and require optimization to obtain consistent measurements. This study demonstrates the potential of LDV to differentiate ossicular pathologies behind an intact tympanic membrane. Future studies will further characterize the clinical role of this diagnostic modality.

Effective locomotion training with robotic exoskeletons requires identification of optimal control algorithms to better facilitate motor learning. Two commonly employed training protocols emphasize use of training stimuli that either augment or reduce performance errors. The current study sought to identify which of these training strategies promote better short-term modification of a typical gait pattern in healthy individuals as a framework for future application to neurologically impaired individuals. Ten subjects were assigned to each of a performance-based error-augmentation or error-reduction training group. All subjects completed a 45-min session of treadmill walking at their preferred speed with a robotic exoskeleton. Target templates prescribed an ankle path for training that corresponded to an increased step height. When subjects' instantaneous ankle positions fell below the inferior virtual wall of the target ankle path, robotic forces were applied that either decreased (error-reduction) or increased (error-augmentation) the deviation from the target path. When the force field was turned on, both groups walked with ankle paths better approximating the target template compared to baseline. When the force field was removed unexpectedly during catch and post-training trials, only the error-augmentation group maintained an ankle path close to the target ankle path. Further investigation is required to determine if a similar training advantage is provided for neurologically impaired individuals., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objectives: Cellular adhesion on the surface of Guglielmi detachable coils (GDC) promotes accelerated occlusion of aneurysms. We hypothesized that coils coated with transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF) will promote clot organization and endothelial or cellular proliferation to facilitate closure of large experimental aneurysms relative to uncoated GDC coils., Methods: GDC were inserted either uncoated, coated with albumin, coated with TGF-beta (500 μg/ml) or with VEGF (500 μg/ml) into the ligated common carotid artery of adult male wistar rats for 14 days. Twenty-four adult male Wistar rats (280-300 g) were divided into four groups (n = 6 per group). Subjects were killed 2 weeks after implantation and common carotid artery (CCA) segments were harvested and coils were removed. Arterial tissue was evaluated histopathologically., Results: Significant differences in the proportion of aneurysm luminal area (mm(2)) was shown among Group i (0·22±0·14 SD) and Group ii (0·16±0·8 SD) compared to Group iii (0·04±0·03 SD; P<0·05), and Group iv (0·02±0·02 SD; P<0·05) analyzed 2 weeks postoperatively. Light microscopy showed well organized fibrous tissue formation of epithelial cells and intimal hyperplasia around the coils when using the coated GDC's (Group iii and Group iv)., Conclusion: The result of this study suggests that the coated GDC with TGF-beta or VEGF appears beneficial in promoting endothelization, clot organization, and cellular tissue integration of the coils.

Objectives/hypothesis: Patulous eustachian tube remains a challenging management problem in otolaryngology. The autophony experienced by this patient population can be severe, and as yet no reliable surgical method exists to reduce or eliminate this annoying symptom. Our objective was to develop a novel endoscopic technique to assist these patients., Study Design: Longitudinal case series., Methods: A prospective longitudinal study was conducted of a series of consecutive patients undergoing surgery for patulous eustachian tube. Under transnasal endoscopic guidance, using a combination of fat plugging, endoluminal cauterization, and suture ligation, 14 ears underwent surgical treatment during a 4-year period. The main outcome measure assessed was the level of autophony present after surgery as compared to baseline. Audiometric outcomes, surgical time, and complications were also recorded., Results: There was sustained satisfactory subjective improvement in the autophony in 12 of the 14 ears (85.7%) at primary surgery, with nine of these 12 ears (75%) demonstrating full autophony cessation. Wilcoxon signed rank test showed a significant improvement in autophony in the study population compared to baseline (z = 3.16, P < .001). The mean operating length of time per ear over the full duration of our series was approximately 45 minutes. Postoperative audiometry showed that surgery had no impact on hearing., Conclusions: Multilayer endoscopic ligation of the patulous eustachian tube resulted in a high autophony improvement rate. The procedure is technically straightforward, and results were sustained at 6-month follow-up., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure.

Purpose of Review: To highlight the recent advances in the understanding of the diagnosis and management of viral inner ear disorders. Congenital sensorineural hearing loss (cSNHL), sudden sensorineural hearing loss (SSNHL), Ménière's disease, and vestibular neuritis/viral labyrinthitis are discussed., Recent Findings: Cytomegalovirus infection during pregnancy is an under-recognized cause of hearing loss and central nervous system disease amongst the general population. Prevention of maternal infection and treatment of affected newborns with ganciclovir are promising interventions. Recent evidence in SSNHL patients has resulted in recommendations against viral serology or the use of antivirals. There appears to be an increased risk of SSNHL in patients with comorbid hypertension and diabetes. The viral hypothesis of Ménière's disease remains unproven. In patients with an acute episode of vestibular neuritis, there is presently not sufficient evidence to support the routine use of corticosteroids or antiviral medications., Summary: cSNHL remains the most clearly defined of the viral inner ear disorders. The evidence for viral involvement in SSNHL, Ménière's disease, and vestibular neuritis is indirect and equivocal. This review highlights the recent advancements in the diagnosis and management of these disorders.

Objectives/hypothesis: Transmastoid occlusion of the superior semicircular canal in superior semicircular canal dehiscence (SSCD) syndrome and the posterior semicircular canal in intractable benign paroxysmal positional vertigo (BPPV) will produce resolution of preoperative symptoms., Study Design: Retrospective review, quality assurance., Methods: Sixteen patients with SSCD and 61 patients (65 ears) with intractable BPPV who underwent canal occlusion were reviewed. All patients underwent occlusion of the affected semicircular canal through a transmastoid approach., Results: Preoperative symptoms (vestibular, 13 patients; pulsatile tinnitus, 2 patients; or hyperacusis, 1 patient) were greatly improved or completely resolved in 15 of the 16 SSCD patients who underwent transmastoid occlusion of the superior canal. Hearing was preserved in 14 patients and improved in two patients. Vestibular symptoms were resolved in all intractable BPPV patients who underwent transmastoid occlusion of the posterior canal. One patient had a late recurrence of atypical BPPV. Almost all BPPV patients with normal preoperative hearing have an initial transient postoperative hearing loss, which when tested for is usually a mild to moderate mixed loss. Delayed sensorineural hearing loss was noted in three patients; one loss was profound whereas two were mild., Conclusions: The transmastoid approach to canal plugging is successful in the treatment of symptoms in both SSCD and intractable BPPV, and is a familiar approach for the otologist. This is a viable alternative to the middle fossa approach for SSCD, thereby avoiding a craniotomy. Transmastoid is the definitive approach for posterior canal occlusion., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Objectives/hypothesis: Surgical simulation is becoming an increasingly common training tool in residency programs. The first objective was to implement real-time soft-tissue deformation and cutting into a virtual reality myringotomy simulator. The second objective was to test the various implemented incision algorithms to determine which most accurately represents the tympanic membrane during myringotomy., Study Design: Descriptive and face-validity testing., Methods: A deformable tympanic membrane was developed, and three soft-tissue cutting algorithms were successfully implemented into the virtual reality myringotomy simulator. The algorithms included element removal, direction prediction, and Delaunay cutting. The simulator was stable and capable of running in real time on inexpensive hardware. A face-validity study was then carried out using a validated questionnaire given to eight otolaryngologists and four senior otolaryngology residents. Each participant was given an adaptation period on the simulator, was blinded to the algorithm being used, and was presented the three algorithms in a randomized order., Results: A virtual reality myringotomy simulator with real-time soft-tissue deformation and cutting was successfully developed. The simulator was stable, ran in real time on inexpensive hardware, and incorporated haptic feedback and stereoscopic vision. The Delaunay cutting algorithm was found to be the most realistic algorithm representing the incision during myringotomy (P < .05). The Likert and visual analog scales had strong correlations, suggesting good internal reliability., Conclusions: The first virtual reality myringotomy simulator is being developed and now integrates a real-time deformable tympanic membrane that appears to have face validity. Further development and validation studies are necessary before the simulator can be studied with respect to training efficacy and clinical impact., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Objective: Calcium overloading is responsible for initiating the cell death in neuronal tissue after hypoxic injury. Inositol 1,4,5-triphosphate receptors (IP3Rs) is an important calcium channel which regulates cellular calcium homeostasis. IP3R1 is widely expressed in brain and spinal tissue. In the present study, we have studied the regulation of IP3R1 in hypoxic/reperfusion injury of spinal cord dorsal column in vitro., Methods: Dorsal columns were isolated from the spinal cord of adult rats and injury was induced by exposing to hypoxic condition for 1 hour. After injury, reperfusion was carried out for 0, 2, 4, and 8 hours. Tissues were collected and processed for western blotting, immunohistochemistry and real-time PCR., Results: In the present study, we have found increased expression of IP3R1 after hypoxic/reperfusion injury of spinal cord dorsal column in vitro. Maximum expression of IP3R1 has been seen at 4 hours after hypoxia. Double immunofluorescence studies show the localization of IP3R1 in axons and astrocytes. Further identifying the signaling pathway involved in the regulation, we found Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-62 and c-Jun N-terminal kinase (JNK) inhibitor SP600125 reduced the expression of IP3R1 suggesting the role of CaMKII and JNK in the regulation of IP3R1 expression. We did not find role of ERK and p38 in the regulation IP3R1 expression in hypoxic/reperfusion injury of dorsal column in vitro., Discussion: The result presented in this study showed that IP3R1 expression is increased in hypoxic/reperfusion injury of spinal cord white matter and it is regulated by the CaMKII-JNK pathway.

Calcium influx into cells is responsible for initiating the cell death in neuronal tissue after hypoxic injury. Changes in intracellular calcium with subsequent increased expression of ryanodine receptor 2 (RyR2) are hypothesized to cause cell death after hypoxic injury. In the present study we have examined the time-dependent changes of RyR2 expression in hypoxic/reperfusion injury of spinal cord dorsal column. In this study we used western blotting, real time PCR (RT-PCR) and immunohistochemistry to examine changes in protein and gene expression of RyR2 after spinal cord injury (SCI) in the rat. Quantitative immunoblotting showed increase in the expression of RyR2 at 4 h during hypoxic/reperfusion injury of dorsal column. Moreover, RT-PCR showed 36-fold increases in mRNA of RyR2 after 4 h of hypoxic injury of white matter. By double immunofluorescence staining, RyR2 was localized on axons and astrocytes in the white matter of the spinal cord. After treatment with KN-62; (inhibitor of CaMKII) and SP600125 (inhibitor of JNK), there is a significant reduction in the expression of RyR2, indicating the role of these molecules in RyR2 regulation. Further removal of extracellular calcium does not have significant effect on RyR2 expression and phosphorylation of CaMKII, which was further confirmed by treatment with intracellular Ca(++) chelator BAPTA-AM. Finally, bioassay with quantitative analysis showed that treatment with inhibitor significantly reduced the cellular oxidative stress suggesting RyR2 is responsible for increased cellular oxidative load. In summary, we provide evidence that RyR2 gene and protein expression in astrocyte and axons is markedly increased after hypoxic injury. Further CaMKII/JNK pathway upregulates RyR2 expression after hypoxic injury. Therefore we propose that inhibitors of CaMKII/JNK pathway would reduce the cellular oxidative load and thereby have a neuroprotective role.

Object: Cerebrospinal fluid shunt systems malfunction for a multitude of reasons, including malpostitioning, obstruction of the ventricular or distal catheter, obstruction of the shunt valve, and catheter disruptions or disconnections. The goal of this study was to examine the hydrodynamic resistance and flow in new and explanted catheters and also in catheters with 1 or 2 straight connectors., Methods: Explanted catheters of multiple lengths, 2-piece catheters, 3-piece catheters, and new catheters were attached to a proximal and distal manometer. A flask with artificial CSF attached to the proximal end provided flow. The flow was allowed to stabilize over 1 hour; then the change in pressure between the proximal and distal end of the catheter was measured., Results: The resistance to flow was calculated for new, never-implanted catheters and compared with the resistance of explanted distal shunt catheters. The resistance of the new catheters was examined after the addition of 1 and 2 straight connectors. Explanted catheters exhibited a slight increase in the resistance to flow of artificial CSF compared with new catheters. Two-piece and 3-piece catheters had a significant increase in resistance to flow compared with new catheters. For all catheters, resistance to flow increased as length increased (new, p = 0.01; explanted, p = 0.009; 1 connector, p = 0.01; 2 connectors, p = 0.03). In this paper, effective diameter is defined as the available cross-sectional area of catheter contacted by the artificial CSF. For new and explanted catheters, a decrease in the effective diameter of the catheter was associated with an increase in the resistance to flow of artificial CSF (new, p = 0.1083; explanted, p = 0.0091). However, after the addition of 1 or 2 connectors, an inverse trend was observed: resistance to flow increased with effective diameter., Conclusions: There appears to be some increase in resistance of CSF shunt catheters as they age, altering flow dynamics. In addition, the use of straight connectors within a CSF shunt system increases the resistance to flow of artificial CSF within the shunt system. The increase in resistance appears to be related to the duration of implantation and the length of the catheter and inversely related to the diameter of the catheter. This increase in resistance may be related to sterile shunt malfunction. The addition of straight connectors is associated with a significant increase in resistance in comparison with catheters without connectors (p = 0.005).

In the present study root extracts of Schleichera oleosa were prepared and analysed for hydroxyl radical scavenging potential in different in vitro models, such as deoxyribose degradation (site-specific and non-site specific) and plasmid nicking assays. The extracts were found to have profound effects in both assays by scavenging of hydroxyl radicals. The extracts were also assessed for in vitro cytotoxicity in a sulphorhodamine B dye assay against a panel of cell lines representing different types of human cancers and tissues, wherein the methanol, ethyl acetate and water extracts were found to effectively inhibit the growth of selective cell lines. The results of the present study suggests the presence of antioxidant constituents in the methanol and ethyl acetate extracts of the roots of S. oleosa, results which are in concurrence with preliminary ¹H NMR and IR studies that suggest the presence of polyphenolic compounds.

The application of external constraints and/or applied forces during movement can lead to reactive as well as adaptive changes in human motion. Previous researches in the literature have usually focused on adaptation in human kinematics when external forces were applied using exoskeletons during the swing phase of gait. This work aims to study adaptation in human walking when externally applied forces are present on the pelvis both during the swing and stance phases of the gait. A novel tethered pelvic assist device (TPAD) was used to passively apply downward forces on the human pelvis while walking. During the experiment, healthy subjects walked on a treadmill at a constant speed while their kinematics and foot pressure data were recorded. Data analysis revealed that the healthy subjects exhibited both reactive as well as adaptive changes in their gait parameters. The immediate response of the subjects was to increase their hip flexion to clear their foot off the ground as they were unable to lift their pelvis to their usual height during normal motion. Seven out of eight subjects in the study resisted the downward forces to move their pelvis up. Eventually, they reached a level of downward force that they could sustain over the training. This adaptation to the downward force was reflected in the heel peak pressure values during the cycles of the gait. On removing the tethers, aftereffects in heel peak pressure during the gait cycles were observed.

The broader goal of our research is to train infants with special needs to safely and purposefully drive a mobile robot to explore the environment. The hypothesis is that these impaired infants will benefit from mobility in their early years and attain childhood milestones, similar to their healthy peers. In this paper, we present an algorithm and training method using a force-feedback joystick with an "assist-as-needed" paradigm for driving training. In this "assist-as-needed" approach, if the child steers the joystick outside a force tunnel centered on the desired direction, the driver experiences a bias force on the hand. We show results with a group study on typically developing toddlers that such a haptic guidance algorithm is superior to training with a conventional joystick. We also provide a case study on two special needs children, under three years old, who learn to make sharp turns during driving, when trained over a five-day period with the force-feedback joystick using the algorithm.

This paper presents a novel assistive control for lower limb exoskeletons. The controller provides the user with a scaled version of the Winter's nominal torque profile, which is adapted online to the specific gait features of the user. The proposed assistive controller is implemented on the ALEX II exoskeleton and tested on two healthy subjects. Experimental results show that when assisted by the exoskeleton users can reduce the muscle effort compared to free walking.

An upper-arm wearable exoskeleton has been designed for the assistance and functional training of humans. One of the goals of this design is to provide passive assistance to a user by gravity balancing, while keeping the transmitted forces to the shoulder joints at a minimum. Consistent with this goal, this paper discusses: analytical gravity balancing design conditions for the structure of the exoskeleton; a possible implementation of these conditions into practical designs; the minimization of transmitted joint forces to the shoulder while satisfying the gravity balancing conditions; the numerical optimization of the system for gravity balancing and minimization of transmitted forces; and the effect of parameter variation on joint moments and joint forces via numerical optimization. An implementation of the design was undertaken using zero-free-length springs. The design idea presented in this paper may be useful in relieving the actuators effort of exoskeletons to support the weight of the arm and therefore the possibility of using small actuators and making the system light and portable or even a stand-alone passive support device can be developed based on these gravity balancing conditions.