Assisting hand function after spinal cord injury with a fabric-based soft robotic glove.

BACKGROUND: Spinal cord injury is a devastating condition that can dramatically impact hand motor function. Passive and active assistive devices are becoming more commonly used to enhance lost hand strength and dexterity. Soft robotics is an emerging discipline that combines the classical principles of robotics with soft materials and could provide a new class of active assistive devices. Soft robotic assistive devices enable a human-robot interaction facilitated by compliant and light-weight structures. The scope of this work was to demonstrate that a fabric-based soft robotic glove can effectively assist participants affected by spinal cord injury in manipulating objects encountered in daily living. METHODS: The Toronto Rehabilitation Institute Hand Function Test was administered to 9 participants with C4-C7 spinal cord injuries to assess the functionality of the soft robotic glove. The test included object manipulation tasks commonly encountered during activities of daily living (ADL) and lift force measurements. The test was administered to each participant twice; once without the assistive glove to provide baseline data and once while wearing the assistive glove. The object manipulation subtests were evaluated using a linear mixed model, including interaction effects of variables such as time since injury. The lift force measures were separately evaluated using the Wilcoxon signed-rank test. RESULTS: The soft robotic glove improved object manipulation in ADL tasks. The difference in mean scores between baseline and assisted conditions was significant across all participants and for all manipulated objects. An improvement of 33.42 ± 15.43% relative to the maximal test score indicates that the glove sufficiently enhances hand function during ADL tasks. Moreover, lift force also increased when using the assistive soft robotic glove, further demonstrating the effectiveness of the device in assisting hand function. CONCLUSIONS: The results gathered in this study validate our fabric-based soft robotic glove as an effective device to assist hand function in individuals who have suffered upper limb paralysis following a spinal cord injury.

A portable inflatable soft wearable robot to assist the shoulder during industrial work.

Repetitive overhead tasks during factory work can cause shoulder injuries resulting in impaired health and productivity loss. Soft wearable upper extremity robots have the potential to be effective injury prevention tools with minimal restrictions using soft materials and active controls. We present the design and evaluation of a portable inflatable shoulder wearable robot for assisting industrial workers during shoulder-elevated tasks. The robot is worn like a shirt with integrated textile pneumatic actuators, inertial measurement units, and a portable actuation unit. It can provide up to 6.6 newton-meters of torque to support the shoulder and cycle assistance on and off at six times per minute. From human participant evaluations during simulated industrial tasks, the robot reduced agonist muscle activities (anterior, middle, and posterior deltoids and biceps brachii) by up to 40% with slight changes in joint angles of less than 7% range of motion while not increasing antagonistic muscle activity (latissimus dorsi) in current sample size. Comparison of controller parameters further highlighted that higher assistance magnitude and earlier assistance timing resulted in statistically significant muscle activity reductions. During a task circuit with dynamic transitions among the tasks, the kinematics-based controller of the robot showed robustness to misinflations (96% true negative rate and 91% true positive rate), indicating minimal disturbances to the user when assistance was not required. A preliminary evaluation of a pressure modulation profile also highlighted a trade-off between user perception and hardware demands. Finally, five automotive factory workers used the robot in a pilot manufacturing area and provided feedback.

Combining soft robotics and telerehabilitation for improving motor function after stroke.

Telerehabilitation and robotics, either traditional rigid or soft, have been extensively studied and used to improve hand functionality after a stroke. However, a limited number of devices combined these two technologies to such a level of maturity that was possible to use them at the patients' home, unsupervised. Here we present a novel investigation that demonstrates the feasibility of a system that integrates a soft inflatable robotic glove, a cloud-connected software interface, and a telerehabilitation therapy. Ten chronic moderate-to-severe stroke survivors independently used the system at their home for 4 weeks, following a software-led therapy and being in touch with occupational therapists. Data from the therapy, including automatic assessments by the robot, were available to the occupational therapists in real-time, thanks to the cloud-connected capability of the system. The participants used the system intensively (about five times more movements per session than the standard care) for a total of more than 8 hr of therapy on average. We were able to observe improvements in standard clinical metrics (FMA +3.9 ± 4.0, p < .05, COPM-P + 2.5 ± 1.3, p < .05, COPM-S + 2.6 ± 1.9, p < .05, MAL-AOU +6.6 ± 6.5, p < .05) and range of motion (+88%) at the end of the intervention. Despite being small, these improvements sustained at follow-up, 2 weeks after the end of the therapy. These promising results pave the way toward further investigation for the deployment of combined soft robotic/telerehabilitive systems at-home for autonomous usage for stroke rehabilitation.

Higher Expression of Annexin A2 in Metastatic Bladder Urothelial Carcinoma Promotes Migration and Invasion.

In this study, we aim to evaluate the significance of AnxA2 in BLCA and establish its metastatic role in bladder cancer cells. Analysis of TCGA data showed that AnxA2 mRNA expression was significantly higher in BLCA tumors than in normal bladder tissues. High mRNA expression of AnxA2 in BLCA was significantly associated with high pathological grades and stages, non-papillary tumor histology, and poor overall survival (OS), progression-free survival (PFS), and diseases specific survival (DSS). Similarly, we found that AnxA2 expression was higher in bladder cancer cells derived from high-grade metastatic carcinoma than in cells derived from low-grade urothelial carcinoma. AnxA2 expression significantly mobilized to the surface of highly metastatic bladder cancer cells compared to cells derived from low-grade tumors and associated with high plasmin generation and AnxA2 secretion. In addition, the downregulation of AnxA2 cells significantly inhibited the proliferation, migration, and invasion in bladder cancer along with the reduction in proangiogenic factors and cytokines such as PDGF-BB, ANGPT1, ANGPT2, Tie-2, bFGF, GRO, IL-6, IL-8, and MMP-9. These findings suggest that AnxA2 could be a promising biomarker and therapeutic target for high-grade BLCA.

Improving Grasp Function After Spinal Cord Injury With a Soft Robotic Glove.

People with tetraplegia resulting from spinal cord injury experience debilitating hand impairments that may lead to lifelong dependence on others to perform activities of daily living. Wearable robotic devices that actively support hand function during daily living tasks could bring great benefits to this population. In this work, the performance of a textile-based soft robotic glove controlled by the user with a button was evaluated in thirteen participants with tetraplegia. Performance outcomes included activities of daily living using the Jebsen Taylor Hand Function Test, active range of motion of the fingers, and grasp strength for power and pinch grasps. In the Jebsen Test, participants showed significant improvements in performance of activities of daily living with glove assistance, completing a median of 50% more tasks than in their baseline attempt without the glove. Significant improvements were also found for power and pinch grasp forces and active range of motion of the fingers with the glove assistance. Participants with lower baseline motor function received greater benefits from glove assistance. This work demonstrates the effectiveness of a user-controlled textile-based soft robotic glove to improve activity of daily living abilities in individuals with hand impairments resulting from spinal cord injury.

The slow Wallerian degeneration protein, WldS, binds directly to VCP/p97 and partially redistributes it within the nucleus.

Slow Wallerian degeneration (Wld(S)) mutant mice express a chimeric nuclear protein that protects sick or injured axons from degeneration. The C-terminal region, derived from NAD(+) synthesizing enzyme Nmnat1, is reported to confer neuroprotection in vitro. However, an additional role for the N-terminal 70 amino acids (N70), derived from multiubiquitination factor Ube4b, has not been excluded. In wild-type Ube4b, N70 is part of a sequence essential for ubiquitination activity but its role is not understood. We report direct binding of N70 to valosin-containing protein (VCP; p97/Cdc48), a protein with diverse cellular roles including a pivotal role in the ubiquitin proteasome system. Interaction with Wld(S) targets VCP to discrete intranuclear foci where ubiquitin epitopes can also accumulate. Wld(S) lacking its N-terminal 16 amino acids (N16) neither binds nor redistributes VCP, but continues to accumulate in intranuclear foci, targeting its intrinsic NAD(+) synthesis activity to these same foci. Wild-type Ube4b also requires N16 to bind VCP, despite a more C-terminal binding site in invertebrate orthologues. We conclude that N-terminal sequences of Wld(S) protein influence the intranuclear location of both ubiquitin proteasome and NAD(+) synthesis machinery and that an evolutionary recent sequence mediates binding of mammalian Ube4b to VCP.

Exploiting Textile Mechanical Anisotropy for Fabric-Based Pneumatic Actuators.

Knit, woven, and nonwoven fabrics offer a diverse range of stretch and strain limiting mechanical properties that can be leveraged to produce tailored, whole-body deformation mechanics of soft robotic systems. This work presents new insights and methods for combining heterogeneous fabric material layers to create soft fabric-based actuators. This work demonstrates that a range of multi-degree-of-freedom motions can be generated by varying fabrics and their layered arrangements when a thin airtight bladder is inserted between them and inflated. Specifically, we present bending and straightening fabric-based actuators that are simple to manufacture, lightweight, require low operating pressures, display a high torque-to-weight ratio, and occupy a low volume in their unpressurized state. Their utility is demonstrated through their integration into a glove that actively assists hand opening and closing.

Seroprevalence of Leptospira spp infection and its risk factors among domestic dogs in Bogotá, Colombia.

Different analytical tools were used to determine the seroprevalence of and risk factors associated with Leptospira spp infection in 192 domestic dogs (Canis familiaris) in Bogotá, Colombia. Using the microscopic agglutination test (MAT), a battery of 16 Leptospira serovars were tested. The seroprevalence of Leptospira spp was calculated as 36.46% (95% CI 0.30-0.43). A questionnaire was applied to the dogs' owners at the time of sampling and the variables "Water sources near home" and "Dog hunting rodents" were identified as risk factors for leptospirosis occurrence in the urban area of Bogotá. Geographical coordinates relating to the dogs' households were obtained in order to map out the spatial distribution of reactive and unreactive dogs. Additionally, we found that the mean annual precipitation was higher at geographical locations with reactive animals than at those with unreactive dogs (p < 0.05). Preventing exposure of dogs to rodents and waste-water bodies that could be contaminated with Leptospira might effectively reduce occurrences of leptospirosis. Moreover, promoting preventive programs and vaccination of dogs against leptospirosis in areas of higher precipitation and prior to rainy months could be an effective strategy for leptospirosis prevention.

The slow Wallerian degeneration gene, WldS, inhibits axonal spheroid pathology in gracile axonal dystrophy mice.

Axonal dystrophy is the hallmark of axon pathology in many neurodegenerative disorders of the CNS, including Alzheimer's disease, Parkinson's disease and stroke. Axons can also form larger swellings, or spheroids, as in multiple sclerosis and traumatic brain injury. Some spheroids are terminal endbulbs of axon stumps, but swellings may also occur on unbroken axons and their role in axon loss remains uncertain. Similarly, it is not known whether spheroids and axonal dystrophy in so many different CNS disorders arise by a common mechanism. These surprising gaps in current knowledge result largely from the lack of experimental methods to manipulate axon pathology. The slow Wallerian degeneration gene, Wld(S), delays Wallerian degeneration after injury, and also delays 'dying-back' in peripheral nervous system disorders, revealing a mechanistic link between two forms of axon degeneration traditionally considered distinct. We now report that Wld(S) also inhibits axonal spheroid pathology in gracile axonal dystrophy (gad) mice. Both gracile nucleus (P < 0.001) and cervical gracile fascicle (P = 0.001) contained significantly fewer spheroids in gad/Wld(S) mice, and secondary signs of axon pathology such as myelin loss were also reduced. Motor nerve terminals at neuromuscular junctions continued to degenerate in gad/Wld(S) mice, consistent with previous observations that Wld(S) has a weaker effect on synapses than on axons, and probably contributing to the fact that Wld(S) did not alleviate gad symptoms. Wld(S) acts downstream of the initial pathogenic events to block gad pathology, suggesting that its effect on axonal swelling need not be specific to this disease. We conclude that axon degeneration mechanisms are more closely related than previously thought and that a link exists in gad between spheroid pathology and Wallerian degeneration that could hold for other disorders.

The progressive nature of Wallerian degeneration in wild-type and slow Wallerian degeneration (WldS) nerves.

BACKGROUND: The progressive nature of Wallerian degeneration has long been controversial. Conflicting reports that distal stumps of injured axons degenerate anterogradely, retrogradely, or simultaneously are based on statistical observations at discontinuous locations within the nerve, without observing any single axon at two distant points. As axon degeneration is asynchronous, there are clear advantages to longitudinal studies of individual degenerating axons. We recently validated the study of Wallerian degeneration using yellow fluorescent protein (YFP) in a small, representative population of axons, which greatly improves longitudinal imaging. Here, we apply this method to study the progressive nature of Wallerian degeneration in both wild-type and slow Wallerian degeneration (WldS) mutant mice. RESULTS: In wild-type nerves, we directly observed partially fragmented axons (average 5.3%) among a majority of fully intact or degenerated axons 37-42 h after transection and 40-44 h after crush injury. Axons exist in this state only transiently, probably for less than one hour. Surprisingly, axons degenerated anterogradely after transection but retrogradely after a crush, but in both cases a sharp boundary separated intact and fragmented regions of individual axons, indicating that Wallerian degeneration progresses as a wave sequentially affecting adjacent regions of the axon. In contrast, most or all WldS axons were partially fragmented 15-25 days after nerve lesion, WldS axons degenerated anterogradely independent of lesion type, and signs of degeneration increased gradually along the nerve instead of abruptly. Furthermore, the first signs of degeneration were short constrictions, not complete breaks. CONCLUSIONS: We conclude that Wallerian degeneration progresses rapidly along individual wild-type axons after a heterogeneous latent phase. The speed of progression and its ability to travel in either direction challenges earlier models in which clearance of trophic or regulatory factors by axonal transport triggers degeneration. WldS axons, once they finally degenerate, do so by a fundamentally different mechanism, indicated by differences in the rate, direction and abruptness of progression, and by different early morphological signs of degeneration. These observations suggest that WldS axons undergo a slow anterograde decay as axonal components are gradually depleted, and do not simply follow the degeneration pathway of wild-type axons at a slower rate.

Quantitative and qualitative analysis of Wallerian degeneration using restricted axonal labelling in YFP-H mice.

We investigated the usefulness of YFP-H transgenic mice [Neuron 28 (2000) 41] which express yellow fluorescent protein (YFP) in a restricted subset of neurons to study Wallerian degeneration in the PNS. Quantification of YFP positive axons and myelin basic protein (MBP) immunocytochemistry revealed that YFP was randomly distributed to approximately 3% of myelinated motor and sensory fibres. Axotomy-induced Wallerian degeneration appeared as fragmentation of fluorescent signals in individual YFP positive axons with a morphology and timing similar to Wallerian degeneration observed by more traditional methods. In YFP-H transgenic mice co-expressing a high dosage of WldS, a chimeric gene that protects from Wallerian degeneration [Nat Neurosci. 4 (2001) 1199], axonal fragmentation in distal tibial nerves after sciatic nerve axotomy was approximately 10 times delayed. Considerable retardations of Wallerian degeneration using the same transgenic expression system were also observed in cultures of nerve explants, enabling in vitro real-time imaging of axonal fragmentation. Remarkably, single YFP-labelled axons could be traced in peripheral nerves for unusually long distances of up to 2.9 cm exploiting confocal fluorescence imaging. Altogether transgenic YFP-H mice prove to be a valuable tool to study mechanisms of Wallerian degeneration in vivo and in vitro.

Safety of vitamin D replacement in patients with primary hyperparathyroidism and concomitant vitamin D deficiency.

OBJECTIVE: To evaluate the safety of vitamin D replacement in patients with vitamin D deficiency and primary hyperparathyroidism. METHODS: Retrospective chart review of 35 patients from our endocrine clinic, age 22 to 89 years, diagnosed with primary hyperparathyroidism and vitamin D deficiency, and treated with either 1,000 to 2,000 international units (IU) of vitamin D daily or 50,000 IU of vitamin D weekly for 5 months. Data were collected before and after treatment on serum calcium, 25-hydroxyvitamin D (25-OH D), intact parathyroid hormone (iPTH), phosphorus, alkaline phosphatase, nephrolithiasis, fractures, and osteoporosis. RESULTS: 25-OH D increased significantly, from a baseline of 14.65 ± 6.57 ng/mL to 42.17 ± 12.98 ng/mL after weekly treatment with 50,000 IU of vitamin D (P<.0001), and from 22.42 ± 5.47 ng/mL to 33.33 ± 6.39 ng/mL following daily treatment with 1,000 to 2,000 IU of vitamin D (P<.0001). Pre- and posttreatment unadjusted serum calcium remained stable in the high-dose group (10.80 ± 0.43 mg/dL vs. 10.72 ± 0.67 mg/dL; P = .47), but decreased slightly in the low-dose group (10.76 ± 0.58 mg/dL vs. 10.11 ± 0.54 mg/dL; P = .0007). After adjusting for age, sex, vitamin D, and PTH levels, the small calcium difference in the low-dose group became statistically insignificant. Treatment with either high or low doses of vitamin D did not significantly change iPTH levels. Creatinine remained stable in all patients, and no new cases of nephrolithiasis were reported. CONCLUSION: Replacing vitamin D in mild primary hyperparathyroidism is safe, effective, and does not increase calcium to dangerous levels.

Reducing expression of NAD+ synthesizing enzyme NMNAT1 does not affect the rate of Wallerian degeneration.

NAD(+) synthesizing enzyme NMNAT1 constitutes most of the sequence of neuroprotective protein Wld(S), which delays axon degeneration by 10-fold. NMNAT1 activity is necessary but not sufficient for Wld(S) neuroprotection in mice and 70 amino acids at the N-terminus of Wld(S), derived from polyubiquitination factor Ube4b, enhance axon protection by NMNAT1. NMNAT1 activity can confer neuroprotection when redistributed outside the nucleus or when highly overexpressed in vitro and partially in Drosophila. However, the role of endogenous NMNAT1 in normal axon maintenance and in Wallerian degeneration has not been elucidated yet. To address this question we disrupted the Nmnat1 locus by gene targeting. Homozygous Nmnat1 knockout mice do not survive to birth, indicating that extranuclear NMNAT isoforms cannot compensate for its loss. Heterozygous Nmnat1 knockout mice develop normally and do not show spontaneous neurodegeneration or axon pathology. Wallerian degeneration after sciatic nerve lesion is neither accelerated nor delayed in these mice, consistent with the proposal that other endogenous NMNAT isoforms play a principal role in Wallerian degeneration.

A rat model of slow Wallerian degeneration (WldS) with improved preservation of neuromuscular synapses.

The slow Wallerian degeneration phenotype, Wld(S), which delays Wallerian degeneration and axon pathology for several weeks, has so far been studied only in mice. A rat model would have several advantages. First, rats model some human disorders better than mice. Second, the larger body size of rats facilitates more complex surgical manipulations. Third, rats provide a greater yield of tissue for primary culture and biochemical investigations. We generated transgenic Wld(S) rats expressing the Ube4b/Nmnat1 chimeric gene in the central and peripheral nervous system. As in Wld(S) mice, their axons survive up to 3 weeks after transection and remain functional for at least 1 week. Protection of axotomized nerve terminals is stronger than in mice, particularly in one line, where 95-100% of neuromuscular junctions remained intact and functional after 5 days. Furthermore, the loss of synaptic phenotype with age was much less in rats than in mice. Thus, the slow Wallerian degeneration phenotype can be transferred to another mammalian species and synapses may be more effectively preserved after axotomy in species with longer axons.

Proteasome inhibition arrests neurite outgrowth and causes "dying-back" degeneration in primary culture.

Proteasome inhibitors such as lactacystin were first isolated when assaying their ability to stimulate neurite outgrowth in neuronal-like cell lines; however, their effect on neurites in primary culture has been largely neglected. We report here that lactacystin causes immediate arrest of nerve growth factor (NGF)-stimulated neurite outgrowth in sympathetic and sensory explant cultures. This is followed by neurite degeneration that in sympathetic cultures has a distinctive "dying-back" morphology. Remarkably, this occurs even at concentrations below that required to induce neurite outgrowth in PC12 cells. Thus, lactacystin opposes rather than potentiates the effect of NGF on sympathetic neurite outgrowth and the role of the ubiquitin proteasome pathway in growth and long-term maintenance of axons and dendrites differs from that in neuritogenesis in neuronal-like cell lines. Retrograde degeneration caused by blocking of the ubiquitin proteasome pathway may mimic some aspects of gracile axonal dystrophy, a dying-back axonopathy in mice caused by ubiquitin hydrolase (Uch-l1) deficiency, and may be relevant to human neurodegenerative diseases involving ubiquitination or proteasome abnormalities.

Evaluación de la confiabilidad y la validez de un cuestionario breve de autoinforme para el diagnóstico de la fobia socia / Reliability and validity of a brief self-report questionnaire for the diagnosis of social phobia

El objetivo fue evaluar la confiabilidad y la validez de un cuestionario breve de autoinforme dirigido al diagnóstico de la fobia social, basado en los criterios diagnósticos de la Asociación Psiquiátrica Americana (2002), para lo cual se contó con una muestra incidental de 532 estudiantes vinculados a cuatro universidades privadas y una pública de la ciudad de Bogotá (Colombia), entre 15 y 42 años de edad (media de 21.1 años) y todos los estratos socioeconómicos. La confiabilidad del instrumento se evaluó a través de la técnica test-retest y se valoró su validez de contenido y su validez de constructo. El análisis estadístico de la confiabilidad realizado con 250 comparaciones (Spearman), arrojó una correlación positiva altamente significativa entre las puntuaciones test-retest, mientras que los análisis de la validez de constructo (Chi Cuadrado, Tau-b de Kendall y Spearman) mostraron correlaciones positivas altamente significativas entre el diagnóstico de fobia social y la obtención de una puntuación considerada alta en los tres instrumentos mencionados.

This investigation evaluated the reliability and validity of a brief self report questionnaire for the social phobia diagnosis (BSQ-SP), based upon the diagnostic criteria of the American Psychiatric Association (2002), withan intentional sample of 532 students of four private and one public universities of Bogotá (Colombia), aged 15 to 42 (average of 21.1 years) and coming from every socioeconomic strata. The reliability of the instrument was evaluated through of test-retest technique, with regards to content and construct validity. The statistical analysis of reliability carried out with250 comparisons (Spearman) shows a highly significant positive correlationamong the test-retest scores, while the analyses of the construct validity(Squared Chi, Tau-b of Kendall and Spearman) showed highly significantpositive correlations between the diagnosis of social phobia and the scoresconsidered high in the three mentioned instruments.