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The rate of upper-limb amputations is increasing, and the rejection rate of prosthetic devices remains high. People with upper-limb amputation do not fully incorporate prosthetic devices into their activities of daily living. By understanding the reaching behaviors of prosthesis users, researchers can alter prosthetic devices and develop training protocols to improve the acceptance of prosthetic limbs. By observing the reaching characteristics of the nondisabled arms of people with amputation, we can begin to understand how the brain alters its motor commands after amputation. We asked subjects to perform rapid reaching movements to two targets with and without visual feedback. Subjects performed the tasks with both their prosthetic and nondisabled arms. We calculated endpoint error, trajectory error, and variability and compared them with those of nondisabled control subjects. We found no significant abnormalities in the prosthetic limb. However, we found an abnormal leftward trajectory error (in right arms) in the nondisabled arm of prosthetic users in the vision condition. In the no-vision condition, the nondisabled arm displayed abnormal leftward endpoint errors and abnormally higher endpoint variability. In the vision condition, peak velocity was lower and movement duration was longer in both arms of subjects with amputation. These abnormalities may reflect the cortical reorganization associated with limb loss. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis Type IIIA (MPSIIIA) is a rare inherited lysosomal storage disease caused by mutations in the SGSH gene. This genetic variation results in the deficiency of the N-sulfoglucosamine sulfohydrolase enzyme, preventing the breakdown of heparan sulfate within lysosomes. The progressive accumulation of partially degraded substrate ultimately leads to brain pathology, for which there is currently no approved treatment. An established MPSIIIA mouse model has proved to be a vital asset to test several brain-targeting strategies. Nonetheless, the assessment of human stem cell-based products, an emerging research field, necessitates the use of an immunocompromised xenogeneic disease model. In the present study, we addressed this issue by generating a highly immunodeficient mouse model of MPSIIIA (NOD/SCID/GammaC chain null-MPSIIIA) through five generations of crossing an established MPSIIIA mouse model and a NOD/SCID/GammaC chain null (NSG) mouse. The immune system composition, behavioural phenotype and histopathological hallmarks of the NSG-MPSIIIA model were then evaluated. We demonstrated that NSG-MPSIIIA mice display compromised adaptive immunity, ultimately facilitating the successful engraftment of human iPSC-derived neural progenitor cells in the brain up to three months post-delivery. Furthermore, female NSG-MPSIIIA exhibit spatial working memory deficits and hyperactive behaviour, similar to MPSIIIA mice, which usually manifest around 5 months of age. NSG-MPSIIIA mice also developed primary disease-related neuropathological features in common with the MPSIIIA model, including lysosomal enlargement with storage of excess sulphated heparan sulphate and increased gliosis in several areas of the brain. In the future, the NSG-MPSIIIA mouse model holds the potential to serve as a valuable platform for evaluating human stem-cell based therapies for MPSIIIA patients., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Mucopolysaccharidosis type IIIA (MPS IIIA) is a rare paediatric lysosomal storage disorder, caused by the progressive accumulation of heparan sulphate, resulting in neurocognitive decline and behavioural abnormalities. Anecdotal reports from paediatricians indicate a more severe neurodegeneration in MPS IIIA patients, following infection, suggesting inflammation as a potential driver of neuropathology. To test this hypothesis, we performed acute studies in which WT and MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C). The challenge with an acute high poly(I:C) dose exacerbated systemic and brain cytokine expression, especially IL-1β in the hippocampus. This was accompanied by an increase in caspase-1 activity within the brain of MPS IIIA mice with concomitant loss of hippocampal GFAP and NeuN expression. Similar levels of cell damage, together with exacerbation of gliosis, were also observed in MPS IIIA mice following low chronic poly(I:C) dosing. While further investigation is warranted to fully understand the extent of IL-1β involvement in MPS IIIA exacerbated neurodegeneration, our data robustly reinforces our previous findings, indicating IL-1β as a pivotal catalyst for neuropathological processes in MPS IIIA., (© 2024. The Author(s).)

Mucopolysaccharidosis type II (MPSII) is a rare pediatric X-linked lysosomal storage disease, caused by heterogeneous mutations in the iduronate-2-sulfatase ( IDS ) gene, which result in accumulation of heparan sulfate (HS) and dermatan sulfate within cells. This leads to severe skeletal abnormalities, hepatosplenomegaly, and cognitive deterioration. The progressive nature of the disease is a huge obstacle to achieve full neurological correction. Although current therapies can only treat somatic symptoms, a lentivirus-based hematopoietic stem cell gene therapy (HSCGT) approach has recently achieved improved central nervous system (CNS) neuropathology in the MPSII mouse model following transplant at 2 months of age. In this study, we evaluate neuropathology progression in 2-, 4- and 9-month-old MPSII mice, and using the same HSCGT strategy, we investigated somatic and neurological disease attenuation following treatment at 4 months of age. Our results showed gradual accumulation of HS between 2 and 4 months of age, but full manifestation of microgliosis/astrogliosis as early as 2 months. Late HSCGT fully reversed the somatic symptoms, thus achieving the same degree of peripheral correction as early therapy. However, late treatment resulted in slightly decreased efficacy in the CNS, with poorer brain enzymatic activity, together with reduced normalization of HS oversulfation. Overall, our findings confirm significant lysosomal burden and neuropathology in 2-month-old MPSII mice. Peripheral disease is readily reversible by LV.IDS-HSCGT regardless of age of transplant, suggesting a viable treatment for somatic disease. However, in the brain, higher IDS enzyme levels are achievable with early HSCGT treatment, and later transplant seems to be less effective, supporting the view that the earlier patients are diagnosed and treated, the better the therapy outcome.

Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accumulation. Interleukin (IL)-1β and interleukin-1 receptor antagonist (IL-1Ra) expression were significantly increased in both murine models and human MPSIII patients. We identified pathogenic mechanisms of inflammasome activation, including that disease-specific 2-O-sulphated heparan sulphate was essential for priming an IL-1β response via the Toll-like receptor 4 complex. However, mucopolysaccharidosis IIIA primary and secondary storage substrates, such as amyloid beta, were both required to activate the NLRP3 inflammasome and initiate IL-1β secretion. IL-1 blockade in mucopolysaccharidosis IIIA mice using IL-1 receptor type 1 knockout or haematopoietic stem cell gene therapy over-expressing IL-1Ra reduced gliosis and completely prevented behavioural phenotypes. In conclusion, we demonstrate that IL-1 drives neuroinflammation, behavioural abnormality and cognitive decline in mucopolysaccharidosis IIIA, highlighting haematopoietic stem cell gene therapy treatment with IL-1Ra as a potential neuronopathic lysosomal disease treatment., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Current materials used for in vitro 3D cell culture are often limited by their poor similarity to human tissue, batch-to-batch variability and complexity of composition and manufacture. Here, we present a "blank slate" culture environment based on a self-assembling peptide gel free from matrix motifs. The gel can be customised by incorporating matrix components selected to match the target tissue, with independent control of mechanical properties. Therefore the matrix components are restricted to those specifically added, or those synthesised by encapsulated cells. The flexible 3D culture platform provides full control over biochemical and physical properties, allowing the impact of biochemical composition and tissue mechanics to be separately evaluated in vitro. Here, we demonstrate that the peptide gels support the growth of a range of cells including human induced pluripotent stem cells and human cancer cell lines. Furthermore, we present proof-of-concept that the peptide gels can be used to build disease-relevant models. Controlling the peptide gelator concentration allows peptide gel stiffness to be matched to normal breast (<1 kPa) or breast tumour tissue (>1 kPa), with higher stiffness favouring the viability of breast cancer cells over normal breast cells. In parallel, the peptide gels may be modified with matrix components relevant to human breast, such as collagen I and hyaluronan. The choice and concentration of these additions affect the size, shape and organisation of breast epithelial cell structures formed in co-culture with fibroblasts. This system therefore provides a means of unravelling the individual influences of matrix, mechanical properties and cell-cell interactions in cancer and other diseases., (Copyright © 2019. Published by Elsevier B.V.)

Patients with the lysosomal storage disease mucopolysaccharidosis IIIA (MPSIIIA) lack the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH), one of the many enzymes involved in degradation of heparan sulfate. Build-up of un-degraded heparan sulfate results in severe progressive neurodegeneration for which there is currently no treatment. Experimental gene therapies based on gene addition are currently being explored. Following preclinical evaluation in MPSIIIA mice, an adeno-associated virus vector of serotype rh10 designed to deliver SGSH and sulfatase modifying factor 1 (SAF301) was trialed in four MPSIIIA patients, showing good tolerance and absence of adverse events with some improvements in neurocognitive measures. This study aimed to improve SAF301 further by removing sulfatase modifying factor 1 (SUMF1) and assessing if expression of this gene is needed to increase the SGSH enzyme activity (SAF301b). Second, the murine phosphoglycerate kinase (PGK) promotor was exchanged with a chicken beta actin/CMV composite (CAG) promotor (SAF302) to see if SGSH expression levels could be boosted further. The three different vectors were administered to MPSIIIA mice via intracranial injection, and SGSH expression levels were compared 4 weeks post treatment. Removal of SUMF1 resulted in marginal reductions in enzyme activity. However, promotor exchange significantly increased the amount of SGSH expressed in the brain, leading to superior therapeutic correction with SAF302. Biodistribution of SAF302 was further assessed using green fluorescent protein (GFP), indicating that vector spread was limited to the area around the injection tract. Further modification of the injection strategy to a single depth with higher injection volume increased vector distribution, leading to more widespread GFP distribution and sustained expression, suggesting this approach should be adopted in future trials.

Neurological lysosomal storage diseases are rare, inherited conditions resulting mainly from lysosomal enzyme deficiencies. Current treatments, such as enzyme replacement therapy and hematopoietic stem cell transplantation, fail to effectively treat neurological disease due to insufficient brain delivery of the missing enzyme. Ex vivo gene therapy approaches to overexpress the missing enzyme in hematopoietic stem cells prior to transplant are an emerging technology that has the potential to offer a viable therapy for patients with these debilitating diseases.

Recombinant adeno-associated viruses (AAVs) are popular in vivo gene transfer vehicles. However, vector doses needed to achieve therapeutic effect are high and some target tissues in the central nervous system remain difficult to transduce. Gene therapy trials using AAV for the treatment of neurological disorders have seldom led to demonstrated clinical efficacy. Important contributing factors are low transduction rates and inefficient distribution of the vector. To overcome these hurdles, a variety of capsid engineering methods have been utilized to generate capsids with improved transduction properties. Here we describe an alternative approach to capsid engineering, which draws on the natural evolution of the virus and aims to yield capsids that are better suited to infect human tissues. We generated an AAV capsid to include amino acids that are conserved among natural AAV2 isolates and tested its biodistribution properties in mice and rats. Intriguingly, this novel variant, AAV-TT, demonstrates strong neurotropism in rodents and displays significantly improved distribution throughout the central nervous system as compared to AAV2. Additionally, sub-retinal injections in mice revealed markedly enhanced transduction of photoreceptor cells when compared to AAV2. Importantly, AAV-TT exceeds the distribution abilities of benchmark neurotropic serotypes AAV9 and AAVrh10 in the central nervous system of mice, and is the only virus, when administered at low dose, that is able to correct the neurological phenotype in a mouse model of mucopolysaccharidosis IIIC, a transmembrane enzyme lysosomal storage disease, which requires delivery to every cell for biochemical correction. These data represent unprecedented correction of a lysosomal transmembrane enzyme deficiency in mice and suggest that AAV-TT-based gene therapies may be suitable for treatment of human neurological diseases such as mucopolysaccharidosis IIIC, which is characterized by global neuropathology.

The pediatric lysosomal storage disorder mucopolysaccharidosis type II is caused by mutations in IDS, resulting in accumulation of heparan and dermatan sulfate, causing severe neurodegeneration, skeletal disease, and cardiorespiratory disease. Most patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood-brain barrier. We tested a brain-targeted hematopoietic stem cell gene therapy approach using lentiviral IDS fused to ApoEII (IDS.ApoEII) compared to a lentivirus expressing normal IDS or a normal bone marrow transplant. In mucopolysaccharidosis II mice, all treatments corrected peripheral disease, but only IDS.ApoEII mediated complete normalization of brain pathology and behavior, providing significantly enhanced correction compared to IDS. A normal bone marrow transplant achieved no brain correction. Whilst corrected macrophages traffic to the brain, secreting IDS/IDS.ApoEII enzyme for cross-correction, IDS.ApoEII was additionally more active in plasma and was taken up and transcytosed across brain endothelia significantly better than IDS via both heparan sulfate/ApoE-dependent receptors and mannose-6-phosphate receptors. Brain-targeted hematopoietic stem cell gene therapy provides a promising therapy for MPS II patients., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Mucopolysaccharidosis IIIB is a paediatric lysosomal storage disease caused by deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU), involved in the degradation of the glycosaminoglycan heparan sulphate. Absence of NAGLU leads to accumulation of partially degraded heparan sulphate within lysosomes and the extracellular matrix, giving rise to severe CNS degeneration with progressive cognitive impairment and behavioural problems. There are no therapies. Haematopoietic stem cell transplant shows great efficacy in the related disease mucopolysaccharidosis I, where donor-derived monocytes can transmigrate into the brain following bone marrow engraftment, secrete the missing enzyme and cross-correct neighbouring cells. However, little neurological correction is achieved in patients with mucopolysaccharidosis IIIB. We have therefore developed an ex vivo haematopoietic stem cell gene therapy approach in a mouse model of mucopolysaccharidosis IIIB, using a high-titre lentiviral vector and the myeloid-specific CD11b promoter, driving the expression of NAGLU (LV.NAGLU). To understand the mechanism of correction we also compared this with a poorly secreted version of NAGLU containing a C-terminal fusion to IGFII (LV.NAGLU-IGFII). Mucopolysaccharidosis IIIB haematopoietic stem cells were transduced with vector, transplanted into myeloablated mucopolysaccharidosis IIIB mice and compared at 8 months of age with mice receiving a wild-type transplant. As the disease is characterized by increased inflammation, we also tested the anti-inflammatory steroidal agent prednisolone alone, or in combination with LV.NAGLU, to understand the importance of inflammation on behaviour. NAGLU enzyme was substantially increased in the brain of LV.NAGLU and LV.NAGLU-IGFII-treated mice, with little expression in wild-type bone marrow transplanted mice. LV.NAGLU treatment led to behavioural correction, normalization of heparan sulphate and sulphation patterning, reduced inflammatory cytokine expression and correction of astrocytosis, microgliosis and lysosomal compartment size throughout the brain. The addition of prednisolone improved inflammatory aspects further. Substantial correction of lysosomal storage in neurons and astrocytes was also achieved in LV.NAGLU-IGFII-treated mice, despite limited enzyme secretion from engrafted macrophages in the brain. Interestingly both wild-type bone marrow transplant and prednisolone treatment alone corrected behaviour, despite having little effect on brain neuropathology. This was attributed to a decrease in peripheral inflammatory cytokines. Here we show significant neurological disease correction is achieved using haematopoietic stem cell gene therapy, suggesting this therapy alone or in combination with anti-inflammatories may improve neurological function in patients., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Severe mucopolysaccharidosis type II (MPS II) is a progressive lysosomal storage disease caused by mutations in the IDS gene, leading to a deficiency in the iduronate-2-sulfatase enzyme that is involved in heparan sulphate and dermatan sulphate catabolism. In constitutive form, MPS II is a multi-system disease characterised by progressive neurocognitive decline, severe skeletal abnormalities and hepatosplenomegaly. Although enzyme replacement therapy has been approved for treatment of peripheral organs, no therapy effectively treats the cognitive symptoms of the disease and novel therapies are in development to remediate this. Therapeutic efficacy and subsequent validation can be assessed using a variety of outcome measures that are translatable to clinical practice, such as behavioural measures. We sought to consolidate current knowledge of the cognitive, skeletal and motor abnormalities present in the MPS II mouse model by performing time course behavioural examinations of working memory, anxiety, activity levels, sociability and coordination and balance, up to 8 months of age. Cognitive decline associated with alterations in spatial working memory is detectable at 8 months of age in MPS II mice using spontaneous alternation, together with an altered response to novel environments and anxiolytic behaviour in the open-field. Coordination and balance on the accelerating rotarod were also significantly worse at 8 months, and may be associated with skeletal changes seen in MPS II mice. We demonstrate that the progressive nature of MPS II disease is also seen in the mouse model, and that cognitive and motor differences are detectable at 8 months of age using spontaneous alternation, the accelerating rotarod and the open-field tests. This study establishes neurological, motor and skeletal measures for use in pre-clinical studies to develop therapeutic approaches in MPS II.

Objective: To improve measurement of upper extremity (UE) use in the community by evaluating the feasibility of using body-worn sensor data and machine learning models to distinguish productive prehensile and bimanual UE activity use from extraneous movements associated with walking., Design: Comparison of machine learning classification models with criterion standard of manually scored videos of performance in UE prosthesis users., Setting: Rehabilitation hospital training apartment., Participants: Convenience sample of UE prosthesis users (n=5) and controls (n=13) similar in age and hand dominance (N=18)., Interventions: Participants were filmed executing a series of functional activities; a trained observer annotated each frame to indicate either UE movement directed at functional activity or walking. Synchronized data from an inertial sensor attached to the dominant wrist were similarly classified as indicating either a functional use or walking. These data were used to train 3 classification models to predict the functional versus walking state given the associated sensor information. Models were trained over 4 trials: on UE amputees and controls and both within subject and across subject. Model performance was also examined with and without preprocessing (centering) in the across-subject trials., Main Outcome Measure: Percent correct classification., Results: With the exception of the amputee/across-subject trial, at least 1 model classified >95% of test data correctly for all trial types. The top performer in the amputee/across-subject trial classified 85% of test examples correctly., Conclusions: We have demonstrated that computationally lightweight classification models can use inertial data collected from wrist-worn sensors to reliably distinguish prosthetic UE movements during functional use from walking-associated movement. This approach has promise in objectively measuring real-world UE use of prosthetic limbs and may be helpful in clinical trials and in measuring response to treatment of other UE pathologies., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Robots are a promising tool for rehabilitation, and research suggests combining assistance with subject participation to maintain motivation and engagement. In this study, we compare two different types of robotic assistance for hand rehabilitation: Tone, a novel method designed to directly compensate for the user's hypertonia, and Spring, a commonly used method simulating a spring-like force attracting the subject to the target position. Eight chronic stroke subjects played a Gate Game, where they guide a ball through a sweeping, on-screen gate. Each subject was exposed to 5 modes: unassisted, assisted by the Spring and Tone modes, and "delay" modes where the assistance was provided after a period without assistance. Compared to unassisted trials, subjects produced less positive work and more negative work with all types of assistance but also reached a larger ROM and scored higher on the game. Notably, subjects produced more positive work overall with Tone compared to Spring. Further, subjects produced positive work over a significantly shorter range with Spring compared to Unassisted, while there was no difference between Tone and Unassisted. While both modes were effective at enabling the training of a larger workspace, these results suggest Tone assistance maintains a greater level of subject engagement and participation, likely making it a useful tool for hand rehabilitation.

The ability to characterize alterations in heparan sulfate (HS) structure during development or as a result of loss or mutation of one or more components of the HS biosynthetic pathway is essential for broad understanding of the effects these changes may have on cell/tissue function. The use of anti-HS antibodies provides an opportunity to study HS chain composition in situ, with a multitude of different antibodies having been generated that recognize subtle differences in HS patterning, with the number and positioning of sulfate groups influencing antibody binding affinity. Flow cytometry is a valuable technique to enable the rapid characterization of the changes in HS-specific antibody binding in situ, allowing multiple cell types to be directly compared. Additionally fluorescent-activated cell sorting (FACS) allows fractionation of cells based on their HS-epitope expression.

Mucopolysaccharidosis I Hurler (MPSI-H) is a pediatric lysosomal storage disease caused by genetic deficiencies in IDUA, coding for α-l-iduronidase. Idua(-/-) mice share similar clinical pathology with patients, including the accumulation of the undegraded glycosaminoglycans (GAGs) heparan sulfate (HS), and dermatan sulfate (DS), progressive neurodegeneration, and dysostosis multiplex. Hematopoietic stem cell transplantation (HSCT) is the most effective treatment for Hurler patients, but reduced intensity conditioning is a risk factor in transplantation, suggesting an underlying defect in hematopoietic cell engraftment. HS is a co-receptor in the CXCL12/CXCR4 axis of hematopoietic stem and progenitor cell (HSPC) migration to the bone marrow (BM), but the effect of HS alterations on HSPC migration, or the functional role of HS in MPSI-H are unknown. We demonstrate defective WT HSPC engraftment and migration in Idua(-/-) recipient BM, particularly under reduced intensity conditioning. Both intra- but especially extracellular Idua(-/-) BM HS was significantly increased and abnormally sulfated. Soluble heparinase-sensitive GAGs from Idua(-/-) BM and specifically 2-O-sulfated HS, elevated in Idua(-/-) BM, both inhibited CXCL12-mediated WT HSPC transwell migration, while DS had no effect. Thus we have shown that excess overly sulfated extracellular HS binds, and sequesters CXCL12, limiting hematopoietic migration and providing a potential mechanism for the limited scope of HSCT in Hurler disease., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Internal models allow unimpaired individuals to appropriately scale grip force when grasping and lifting familiar objects. In prosthesis users, the internal model must adapt to the characteristics of the prosthetic devices and reduced sensory feedback. We studied the internal models of 11 amputees and eight unimpaired controls when grasping and lifting a fragile object. When the object was modified from a rigid to fragile state, both subject groups adapted appropriately by significantly reducing grasp force on the first trial with the fragile object compared to the rigid object (p < 0.020). There was a wide range of performance skill illustrated by amputee subjects when lifting the fragile object in 10 repeated trials. One subject, using a voluntary close device, never broke the object, four subjects broke the fragile device on every attempt and seven others failed on their initial attempts, but improved over the repeated trials. Amputees decreased their grip forces 51 ± 7 % from the first to the last trial (p < 0.001), indicating a practice effect. However, amputees used much higher levels of force than controls throughout the testing (p < 0.015). Amputees with better performance on the Box and Blocks test used lower grip force levels (p = 0.006) and had more successful lifts of the fragile object (p = 0.002). In summary, amputees do employ internal models when picking up objects; however, the accuracy of these models is poor and grip force modulation is significantly impaired. Further studies could examine the alternative sensory modalities and training parameters that best promote internal model formation.

Purpose: Heparan sulfate (HS) has been implicated in age-related macular degeneration (AMD), since it is the major binding partner for complement factor H (CFH) in human Bruch's membrane (BrM), and CFH has a central role in inhibiting complement activation on extracellular matrices. The aim was to investigate potential aging changes in HS quantity and composition in human BrM., Methods: Postmortem human ocular tissue was obtained from donors without known retinal disease. The HS was purified from BrM and neurosensory retina, and after digestion to disaccharides, fluorescently labeled and analyzed by reverse-phase HPLC. The HS and heparanase-1 were detected by immunohistochemistry in macular tissue sections from young and old donors, and binding of exogenously applied recombinant CCP6-8 region of CFH (402Y and 402H variants) was compared., Results: Disaccharide analysis demonstrated that the mean quantity of HS in BrM was 50% lower (P = 0.006) in old versus young donors (average 82 vs. 32 years). In addition, there was a small, but significant decrease in HS sulfation in old BrM. Immunohistochemistry revealed approximately 50% (P = 0.02) less HS in macular BrM in old versus young donors, whereas heparanase-1 increased by 24% in old macular BrM (P = 0.56). In young donor tissue the AMD-associated 402H CCP6-8 bound relatively poorly to BrM, compared to the 402Y form. In BrM from old donors, this difference was significantly greater (P = 0.019)., Conclusions: The quantity of HS decreases substantially with age in human BrM, resulting in fewer binding sites for CFH and especially affecting the ability of the 402H variant of CFH to bind BrM., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Differentiation and subsequent specialization of every cell within an organism is an intricate interwoven process. A complex network of signalling pathways eventually leads to the specification of a multitude of different cell types able to function co-operatively. HS (heparan sulfate) is a highly sulfated linear polysaccharide that resides at the pericellular cell-matrix interface where it dictates the binding and activity of a large number of proteins, including growth factors and morphogens such as members of the FGF (fibroblast growth factor) and BMP (bone morphogenetic protein) families. Embryonic stem cells derived from mice with mutations in components of the HS biosynthetic pathway provide an opportunity to dissect the contribution of HS to signalling pathways critical for regulating stem cell maintenance and differentiation. In addition to improving our understanding of signalling mechanisms, this knowledge enables the selection of exogenous HS saccharides to improve the efficiency and selectivity of directed differentiation protocols, offering a cost-effective alternative to high concentrations of expensive growth factors to drive differentiation towards a particular therapeutically relevant cell type.

Background: Individuals with chronic stroke often have long-lasting upper extremity impairments that impede function during activities of daily living. Rehabilitation robotics have shown promise in improving arm function, but current systems do not allow realistic training of activities of daily living. We have incorporated the ARMin III and HandSOME device into a novel robotic therapy modality that provides functional training of reach and grasp tasks., Objective: To compare the effects of equal doses of robotic and conventional therapy in individuals with chronic stroke., Methods: Subjects were randomized to 12 hours of robotic or conventional therapy and then crossed over to the other therapy type after a 1-month washout period. Twelve moderate to severely impaired individuals with chronic stroke were enrolled, and 10 completed the study., Results: Across the 3-month study period, subjects showed significant improvements in the Fugl-Meyer (P = .013) and Box and Blocks tests (P = .028). The robotic intervention produced significantly greater improvements in the Action Research Arm Test than conventional therapy (P = .033). Gains in the Box and Blocks test from conventional therapy were larger than from robotic therapy in subjects who received conventional therapy after robotic therapy (P = .044)., Conclusions: Data suggest that robotic therapy can elicit improvements in arm function that are distinct from conventional therapy and supplements conventional methods to improve outcomes. Results from this pilot study should be confirmed in a larger study.

Objective: The goals of this pilot study were to quantify the clinical benefits of using the Hand Exoskeleton Rehabilitation Robot for hand rehabilitation after stroke and to determine the population best served by this intervention., Design: Nine subjects with chronic stroke (one excluded from analysis) completed 18 sessions of training with the Hand Exoskeleton Rehabilitation Robot and a preevaluation, a postevaluation, and a 90-day clinical evaluation., Results: Overall, the subjects improved in both range of motion and clinical measures. Compared with the preevaluation, the subjects showed significant improvements in range of motion, grip strength, and the hand component of the Fugl-Meyer (mean changes, 6.60 degrees, 8.84 percentage points, and 1.86 points, respectively). A subgroup of six subjects exhibited lower tone and received a higher dosage of training. These subjects had significant gains in grip strength, the hand component of the Fugl-Meyer, and the Action Research Arm Test (mean changes, 8.42 percentage points, 2.17 points, and 2.33 points, respectively)., Conclusions: Future work is needed to better manage higher levels of hypertonia and provide more support to subjects with higher impairment levels; however, the current results support further study into the Hand Exoskeleton Rehabilitation Robot treatment.

We have developed a novel robotic modality called Time Independent Functional Training (TIFT) that provides focused retraining of interjoint coordination after stroke. TIFT was implemented on the ARMin III exoskeleton and provides joint space walls that resist movement patterns that are inconsistent with the targeted interjoint coordination pattern. In a single test session, ten moderate to severely impaired individuals with chronic stroke practiced synchronous shoulder abduction and elbow extension in TIFT and also in a comparison mode commonly used in robotic therapy called end point tunnel training (EPTT). In EPTT, error is limited by forces applied to the hand that are normal to the targeted end point trajectory. The completion percentage of the movements was comparable between modes, but the coordination patterns used by subjects differed between modes. In TIFT, subjects performed the targeted pattern of synchronous shoulder abduction and elbow extension, while in EPTT, movements were completed with compensatory strategies that incorporated the flexor synergy (shoulder abduction with elbow flexion) or the extensor synergy (shoulder adduction with elbow extension). There were immediate effects on free movements, with TIFT resulting in larger improvements in interjoint coordination than EPTT. TIFT's ability to elicit normal coordination patterns merits further investigation into the effects of longer duration training.

As our understanding of what guides the behavior of multi- and pluripotent stem cells deepens, so too does our ability to utilize certain cues to manipulate their behavior and maximize their therapeutic potential. Engineered, biologically functionalized materials have the capacity to influence stem cell behavior through a powerful combination of biological, mechanical, and topographical cues. Here, we present the development of a novel electrospun scaffold, functionalized with glycosaminoglycans (GAGs) ionically immobilized onto the fiber surface. Bound GAGs retained the ability to interact with GAG-binding molecules and, crucially, presented GAG sulfation motifs fundamental to mediating stem cell behavior. Bound GAG proved to be biologically active, rescuing the neural differentiation capacity of heparan sulfate-deficient mouse embryonic stem cells and functioning in concert with FGF4 to facilitate the formation of extensive neural processes across the scaffold surface. The combination of GAGs with electrospun scaffolds creates a biomaterial with potent applicability for the propagation and effective differentiation of pluripotent stem cells.

Objective: To characterize the compensatory movements of the trunk during functional reaching tasks performed by upper limb prosthesis users., Design: Survey., Setting: Clinical laboratory at a national rehabilitation hospital., Participants: Transhumeral and transradial prosthesis users (n=10) and uninjured control subjects (n=10)., Interventions: Not applicable., Main Outcome Measures: Three-dimensional motion analysis data were collected during simulated reaching tasks, such as donning a cap, placing a nut, and sorting clothes. The metrics were range of motion of the trunk in the 3 anatomical directions and elbow and shoulder path distance., Results: Prosthesis users had significantly larger truncal movements than controls during all 3 reaching tasks in all 3 directions (P≤.03). Shoulder path distance in persons with amputation was larger than in controls in all 3 tasks (P<.01). Elbow path distance in persons with amputation was larger than in controls in the nut and clothes tasks (P≤.02). The subgroup of transradial prosthesis users displayed these abnormal movements despite the presence of an intact elbow., Conclusions: The altered physiologic structure of the arm caused the individuals to develop a different motor control strategy than an intact arm. Functional limitations, such as the loss of distal degrees of freedom, required persons with amputation to use trunk displacement in place of arm/hand movement. These compensatory movements during reaching tasks may be a cause of prosthesis rejection and, in some cases, may be resolved with proper rehabilitative training. Analysis of compensatory trunk movements may also provide a useful endpoint for evaluating new prosthesis designs., (Copyright © 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

The goal of this review was to discuss the impairments in hand function after stroke and present previous work on robot-assisted approaches to movement neurorehabilitation. Robotic devices offer a unique training environment that may enhance outcomes beyond what is possible with conventional means. Robots apply forces to the hand, allowing completion of movements while preventing inappropriate movement patterns. Evidence from the literature is emerging that certain characteristics of the human-robot interaction are preferable. In light of this evidence, the robotic hand devices that have undergone clinical testing are reviewed, highlighting the authors' work in this area. Finally, suggestions for future work are offered. The ability to deliver therapy doses far higher than what has been previously tested is a potentially key advantage of robotic devices that needs further exploration. In particular, more efforts are needed to develop highly motivating home-based devices, which can increase access to high doses of assisted movement therapy.

Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo disease) is a neurodegenerative disorder caused by a deficiency in the lysosomal enzyme sulfamidase (SGSH), catabolizing heparan sulfate (HS). Affected children present with severe behavioral abnormalities, sleep disturbances, and progressive neurodegeneration, leading to death in their second decade. MPS I, a similar neurodegenerative disease accumulating HS, is treated successfully with hematopoietic stem cell transplantation (HSCT) but this treatment is ineffectual for MPS IIIA. We compared HSCT in MPS IIIA mice using wild-type donor cells transduced ex vivo with lentiviral vector-expressing SGSH (LV-WT-HSCT) versus wild-type donor cell transplant (WT-HSCT) or lentiviral-SGSH transduced MPS IIIA cells (LV-IIIA-HSCT). LV-WT-HSCT results in 10% of normal brain enzyme activity, near normalization of brain HS and GM2 gangliosides, significant improvements in neuroinflammation and behavioral correction. Both WT-HSCT and LV-IIIA-HSCT mediated improvements in GM2 gangliosides and neuroinflammation but were less effective at reducing HS or in ameliorating abnormal HS sulfation and had no significant effect on behavior. This suggests that HS may have a more significant role in neuropathology than neuroinflammation or GM2 gangliosides. These data provide compelling evidence for the efficacy of gene therapy in conjunction with WT-HSCT for neurological correction of MPS IIIA where conventional transplant is ineffectual.

Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events.Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4-9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4-9 months.

Mucopolysaccharide (MPS) diseases are characterized by accumulation of glycosaminoglycans (GAGs) due to deficiencies in lysosomal enzymes responsible for GAG breakdown. Using a murine model of MPSI Hurler (MPSIH), we have quantified the heparan sulfate (HS) accumulation resulting from α-l-iduronidase (Idua) deficiency. HS levels were significantly increased in liver and brain tissue from 12-week-old Idua(-/-) mice by 87- and 20-fold, respectively. In addition, HS chains were shown to contain significantly increased N-, 2-O-, and 6-O-sulfation. Disaccharide compositional analyses also uncovered an HS disaccharide uniquely enriched in MPSIH, representing the terminal iduronic acid residue capping the non-reducing end of the HS chain, where no further degradation can occur in the absence of Idua. Critically, we identified that excess HS, some of which is colocalized to the Golgi secretory pathway, acts as a positive regulator of HS-sulfation, increasing the N-sulfotransferase activity of HS-modifying N-deacetylase/N-sulfotransferase enzymes. This mechanism may have severe implications during disease progression but, now identified, could help direct improved therapeutic strategies.

PURPOSE. To map the distribution of different classes of glycosaminoglycans (GAGs) in the healthy human retina, choroid, and sclera. METHODS. Frozen tissue sections were made from adult human donor eyes. The GAG chains of proteoglycans (PGs) were detected with antibodies directed against various GAG structures (either directly or after pretreatment with GAG-degrading enzymes); hyaluronan (HA) was detected using biotinylated recombinant G1-domain of human versican. The primary detection reagents were identified with FITC-labeled probes and analyzed by fluorescence microscopy. RESULTS. Heparan sulfate (HS), chondroitin sulfate (CS), dermatan sulfate (DS), and HA were present throughout the retina and choroid, but keratan sulfate (KS) was detected only in the sclera. HS labeling was particularly strong in basement membrane-containing structures, the nerve fiber layer (NFL), and retinal pigment epithelium (RPE)-for example, intense staining was seen with an antibody that binds strongly to sequences containing 3-O-sulfation in the internal limiting membrane (ILM) and in the basement membrane of blood vessels. Unsulfated CS was seen throughout the retina, particularly in the ILM and interphotoreceptor matrix (IPM) with 6-O-sulfated CS also prominent in the IPM. There was labeling for DS throughout the retina and choroid, especially in the NFL, ganglion cell layer, and blood vessels. CONCLUSIONS. The detection of GAG chains with specific probes and fluorescence microscopy provides for the first time a detailed analysis of their compartmentalization in the human retina, by both GAG chain type and sulfation pattern. This reference map provides a basis for understanding the functional regulation of GAG-binding proteins in health and disease processes.

Stroke patients often have flexor hypertonia and finger extensor weakness, which makes it difficult to open their affected hand for functional grasp. Because of this impairment, hand rehabilitation after stroke is essential for restoring functional independent lifestyles. The goal of this study is to develop a passive, lightweight, wearable device to assist with hand function during performance of activities of daily living. The device, Hand Spring Operated Movement Enhancer (HandSOME), assists with opening the patient's hand using a series of elastic cords that apply extension torques to the finger joints and compensates for the flexor hypertonia. Device design and calibration are described as well as functional and usability testing with stroke subjects with a wide range of hand impairments. In initial testing with eight stroke subjects with finger flexor hypertonia, use of the HandSOME significantly increased range of motion and functional ability (p=0.002) . There was some decrease in grip strength with the HandSOME device at the subject's ideal setting, however this was not statistically significant (p=0.167) and did not seem to have a significant effect on function. Overall HandSOME shows promise as a training tool to facilitate repetitive task practice for improving hand function in stroke patients. HandSOME can be used as part of a home-based therapy program, or as an orthotic for replacing lost function., (© 2011 IEEE)

Mouse embryonic stem (mES) cells express a low sulfated form of heparan sulfate (HS). HS chains displayed by ES cells and their progeny become more complex and more sulfated during progression from pluripotency to neuroectodermal precursors. Sulfated epitopes are important for recognition and binding of a variety of ligands including members of the fibroblast growth factor (FGF) family. We demonstrated previously that mES cells lacking HS cannot undergo neural specification but this activity can be recovered by adding soluble heparin, a highly sulfated glycosaminoglycan (GAG). Therefore, we hypothesized that soluble GAGs might be used to support neural differentiation of HS competent cells and that the mechanisms underlying this activity might provide useful information about the signaling pathways critical for loss of pluripotency and early lineage commitment. In this study, we demonstrate that specific HS/heparin polysaccharides support formation of Sox1(+) neural progenitor cells from wild-type ES cells. This effect is dependent on sulfation pattern, concentration, and length of saccharide. Using a selective inhibitor of FGF signal transduction, we show that heparin modulates signaling events regulating exit from pluripotency and commitment to primitive ectoderm and subsequently neuroectoderm. Interestingly, we were also able to demonstrate that multiple receptor tyrosine kinases were influenced by HS in this system. This suggests roles for additional factors, possibly in cell proliferation or protection from apoptosis, during the process of neural specification. Therefore, we conclude that soluble GAGs or synthetic mimics could be considered as suitable low-cost factors for addition to ES cell differentiation regimes., (Copyright © 2011 AlphaMed Press.)

Heparan sulfate proteoglycans (HSPG) encompass some of the most abundant macromolecules on the surface of almost every cell type. Heparan sulfate (HS) chains provide a key interaction surface for the binding of numerous proteins such as growth factors and morphogens, helping to define the ability of a cell to respond selectively to environmental cues. The specificity of HS-protein interactions are governed predominantly by the order and positioning of sulfate groups, with distinct cell types expressing unique sets of HS epitopes. Embryos deficient in HS-synthesis (Ext1(-/-)) exhibit pre-gastrulation lethality and lack recognizable organized mesoderm and extraembryonic tissues. Here we demonstrate that embryonic stem cells (ESCs) derived from Ext1(-/-) embryos are unable to differentiate into hematopoietic lineages, instead retaining ESC marker expression throughout embryoid body (EB) culture. However hematopoietic differentiation can be restored by the addition of soluble heparin. Consistent with specific size and composition requirements for HS:growth factor signaling, chains measuring at least 12 saccharides were required for partial rescue of hematopoiesis with longer chains (18 saccharides or more) required for complete rescue. Critically N- and 6-O-sulfate groups were essential for rescue. Heparin addition restored the activity of multiple signaling pathways including bone morphogenic protein (BMP) with activation of phospho-SMADs re-established by the addition of heparin. Heparin addition to wild-type cultures also altered the outcome of differentiation, promoting hematopoiesis at low concentrations, yet inhibiting blood formation at high concentrations. Thus altering the levels of HS and HS sulfation within differentiating ESC cultures provides an attractive and accessible mechanism for influencing cell fate.

Robotic rehabilitation techniques have the capacity to provide high dosage therapy without the labor burden of conventional methods. The most effective means of using robots to retrain function is not yet known, though many studies now support providing assistance to movement while the user actively participates in that movement. In this study, we compare, in three chronic stroke subjects, a novel Tone assistance mode to a Spring assistance method commonly used in other robots. The Tone mode provides assistance comparable to the subject's own resistance to extension while Spring mode provides a spring-like force to pull the subject to the target. All three subjects produced larger finger movements with robotic assistance, but they also produced much more positive work with the Tone assistance compared to the Spring assistance. This demonstrates that subjects were actively driving the movements in Tone mode to a greater extent than in Spring mode. Two out of three subjects showed similar results in the thumb. In the third subject, work was comparable across all modes. With Tone assistance, subjects produced movement and torque profiles more similar to that of Unassisted movement than Spring-assisted movement for both fingers and thumb. These results suggest that providing assistance tailored to the user's own tone profile may be an effective means of enhancing range of motion to ultimately enable gains in hand function.

After a stroke abnormal joint coordination of the arm may limit functional movement and recovery. To aid in training inter-joint movement coordination a haptic guidance method for functional driven rehabilitation after stroke called Time Independent Functional Training (TIFT) has been developed for the ARMin III robot. The mode helps retraining inter-joint coordination during functional movements, such as putting an object on a shelf, pouring from a pitcher, and sorting objects into bins. A single chronic stroke subject was tested for validation of the modality. The subject was given 1.5 hrs of robotic therapy twice a week for 4 weeks. The therapy and the results of training the single stroke subject are discussed. The subject showed a decrease in training joint error for the sorting task across training sessions and increased self-selected movement time in training. In kinematic reaching analysis the subject showed improvements in range of motion and joint coordination in a reaching task, as well as improvements in supination-pronation range of motion at the wrist., (© 2011 IEEE)

ES (embryonic stem) cell differentiation is dependent on the presence of HS (heparan sulfate). We have demonstrated that, during differentiation, the evolution of specific cell lineages is associated with particular patterns of GAG (glycosaminoglycan) expression. For example, different HS epitopes are synthesized during neural or mesodermal lineage formation. Cell lines mutant for various components of the HS biosynthetic pathway are selectively impaired in their differentiation, with lineage-specific effects observed for some lines. We have also observed that the addition of soluble GAG saccharides to cells, with or without cell-surface HS, can influence the pace and outcome of differentiation, again highlighting specific pattern requirements for particular lineages. We are combining this work with ongoing studies into the design of artificial cell environments where we have optimized three-dimensional scaffolds, generated by electrospinning or by the formation of hydrogels, for the culture of ES cells. By permeating these scaffolds with defined GAG oligosaccharides, we intend to control the mechanical environment of the cells (via the scaffold architecture) as well as their biological signalling environment (using the oligosaccharides). We predict that this will allow us to control ES cell pluripotency and differentiation in a three-dimensional setting, allowing the generation of differentiated cell types for use in drug discovery/testing or in therapeutics.

Background: Following acute therapeutic interventions, the majority of stroke survivors are left with a poorly functioning hemiparetic hand. Rehabilitation robotics has shown promise in providing patients with intensive therapy leading to functional gains. Because of the hand's crucial role in performing activities of daily living, attention to hand therapy has recently increased., Methods: This paper introduces a newly developed Hand Exoskeleton Rehabilitation Robot (HEXORR). This device has been designed to provide full range of motion (ROM) for all of the hand's digits. The thumb actuator allows for variable thumb plane of motion to incorporate different degrees of extension/flexion and abduction/adduction. Compensation algorithms have been developed to improve the exoskeleton's backdrivability by counteracting gravity, stiction and kinetic friction. We have also designed a force assistance mode that provides extension assistance based on each individual's needs. A pilot study was conducted on 9 unimpaired and 5 chronic stroke subjects to investigate the device's ability to allow physiologically accurate hand movements throughout the full ROM. The study also tested the efficacy of the force assistance mode with the goal of increasing stroke subjects' active ROM while still requiring active extension torque on the part of the subject., Results: For 12 of the hand digits'15 joints in neurologically normal subjects, there were no significant ROM differences (P > 0.05) between active movements performed inside and outside of HEXORR. Interjoint coordination was examined in the 1st and 3rd digits, and no differences were found between inside and outside of the device (P > 0.05). Stroke subjects were capable of performing free hand movements inside of the exoskeleton and the force assistance mode was successful in increasing active ROM by 43 +/- 5% (P < 0.001) and 24 +/- 6% (P = 0.041) for the fingers and thumb, respectively., Conclusions: Our pilot study shows that this device is capable of moving the hand's digits through nearly the entire ROM with physiologically accurate trajectories. Stroke subjects received the device intervention well and device impedance was minimized so that subjects could freely extend and flex their digits inside of HEXORR. Our active force-assisted condition was successful in increasing the subjects' ROM while promoting active participation.

After a stroke, many survivors have impaired motor function. Robotic rehabilitation techniques have emerged to provide a repetitive, activity-based therapy at potentially lower cost than conventional methods. Many patients exhibit intrinsic resistance to hand extension in the form of spasticity and/or hypertonia. We have developed a therapy program using the Hand Exoskeleton Rehabilitation Robot (HEXORR) that is capable of compensating for tone to assist patients in opening the paretic hand. The system can move the user's hand, assist movement, allow free movement, or restrict movement to allow static force production. These options combine with an interactive virtual reality game to enhance user motivation. Four chronic stroke subjects received 18 sessions of robot therapy as well as pre and post evaluation sessions. All subjects showed at least modest gains in active finger range of motion (ROM) measured in the robot, and all but one subject had gains in active thumb ROM. Most of these gains carried over to ROM gains outside of the robot. The clinical measures (Fugl-Meyer, Box-and-Blocks) showed clear improvements in two subjects and mixed results in two subjects. Overall, the robot therapy was well received by subjects and shows promising results. We conclude HEXORR therapy is best suited for patients with mild-moderate tone and at least minimal extension.

Hand rehabilitation after stroke is essential for restoring functional independent lifestyles. After stroke, patients often have flexor hypertonia, making it difficult to open their hand for functional grasp. The development and initial testing of a passive hand rehabilitation device is discussed. The device, Hand Spring Operated Movement Enhancer (HandSOME), assists with opening the patient's hand using a series of bungee cords that apply extension torques to the finger joints that compensate for the flexor hypertonia. This results in significant increase in range of motion and functional use when wearing HandSOME, even in severely impaired subjects. Device design, calibration, and range of motion are described as well as functional and usability testing with stroke subjects.

This study investigated differences in adaptation to a novel dynamic environment between eight trans-radial upper extremity (UE) prosthetic users and eight naive, neurologically intact subjects. Participants held onto the handle of a robotic manipulandum and executed reaching movements within a horizontal plane following a pseudo-random sequence of targets. Curl field perturbations were imposed by the robot motors, and we compared the rate and quality of adaptation between the prosthetic and control subjects. Adaptation was quantitatively assessed by peak error, defined as the maximum orthogonal distance between an observed trajectory and an ideal straight trajectory. Initial exposure to the curl field resulted in large errors, and as the subjects adapted to the novel environment, the errors decreased. During the early phase of adaptation, group differences in the rate of motor adaptation were not significant. However, during late learning, both error magnitude and variability were larger in the prosthetic group. The quality of adaptation, as indicated by the magnitude of the aftereffects, was similar between groups. We conclude that in persons with trans-radial arm amputation, motor adaptation to curl fields during reaching is similar to unimpaired individuals. These findings are discussed in relation to mechanisms of motor adaptation, neural plasticity following an upper extremity amputation (UEA), and potential motor recovery therapies for prosthetic users.

Objectives: To examine the impact of a new prosthesis on an experienced and highly motivated prosthetic limb user, to evaluate the effects of training and the ability of clinical measures to detect change, and to gain insight into the mechanisms by which improvement occurs., Design: A single-case study., Setting: An outpatient clinic., Participant: A bilateral high-arm amputee (right shoulder disarticulation, left above elbow)., Interventions: Provision of new prosthesis and occupational therapy., Main Outcome Measures: Action Research Arm Test, box and block test of manual dexterity, Jebsen-Taylor Hand Function Test, and speed and accuracy of reaching movements with and without visual guidance., Results: In this experienced prosthesis user, provision of a new prosthesis led to an immediate worsening in functional limitation. With training, the subject recovered his baseline status and then exceeded it in both proximal and distal function. All study clinical measures detected change, but the change detected varied as much as 300-fold depending on the measure chosen. The clinical improvements were associated with modest improvements in the speed of reaching but not the accuracy of reaching under visual guidance. Improvements in reaching accuracy without visual guidance were seen after 10 trials, suggesting that some motor learning had occurred., Conclusions: Provision of a new prosthesis can cause functional decline even in an experienced user; this decline can be reversed with training. There is wide variability in sensitivity to change among functional limitation measures. Although some training-related improvements may have been due to increased speed and accuracy of reaching without visual guidance, skill in prosthesis use also plays a role.

Rising hospital costs in New York have mandated closing or converting excess hospital beds. An evaluation of two state-subsidized programs for displaced employees shows a successful adaptation to the changes, despite personnel problems relating to salary, benefits, and work schedules.