36 months observational clinical study of 38 adult Pompe disease patients under alglucosidase alfa enzyme replacement therapy.

OBJECTIVES: Glycogen storage disease type 2(GSD2)/Pompe disease is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. METHODS: We present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 38 adult-onset GSD2 patients (20 female, 18 male) with a mean age at disease onset of 36.2 ± 10.5 years. Mean delay between symptom onset and start of ERT was 14.5 ± 7.2 years. Assessments included serial Walton Gardner Medwin scale, arm function tests, timed 10-meter walk tests, 4- stair climb tests, modified Gowers' maneuvers, 6-minute walk test (6MWT), MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels, and SF-36 selfreporting questionnaires. All tests were performed at baseline and every 12 months for 36 months of ERT. RESULTS: In the 6MWT we found 21 patients able to walk at baseline a mean distance of 312 ± 165.5 m, improving to 344 ± 165.8 m after 12 months (p=0.006), remaining at 356.4 ± 155.9 m at 24 months (p=0.033), and declining to 325.6 ± 174.8 m after 36 months of ERT (p=0.49, n.s.). The mean FVC in 28 patients was 80.27 ± 14.08% of predicted normal at baseline, after 12 months 79.19 ± 13.09%, at 24 months 78.62 ± 16.55%, and 77.19 ± 18.05%after 36 months. Only mean CK levels were significantly decreased by 8.8% (p=0.041). All other tests were statistically nonsignificant changed. CONCLUSION: Our data denote a rather variable course of neuromuscular deficits in chronic adult-onset Pompe patients during 36 months of alglucosidase alfa ERT.

Usability and acceptability by a younger and older user group regarding a mobile robot-supported gait rehabilitation system.

The aim of the study was to identify differences regarding usability, acceptability, and barriers of usage of a robot-supported gait rehabilitation system between a younger and older group of patients with gait impairments. A mobile robot-supported gait rehabilitation prototype was tested on a group of geriatric patients aged 60 and above, and on a group of young patients aged 59 and below in a clinical setting during five therapy sessions. The involved therapists received 2 days training with the system and could test it profoundly. Data on usability, acceptability, and barriers to system usage were collected with questionnaires and structured interviews with the patients. The robotic system received overall moderate usability and good acceptability ratings; it was rated as clearly structured, practical, and safe. Analyses identified a few barriers, such as time-intensive setup of the system or tight leg shells, which can be minimized with regular training and system adaptations. Differences between the two user groups could be revealed and will be used for future investigation. This study showed the potential of the mobile robot-supported system for gait rehabilitation, but also pointed out further need for action. Efficacy studies are the next step in the evaluation process.

Gait assessment system based on novel gait variability measures.

In this paper, a novel gait assessment system based on measures of gait variability reflected through the variability of shapes of gait cycles trajectories is proposed. The presented gait assessment system is based on SVM (support vector machine) classifier and on gait variability-based features calculated from the hip and knee joint angle trajectories recorded using wearable IMUs during walking trials. A system classifier was trained to distinguish healthy gait patterns from the pathological ones. The features were extracted by calculating the distances between the joint trajectories of the individual gait cycles using 4 different distance functions. As result, the system is able to provide a Gait Variability Index (GVI), which is a numeric value that can be used as an indicator of a degree to which a pathological gait pattern is close to a healthy gait pattern. The system and GVI were tested in three experiments, involving subjects suffering from gait disorders caused by different neurological diseases. The results demonstrated that the proposed gait assessment system would be suitable for supporting clinicians in the evaluation of gait performances during the gait rehabilitation procedures.

Regulation of Nerve Growth Factor (NGF) Synthesis in the Rat Central Nervous System: Comparison between the Effects of Interleukin-1 and Various Growth Factors in Astrocyte Cultures and in vivo.

In order to obtain information on the physiological regulation of NGF-synthesis in the central nervous system (CNS) we investigated the effects of a series of growth factors (known to be present in the CNS) in cultures of purified rat astrocytes and compared these effects with those observed after intraventricular injection of the same molecules. After preliminary experiments had shown that 10% fetal calf serum (FCS) produced a marked increase in NGF-mRNA levels in astrocytes (but neither in microglia nor oligodendrocytes) as demonstrated by Northern blot analysis and in situ hybridization the experiments were performed at low (0.5%) FCS concentrations. Supramaximal concentrations of IL-1 and various growth factors caused a 5- to 7-fold increase in NGF-mRNA after 6 h. By 24 h the NGF-mRNA levels approached control values again, most probably due to inactivation of the added factors since after readdition after 24 h the response was about the same as the initial one. Norepinephrine and 8-bromo-cAMP did not change NGF-mRNA levels. The growth factor-mediated changes in NGF-mRNA levels in astrocyte cultures were not consistently reflected by the changes observed after intraventricular injection. IL-1 produced by far the largest increase in hippocampal NGF-mRNA after intraventricular injection. This large response to IL-1 could result from a positive feedback mechanism, since IL-1beta injection not only increases NGF-mRNA but also IL-1beta-mRNA in the hippocampus. The understanding of the physiological regulation of NGF synthesis in the CNS is the basis for a rational approach to its pharmacological modification. This, in turn, is an attractive alternative to the (long-term) infusion of NGF or the transplantation of NGF-secreting cells with the goal of providing trophic support to the cholinergic neurons of the basal forebrain nuclei. These neurons are consistently affected in the early stages of Alzheimer's disease, their impaired function being essentially responsible for the cognitive deficits.

A novel role of interleukin-1-converting enzyme in cytokine-mediated inducible nitric oxide synthase gene expression: Implications for neuroinflammatory diseases.

Inducible nitric oxide synthase (iNOS)-derived NO plays an important role in several neurological disorders. Understanding of mechanisms involved in the regulation of iNOS induction is of particular interest. Here, we investigated mechanisms of iNOS induction in rat astrocytes (AC) and in brain endothelial cells (BEC). We find that activation of AC or BEC with pro-inflammatory cytokines reveals a different cell-specific activation pattern for iNOS expression. Despite these differences, in both cell types iNOS expression and activity exclusively depends on the endogenous availability of bioactive IL-1beta as inhibition of ICE activity significantly decreases iNOS promoter activity, iNOS expression and enzyme activity. In summary, we here provide evidence that ICE represents a target for modulating iNOS expression and high-output NO formation in AC and BEC, to our knowledge the first report of a role of ICE in iNOS expression and the advantage of ICE inhibition in attenuating NO mediated inflammation and pathology.