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Objective: To investigate whether low intensity transcranial electrical stimulation (TES) can be used to condition post-activation depression of the H-reflex and simultaneously monitor the integrity of spinal motor pathways during spinal deformity correction surgery., Methods: In 20 pediatric patients undergoing corrective surgery for spinal deformity, post-activation depression of the medial gastrocnemius H-reflex was initiated by delivering two pulses 50-125ms apart, and the second H-reflex was conditioned by TES., Results: Low intensity TES caused no visible shoulder or trunk movements during 19/20 procedures and the stimulation reduced post-activation depression of the H-reflex. The interaction was present in 20/20 patients and did not diminish throughout the surgical period. In one case, the conditioning effect was lost within minutes of the disappearance of the lower extremity motor evoked potentials., Conclusion: Post-activation depression was used to detect the arrival of a subthreshold motor evoked potential at the lower motor neuron. The interaction produced minimal movement within the surgical field and remained stable throughout the surgical period., Significance: This is the first use of post-activation depression during intraoperative neurophysiological monitoring to directly assess the integrity of descending spinal motor pathways., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To determine the mechanisms underlying the mirroring of distal movements in both upper and lower limbs present in one individual from birth., Methods: Transcranial magnetic stimulation (TMS), magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), voluntary and reflexly evoked electromyograms (EMG) and force measurements were used to obtain information about the motor pathways responsible for the mirror movements., Results: MRI showed a significant loss of brain tissue from one hemisphere and fMRI indicated a significant functional reorganization had taken place. An obligatory mirroring of voluntary movement on the sound side occurs on the affected side, but some independent movement can be produced on the affected side, if enabled by weak contractions on the sound side. TMS mapping revealed bilateral projections from one hemisphere and virtually absent projections from the primary motor cortex of the other hemisphere. Spinal reflexes were restricted to the stimulated side. Transcortical reflexes were evoked bilaterally from the sound side, but not from the affected side., Conclusions: The physiological and imaging data are consistent with a mirroring from the intact motor cortex via the supplementary motor area., Significance: Mirror movements in this individual represent a major cortical reorganization and a partial solution to the neonatal loss of substantial amounts of brain tissue.

To compare various novel and conventional systems for locomotion, a 25-year-old man was studied with motor complete spinal cord injury at the T4/5 level. He used various devices in the community, and changes in speed, physiological cost index (PCI), and oxygen consumption were measured periodically. Speed was fastest with a conventional manual wheelchair (nearly 120 m/min in a 4-min test). Speed was about 30% less, but the PCI was lowest (highest efficiency) using functional electrical stimulation (FES) of the quadriceps and hamstring muscles to propel a novel wheelchair. He walked with knee-ankle-foot orthoses (KAFO) at much lower speed (8.8 m/min) and higher PCI. He walked with an alternating gait using a new stance-control KAFO with FES. The speed was still slow (5 m/min), but he prefers the more normal-looking gait and uses it daily. Walking with FES and ankle-foot orthoses (AFO) was slowest (3.5 m/min) and had the highest PCI. In conclusion, the leg-propelled wheelchair provides a more efficient method of locomotion. A new stance-controlled KAFO with FES may provide a more acceptable walking system, but must be tested on other subjects.

Thrombocytopenia is a relatively common side effect observed during glycoprotein (GP) IIb/IIIa antagonist therapy. With the oral antagonist roxifiban, we observed thrombocytopenia, defined as 50% reduction of platelets over predose values or below 90 000/microL (9 x 10(10)/L), with a frequency of 2% (8 of 386). Thrombocytopenia occurred either early (days 2 to 4) or delayed (days 11 to 16). No additional cases were observed with up to 6 months of treatment. Retrospective analysis provided evidence for drug-dependent antibodies (DDABs) to GP IIb/IIIa in 5 of 6 subjects, suggestive of an immune etiology of thrombocytopenia. The hypothesis that excluding patients based on positive DDAB reaction would reduce the frequency of thrombocytopenia was tested. Patients were screened for DDABs during the study qualification period and, overall, 3.9% of the patients were excluded based on pre-existing DDAB concentrations above a statistically defined medical decision limit. An additional 2.6% were excluded based on therapy-related antibody production during the first 2 weeks. With antibody testing, 0.2% of patients (2 of 1044) developed immune-mediated thrombocytopenia. One case developed a rapidly increasing antibody concentration and presented with thrombocytopenia despite discontinuation of roxifiban therapy. The second case was related to a false-negative test result. The frequency of thrombocytopenia was statistically significantly reduced from 2% to 0.2% (P =.0007) comparing nonscreened and screened patients. Testing for DDABs can reduce the frequency of thrombocytopenia in patients treated with roxifiban and, by analogy, other GP IIb/IIIa antagonists. Thus, DDAB testing may be employed to increase the safety of GP IIb/IIIa antagonists.

This article reviews the use of therapeutic and functional electrical stimulation in subjects after a spinal cord injury (SCI). Muscles become much weaker and more fatigable, while bone density decreases dramatically after SCI. Therapeutic stimulation of paralyzed muscles for about 1 h/day can reverse the atrophic changes and markedly increase muscle strength and endurance as well as bone density. Functional electrical stimulation can also improve the speed and efficiency of walking in people with an incomplete SCI. Finally, a modified wheelchair is described in which electrical stimulation or residual voluntary activation of leg muscles can produce movements of a footrest that is coupled to the wheels. The wheelchair can provide greater mobility and fitness to persons who are not functional walkers and currently use their arms to propel a wheelchair.

The treatment of Crohn's disease and ulcerative colitis has evolved and has improved the quality of life of patients afflicted with these disorders. Immune modulators such as azathioprine and 6-mercaptopurine are an important class of medications used for the treatment of patients with inflammatory bowel disease. Controlled studies have demonstrated their efficacy in both induction and maintenance of remission in Crohn's disease, and similarly, for the induction and maintenance of remission in patients with ulcerative colitis. These agents have had an increasing importance in the management of steroid-resistant, steroid-dependent diseases, and fistulizing Crohn's disease. The primary limitations to these agents have been their slow onset of action and their side effect profile. Despite these limitations, these agents have demonstrated efficacy and have become paramount to the management of patients with these incurable potentially disabling disorders. The precise role of azathioprine/6-mercaptopurine, their limitations and their safety are reviewed in this paper.

Granulocyte colony-stimulating factor (G-CSF) is the major regulator of proliferation and differentiation of neutrophilic granulocyte precursor cells. G-CSF activates multiple signaling molecules, including the JAK1 and JAK2 kinases and the STAT transcription factors. To investigate G-CSF signaling events regulated by the JAK-STAT pathway, we have generated UT7-epo cells stably expressing either wild-type (wt) G-CSF receptor or a series of C-terminal deletion mutants. Gel mobility shift and immunoprecipitation/Western analysis showed that STAT5 is rapidly activated by G-CSF in cells expressing the wt G-CSF receptor, in addition to the previously reported STAT3 and STAT1. Mutants lacking any tyrosine residues in the cytoplasmic domain maintain their ability to activate STAT5 and STAT1 but cannot activate STAT3, implying that STAT5 and STAT1 activation does not require receptor tyrosine phosphorylation. We also observed significant changes in the ratio of STAT1:STAT3:STAT5 activated by various G-CSF receptor C-terminal deletion mutants. These mutant receptors were further used to investigate the role of JAKs and STATs in G-CSF-mediated responses in these cells. We found that JAK activation correlates with G-CSF-induced cell proliferation, whereas STAT activation is not required. We have also identified three classes of G-CSF immediate early genes, whose activation correlates with the activation of distinct JAK-STAT pathways. Our data show that, whereas c-fos is regulated through a pathway independent of STAT activation, oncostatin M, IRF-1, and egr-1 are regulated by an STAT5-dependent pathway and fibrinogen is regulated by an STAT3-dependent pathway. In conclusion, our results suggest that G-CSF regulates its complex biologic activities by selectively activating distinct early response genes through different JAK-STAT signaling molecules.

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates proliferation and differentiation of progenitor cells of neutrophils by signaling through its receptor (G-CSFR). Although the G-CSFR belongs to the cytokine receptor superfamily, which lacks an intracellular kinase domain, G-CSF-induced tyrosine phosphorylation of cellular proteins is critical for its biologic activities. We report here that JAK1 and JAK2 tyrosine kinases are tyrosine phosphorylated in response to G-CSF induction. We also demonstrate that the DNA-binding protein STAT3 (also called the acute-phase response factor [APRF], activated by interleukin-6) is an early target of G-CSF-induced tyrosine phosphorylation. G-CSF induces two DNA-binding complexes; the major complex contains tyrosine phosphorylated STAT3 protein and the minor complex appears to be a heterodimer of the STAT1 (previously p91, a component of DNA-binding complexes activated by interferons) and STAT3 proteins. Antiphosphotyrosine antibody interferes with the DNA binding activity of activated STAT3, indicating that tyrosine phosphorylation of STAT3 is important for the DNA binding activity. These results identify a signal transduction pathway activated in response to G-CSF and provide a mechanism for the rapid modulation of gene expression by G-CSF.

Many cytokines and growth factors trigger rapid changes in gene expression upon binding to their receptors. In many cases, the mechanism by which these changes are affected is unknown. In this report, we show that interleukin-2 (IL-2), IL-3, IL-4, IL-6, leukemia inhibitory factor (LIF), erythropoietin (Epo), and granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of cells causes rapid activation of DNA-binding activities that recognize a DNA sequence element previously implicated in regulation of gene expression by interferon gamma (IFN gamma). The IL-4-, IL-6-, and GM-CSF-induced complexes can be distinguished from the recently characterized IFN gamma-activated protein p91 on the basis of mobility in polyacrylamide gels, sequence preferences, and lack of reactivity with an anti-p91 antiserum. The IL-4- and GM-CSF-induced complexes react with antiphosphotyrosine antibodies, demonstrating the presence of phosphotyrosine-containing proteins in these DNA-binding complexes. Transcriptional activation of a reporter gene linked to a synthetic IFN gamma-responsive promoter is observed in response to IFN gamma, IL-6, and LIF. These data suggest a pathway by which cytokines induce rapid changes in gene expression.

The trajectories observed for the limb during human locomotion are determined by a mixture of influences, some arising from neural circuits entirely within the central nervous system and others arising from a variety of sensory receptors. Muscle reflexes are highly modulated during locomotion in an adaptive manner within each phase of the step cycle. Furthermore, the modulation can be modified quickly for different tasks such as standing, walking and running, probably by changes in presynaptic inhibition. This modulation is often lost or severely reduced in patients with spasticity after spinal cord or head injury. In normal subjects cutaneous reflexes can be completely reversed from exciting to inhibiting a muscle during each step cycle, particularly in muscles that normally show two bursts of activity per cycle (e.g., tibialis anterior). In some patients stimulation of a mixed nerve (e.g., common peroneal) can directly produce muscle contraction, generate a reflex response (flexor reflex) and transiently reduce spasticity in antagonist (extensor) muscles. Thus, simple systems employing stimulation can enhance gait to a certain extent in patients with incomplete injuries.

Some normal human subjects show definite synchronization of the motor units in hand muscles (i.e., the impulses from two or more motor units coincide in time more frequently than expected for independent random processes). Subjects who show synchronization tend to use their hands to exert large, brief forces, either in their work (e.g., manual laborers) or recreational activities (e.g., weightlifters). In this study all seven weightlifters examined showed a significant degree of synchronization. Furthermore, after 6 weeks of using the first dorsal interosseus muscle of the hand to exert maximal, voluntary contractions, the level of synchronization increased substantially in four control subjects, and the average level became significantly different from zero. Weightlifters also showed greater late reflex responses than control subjects, but no significant difference in earlier spinal reflexes. Two late reflex waves are described which probably involve fast pathways to and from motor cortes. We suggest that supraspinal connections from motor cortex directly to spinal motoneurons may be enhanced as a result of training to the point where they produce a significant synchronization of motor units during steady, voluntary contractions.

In principle tremors can be produced by (1) mechanical oscillators (combination of masses and springs), (2) reflex oscillators arising from sensory feedback pathways, or (3) central oscillators generated by single "pacemaker" neurones or interconnected networks. Recent studies supporting each of these mechanisms under certain conditions are discussed. Differences between these mechanisms are clarified by recent studies in Edmonton on the premammillary cat. This preparation shows a prominent reflexly-induced tremor which can be modified by mechanical loading and electrical stimulation. It also shows spontaneous stepping on a treadmill which is known to be produced by a spinal "stepping generator", but can be modified in interesting ways by sensory perturbations. The applicability of these animal studies to human tremors is considered in relation to preliminary studies in Calgary on patients with Parkinson's disease or essential tremor. We have attempted to modify these tremors by application of torque pulses applied to the wrist. The results are described in terms of a normalized "resetting" index which has a high value (greater than 0.6) for all essential tremor patients studied, and a wide range of values for different parkinsonian patients. The resetting index may be useful in determining the relative importance of peripheral and central factors in producing tremor in a variety of patients.