Head Control Contributes to Prediction of Emergence From the Minimally Conscious State in Children Admitted to Inpatient Rehabilitation.

OBJECTIVE: To examine the utility of head and trunk control, assessed using the Physical Abilities and Mobility Scale, for predicting emergence from a minimally conscious state (eMCS) among children with acquired brain injury admitted to inpatient rehabilitation in a disorder of consciousness (DoC). DESIGN: Retrospective study. SETTING: Pediatric inpatient rehabilitation hospital. PARTICIPANTS: Forty patients (2-21 years-old) directly admitted from acute care to pediatric inpatient brain injury rehabilitation in a DoC (average length of stay=85 days; N=40). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: State of consciousness (eMCS vs not) at discharge from inpatient rehabilitation. RESULTS: Forty-five percent of patients emerged from a minimally conscious state during inpatient rehabilitation. Admission state of consciousness and head control (but not trunk control) were significantly associated with eMCS and provided complementary prognostic information. Admission state of consciousness (ie, admitting in a vegetative state/unresponsive wakefulness syndrome) afforded the greatest negative predictive value (93.8%), whereas admission head control ability afforded the greatest positive predictive value (81.8% for any independent head control; 100% for maintaining head-up position for >30 seconds). Fifty percent of patients who emerged during the inpatient stay did not have independent head control at admission, highlighting the importance of exploring head control as a prognostic marker in conjunction with indicators with greater sensitivity (eg, state of consciousness at admission). CONCLUSIONS: A brief measure of head control at admission may contribute to identification of a subgroup of patients who are likely to emerge.

Design and Evaluation of an Interprofessional Preceptor Development Mini-Fellowship Program.

INTRODUCTION: Health professions preceptors require skills and knowledge to effectively meet the educational needs of interprofessional students in clinical environments. We implemented a mini-fellowship program to enhance the knowledge, skills, and self-efficacy of preceptors teaching students and applying quality improvement (QI) methods across disciplines and patient care settings. METHOD: The design, implementation, and evaluation of the program were informed by the faculty development literature, principles of adult learning, and preceptor needs. The 3-day program included workshops on curriculum design, clinical teaching methods, QI, social determinants of health, cultural humility, and interprofessional teamwork. Quantitative and qualitative evaluation methods were used including preprogram and postprogram knowledge and self-efficacy surveys, along with end-of-session and program evaluations. RESULTS: Five annual cohorts involving 41 preceptors with varied demographics, professions, and clinical practices completed the mini-fellowship program. Participants' percentage of items answered correctly on a QI knowledge test increased from 79.2% (pretest) to 85.5% (post-test), a gain of 6.3% (90% CI: 2.9-9.7%; P < .003). The average QI self-efficacy scores improved from 2.64 to 3.82, a gain of 1.18 points on a five-point scale (P < .001). The average education/teaching self-efficacy increased from 2.79 to 3.80 on a five-point scale (P < .001). Ultimately, 94% would recommend the program to other preceptors. DISCUSSION: An interprofessional preceptor development program designed to train clinicians to effectively teach in the clinical setting and to conduct QI projects with students was achievable and effective. This program can serve as a model for academic centers charged with training future health care workers and supporting their community-based preceptors' training needs.

Differences in Safety Report Event Types Submitted by Graduate Medical Education Trainees Compared With Other Healthcare Team Members.

OBJECTIVES: Graduate medical education (GME) trainees have a unique perspective from which to identify and report patient safety concerns. However, it is not known how safety reports submitted by GME trainees differ from those submitted by other clinical staff. We hypothesized that GME trainees were more likely to submit safety reports regarding transitions of care, delays in care, and lapses in communication, and reports of higher severity compared with other frontline staff such as nurses, pharmacists, and other providers. METHODS: Patient safety reports submitted by clinical staff for 1 year at an academic tertiary care children's hospital were retrospectively reviewed and categorized by reporter type. Severity level and event type were analyzed by reporter type, and repeat χ2 tests were used to compare the percentage of reports at each severity level and in each event type submitted by GME trainees compared with each other reporter type. RESULTS: Graduate medical education trainees submitted reports of greater severity (level E/F/G) compared with nurses (10% versus 5%, P = 0.021) and pharmacists (10% versus 2%, P = 0.001). A greater percent of GME trainees' reports were categorized as errors in transitions of care, diagnosis, ordering, laboratory collection, and care delays compared with several other reporter types. CONCLUSIONS: Graduate medical education trainees identify system vulnerabilities not detected by other personnel, supporting efforts to increase safety reporting by GME trainees.

Initial Modified Pulmonary Index Score Predicts Hospital Length of Stay for Asthma Subjects Admitted to the Pediatric Intensive Care Unit.

BACKGROUND: Scoring systems are frequently used to assess the severity of pediatric asthma exacerbations. The modified pulmonary index score (MPIS) has been found to be highly correlated with length of stay (LOS) in the pediatric intensive care unit (PICU). We sought to evaluate the use of the MPIS to predict hospital LOS for patients admitted to our PICU. METHODS: We retrospectively reviewed the medical records of pediatric asthma subjects aged 2-17 y admitted to our PICU between June 2014 and November 2017. We divided subjects a priori into 3 groups (low: MPIS 0-5; medium: MPIS 6-9; high: MPIS ≥ 10) based upon each subject's first MPIS documented in the PICU. Hospital LOS, PICU LOS, time on continuous albuterol, and increased respiratory support were compared between groups. RESULTS: 143 subjects were included. There were no differences for demographics, medical history, cause of exacerbations, or mean heart rate between groups. There were significant differences between groups for mean breathing frequency (P < .001), [Formula: see text] (P = .01), and [Formula: see text] (P < .004). There were significant differences between groups for route of admission (P = .02), high-flow nasal cannula use (P < .001), and use of a helium-oxygen mixture (P < .001). There were significant differences between groups for median hospital LOS (1.2 vs 2.3 vs 3.4 d, P < .001), PICU LOS (0.39 vs 1.3 vs 2 d, P < .001), and time on continuous albuterol (7.4 vs 20.6 vs 34.7 h, P < .001). After adjusting for demographics and medical history, the incidence risk ratio for hospital LOS was 2.09 for PICU admission for an MPIS of 6-9 and 2.68 for an MPIS ≥ 10 when compared to an MPIS < 6. CONCLUSIONS: The MPIS thresholds used in our pathway appropriately predicted LOS in our cohort of subjects with asthma admitted to the PICU. Higher MPIS was associated with increased hospital LOS, PICU LOS, and time on continuous albuterol.

A Respiratory Therapist-Driven Asthma Pathway Reduced Hospital Length of Stay in the Pediatric Intensive Care Unit.

BACKGROUND: Asthma is a common reason for admissions to the pediatric intensive care unit (PICU). Since June 2014, our institution has used a pediatric asthma clinical pathway for all patients, including those in PICU. The pathway promotes respiratory therapist-driven bronchodilator weaning based on the Modified Pulmonary Index Score (MPIS). This pathway was associated with decreased hospital length of stay (LOS) for all pediatric asthma patients; however, the effect on PICU patients was unclear. We hypothesized that the implementation of a pediatric asthma pathway would reduce hospital LOS for asthmatic patients admitted to the PICU. METHODS: We retrospectively reviewed the medical records of all pediatric asthma subjects 2-17 y old admitted to our PICU before and after pathway initiation. Primary outcome was hospital LOS. Secondary outcomes were PICU LOS and time on continuous albuterol. Data were analyzed using the chi-square test for categorical data, the t test for normally distributed data, and the Mann-Whitney test for nonparametric data. RESULTS: A total of 203 eligible subjects (49 in the pre-pathway group, 154 in the post group) were enrolled. There were no differences between groups for age, weight, gender, home medications, cause of exacerbation, medical history, or route of admission. There were significant decreases in median (interquartile range) hospital LOS (4.4 [2.9-6.6] d vs 2.7 [1.6-4.0] d, P < .001), median PICU LOS (2.1 [1.3-4.0] d vs 1.6 [0.8-2.4] d, P = .003), and median time on continuous albuterol (39 [25-85] h vs 27 [13-42] h, P = .001). Significantly more subjects in the post-pathway group were placed on high-flow nasal cannula (32% vs 6%, P = .001) or noninvasive ventilation (10% vs 4%, P = .02). CONCLUSION: The implementation of an asthma pathway was associated with decreased hospital LOS, PICU LOS, and time on continuous albuterol. There was also an increase in the use of high-flow nasal cannula and noninvasive ventilation after the implementation of this clinical pathway.

A Light-Controlled Allosteric Modulator Unveils a Role for mGlu4 Receptors During Early Stages of Ischemia in the Rodent Cerebellar Cortex.

Metabotropic glutamate receptors (mGlus) are G Protein coupled-receptors that modulate synaptic transmission and plasticity in the central nervous system. Some act as autoreceptors to control neurotransmitter release at excitatory synapses and have become attractive targets for drug therapy to treat certain neurological disorders. However, the high degree of sequence conservation around the glutamate binding site makes the development of subtype-specific orthosteric ligands difficult to achieve. This problem can be circumvented by designing molecules that target specific less well conserved allosteric sites. One such allosteric drug, the photo-switchable compound OptoGluNAM4.1, has been recently employed to reversibly inhibit the activity of metabotropic glutamate 4 (mGlu4) receptors in cell cultures and in vivo. We studied OptoGluNAM4.1 as a negative modulator of neurotransmission in rodent cerebellar slices at the parallel fiber - Purkinje cell synapse. Our data show that OptoGluNAM4.1 antagonizes pharmacological activation of mGlu4 receptors in a fully reversible and photo-controllable manner. In addition, for the first time, this new allosteric modulator allowed us to demonstrate that, in brain slices from the rodent cerebellar cortex, mGlu4 receptors are endogenously activated in excitotoxic conditions, such as the early phases of simulated cerebellar ischemia, which is associated with elevated levels of extracellular glutamate. These findings support OptoGluNAM4.1 as a promising new tool for unraveling the role of mGlu4 receptors in the central nervous system in physio-pathological conditions.

Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites.

A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an l-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu4 subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential.

Allosteric nanobodies uncover a role of hippocampal mGlu2 receptor homodimers in contextual fear consolidation.

Antibodies have enormous therapeutic and biotechnology potential. G protein-coupled receptors (GPCRs), the main targets in drug development, are of major interest in antibody development programs. Metabotropic glutamate receptors are dimeric GPCRs that can control synaptic activity in a multitude of ways. Here we identify llama nanobodies that specifically recognize mGlu2 receptors, among the eight subtypes of mGluR subunits. Among these nanobodies, DN10 and 13 are positive allosteric modulators (PAM) on homodimeric mGlu2, while DN10 displays also a significant partial agonist activity. DN10 and DN13 have no effect on mGlu2-3 and mGlu2-4 heterodimers. These PAMs enhance the inhibitory action of the orthosteric mGlu2/mGlu3 agonist, DCG-IV, at mossy fiber terminals in the CA3 region of hippocampal slices. DN13 also impairs contextual fear memory when injected in the CA3 region of hippocampal region. These data highlight the potential of developing antibodies with allosteric actions on GPCRs to better define their roles in vivo.

Native metabotropic glutamate receptor 4 depresses synaptic transmission through an unusual Gαq transduction pathway.

In cerebellar cortex, mGlu4 receptors located on parallel fibers play an essential role in normal motor function, but the molecular mechanisms involved are not yet completely understood. Using a strategy combining biochemical and electrophysiological approaches in the rodent cerebellum, we demonstrate that presynaptic mGlu4 receptors control synaptic transmission through an atypical activation of Gαq proteins. First, the Gαq subunit, PLC and PKC signaling proteins present in cerebellar extracts are retained on affinity chromatography columns grafted with different sequences of the cytoplasmic domain of mGlu4 receptor. The i2 loop and the C terminal domain were used as baits, two domains that are known to play a pivotal role in coupling selectivity and efficacy. Second, in situ proximity ligation assays show that native mGlu4 receptors and Gαq subunits are in close physical proximity in cerebellar cortical slices. Finally, electrophysiological experiments demonstrate that the molecular mechanisms underlying mGlu4 receptor-mediated inhibition of transmitter release at cerebellar Parallel Fiber (PF) - Molecular Layer Interneuron (MLI) synapses involves the Gαq-PLC signaling pathway. Taken together, our results provide compelling evidence that, in the rodent cerebellar cortex, mGlu4 receptors act by coupling to the Gαq protein and PLC effector system to reduce glutamate synaptic transmission.

Good to Great: Quality-Improvement Initiative Increases and Sustains Pediatric Health Care Worker Hand Hygiene Compliance.

OBJECTIVE: The Joint Commission, the Centers for Disease Control and Prevention, and the World Health Organization challenge hospitals to achieve and sustain compliance with effective hand hygiene (HH) practice; however, many inpatient units fail to achieve a high level of reliability. The aim of the project was to increase and sustain health care worker (HCW) compliance with HH protocols from 87% (level of reliability [LOR] 1) to ≥95% (LOR 2) within 9 months on 2 pediatric inpatient units in an academic children's hospital. METHODS: This study was a time-series, quality-improvement project. Interventions were tested through multiple plan-do-study-act cycles on 2 pediatric inpatient units. HH compliance audits of HCWs on these units were performed randomly each week by the hospital infection prevention program. Control charts of percentages of HCW HH compliance were constructed with 3-σ (data within 3 SDs from a mean) control limits. These control limits were adjusted after achieving significant improvements in performance over time. Charts were annotated with interventions including (1) increasing awareness, (2) providing timely feedback, (3) empowering patients and families to participate in mitigation, (4) providing focused education, and (5) developing interdisciplinary HH champions. RESULTS: HH compliance rates improved from an average of 87% (LOR 1) to ≥95% (LOR 2) within 9 months, and this improvement has been sustained for >2 years on both pediatric inpatient units. CONCLUSIONS: Significant and sustained gains in HH compliance rates of ≥95% (LOR 2) can be achieved by applying high-reliability human-factor interventions.

Improving the Efficiency of Care for Pediatric Patients Hospitalized With Asthma.

BACKGROUND: Asthma exacerbations are a leading cause of hospitalization among children. Despite the existence of national pediatric asthma guidelines, significant variation in care persists. At Duke Children's Hospital, we determined that our average length of stay (ALOS) and cost for pediatric asthma admissions exceeded that of our peers. Our aim was to reduce the ALOS of pediatric patients hospitalized with asthma from 2.9 days to 2.6 days within 12 months by implementing an asthma pathway within our new electronic health record. METHODS: We convened a multidisciplinary committee charged with reducing variability in practice, ALOS, and cost of inpatient pediatric asthma care, while adhering to evidence-based guidelines. Interventions were tested through multiple "plan-do-study-act" cycles. Control charts of the ALOS were constructed and annotated with interventions, including testing of an asthma score, implementation of order sets, use of a respiratory therapy-driven albuterol treatment protocol, and provision of targeted education. Order set usage was audited as a process measure. Readmission rates were monitored as a balancing measure. RESULTS: The ALOS of pediatric patients hospitalized with asthma decreased significantly from 2.9 days to 2.3 days. Comparing baseline with intervention variable direct cost data revealed a savings of $1543 per case. Improvements occurred in the context of high compliance with the asthma pathway order sets. Readmission rates remained stable throughout the study period. CONCLUSIONS: Implementation of an asthma care pathway based on the electronic health record improved the efficiency and variable direct costs of hospital care, reduced variability in practice, and ensured adherence to high-quality national guidelines.

The secure base script: associated with early maladaptive schemas related to attachment.

OBJECTIVES: To examine the relations between traditionally assessed early maladaptive schemas and the attachment-specific secure base script (a script-like representation of what individuals expect to happen when they face distress), to inform our understanding of beliefs about the self in relation to others. The present study took an ecologically driven approach, assessing knowledge of the secure base script from descriptions of current relationships. DESIGN: A cross-sectional design was used. METHODS: One hundred forty-six undergraduate students, recruited as part of a larger study on adversity and self-concept, provided narrative descriptions of their current relationships. Narratives were coded for attachment-related 'secure base' content using a secure base script scale for relationship narratives. Early maladaptive schemas were assessed with the Young Schema Questionnaire, and attachment was additionally evaluated using the Experiences in Close Relationships questionnaire. RESULTS: Self-reported attachment avoidance and anxiety were related to secure base script content in theory-consistent ways. The extent to which participants described secure base script content was inversely associated with four out of five maladaptive schemas characterized most centrally by disconnection from others. Furthermore, these associations remained significant when controlling for self-reported attachment style. Self-reported attachment avoidance and anxiety also were related to maladaptive schemas in a predictable pattern. CONCLUSIONS: Results bridge cognitive and attachment theories, supporting the interrelatedness of secure base script knowledge assessed in current relationships, and schema-related content regarding connectedness with others. Better integration of theories regarding internal representations may serve to enrich psychotherapeutic formulation from a variety of clinical perspectives. PRACTITIONER POINTS: Schema Therapy's (Young, Klosko, & Weishaar, 2003 , Schema therapy: A practitioner's guide. New York: Guilford Press) early maladaptive schemas, with themes of disconnection from others/in relationships, are related to the attachment construct of knowledge of a secure base script. Applying secure base script coding procedure to a relationship speech task provides a potentially valuable performance-based tool for evaluating important attachment related constructs in a brief, non-obtrusive format. Better understanding of how self-schema and attachment constructs are associated may be of benefit to case formulation for psychotherapeutic intervention.

Choosing wisely in pediatric hospital medicine: five opportunities for improved healthcare value.

BACKGROUND: Despite estimates that waste constitutes up to 20% of healthcare expenditures in the United States, overuse of tests and therapies is significantly under-recognized in medicine, particularly in pediatrics. The American Board of Internal Medicine Foundation developed the Choosing Wisely campaign, which challenged medical societies to develop a list of 5 things physicians and patients should question. The Society of Hospital Medicine (SHM) joined this effort in the spring of 2012. This report provides the pediatric work group's results. METHODS: A work group of experienced and geographically dispersed pediatric hospitalists was convened by the Quality and Safety Committee of the SHM. This group developed an initial list of 20 recommendations, which was pared down through a modified Delphi process to the final 5 listed below. RESULTS: The top 5 recommendations proposed for pediatric hospital medicine are: (1) Do not order chest radiographs in children with asthma or bronchiolitis. (2) Do not use systemic corticosteroids in children under 2 years of age with a lower respiratory tract infection. (3) Do not use bronchodilators in children with bronchiolitis. (4) Do not treat gastroesophageal reflux in infants routinely with acid suppression therapy. (5) Do not use continuous pulse oximetry routinely in children with acute respiratory illness unless they are on supplemental oxygen. CONCLUSION: We recommend that pediatric hospitalists use this list to prioritize quality improvement efforts and include issues of waste and overuse in their efforts to improve patient care.

Repeated split-belt treadmill training improves poststroke step length asymmetry.

BACKGROUND AND OBJECTIVE: Previous studies suggest that error augmentation may be used as a strategy to achieve longer-term changes in gait deficits after stroke. The purpose of this study was to determine whether longer-term improvements in step length asymmetry could be achieved with repeated split-belt treadmill walking practice using an error augmentation strategy. METHODS: 13 persons with chronic stroke (>6 months) participated in testing: (1) prior to 12 sessions of split-belt treadmill training, (2) after the training, and (3) in follow-up testing at 1 and 3 months. Step length asymmetry was the target of training, so belt speeds were set to augment step length asymmetry such that aftereffects resulted in reduced step length asymmetry during overground walking practice. Each individual was classified as a "responder" or "nonresponder" based on whether their reduction in step length asymmetry exceeded day-to-day variability. RESULTS: For the group and for the responders (7 individuals), step length asymmetry improved from baseline to posttesting (P < .05) through an increased step length on both legs but a relatively larger change on the shorter step side (P < .05). Other parameters that were not targeted (e.g., stance time asymmetry) did not change over the intervention. CONCLUSIONS: This study demonstrates that short-term adaptations can be capitalized on through repetitive practice and can lead to longer-term improvements in gait deficits poststroke. The error augmentation strategy, which promotes stride-by-stride adjustment to reduce asymmetry and results in improved asymmetry during overground walking practice, appears to be critical for obtaining the improvements observed.

Use of ketamine during procedural sedation: indications, controversies, and side effects.

Ketamine is a well-described anesthetic and analgesic, unique in its ability to preserve laryngeal reflexes and airway protection, and offered to a wide range of patients, although not necessarily widely used. Because it is considered an anesthetic, widespread use by all sedation providers is often limited despite its long history as a safe sedative. Because of its sympathomimetic effects, ketamine may be used in patients who are hypovolemic, including those who are experiencing traumatic or obstetric emergencies. The use of ketamine in patients with epilepsy or traumatic brain injury is more controversial. This article will explore the side effects of ketamine and current research that support or discourage its use in a variety of settings.

A new signalling pathway for parallel fibre presynaptic type 4 metabotropic glutamate receptors (mGluR4) in the rat cerebellar cortex.

In the rodent cerebellum, pharmacological activation of mGluR4 acutely depresses excitatory synaptic transmission at parallel fibre­Purkinje cell synapses. This depression involves the inhibition of presynaptic calcium (Ca2+) influx that ultimately controls glutamate release. In this study, we investigate the molecular basis of mGluR4-mediated inhibition of presynaptic Ca2+ transients. Our results demonstrate that the mGluR4 effect does not depend on selective inhibition of a specific type of presynaptic voltage-gated Ca2+ channel, but rather involves modulation of all classes of Ca2+ channels present in the presynaptic terminals. In addition, this inhibitory effect does not involve the activation of G protein-activated inwardly rectifying potassium channels, TEA-sensitive potassium channels or two-pore-domain potassium channels. Furthermore, this inhibition does not require pertussis toxin-sensitive G proteins, and is independent of any effect on adenylyl cyclases, protein kinase A, mitogen-activated protein kinases or phosphoinositol-3 kinase activity. Interestingly we found that mGluR4 inhibition of presynaptic Ca2+ influx employs a newly defined signalling pathway, notably that involving the activation of phospholipase C and ultimately protein kinase C.

A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential.

Metabotropic glutamate (mGlu) receptors are promising targets to treat numerous brain disorders. So far, allosteric modulators are the only subtype selective ligands, but pure agonists still have strong therapeutic potential. Here, we aimed at investigating the possibility of developing subtype-selective agonists by extending the glutamate-like structure to hit a nonconsensus binding area. We report the properties of the first mGlu4-selective orthosteric agonist, derived from a virtual screening hit, LSP4-2022 using cell-based assays with recombinant mGlu receptors [EC(50): 0.11 ± 0.02, 11.6 ± 1.9, 29.2 ± 4.2 µM (n>19) in calcium assays on mGlu4, mGlu7, and mGlu8 receptors, respectively, with no activity at the group I and -II mGlu receptors at 100 µM]. LSP4-2022 inhibits neurotransmission in cerebellar slices from wild-type but not mGlu4 receptor-knockout mice. In vivo, it possesses antiparkinsonian properties after central or systemic administration in a haloperidol-induced catalepsy test, revealing its ability to cross the blood-brain barrier. Site-directed mutagenesis and molecular modeling was used to identify the LSP4-2022 binding site, revealing interaction with both the glutamate binding site and a variable pocket responsible for selectivity. These data reveal new approaches for developing selective, hydrophilic, and brain-penetrant mGlu receptor agonists, offering new possibilities to design original bioactive compounds with therapeutic potential.

Role of the vesicular transporter VGLUT3 in retrograde release of glutamate by cerebellar Purkinje cells.

In the cerebellum, retrograde release of glutamate (Glu) by Purkinje cells (PCs) participates in the control of presynaptic neurotransmitter release responsible for the late component of depolarization-induced suppression of excitation (DSE), as well as for depolarization-induced potentiation of inhibition (DPI). It might also participate in the depolarization-induced slow current (DISC) in PCs, although this contribution was later challenged. We also know that both DPI and DISC are soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent processes, although the molecular nature of the vesicular transporter was not determined. In PCs, VGLUT3 is the only known vesicular glutamate transporter identified and is expressed during the same developmental frame as when DPI, DISC, and the Glu-dependent component of DSE are observed. We therefore tested the hypothesis that all these processes depend on the presence of VGLUT3 by comparing the Glu-dependent component of DSE, DPI, and DISC in nearly mature (2- to 3-wk-old) wild-type and VGLUT3 knockout mice. Our data demonstrate that, in nearly mature mice, the slow component of DSE occurs through vesicular release of Glu that involves VGLUT3. This Glu-dependent component of DSE is no longer present in fully mature mice. This study also establishes that, in nearly mature mice, DPI also depends on the presence of VGLUT3, whereas this is not the case for DISC. Finally, the unusually large basal paired-pulse facilitation observed in nearly mature VGLUT3(-/-) mice but not in adult ones suggests that some basal retrograde release of Glu occurs during development and contributes to basal concentrations of extracellular Glu.

Split-belt treadmill training poststroke: a case study.

BACKGROUND AND PURPOSE: Even after rehabilitation, many individuals with strokes have residual gait deviations and limitations in functional walking. Applying the principles of motor adaptation through a split-belt treadmill walking paradigm can lead to short-term improvements in step length asymmetry after stroke. The focus of this case study was to determine whether it is possible to capitalize on these improvements for long-term gain. CASE DESCRIPTION: The participant was a 36-year-old woman who was 1.6 years poststroke. She had a slow walking speed and multiple specific gait deviations, including step length asymmetry. INTERVENTION: The participant walked on a split-belt treadmill 3 d/wk for 4 weeks, with the paretic leg on the slower of the two treadmill belts. The goal was 30 minutes of split-belt treadmill walking each day, followed by overground walking practice to reinforce improvements in step length symmetry. OUTCOMES: With training, step length asymmetry decreased from 21% to 9% and decreased further to 7% asymmetry 1 month after training. Self-selected walking speed increased from 0.71 m/s to 0.81 m/s after training and 0.86 m/s 1 month later. Percent recovery, measured by the Stroke Impact Scale (SIS), increased from 40% to 50% posttraining and to 60% 1 month later. DISCUSSION: Improvements in step length symmetry were observed following training and these improvements were maintained 1 month later. Concomitant changes in clinical measures were also observed, although these improvements were modest. The outcomes for this participant are encouraging given the relatively small dose of training. They suggest that after stroke, short-term adaptation can be capitalized on through repetitive practice and can lead to longer-term improvements stroke.