Conditional Astrocyte Rac1KO Attenuates Hyperreflexia after Spinal Cord Injury.

Spasticity is a hyperexcitability disorder that adversely impacts functional recovery and rehabilitative efforts after spinal cord injury (SCI). The loss of evoked rate-dependent depression (RDD) of the monosynaptic H-reflex is indicative of hyperreflexia, a physiological sign of spasticity. Given the intimate relationship between astrocytes and neurons, that is, the tripartite synapse, we hypothesized that astrocytes might have a significant role in post-injury hyperreflexia and plasticity of neighboring neuronal synaptic dendritic spines. Here, we investigated the effect of selective Rac1KO in astrocytes (i.e., adult male and female mice, transgenic cre-flox system) on SCI-induced spasticity. Three weeks after a mild contusion SCI, control Rac1wt animals displayed a loss of H-reflex RDD, that is, hyperreflexia. In contrast, transgenic animals with astrocytic Rac1KO demonstrated near-normal H-reflex RDD similar to pre-injury levels. Reduced hyperreflexia in astrocytic Rac1KO animals was accompanied by a loss of thin-shaped dendritic spine density on α-motor neurons in the ventral horn. In SCI-Rac1wt animals, as expected, we observed the development of dendritic spine dysgenesis on α-motor neurons associated with spasticity. As compared with WT animals, SCI animals with astrocytic Rac1KO expressed increased levels of the glial-specific glutamate transporter, glutamate transporter-1 in the ventral spinal cord, potentially enhancing glutamate clearance from the synaptic cleft and reducing hyperreflexia in astrocytic Rac1KO animals. Taken together, our findings show for the first time that Rac1 activity in astrocytes can contribute to hyperreflexia underlying spasticity following SCI. These results reveal an opportunity to target cell-specific molecular regulators of H-reflex excitability to manage spasticity after SCI.Significance Statement Spinal cord injury leads to stretch reflex hyperexcitability, which underlies the clinical symptom of spasticity. This study shows for the first time that astrocytic Rac1 contributes to the development of hyperreflexia after SCI. Specifically, astrocytic Rac1KO reduced SCI-related H-reflex hyperexcitability, decreased dendritic spine dysgenesis on α-motor neurons, and elevated the expression of the astrocytic glutamate transporter-1 (GLT-1). Overall, this study supports a distinct role for astrocytic Rac1 signaling within the spinal reflex circuit and the development of SCI-related spasticity.

A single sequence of intermittent hypoxia does not alter stretch reflex excitability in able-bodied individuals.

Spasticity attributable to exaggerated stretch reflex pathways, particularly affecting the ankle plantar flexors, often impairs overground walking in persons with incomplete spinal cord injury. Compelling evidence from rodent models underscores how exposure to acute intermittent hypoxia (AIH) can provide a unique medium to induce spinal plasticity in key inhibitory pathways mediating stretch reflex excitability and potentially affect spasticity. In this study, we quantify the effects of a single exposure to AIH on the stretch reflex in able-bodied individuals. We hypothesized that a single sequence of AIH will increase the stretch reflex excitability of the soleus muscle during ramp-and-hold angular perturbations applied to the ankle joint while participants perform passive and volitionally matched contractions. Our results revealed that a single AIH exposure did not significantly change the stretch reflex excitability during both passive and active matching conditions. Furthermore, we found that able-bodied individuals increased their stretch reflex response from passive to active matching conditions after both sham and AIH exposures. Together, these findings suggest that a single AIH exposure might not engage inhibitory pathways sufficiently to alter stretch reflex responses in able-bodied persons. However, the generalizability of our present findings requires further examination during repetitive exposures to AIH along with potential reflex modulation during functional movements, such as overground walking.

Enhanced motor learning and motor savings after acute intermittent hypoxia are associated with a reduction in metabolic cost.

Breathing mild bouts of low oxygen air (i.e. acute intermittent hypoxia, AIH) has been shown to improve locomotor function in humans after a spinal cord injury. How AIH-induced gains in motor performance are achieved remains unclear. We examined the hypothesis that AIH augments motor learning and motor retention during a locomotor adaptation task. We further hypothesized that gains in motor learning and retention will be associated with reductions in net metabolic power, consistent with the acquisition of energetically favourable mechanics. Thirty healthy individuals were randomly allocated into either a control group or an AIH group. We utilized a split-belt treadmill to characterize adaptations to an unexpected belt speed perturbation of equal magnitude during an initial exposure and a second exposure. Adaptation was characterized by changes in spatiotemporal step asymmetry, anterior-posterior force asymmetry, and net metabolic power. While both groups adapted by reducing spatial asymmetry, only the AIH group achieved significant reductions in double support time asymmetry and propulsive force asymmetry during both the initial and the second exposures to the belt speed perturbation. Net metabolic power was also significantly lower in the AIH group, with significant reductions from the initial perturbation exposure to the second. These results provide the first evidence that AIH mediates improvements in both motor learning and retention. Further, our results suggest that reductions in net metabolic power continue to be optimized upon subsequent learning and are driven by more energetically favourable temporal coordination strategies. Our observation that AIH facilitates motor learning and retention can be leveraged to design rehabilitation interventions that promote functional recovery. KEY POINTS: Brief exposures to low oxygen air, known as acute intermittent hypoxia (AIH), improves locomotor function in humans after a spinal cord injury, but it remains unclear how gains in motor performance are achieved. In this study, we tested the hypothesis that AIH induces enhancements in motor learning and retention by quantifying changes in interlimb coordination, anterior-posterior force symmetry and metabolic cost during a locomotor adaptation task. We show the first evidence that AIH improves both motor learning and savings of newly learned temporal interlimb coordination strategies and force asymmetry compared to untreated individuals. We further demonstrate that AIH elicits greater reductions in metabolic cost during motor learning that continues to be optimized upon subsequent learning. Our findings suggest that AIH-induced gains in locomotor performance are facilitated by enhancements in motor learning and retention of more energetically favourable coordination strategies.

Increased astrocytic GLT-1 expression in tripartite synapses is associated with SCI-induced hyperreflexia.

Spasticity is a chronic neurological complication associated with spinal cord injury (SCI), characterized by increased muscle tone and stiffness. A physiological sign of spasticity is hyperreflexia, evident by the loss of evoked rate-dependent depression (RDD) in the H-reflex. Although previous work has shown that SCI-induced astrogliosis contributes to hyperexcitability disorders, including neuropathic pain and spasticity, it is unclear how reactive astrocytes can modulate synaptic transmission within the injured spinal cord. To study astrocytes' role in post-SCI hyperreflexia, we examined glutamate transporter-1 (GLT-1) and postsynaptic density protein 95 (PSD-95) proteins in astrocytes and neurons, respectively, within the ventral horn (lamina IX) below the level of injury (spinal segment L4-5). The close juxtaposition of GLT-1 and PSD-95 markers is a molecular correlate of tripartite synapses and is thought to be a key element in the astrocyte-induced plasticity of neuronal synapses. Our study compared animals with and without SCI-induced hyperreflexia and spasticity and investigated potential synaptic abnormalities associated with astrocyte involvement. As expected, 4 wk after SCI, we observed a loss in evoked H-reflex RDD in hindlimb electromyogram recordings, i.e., hyperreflexia, in contrast to uninjured sham. Importantly, our main findings show a significant increase in the presence of GLT-1-PSD-95 tripartite synapses in the ventral spinal cord motor regions of animals exhibiting SCI-induced hyperreflexia. Taken together, our study suggests the involvement of astrocyte-neuron synaptic complexes in the plasticity-driven progression of chronic spasticity.NEW & NOTEWORTHY The role of astrocytes in H-reflex hyperexcitability following SCI remains understudied. Our findings establish a relationship between GLT-1 expression, its proximity to neuronal PSD-95 in the spinal cord ventral horn, and the loss of H-reflex RDD, i.e., hyperreflexia. Our findings provide a new perspective on synaptic alterations and the development of SCI-related spasticity.

A nonlinear hidden layer enables actor-critic agents to learn multiple paired association navigation.

Navigation to multiple cued reward locations has been increasingly used to study rodent learning. Though deep reinforcement learning agents have been shown to be able to learn the task, they are not biologically plausible. Biologically plausible classic actor-critic agents have been shown to learn to navigate to single reward locations, but which biologically plausible agents are able to learn multiple cue-reward location tasks has remained unclear. In this computational study, we show versions of classic agents that learn to navigate to a single reward location, and adapt to reward location displacement, but are not able to learn multiple paired association navigation. The limitation is overcome by an agent in which place cell and cue information are first processed by a feedforward nonlinear hidden layer with synapses to the actor and critic subject to temporal difference error-modulated plasticity. Faster learning is obtained when the feedforward layer is replaced by a recurrent reservoir network.

Conflicting signals: Exploring the socioeconomic implications of gender discordant names.

We investigate the educational and employment consequences of having a gender discordant name - one that is also given to people of a different gender. People with discordant names may be more likely to experience stigma due to the conflicting signal between their gender and the perceptions of femininity or masculinity associated with their names. Our primary measure of discordance is based on the percentage of men and women with each first name, using a large administrative dataset from Brazil. We find that both men and women with gender discordant names attain significantly less education. Gender discordant names are also negatively and significantly associated with earnings though, after controlling for educational attainment, only people with the most discordant names have significantly lower earnings. These results are corroborated when using crowd-sourced gender perceptions of names in our dataset, which suggests that stereotypes and the judgments of others are a probable mechanism for the observed disparities.

Examining Ethnicity: Patterns of Minority Identification Among Children of Interethnic Marriages in China.

Ethnic identity is a highly contested issue in China. Yet, the literature on the social construction of ethnoracial identity is dominated by research on the Americas. In this study, we investigate patterns of ethnic identification among children of interethnic parents in China using census data from 2000 and survey data from 2010-2018. We focus on children who are aged 20 or younger and have one parent identified as an ethnic minority and one parent identified as an ethnic Han. We find that the strongest predictor of a child's minority identification is the father's ethnicity. Minority identification is also associated with gender, birth year, mother's education, household income, migration status, parent's perception of the child's diligence, the geographic concentration of minorities, and eligibility for ethnicity-based bonus points on the college entrance examination. Taken together, the results suggest that children's ethnoracial identity is shaped by family demographic characteristics as well as by education policy.

Pareto-Optimal Clustering with the Primal Deterministic Information Bottleneck.

At the heart of both lossy compression and clustering is a trade-off between the fidelity and size of the learned representation. Our goal is to map out and study the Pareto frontier that quantifies this trade-off. We focus on the optimization of the Deterministic Information Bottleneck (DIB) objective over the space of hard clusterings. To this end, we introduce the primal DIB problem, which we show results in a much richer frontier than its previously studied Lagrangian relaxation when optimized over discrete search spaces. We present an algorithm for mapping out the Pareto frontier of the primal DIB trade-off that is also applicable to other two-objective clustering problems. We study general properties of the Pareto frontier, and we give both analytic and numerical evidence for logarithmic sparsity of the frontier in general. We provide evidence that our algorithm has polynomial scaling despite the super-exponential search space, and additionally, we propose a modification to the algorithm that can be used where sampling noise is expected to be significant. Finally, we use our algorithm to map the DIB frontier of three different tasks: compressing the English alphabet, extracting informative color classes from natural images, and compressing a group theory-inspired dataset, revealing interesting features of frontier, and demonstrating how the structure of the frontier can be used for model selection with a focus on points previously hidden by the cloak of the convex hull.

Dendritic Spine Dynamics after Peripheral Nerve Injury: An Intravital Structural Study.

Neuropathic pain is an intractable medical condition with few or no options for effective treatment. Emerging evidence shows a strong structure-function relationship between dendritic spine dysgenesis and the presence of neuropathic pain. Postmortem tissue analyses can only imply dynamic structural changes associated with injury-induced pain. Here, we profiled the in vivo dynamics of dendritic spines over time on the same superficial dorsal horn (lamina II) neurons before and after peripheral nerve injury-induced pain. We used a two-photon, whole-animal imaging paradigm that permitted repeat imaging of the same dendritic branches of these neurons in C57/Bl6 Thy1-YFP male mice. Our study demonstrates, for the first time, the ongoing, steady-state changes in dendritic spine dynamics in the dorsal horn associated with peripheral nerve injury and pain. Ultimately, the relationship between altered dendritic spine dynamics and neuropathic pain may serve as a structure-based opportunity to investigate mechanisms of pain following injury and disease.SIGNIFICANCE STATEMENT This work is important because it demonstrates for the first time: (1) the powerful utility of intravital study of dendritic spine dynamics in the superficial dorsal horn; (2) that nerve injury-induced pain triggers changes in dendritic spine steady-state behavior in the spinal cord dorsal horn; and (3) this work opens the door to further investigations in vivo of spinal cord dendritic spine dynamics in the context of injury and disease.

Sodium channel Nav1.6 in sensory neurons contributes to vincristine-induced allodynia.

Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy. The underlying mechanisms are not well understood. In this study, we investigated whether voltage-gated sodium channels are involved in the development of vincristine-induced neuropathy. We established a mouse model in which repeated systemic vincristine treatment results in the development of significant mechanical allodynia. Histological examinations did not reveal major structural changes at proximal sciatic nerve branches or distal toe nerve fascicles at the vincristine dose used in this study. Immunohistochemical studies and in vivo two-photon imaging confirmed that there is no significant change in density or morphology of intra-epidermal nerve terminals throughout the course of vincristine treatment. These observations suggest that nerve degeneration is not a prerequisite of vincristine-induced mechanical allodynia in this model. We also provided the first detailed characterization of tetrodotoxin-sensitive (TTX-S) and resistant (TTX-R) sodium currents in dorsal root ganglion neurons following vincristine treatment. Accompanying the behavioural hyperalgesia phenotype, voltage-clamp recordings of small and medium dorsal root ganglion neurons from vincristine-treated animals revealed a significant upregulation of TTX-S Na+ current in medium but not small neurons. The increase in TTX-S Na+ current density is likely mediated by Nav1.6, because in the absence of Nav1.6 channels, vincristine failed to alter TTX-S Na+ current density in medium dorsal root ganglion neurons and, importantly, mechanical allodynia was significantly attenuated in conditional Nav1.6 knockout mice. Our data show that TTX-S sodium channel Nav1.6 is involved in the functional changes of dorsal root ganglion neurons following vincristine treatment and it contributes to the maintenance of vincristine-induced mechanical allodynia.

Superior Postoperative Stability and Functional Outcomes With Anteromedial Versus Transtibial Technique of Single-Bundle Autologous Hamstring Anterior Cruciate Ligament Reconstruction: A Meta-analysis of Prospective Randomized Controlled Trials.

PURPOSE: The aim of this meta-analysis was to compare the postoperative stability and functional outcomes of anteromedial (AM)- and transtibial (TT)-based single-bundle hamstring anterior cruciate ligament (ACL) reconstruction techniques. METHODS: A meta-analysis comparing the outcomes of single-bundle hamstring ACL reconstruction using the AM and TT techniques was performed. Prospective randomized controlled trials identified from searches of PubMed, Cochrane, and Embase were included in this review. The outcome measures analyzed included postoperative Lachman test and pivot-shift test results, side-to-side difference, International Knee Documentation Committee (IKDC) score, Lysholm score, and Tegner activity score. RESULTS: A total of 7 randomized controlled trials (654 patients) were included in this review. The AM technique, compared with the TT technique, resulted in superior postoperative stability based on the negative Lachman test rate (risk ratio [RR], 1.12; 95% confidence interval [CI], 1.01 to 1.24; P = .03; 95% prediction interval [PI], 0.32 to 3.46), negative pivot-shift test rate (RR, 1.16; 95% CI, 1.06 to 1.28; P = .002; 95% PI, 0.40 to 2.88), and side-to-side difference (weighted mean difference [WMD], -0.32 mm; 95% CI, -0.48 to -0.16; P < .0001; 95% PI, -0.55 to -0.09). Likewise, the AM technique contributed to superior postoperative functional outcomes based on the proportion of IKDC grade A findings (RR, 1.16; 95% CI, 1.02 to 1.32; P = .03; 95% PI, 0.40 to 2.83) and the Lysholm score (WMD, 0.82; 95% CI, 0.23 to 1.41; P = .007; 95% PI, -0.22 to 1.86). However, the AM and TT techniques had comparable subjective IKDC scores (WMD, 0.98; 95% CI, -0.91 to 2.88; P = .31; 95% PI, -3.18 to 5.14) and Tegner activity scores (WMD, 0.32; 95% CI, -0.23 to 0.86; P = .25; 95% PI, -3.84 to 4.48). CONCLUSIONS: The AM method of single-bundle hamstring ACL reconstruction results in superior postoperative stability and functional outcomes compared with the TT method. LEVEL OF EVIDENCE: Level I, systematic review of Level I studies.

Preparing IR for COVID-19: The Singapore Experience.

This paper describes country-wide special measures undertaken for interventional radiology staff during the current coronavirus disease 2019 (COVID-19) pandemic. Although each interventional radiology service around the world faces unique challenges, the principles outlined in this article will be useful when designing or strengthening individual practices and integrating them within wider hospital and national measures. Moving beyond the current outbreak, these measures will be useful for any future infectious diseases which are likely to arise.

Daily acute intermittent hypoxia to improve walking function in persons with subacute spinal cord injury: a randomized clinical trial study protocol.

BACKGROUND: Restoring community walking remains a highly valued goal for persons recovering from traumatic incomplete spinal cord injury (SCI). Recently, studies report that brief episodes of low-oxygen breathing (acute intermittent hypoxia, AIH) may serve as an effective plasticity-inducing primer that enhances the effects of walking therapy in persons with chronic (> 1 year) SCI. More persistent walking recovery may occur following repetitive (weeks) AIH treatment involving persons with more acute SCI, but this possibility remains unknown. Here we present our clinical trial protocol, designed to examine the distinct influences of repetitive AIH, with and without walking practice, on walking recovery in persons with sub-acute SCI (< 12 months) SCI. Our overarching hypothesis is that daily exposure (10 sessions, 2 weeks) to AIH will enhance walking recovery in ambulatory and non-ambulatory persons with subacute (< 12 months) SCI, presumably by harnessing endogenous mechanisms of plasticity that occur soon after injury. METHODS: To test our hypothesis, we are conducting a randomized, placebo-controlled clinical trial on 85 study participants who we stratify into two groups according to walking ability; those unable to walk (non-ambulatory group) and those able to walk (ambulatory group). The non-ambulatory group receives either daily AIH (15, 90s episodes at 10.0% O2 with 60s intervals at 20.9% O2) or daily SHAM (15, 90s episodes at 20.9% O2 with 60s intervals at 20.9% O2) intervention. The ambulatory group receives either 60-min walking practice (WALK), daily AIH + WALK, or daily SHAM+WALK intervention. Our primary outcome measures assess overground walking speed (10-Meter Walk Test), endurance (6-Minute Walk Test), and balance (Timed Up & Go Test). For safety, we also measure levels of pain, spasticity, systemic hypertension, and autonomic dysreflexia. We record outcome measures at baseline, days 5 and 10, and follow-ups at 1 week, 1 month, 6 months, and 12 months post-treatment. DISCUSSION: The goal of this clinical trial is to reveal the extent to which daily AIH, alone or in combination with task-specific walking practice, safely promotes persistent recovery of walking in persons with traumatic, subacute SCI. Outcomes from this study may provide new insight into ways to enhance walking recovery in persons with SCI. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02632422 . Registered 16 December 2015.

Sensory stimulation shifts visual cortex from synchronous to asynchronous states.

In the mammalian cerebral cortex, neural responses are highly variable during spontaneous activity and sensory stimulation. To explain this variability, the cortex of alert animals has been proposed to be in an asynchronous high-conductance state in which irregular spiking arises from the convergence of large numbers of uncorrelated excitatory and inhibitory inputs onto individual neurons. Signatures of this state are that a neuron's membrane potential (Vm) hovers just below spike threshold, and its aggregate synaptic input is nearly Gaussian, arising from many uncorrelated inputs. Alternatively, irregular spiking could arise from infrequent correlated input events that elicit large fluctuations in Vm (refs 5, 6). To distinguish between these hypotheses, we developed a technique to perform whole-cell Vm measurements from the cortex of behaving monkeys, focusing on primary visual cortex (V1) of monkeys performing a visual fixation task. Here we show that, contrary to the predictions of an asynchronous state, mean Vm during fixation was far from threshold (14 mV) and spiking was triggered by occasional large spontaneous fluctuations. Distributions of Vm values were skewed beyond that expected for a range of Gaussian input, but were consistent with synaptic input arising from infrequent correlated events. Furthermore, spontaneous fluctuations in Vm were correlated with the surrounding network activity, as reflected in simultaneously recorded nearby local field potential. Visual stimulation, however, led to responses more consistent with an asynchronous state: mean Vm approached threshold, fluctuations became more Gaussian, and correlations between single neurons and the surrounding network were disrupted. These observations show that sensory drive can shift a common cortical circuitry from a synchronous to an asynchronous state.

Agonist-Antagonist Coactivation Enhances Corticomotor Excitability of Ankle Muscles.

Spinal pathways underlying reciprocal flexion-extension contractions have been well characterized, but the extent to which cortically evoked motor-evoked potentials (MEPs) are influenced by antagonist muscle activation remains unclear. A majority of studies using transcranial magnetic stimulation- (TMS-) evoked MEPs to evaluate the excitability of the corticospinal pathway focus on upper extremity muscles. Due to functional and neural control differences between lower and upper limb muscles, there is a need to evaluate methodological factors influencing TMS-evoked MEPs specifically in lower limb musculature. If and to what extent the activation of the nontargeted muscles, such as antagonists, affects TMS-evoked MEPs is poorly understood, and such gaps in our knowledge may limit the rigor and reproducibility of TMS studies. Here, we evaluated the effect of the activation state of the antagonist muscle on TMS-evoked MEPs obtained from the target (agonist) ankle muscle for both tibialis anterior (TA) and soleus muscles. Fourteen able-bodied participants (11 females, age: 26.1 ± 4.1 years) completed one experimental session; data from 12 individuals were included in the analysis. TMS was delivered during 4 conditions: rest, TA activated, soleus activated, and TA and soleus coactivation. Three pairwise comparisons were made for MEP amplitude and coefficient of variability (CV): rest versus coactivation, rest versus antagonist activation, and agonist activation versus coactivation. We demonstrated that agonist-antagonist coactivation enhanced MEP amplitude and reduced MEP CVs for both TA and soleus muscles. Our results provide methodological considerations for future TMS studies and pave the way for future exploration of coactivation-dependent modulation of corticomotor excitability in pathological cohorts such as stroke or spinal cord injury.

Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury.

Painful burn injuries are among the most debilitating form of trauma, globally ranking in the top 15 leading causes of chronic disease burden. Despite its prevalence, however, chronic pain after burn injury is under-studied. We previously demonstrated the contribution of the Rac1-signaling pathway in several models of neuropathic pain, including burn injury. However, Rac1 belongs to a class of GTPases with low therapeutic utility due to their complex intracellular dynamics. To further understand the mechanistic underpinnings of burn-induced neuropathic pain, we performed a longitudinal study to address the hypothesis that inhibition of the downstream effector of Rac1, Pak1, will improve pain outcome following a second-degree burn injury. Substantial evidence has identified Pak1 as promising a clinical target in cognitive dysfunction and is required for dendritic spine dysgenesis associated with many neurological diseases. In our burn injury model, mice exhibited significant tactile allodynia and heat hyperalgesia and dendritic spine dysgenesis in the dorsal horn. Activity-dependent expression of c-fos also increased in dorsal horn neurons, an indicator of elevated central nociceptive activity. To inhibit Pak1, we repurposed an FDA-approved inhibitor, romidepsin. Treatment with romidepsin decreased dendritic spine dysgenesis, reduced c-fos expression, and rescued pain thresholds. Drug discontinuation resulted in a relapse of cellular correlates of pain and in lower pain thresholds in behavioral tests. Taken together, our findings identify Pak1 signaling as a potential molecular target for therapeutic intervention in traumatic burn-induced neuropathic pain.

Clinical Outcomes, Return to Sports, and Patient Satisfaction After Anterior Cruciate Ligament Reconstruction in Young and Middle-Aged Patients in an Asian Population-A 2-Year Follow-up Study.

PURPOSE: To compare the clinical outcomes of arthroscopic anterior cruciate ligament (ACL) reconstruction in young and middle-aged Asians. METHODS: A retrospective study was performed using prospectively collected data from a tertiary institution ACL registry. All Asian patients with ACL tears who underwent primary arthroscopic ACL reconstruction by a single surgeon between 2008 and 2014, with minimum 2-year follow-up, were included. Patients with previous knee surgery or multiligamentous knee injuries were excluded. Two groups were formed: young patients (YP) (age <30) and middle-aged patients (MP) (age >40). They were compared preoperatively and 6 months, 1 year, and 2 years postoperatively for demographics, knee range of motion, anterior laxity, Tegner level, Lysholm and International Knee Documentation Committee grade, ability to return to preinjury level of activity, and patient satisfaction. RESULTS: YP (n = 84) and MP (n = 22) had differences in mean age (YP = 23.1 years, range 18-29 years; MP = 46.4 years, range 41-59 years, P < .001), preinjury Tegner level (YP = 7.4, MP = 6.4, P = .005), and preoperative Lysholm scores (YP = 65.3, MP = 53.0, P = .034). The incidence of meniscal and chondral injuries was similar. Two years postoperatively, both groups had comparable knee range of motion and anterior laxity. The Tegner score was different (YP = 6.3, MP = 5.2, P = .028), but the proportion of patients returning to preinjury Tegner level (YP = 45.2%, MP = 46.9%, P = .812), Lysholm scores (YP = 92.5, MP = 93.8, P = .794), proportion of patients with knees rated International Knee Documentation Committee A/B (YP = 77.4%, MP = 81.8%, P = .777), and satisfaction levels (YP = 98.5%, MP = 94.1%, P = .370) were similar. There were no graft ruptures or reoperations. CONCLUSIONS: In an Asian, predominantly male population, the clinical outcomes of arthroscopic ACL reconstruction in YP and MP are equally good at 2-year follow-up. MP can benefit as much as younger patients from ACL reconstruction in terms of restoration of knee function and return to preinjury activity level, are equally satisfied with outcomes, and should not be excluded from surgery on the basis of age alone. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Targeted Neuromodulation of Abnormal Interhemispheric Connectivity to Promote Neural Plasticity and Recovery of Arm Function after Stroke: A Randomized Crossover Clinical Trial Study Protocol.

Background: Despite intensive rehabilitation efforts, most stroke survivors have persistent functional disability of the paretic arm and hand. These motor impairments may be due in part to maladaptive changes in structural and functional connections between brain regions. The following early stage clinical trial study protocol describes a noninvasive brain stimulation approach to target transcallosally mediated interhemispheric connections between the ipsi- and contralesional motor cortices (iM1 and cM1) using corticocortical paired associative stimulation (ihPAS). This clinical trial aims to characterize ihPAS-induced modulation of interhemispheric connectivity and the effect on motor skill performance and learning in chronic stroke survivors. Methods/Design: A repeated-measures, cross-over design study will recruit 20 individuals post-stroke with chronic mild-moderate paretic arm impairment. Each participant will complete an active ihPAS and control ihPAS session. Assessments of cortical excitability and motor skill performance will be conducted prior to and at four time points following the ihPAS intervention. The primary outcome measures will be: TMS-evoked interhemispheric motor connectivity, corticomotor excitability, and response time on a modified serial reaction time task. Discussion/Conclusion: The findings from this single-site early stage clinical trial will provide foundational results to inform the design of larger-scale, multisite clinical trials to evaluate the therapeutic potential of ihPAS-based neuromodulation for upper limb recovery after stroke. This trial is registered with NCT02465034.

The Impact of Diabetes on Patient Outcomes After Total Knee Arthroplasty in an Asian Population.

BACKGROUND: Diabetes is implicated with poorer outcomes and more complications after total knee arthroplasty (TKA). We aim to determine whether diabetes affects infection risk, functional outcomes, patient-reported outcome measures, and patient satisfaction in Asian patients after TKA. METHODS: Prospectively collected data for 905 patients who underwent unilateral TKA by a single surgeon from February 2004 to July 2014 were reviewed, of which 123 (13.6%) patients suffered from diabetes. At 2-year follow-up, the change in range of motion of the operated knee, body mass index, Knee Society Score, Oxford Knee Score (OKS), and Short Form-36 from baseline was compared between diabetic and nondiabetic patients. We also analyzed the length of hospitalization stay, infection risk, and patient satisfaction between the 2 groups. RESULTS: Compared with nondiabetic patients, diabetic patients had significantly poorer preoperative OKS (37.6 on 8.3 to 35.8 .38.0, P = .02) and Short Form-36 Mental Component Score (48.3 Me11.2 to 51.7 1.10.7, P = .01). At 2-year follow-up, diabetes continued to be associated with poorer OKS of 21.2 018.4 and Knee Society Score Function score of 64.7 Fu20.9 compared to 19.1 0.6.2 (P = .02) and 71.8 0220.1 (P = .01) respectively in nondiabetic patients. Interestingly, the difference in mental well-being was no longer significant after TKA. A significantly larger proportion of diabetic patients (50%) had a reduction in body mass index after TKA compared to 36% in nondiabetic patients (P < .01). There was no difference in range of motion, length of hospitalization stay, infection risk, and patient satisfaction. CONCLUSION: Despite poorer physical scores throughout, diabetic patients are no less satisfied and had significantly greater improvement in mental well-being and weight reduction after surgery.

Dendritic spine dysgenesis in superficial dorsal horn sensory neurons after spinal cord injury.

Neuropathic pain is a major complication of spinal cord injury, and despite aggressive efforts, this type of pain is refractory to available clinical treatment. Our previous work has demonstrated a structure-function link between dendritic spine dysgenesis on nociceptive sensory neurons in the intermediate zone, laminae IV/V, and chronic pain in central nervous system and peripheral nervous system injury models of neuropathic pain. To extend these findings, we performed a follow-up structural analysis to assess whether dendritic spine remodeling occurs on superficial dorsal horn neurons located in lamina II after spinal cord injury. Lamina II neurons are responsible for relaying deep, delocalized, often thermally associated pain commonly experienced in spinal cord injury pathologies. We analyzed dendritic spine morphometry and localization in tissue obtained from adult rats exhibiting neuropathic pain one-month following spinal cord injury. Although the total density of dendritic spines on lamina II neurons did not change after spinal cord injury, we observed an inverse relationship between the densities of thin- and mushroom-shaped spines: thin-spine density decreased while mushroom-spine density increased. These structural changes were specifically noted along dendritic branches within 150 µm from the soma, suggesting a possible adverse contribution to nociceptive circuit function. Intrathecal treatment with NSC23766, a Rac1-GTPase inhibitor, significantly reduced spinal cord injury-induced changes in both thin- and mushroom-shaped dendritic spines. Overall, these observations demonstrate that dendritic spine remodeling occurs in lamina II, regulated in part by the Rac1-signaling pathway, and suggests that structural abnormalities in this spinal cord region may also contribute to abnormal nociception after spinal cord injury.