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Presents a study that demonstrated the effect of annealing to promote the interdiffusion of chromium (Cr) into doped Fe/Cr multilayers. Mössbauer spectroscopic studies of annealed multilayers; Discussion on the magnetoresistance of doped multilayers; Conclusions.

Presents a study which measured small- and large-angle x-ray scattering from epitaxial iron (001) on a magnesium oxide (001) surface as a function of film thickness, using grazing incidence x-ray scattering. Details on strain relaxation subsequent to agglomeration; Description of epitaxial film preparation; Information on the elastic homogeneous biaxial strain energy in an island.

GABA A receptors containing δ subunits have been shown to mediate tonic/slow inhibition in the CNS. These receptors are typically found extrasynaptically and are activated by relatively low levels of ambient GABA in the extracellular space. In the mouse neocortex, δ subunits are expressed on the surface of some pyramidal cells as well as on parvalbumin positive (PV+) interneurons. An important function of PV+ interneurons is the organization of coordinated network activity that can be measured by EEG; however, it remains unclear what role tonic/slow inhibitory control of PV+ neurons may play in shaping oscillatory activity. After confirming a loss of functional δ mediated tonic currents in PV cells in cortical slices from mice lacking Gabrd in PV+ neurons (PV δcKO), we performed EEG recordings to survey network activity across wake and sleep states. PV δcKO mice showed altered spectral content of EEG during NREM and REM sleep that was a result of increased oscillatory activity in NREM and the emergence of transient high amplitude bursts of theta frequency activity during REM. Viral reintroduction of Gabrd to PV+ interneurons in PV δcKO mice rescued REM EEG phenotypes, supporting an important role for δ subunit mediated inhibition of PV+ interneurons for maintaining normal REM cortical oscillations., Significance Statement: The impact on cortical EEG of inhibition on PV+ neurons was studied by deleting a GABA A receptor subunit selectively from these neurons. We discovered unexpected changes at low frequencies during sleep that were rescued by viral reintroduction.

Objective: Neurostimulation is an emerging treatment for patients with drug-resistant epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model., Methods: We performed high-throughput testing of high-frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of status epilepticus. We evaluated combinations of six anatomic targets and three stimulus amplitudes., Results: We found that the spike-suppressive effects of high-frequency neurostimulation are highly dependent on the stimulation amplitude and location, with higher amplitude stimulation being significantly more effective. Epileptiform spiking activity was significantly reduced with ipsilateral 250 μA stimulation of the CA1 and CA3 hippocampal regions with 21.5% and 22.2% reductions, respectively. In contrast, we found that spiking frequency and amplitude significantly increased with stimulation of the ventral hippocampal commissure. We further found spatial differences with broader effects from CA1 versus CA3 stimulation., Significance: These findings demonstrate that the effects of therapeutic neurostimulation in an acute hippocampal seizure model are highly dependent on the location of stimulation and stimulus amplitude. We provide a platform to optimize the anti-seizure effects of neurostimulation, and demonstrate that an exploration of the large electrical parameter and location space can improve current modalities for treating epilepsy., Plain Language Summary: In this study, we tested how electrical pulses in the brain can help control seizures in mice. We found that the electrode's placement and the stimulation amplitude had a large effect on outcomes. Some brain regions, notably nearby CA1 and CA3, responded positively with reduced seizure-like activities, while others showed increased activity. These findings emphasize that choosing the right spot for the electrode and adjusting the strength of electrical pulses are both crucial when considering neurostimulation treatments for epilepsy., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer's disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-β (Aβ) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice and the 5xFAD mouse model of cerebral amyloidosis, expressing either the humanized TREM2 common variant, the loss-of-function R47H AD-associated risk variant, or without TREM2 expression. Sleep deprivation not only enhanced TREM2-dependent Aβ plaque deposition compared with 5xFAD mice with normal sleeping patterns but also induced microglial reactivity that was independent of the presence of parenchymal Aβ plaques. We investigated lysosomal morphology using transmission electron microscopy and found abnormalities particularly in mice without Aβ plaques and also observed lysosomal maturation impairments in a TREM2-dependent manner in both microglia and neurons, suggesting that changes in sleep modified neuro-immune cross-talk. Unbiased transcriptome and proteome profiling provided mechanistic insights into functional pathways triggered by sleep deprivation that were unique to TREM2 and Aβ pathology and that converged on metabolic dyshomeostasis. Our findings highlight that sleep deprivation directly affects microglial reactivity, for which TREM2 is required, by altering the metabolic ability to cope with the energy demands of prolonged wakefulness, leading to further Aβ deposition, and underlines the importance of sleep modulation as a promising future therapeutic approach.

Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here, we demonstrated that PR-domain containing protein 13 (Prdm13)+ neurons in the dorsomedial hypothalamus (DMH) are activated during sleep deprivation (SD) in young mice but not in old mice. Chemogenetic inhibition of Prdm13+ neurons in the DMH in young mice promotes increase in sleep attempts during SD, suggesting its involvement in sleep control. Furthermore, DMH-specific Prdm13 -knockout (DMH- Prdm13 -KO) mice recapitulated age-associated sleep alterations such as sleep fragmentation and increased sleep attempts during SD. These phenotypes were further exacerbated during aging, with increased adiposity and decreased physical activity, resulting in shortened lifespan. Dietary restriction (DR), a well-known anti-aging intervention in diverse organisms, ameliorated age-associated sleep fragmentation and increased sleep attempts during SD, whereas these effects of DR were abrogated in DMH- Prdm13 -KO mice. Moreover, overexpression of Prdm13 in the DMH ameliorated increased sleep attempts during SD in old mice. Therefore, maintaining Prdm13 signaling in the DMH might play an important role to control sleep-wake patterns during aging., (© 2023 Tsuji et al.)

Objective: Neurostimulation is an emerging treatment for patients with medically refractory epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model., Methods: We performed high-throughput testing of high-frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of temporal lobe epilepsy. We evaluated combinations of six anatomic targets and three stimulus amplitudes., Results: We found that the spike-suppressive effects of high-frequency neurostimulation are highly dependent on the stimulation amplitude and location, with higher amplitude stimulation being significantly more effective. Epileptiform spiking activity was significantly reduced with ipsilateral 250 μA stimulation of the CA1 and CA3 hippocampal regions with 21.5% and 22.2% reductions, respectively. In contrast, we found that spiking frequency and amplitude significantly increased with stimulation of the ventral hippocampal commissure. We further found spatial differences with broader effects from CA1 versus CA3 stimulation., Significance: These findings demonstrate that the effects of therapeutic neurostimulation in an acute hippocampal seizure model are highly dependent on the location of stimulation and stimulus amplitude. We provide a platform to optimize the anti-seizure effects of neurostimulation, and demonstrate that an exploration of the large electrical parameter and location space can improve current modalities for treating epilepsy., Key Points: Evaluated spatial and temporal parameters of neurostimulation in a mouse model of acute seizuresBrief bursts of high-frequency (100 Hz) stimulation effectively interrupted epileptiform activity.The suppressive effect was highly dependent on stimulation amplitude and was maximal at the ipsilateral CA1 and CA3 regions.Pro-excitatory effects were identified with high-amplitude high-frequency stimulation at the ventral hippocampal commissure and contralateral CA1.

Objective: Neonatal cerebral hypoxia-ischemia (HI) results in symptomatic seizures and long-term neurodevelopmental disability. The Rice-Vannucci model of rodent neonatal HI has been used extensively to examine and translate the functional consequences of acute and chronic HI-induced encephalopathy. Yet, longitudinal electrophysiological characterization of this brain injury model has been limited by the size of the neonatal mouse's head and postnatal maternal dependency. We overcome this challenge by employing a novel method of longitudinal single-mouse electroencephalography (EEG) using chronically implanted subcranial electrodes in the term-equivalent mouse pup. We characterize the neurophysiological disturbances occurring during awake and sleep states in the acute and chronic phases following newborn brain injury., Methods: C57BL/6 mice underwent long-term bilateral subcranial EEG and electromyographic electrode placement at postnatal day 9 followed by unilateral carotid cauterization and exposure to 40 minutes of hypoxia the following day. EEG recordings were obtained prior, during, and intermittently after the HI procedure from postnatal day 10 to weaning age. Quantitative EEG and fast Fourier transform analysis were used to evaluate seizures, cortical cerebral dysfunction, and disturbances in vigilance states., Results: We observed neonatal HI-provoked electrographic focal and bilateral seizures during or immediately following global hypoxia and most commonly contralateral to the ischemic injury. Spontaneous chronic seizures were not seen. Injured mice developed long-term asymmetric EEG background attenuation in all frequencies and most prominently during non-rapid eye movement (NREM) sleep. HI mice also showed transient impairments in vigilance state duration and transitions during the first 2 days following injury., Significance: The functional burden of mouse neonatal HI recorded by EEG resembles closely that of the injured human newborn. The use of single-mouse longitudinal EEG in this immature model can advance our understanding of the developmental and pathophysiological mechanisms of neonatal cerebral injury and help translate novel therapeutic strategies against this devastating condition., (© 2022 International League Against Epilepsy.)

Objective: Tuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Seizures in TSC typically first present in infancy or early childhood, including focal seizures and infantile spasms. Infantile spasms in TSC are particularly characteristic in its strong responsiveness to vigabatrin. Although a number of mouse models of epilepsy in TSC have been described, there are very limited electroencephalographic (EEG) or seizure data during the preweanling neonatal and infantile-equivalent mouse periods. Tsc1 GFAP CKO mice are a well-characterized mouse model of epilepsy in TSC, but whether these mice have seizures during early development has not been documented. The objective of this study was to determine whether preweanling Tsc1 GFAP CKO mice have developmental EEG abnormalities or seizures, including spasms., Methods: Longitudinal video-EEG and electromyographic recordings were performed serially on Tsc1 GFAP CKO and control mice from postnatal days 9-21 and analyzed for EEG background abnormalities, sleep-wake vigilance states, and spontaneous seizures. Spasms were also induced with varying doses of N-methyl-D-aspartate (NMDA)., Results: The interictal EEG of Tsc1 GFAP CKO mice had excessive discontinuity and slowing, suggesting a delayed developmental progression compared with control mice. Tsc1 GFAP CKO mice also had increased vigilance state transitions and fragmentation. Tsc1 GFAP CKO mice had spontaneous focal seizures in the early neonatal period and a reduced threshold for NMDA-induced spasms, but no spontaneous spasms were observed., Significance: Neonatal Tsc1 GFAP CKO mice recapitulate early developmental aspects of EEG abnormalities, focal seizures, and an increased propensity for spasms. This mouse model may be useful for early mechanistic and therapeutic studies of epileptogenesis in TSC., (© 2020 International League Against Epilepsy.)

Tuberous sclerosis complex (TSC) is a genetic disease related to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and manifested by neurological symptoms, such as epilepsy and sleep disorders. The pathophysiology of sleep dysfunction is poorly understood and is likely multifactorial, but may involve intrinsic biological regulators in the brain. Here, we characterized a mouse model of sleep disorders in TSC and investigated mechanisms of sleep dysfunction in this conditional knockout model involving inactivation of the Tsc1 gene in neurons and astrocytes (Tsc1 GFAP CKO mice). Sleep studies utilizing EEG, EMG, and behavioral analysis found that Tsc1 GFAP CKO mice have decreased REM sleep and impaired sleep-wake differentiation between light and dark phases. mTOR activity and orexin expression were increased in hypothalamic sections and cultured hypothalamic neurons from Tsc1 GFAP CKO mice. Both the sleep abnormalities and increased orexin expression in Tsc1 GFAP CKO mice were reversed by rapamycin treatment, indicating their dependence on mTOR activation. An orexin antagonist, suvorexant, also restored normal REM levels in Tsc1 GFAP CKO mice. These results identify a novel mechanistic link between mTOR and orexin in the hypothalamus related to sleep dysfunction and suggest a targeted therapeutic approach to sleep disorders in TSC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD + ) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD + metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase ( Nampt ) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD + biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD + -SIRT1-caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD + synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD + biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism., Competing Interests: The authors declare no competing interest.

Pentameric GABA A receptors mediate a large share of CNS inhibition. The γ2 subunit is a typical constituent. At least 11 mutations in the γ2 subunit cause human epilepsies, making the role of γ2-containing receptors in brain function of keen basic and translational interest. How small changes to inhibition may cause brain abnormalities, including seizure disorders, is unclear. In mice, we perturbed fast inhibition with a point mutation T272Y (T6'Y in the second membrane-spanning domain) to the γ2 subunit. The mutation imparts resistance to the GABA A receptor antagonist picrotoxin, allowing verification of mutant subunit incorporation. We confirmed picrotoxin resistance and biophysical properties in recombinant receptors. T6'Y γ2-containing receptors also exhibited faster deactivation but unaltered steady-state properties. Adult T6'Y knockin mice exhibited myoclonic seizures and abnormal cortical EEG, including abnormal hippocampal-associated theta oscillations. In hippocampal slices, picrotoxin-insensitive inhibitory synaptic currents exhibited fast decay. Excitatory/inhibitory balance was elevated by an amount expected from the IPSC alteration. Partial pharmacological correction of γ2-mediated IPSCs with diazepam restored total EEG power toward baseline, but had little effect on the abnormal low-frequency peak in the EEG. The results suggest that at least part of the abnormality in brain function arises from the acute effects of truncated inhibition.

Aging is a significant risk factor for impaired tissue functions and chronic diseases. Age-associated decline in systemic NAD + availability plays a critical role in regulating the aging process across many species. Here, we show that the circulating levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) significantly decline with age in mice and humans. Increasing circulating eNAMPT levels in aged mice by adipose-tissue-specific overexpression of NAMPT increases NAD + levels in multiple tissues, thereby enhancing their functions and extending healthspan in female mice. Interestingly, eNAMPT is carried in extracellular vesicles (EVs) through systemic circulation in mice and humans. EV-contained eNAMPT is internalized into cells and enhances NAD + biosynthesis. Supplementing eNAMPT-containing EVs isolated from young mice significantly improves wheel-running activity and extends lifespan in aged mice. Our findings have revealed a novel EV-mediated delivery mechanism for eNAMPT, which promotes systemic NAD + biosynthesis and counteracts aging, suggesting a potential avenue for anti-aging intervention in humans., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder in which affected children and adults are at a higher risk of sleep disorders. In an effort to identify potential sleep disturbances in a small animal model, we used a previously reported Nf1 conditional knockout (Nf1 CKO ) mouse strain. In contrast to Nf1 mutant flies, the distribution of vigilance states was intact in Nf1 CKO mice. However, Nf1 CKO mice exhibited increased non-REM sleep (NREM)-to-wake and wake-to-NREM transitions. This sleep disruption was accompanied by decreased bout durations during awake and NREM sleep states under both light and dark conditions. Moreover, Nf1 CKO mice have higher percentage delta power during awake and NREM sleep states under all light conditions. Taken together, Nf1 CKO mice phenocopy some of the sleep disturbances observed in NF1 patients and provide a tractable platform to explore the molecular mechanisms governing sleep abnormalities in NF1., (© 2019 European Sleep Research Society.)

Background: There is a paucity of literature describing distal femoral osteotomies (DFO) in regards to complications and outcomes with previously studied cohorts containing primarily older, arthritic subjects. There has been no study to date focusing on younger, pre-arthritic patients., Methods: All service members indicated for distal femoral osteotomy for coronal plane malalignment were isolated from military treatment centers between 2007 and 2013. Demographic and surgical variables were extracted, and perioperative complications, clinical course, and return to military function were extracted using clinical notes and radiographs., Results: A total of 22 knees in 19 patients were identified at an average 3.2 year follow-up, with the exclusion of 16 individuals. Statistical analysis revealed worse outcomes associated with smoking, over correction, breach of the medial cortex, and prior surgeries. Overall 58% of patients left the military as the result of knee dysfunction despite an average improvement in visual analog scores (VAS) from 4.0 to 1.9 (p = 0.004)., Conclusions: While offloading the lateral compartment improves symptoms at short to midterm follow-up preventing progression to arthroplasty, young active duty military members have suboptimal return to duty rates.

Background/aims: Research in music medicine has reported incidence rates of musculoskeletal disorders of approx. 70% in instrumental musicians. String players have the highest risk, with rates of performance-related musculoskeletal disorders (PRMDs) of 65% to 88%. Playing the violin or viola requires complex neuromusculoskeletal skills, and the high frequency of repetitive movements, dynamic and static muscle load, awkward postures, poor technique, and practice time are factors causing musculoskeletal strain. In ergonomic terms, these disorders can be categorized based on extrinsic and intrinsic loads. Identification of intrinsic loads, such as muscle utilization and joint motion, is necessary to understand factors influencing musculoskeletal disorders associated with violin playing. The aim of this study was to review the literature on musculoskeletal demands in violin and viola playing., Methods: A literature search was conducted in the PubMed, COCHRANE, and CINAHL electronic databases from 1999 to 2015 using the search terms violin, viola, high strings, movement, posture, and synonyms. A manual search of Medical Problems of Performing Artists was also conducted. Additional references were identified by searching the citations and reference lists of all identified relevant studies., Results: The results suggest that an asymmetric playing posture, the associated muscle activity, and joint mobility may contribute to musculoskeletal problems in violin and viola players. Evidence suggests an increased load of intrinsic factors in violin/viola performance., Conclusion: The identification of intrinsic loads in violin and viola playing may facilitate the development of prevention strategies and interventions.

Mutations of the transcriptional regulator PHF6 cause the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS), but the pathogenesis of BFLS remains poorly understood. Here, we report a mouse model of BFLS, generated using a CRISPR-Cas9 approach, in which cysteine 99 within the PHD domain of PHF6 is replaced with phenylalanine (C99F). Mice harboring the patient-specific C99F mutation display deficits in cognitive functions, emotionality, and social behavior, as well as reduced threshold to seizures. Electrophysiological studies reveal that the intrinsic excitability of entorhinal cortical stellate neurons is increased in PHF6 C99F mice. Transcriptomic analysis of the cerebral cortex in C99F knockin mice and PHF6 knockout mice show that PHF6 promotes the expression of neurogenic genes and represses synaptic genes. PHF6-regulated genes are also overrepresented in gene signatures and modules that are deregulated in neurodevelopmental disorders of cognition. Our findings advance our understanding of the mechanisms underlying BFLS pathogenesis., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The neonatal brain undergoes rapid maturational changes that facilitate the normal development of the nervous system and also affect the pathological response to brain injury. Electroencephalography (EEG) and analysis of sleep-wake vigilance states provide important insights into the function of the normal and diseased immature brain. While developmental changes in EEG and vigilance states are well-described in people, less is known about the normal maturational properties of rodent EEG, including the emergence and evolution of sleep-awake vigilance states. In particular, a number of developmental EEG studies have been performed in rats, but there is limited comparable research in neonatal mice, especially as it pertains to longitudinal EEG studies performed within the same mouse. In this study, we have attempted to provide a relatively comprehensive assessment of developmental changes in EEG background activity and vigilance states in wild-type mice from postnatal days 9-21. A novel EEG and EMG method allowed serial recording from the same mouse pups. EEG continuity and power and vigilance states were analyzed by quantitative assessment and fast Fourier transforms. During this developmental period, we demonstrate the timing of maturational changes in EEG background continuity, frequencies, and power and the emergence of identifiable wake, NREM, and REM sleep states. These results should serve as important control data for physiological studies of mouse models of normal brain development and neurological disease., Competing Interests: The authors have declared that no competing interests exist.

This study sought to identify patient and operative demographics associated with 30-day perioperative complications in patients undergoing total ankle arthroplasty as recorded in the National Surgical Quality Improvement Project database. Complications were divided into local and systemic and further subcategorized as major and minor. A total of 404 patients underwent total ankle arthroplasty between 2007 and 2014 as captured in the National Surgical Quality Improvement Project database. The overall complication rate was 2.4% with 0.5% mortality and 0.2% infection rate. Length of hospital stay, both as an end point at >5 days and as a continuous variable, was associated with overall complications (odds ratio [OR] = 9.90, P = .002 and OR = 1.52, P = .006, respectively). Patient characteristics that predicted perioperative morbidity included presence of 3 or comorbidities (OR = 8.48, P = 0.038), American Society of Anesthesiologists class III, and history of previous cardiac surgery (OR = 12.22, P = .033). Correct patient selection is imperative in achieving improved outcomes and those that are at risk for complications should be counseled as such., Levels of Evidence: Level III: Database case control study.

Despite timely and appropriate management, displaced femoral neck fractures are often devastating injuries for the young patient. The risk of negative sequelae is further amplified with increasing displacement and vertical fracture patterns. Open anatomic reduction with rigid internal fixation is essential to maximize the healing potential in displaced fractures of the femoral neck. Successful primary osteosynthesis of significantly displaced femoral neck fractures in the young patient has been reported in the literature. We present a unique case of open reduction and internal fixation of a high-energy femoral neck fracture with extrusion of the head through the obturator foramen into the pelvis without associated acetabular or pelvic injury.

Objective: The aim of the study was to identify and systematically categorize musculoskeletal assessments used in quantitatively based studies about posture and movement in musicians playing high string instruments (violin, viola) in order to inform further research and help to identify gaps in knowledge., Methods: A systematic literature search was conducted in the databases Cochrane, CINAHL, and PubMed as well as the journal Medical Problems of Performing Artists. Additional studies were searched within the reference lists of relevant articles. Sixty-four studies conducted since 1999 until May 2017 were included according to predefined inclusion criteria., Results: Various biomechanical measurement instruments were used in 24 of the selected studies in order to collect two- and three-dimensional kinematic data: optoelectronic systems with active and passive markers, electromagnetic systems, ultrasonic motion analysis systems, and image-based analysis of posture. In 11 studies, kinetics were measured by optoelectronic systems, force sensors, and a posturographic device. Further studies used electromyography to evaluate muscle activity (19 studies) as well as instruments to measure range of motion (2 studies). Additionally, a broad range of clinical examination techniques (35 studies) and self-reports (36 studies) were used to assess the musculoskeletal system of high string players., Conclusion: The identified assessments could be used both in further research and in practical work in order to evaluate posture and movement in high string players. For future research, qualitatively based studies as well as psychometrically tested quantitatively based self-report assessments are required.

CCCTC-binding factor (CTCF) is an 11 zinc finger DNA-binding domain protein that regulates gene expression by modifying 3D chromatin structure. Human mutations in CTCF cause intellectual disability and autistic features. Knocking out Ctcf in mouse embryonic neurons is lethal by neonatal age, but the effects of CTCF deficiency in postnatal neurons are less well studied. We knocked out Ctcf postnatally in glutamatergic forebrain neurons under the control of Camk2a-Cre. Ctcf loxP/loxP ; Camk2a-Cre + ( Ctcf CKO) mice of both sexes were viable and exhibited profound deficits in spatial learning/memory, impaired motor coordination, and decreased sociability by 4 months of age. Ctcf CKO mice also had reduced dendritic spine density in the hippocampus and cerebral cortex. Microarray analysis of mRNA from Ctcf CKO mouse hippocampus identified increased transcription of inflammation-related genes linked to microglia. Separate microarray analysis of mRNA isolated specifically from Ctcf CKO mouse hippocampal neurons by ribosomal affinity purification identified upregulation of chemokine signaling genes, suggesting crosstalk between neurons and microglia in Ctcf CKO hippocampus. Finally, we found that microglia in Ctcf CKO mouse hippocampus had abnormal morphology by Sholl analysis and increased immunostaining for CD68, a marker of microglial activation. Our findings confirm that Ctcf KO in postnatal neurons causes a neurobehavioral phenotype in mice and provide novel evidence that CTCF depletion leads to overexpression of inflammation-related genes and microglial dysfunction. SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a DNA-binding protein that organizes nuclear chromatin topology. Mutations in CTCF cause intellectual disability and autistic features in humans. CTCF deficiency in embryonic neurons is lethal in mice, but mice with postnatal CTCF depletion are less well studied. We find that mice lacking Ctcf in Camk2a -expressing neurons ( Ctcf CKO mice) have spatial learning/memory deficits, impaired fine motor skills, subtly altered social interactions, and decreased dendritic spine density. We demonstrate that Ctcf CKO mice overexpress inflammation-related genes in the brain and have microglia with abnormal morphology that label positive for CD68, a marker of microglial activation. Our findings suggest that inflammation and dysfunctional neuron-microglia interactions are factors in the pathology of CTCF deficiency., (Copyright © 2018 the authors 0270-6474/18/380201-20$15.00/0.)

The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC), a regulator of mTOR activity. Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat-shock protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity. The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co-chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1-Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co-chaperones to Hsp90. Our findings establish an active role for Tsc1 as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients-including Tsc2-thereby preventing their ubiquitination and proteasomal degradation., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

Introduction: Historically, Achilles tendon repairs and other surgeries about the hindfoot have demonstrated a significantly higher rate of wound healing complications and surgical site morbidity. The purpose of this study was to evaluate the comprehensive complication profile and risk factors for adverse short-term, clinical outcomes after primary repair of Achilles tendon ruptures., Methods: Between the years 2005 and 2014, all cases of primary Achilles tendon repair (Current Procedural Terminology code 27650) entered into the National Surgical Quality Improvement Project (NSQIP) database were extracted for analysis. Primary outcomes of interest were rates of total complication, reoperation, and rerupture within 30 days of index surgery. Independent risk factors associated with these selected endpoints were assessed with chi-square and logistic regression analysis and odds ratios with 95% confidence intervals were used to express relative risk., Results: Of 1626 patients with an average age of 44 years (SD 13.3), the average ASA classification was 1.69 and hypertension (20.7%), morbid obesity (8.3%), and diabetes (4.9%) were among the most common medical comorbidities. A total of 28 (1.7%) patients sustained perioperative complications, including 1.3% with local complications (0.7% superficial wound infection, 0.4% wound disruption) and no cases of peripheral nerve injury or early repair failure. Systemic complications occurred in 0.4%, most commonly with deep venous thrombosis or nonfatal thromboembolism. Preoperative albumin was independently associated with an increased risk of local wound complications (odds ratio [OR] 28.67; 95% CI 1.42-579.40; P = .029). Chronic obstructive pulmonary disease (OR 22.33, 95% CI 2.49-199.81; P = .006) and bleeding disorder (OR 14.83, 95% CI 1.70-129.50; P = .015) were more likely to result in a systemic complication, and preoperative creatinine correlated with an increased risk of any complication (OR 6.11, 95% CI 1.15-32.34; P = .033). In total there were 5 (0.3%) readmissions with 2 (0.1%) unplanned reoperations attributed to local wound complications., Conclusion: Among a broad-based demographic of the United States, the rate of local wound complications was exceedingly low in the short-term perioperative period, although this risk may be significantly magnified with subtle decreases in albumin levels. Preoperative risk stratifications should carefully scrutinize for subtle abnormalities in nutritional parameters and renal function prior to undergoing Achilles surgery., Levels of Evidence: Therapeutic, Level II: Prospective, comparative trial.

Astrocytes play important roles in normal brain function and neurological diseases. In vivo two-photon excitation laser scanning microscopy has the potential to reveal rapid, dynamic structural changes in cells in a variety of physiological and pathological conditions. The type of in vivo imaging method has been shown to affect the plasticity of dendritic spines of neurons, but the optimal in vivo imaging methods of astrocytes have not been established. We compared open-skull and thinned-skull imaging methods for two-photon laser microscopy of live astrocytes in neocortex of GFAP-GFP transgenic mice. The thinned-skull method provided stable image intensity and morphological features of astrocytes in vivo over at least one week, with no evidence of astrogliosis. In contrast, the open-skull method resulted in significant changes in image intensity and induced astrogliosis. The thinned-skull method is the preferred approach for in vivo imaging of astrocytes under most conditions involving gross astrocyte modulation or causing astrogliosis., Competing Interests: The authors have declared that no competing interests exist.

Fracture of the calcaneal tuberosity with a concomitant Achilles tendon rupture presents a difficult challenge for the treating surgeon. The ultimate goal of treatment is to restore function of both the gastrocnemius-soleus complex and the Achilles tendon. This particular subset of fractures occurs often in diabetics and elderly patients with osteoporosis making fixation of the displaced fragment rather complex. If the Achilles tendon disruption is only discovered later once the fracture is healed, subsequent management is difficult with surgical treatment being more morbid. While this is a rare injury, the consequences of a missed chronic Achilles tendon disruption are severe with significant dysfunction. It is therefore important to have a high index of suspicion for concomitant injury and to be prepared for dual fixation. We present a novel hybrid surgical fixation technique, which may be used in this instance.

Objective: Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by tumor formation in multiple organs and severe neurologic manifestations, including epilepsy, intellectual disability, and autism. Abnormalities of both neurons and astrocytes have been implicated in contributing to the neurologic phenotype of TSC, but the role of microglia in TSC has not been investigated. The objectives of this study were to characterize microglial activation in a mouse model of TSC, involving conditional inactivation of the Tsc1 gene predominantly in glial cells (Tsc1(GFAP) CKO mice), and to test the hypothesis that microglial activation contributes to epileptogenesis in this mouse model., Methods: Microglial and astrocyte activation was examined in Tsc1(GFAP) CKO mice by ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein immunohistochemistry. Cytokine and chemokine expression was evaluated with quantitative polymerase chain reaction. Seizures were monitored by video-electroencephalography (EEG). The effect of minocycline in inhibiting microglial and astrocyte activation, cytokine expression, and seizures was tested., Results: Microglial cell number and size were increased in cortex and hippocampus of 3- to 4-week-old Tsc1(GFAP) CKO mice, which correlated with the onset of seizures. Minocycline treatment prevented the increase in number and cell size of microglia in 4-week-old Tsc1(GFAP) CKO mice. However, minocycline treatment had no effect on astrocyte proliferation and cytokine/chemokine expression and the progression of seizures in Tsc1(GFAP) CKO mice., Significance: Microglia cell number and size are abnormal in Tsc1(GFAP) CKO mice, and minocycline treatment inhibits this microglia activation, but does not suppress seizures. Microglia may play a role in the neurologic manifestations of TSC, but additional studies are needed in other models and human studies to determine whether microglia are critical for epileptogenesis in TSC., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Background: There are limited data evaluating the clinical outcomes of meniscal allograft transplantation (MAT) in physically active cohorts., Purpose: To determine the survivorship, complication rates, and functional outcomes of MAT in an active military population., Study Design: Case series; Level of evidence, 4., Methods: All military patients undergoing MAT between 2007 and 2013 were identified from the Military Health System. Previous/concomitant procedures, perioperative complications, reoperation rate, revision, and initiation of medical discharge for persistent knee disability were recorded. Univariate analysis was performed to identify associations between patient-based and surgical variables on selected endpoints., Results: A total of 230 MATs (227 patients; 228 knees) were identified; the mean patient age was 27.2 years (range, 18-46 years), and the cohort was predominately male (89%). Approximately half (51%) of the patients had undergone prior, nonmeniscal knee procedures. Medial MATs were performed in 160 (69%) cases, and isolated MATs were most common (60%). A total of 51 complications occurred in 46 (21.1%) patients, including a secondary tear or extrusion (9%). At a mean clinical follow-up of 2.14 years, 10 (4.4%) patients required secondary meniscal debridement, while 1 (0.4%) patient required revision MAT and 2 (0.9%) patients underwent total knee arthroplasty. After MAT, 50 (22%) patients underwent knee-related military discharge at a mean of 2.49 years postoperatively. Tobacco use (P = .028) was associated with significantly increased risk of failure, and operation by fellowship-trained surgeons trended toward significance as a protective factor (P = .078). Furthermore, high-volume surgeons (≥1 MAT/year; range, 9-35) had significantly reduced rates of failure (P = .046)., Conclusion: While reporting low reoperation and revision rates, this investigation indicates that 22% of patients with MAT were unable to return to military duty due to persistent knee limitations at short-term follow-up. Increased surgical experience may decrease rates of failure after MAT. Careful patient selection and referral to subspecialty-trained, higher-volume surgeons should be considered to optimize clinical outcomes after MAT., (© 2016 The Author(s).)

Objective: Seizures cause acute structural changes in dendrites, which may contribute to cognitive deficits that occur in epilepsy patients. Disruption of the actin cytoskeleton of dendrites likely mediates the structural changes following seizures, but the upstream signaling mechanisms activated by synchronized physiological activity to cause seizure-induced dendritic injury are not known. In this study, we test the hypothesis that the mechanistic target of rapamycin complex 1 (mTORC1) pathway triggers structural changes in dendrites in response to seizures., Methods: In vivo multiphoton imaging was performed in transgenic mice expressing green fluorescent protein in cortical neurons. The effect of rapamycin pre- and posttreatment was tested on kainate-induced dendritic injury and cofilin-mediated actin depolymerization., Results: Kainate-induced seizures caused acute activation of mTORC1 activity, which was prevented by the mTORC1 inhibitor, rapamycin. Rapamycin pretreatment, and to a lesser degree, posttreatment attenuated acute seizure-induced dendritic injury and correspondingly decreased LIM kinase and cofilin-mediated depolymerization of actin., Interpretation: The mTORC1 pathway mediates seizure-induced dendritic injury via depolymerization of actin. These findings have important mechanistic and translational applications for management of seizure-induced brain injury.

Objective: The purpose was to calculate the incidence rates and determine risk factors for 30-day postoperative mortality and morbidity after ankle fracture open reduction and internal fixation (ORIF)., Methods: The NSQIP database was queried to identify patients undergoing ankle fracture ORIF from 2006 to 2011, with extraction patient-based or surgical variables and a 30-day clinical course. Multivariable logistic regression analysis identified significant predictors on outcome measures., Results: Mean age was 50.3 (±18.2) years while diabetes mellitus (12.8%) and body mass index ≥40 kg/m(2) (9.2%) were documented from a total of 3328 patients identified. The 30-day mortality rate was 0.30%, and complications occurred in 5.1%. Chronic obstructive pulmonary disease [odds ratio (OR): 4.23, 95% confidence interval (CI): 1.19-15.06] and a nonindependent functional status before surgery (OR: 2.25, 95% CI: 1.13-4.51) were the sole independent predictors of mortality and major local complications, respectively. Major local complications occurred in 2.2% of patients, and significant predictors were peripheral vascular disease (OR: 6.14; 95% CI: 1.95-19.35), open wound (OR: 5.04; 95% CI: 2.25-11.27), nonclean wound classification (OR: 3.02; 95% CI: 1.31-6.93), and smoking (OR: 2.85; 95% CI: 1.42-5.70). Independent predictors of hospital stay >3 days were cardiac disease, age 70 years or older, open wound, partially/totally dependent functional status, American Society of Anesthesiologists (ASA) classification ≥3, body mass index ≥40 kg/m(2), bimalleolar or trimalleolar ankle fracture pattern, female sex, and diabetes., Conclusions: Chronic obstructive pulmonary disease increased the risk of mortality after ankle fracture ORIF. Risk factors for postoperative complications included peripheral vascular disease, open wound, nonclean wound classification, age 70 years or older, and ASA classification ≥3., Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.