Activated PMN Exosomes: Pathogenic Entities Causing Matrix Destruction and Disease in the Lung.

Here, we describe a novel pathogenic entity, the activated PMN (polymorphonuclear leukocyte, i.e., neutrophil)-derived exosome. These CD63+/CD66b+ nanovesicles acquire surface-bound neutrophil elastase (NE) during PMN degranulation, NE being oriented in a configuration resistant to α1-antitrypsin (α1AT). These exosomes bind and degrade extracellular matrix (ECM) via the integrin Mac-1 and NE, respectively, causing the hallmarks of chronic obstructive pulmonary disease (COPD). Due to both ECM targeting and α1AT resistance, exosomal NE is far more potent than free NE. Importantly, such PMN-derived exosomes exist in clinical specimens from subjects with COPD but not healthy controls and are capable of transferring a COPD-like phenotype from humans to mice in an NE-driven manner. Similar findings were observed for another neutrophil-driven disease of ECM remodeling (bronchopulmonary dysplasia [BPD]). These findings reveal an unappreciated role for exosomes in the pathogenesis of disorders of ECM homeostasis such as COPD and BPD, providing a critical mechanism for proteolytic damage.

Mesna Improves Outcomes of Sulfur Mustard Inhalation Toxicity in an Acute Rat Model.

Inhalation of high levels of sulfur mustard (SM), a potent vesicating and alkylating agent used in chemical warfare, results in acutely lethal pulmonary damage. Sodium 2-mercaptoethane sulfonate (mesna) is an organosulfur compound that is currently Food and Drug Administration (FDA)-approved for decreasing the toxicity of mustard-derived chemotherapeutic alkylating agents like ifosfamide and cyclophosphamide. The nucleophilic thiol of mesna is a suitable reactant for the neutralization of the electrophilic group of toxic mustard intermediates. In a rat model of SM inhalation, treatment with mesna (three doses: 300 mg/kg intraperitoneally 20 minutes, 4 hours, and 8 hours postexposure) afforded 74% survival at 48 hours, compared with 0% survival at less than 17 hours in the untreated and vehicle-treated control groups. Protection from cardiopulmonary failure by mesna was demonstrated by improved peripheral oxygen saturation and increased heart rate through 48 hours. Additionally, mesna normalized arterial pH and pACO2 Airway fibrin cast formation was decreased by more than 66% in the mesna-treated group at 9 hour after exposure compared with the vehicle group. Finally, analysis of mixtures of a mustard agent and mesna by a 5,5'-dithiobis(2-nitrobenzoic acid) assay and high performance liquid chromatography tandem mass spectrometry demonstrate a direct reaction between the compounds. This study provides evidence that mesna is an efficacious, inexpensive, FDA-approved candidate antidote for SM exposure. SIGNIFICANCE STATEMENT: Despite the use of sulfur mustard (SM) as a chemical weapon for over 100 years, an ideal drug candidate for treatment after real-world exposure situations has not yet been identified. Utilizing a uniformly lethal animal model, the results of the present study demonstrate that sodium 2-mercaptoethane sulfonate is a promising candidate for repurposing as an antidote, decreasing airway obstruction and improving pulmonary gas exchange, tissue oxygen delivery, and survival following high level SM inhalation exposure, and warrants further consideration.

Receptor-mediated activation of CFTR via prostaglandin signaling pathways in the airway.

Cystic fibrosis (CF) is a genetic disease caused by mutations of the gene encoding a cAMP-activated Cl- channel, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR modulator therapies consist of small-molecule drugs that rescue mutant CFTR. Regimens of single or combinations of CFTR modulators still rely on endogenous levels of cAMP to regulate CFTR activity. We investigated CFTR activation by the natural mediator prostaglandin E2 (PGE2) and lubiprostone (a Food and Drug Administration-approved drug known to target prostaglandin receptors) and tested the hypothesis that receptor-mediated CFTR activators can be used in combination with currently available CFTR modulators to increase function of mutant CFTR. Primary-cultured airway epithelia were assayed in Ussing chambers. Experimental CFTR activators and established CFTR modulators were applied for 24 h and/or acutely and analyzed for their effect on CFTR activity as measured by changes in short-circuit current (ISC). In non-CF airway epithelia, acute application of lubiprostone and PGE2 activated CFTR to the levels comparable to forskolin (Fsk). Pretreatment (24 h) with antagonists to prostaglandin receptors EP2 and EP4 abolished the ability of lubiprostone to acutely activate CFTR. In F508del homozygous airway epithelia pretreated with the triple combination of elexacaftor, tezacaftor, and ivacaftor (ELEXA/TEZ/IVA; i.e., Trikafta), acute application of lubiprostone was able to maximally activate CFTR. Prolonged (24 h) cotreatment of F508del homozygous epithelia with ELEXA/TEZ/IVA and lubiprostone increased acute CFTR activation by ∼60% compared with the treatment with ELEXA/TEZ/IVA alone. This work establishes the feasibility of targeting prostaglandin receptors to activate CFTR on the airway epithelia and demonstrates that cotreatment with lubiprostone can further restore modulator-rescued CFTR.

Acute vaping in a golden Syrian hamster causes inflammatory response transcriptomic changes.

E-cigarette vaping is a major aspect of nicotine consumption, especially for children and young adults. Although it is branded as a safer alternative to cigarette smoking, murine and rat models of subacute and chronic e-cigarette vaping exposure have shown many proinflammatory changes in the respiratory tract. An acute vaping exposure paradigm has not been demonstrated in the golden Syrian hamster, and the hamster is a readily available small animal model that has the unique benefit of becoming infected with and transmitting respiratory viruses, including SARS-CoV-2, without genetic alteration of the animal or virus. Using a 2-day, whole body vaping exposure protocol in male golden Syrian hamsters, we evaluated serum cotinine, bronchoalveolar lavage cells, lung, and nasal histopathology, and gene expression in the nasopharynx and lung through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Depending on the presence of nonnormality or outliers, statistical analysis was performed by ANOVA or Kruskal-Wallis tests. For tests that were statistically significant (P < 0.05), post hoc Tukey-Kramer and Dunn's tests, respectively, were performed to make pairwise comparisons between groups. In nasal tissue, RT-qPCR analysis revealed nicotine-dependent increases in gene expression associated with type 1 inflammation (CCL-5 and CXCL-10), fibrosis [transforming growth factor-ß (TGF-ß)], nicotine-independent increase oxidative stress response (SOD-2), and a nicotine-independent decrease in vasculogenesis/angiogenesis (VEGF-A). In the lung, nicotine-dependent increases in the expression of genes involved in the renin-angiotensin pathway [angiotensin-converting enzyme (ACE), ACE2], coagulation (tissue factor, Serpine-1), extracellular matrix remodeling (MMP-2, MMP-9), type 1 inflammation (IL-1ß, TNF-α, and CXCL-10), fibrosis (TGF-ß and Serpine-1), oxidative stress response (SOD-2), neutrophil extracellular traps release (ELANE), and vasculogenesis and angiogenesis (VEGF-A) were identified. To our knowledge, this is the first demonstration that the Syrian hamster is a viable model of e-cigarette vaping. In addition, this is the first report that e-cigarette vaping with nicotine can increase tissue factor gene expression in the lung. Our results show that even an acute exposure to e-cigarette vaping causes significant upregulation of mRNAs in the respiratory tract from pathways involving the renin-angiotensin system, coagulation, extracellular matrix remodeling, type 1 inflammation, fibrosis, oxidative stress response, neutrophil extracellular trap release (NETosis), vasculogenesis, and angiogenesis.

Proline-Glycine-Proline Peptides Are Critical in the Development of Smoke-induced Emphysema.

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality worldwide and is characterized by an excessive airway neutrophilic response. The neutrophil chemoattractant proline-glycine-proline (PGP) and its more potent acetylated form (acPGP) have been found to be elevated in patients with COPD and act via CXCR2. Here, we investigated the impact of neutralizing PGP peptides in a murine model for emphysema. The PGP-neutralizing peptide l-arginine-threonine-arginine (RTR) was used first in a 6-week model of cigarette smoke exposure, where it attenuated lung inflammation. Then, in a model of chronic smoke exposure, mice were exposed to cigarette smoke and RTR treatment was initiated after 10 weeks of smoke exposure. This treatment was continued together with smoke exposure for another 13 weeks, for a total of 23 weeks of smoke exposure. RTR significantly inhibited neutrophil and macrophage influx into the lungs in the 6-week model of exposure. RTR also attenuated the development of emphysema, normalized lung volumes, and reduced right ventricular hypertrophy in the chronic exposure model. Murine epithelia expressed CXCR2, and this expression was increased after smoke exposure. In vitro, human bronchial epithelial cells also demonstrated robust expression of CXCR2, and stimulation of primary human bronchial epithelial cells with acPGP led to increased release of MMP-9 and IL-8. Overall, these results provide evidence that acPGP plays a critical role during the development of emphysema in cigarette smoke-induced injury, and highlight a new epithelial mechanism by which acPGP augments neutrophilic inflammation.

Wheel running exercise protects against retinal degeneration in the I307N rhodopsin mouse model of inducible autosomal dominant retinitis pigmentosa.

Purpose: We previously reported that modest running exercise protects photoreceptors in mice undergoing light-induced retinal degeneration and in the rd10 mouse model of autosomal recessive retinitis pigmentosa (arRP). We hypothesized that exercise would protect against other types of retinal degeneration, specifically, in autosomal dominant inherited disease. We tested whether voluntary running wheel exercise is protective in a retinal degeneration mouse model of class B1 autosomal dominant RP (adRP). Methods: C57BL/6J mice heterozygous for the mutation in I307N rhodopsin (Rho) (also known as RHOTvrm4/+, or Tvrm4) are normal until exposed to brief but bright light, whereupon rod photoreceptor degeneration ensues. I307N Rho mice were given access to free spinning (active) or locked (inactive) running wheels. Five weeks later, half of each cohort was treated with 0.2% atropine eye drops and exposed to white LED light (6,000 lux) for 5 min, then returned to maintenance housing with wheels. At 1 week or 4 weeks after induction, retinal and visual function was assessed with electroretinogram (ERG) and optomotor response (OMR). In vivo retinal morphology was assessed with optical coherence tomography (OCT), and fundus blue autofluorescence assessed using a scanning laser ophthalmoscope. The mice were then euthanized, and the eyes fixed for paraffin sectioning or flatmounting. The paraffin sections were stained with hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) to assess retina morphology and apoptosis. Half of the flatmounts were stained for ZO-1 and α-catenin to assess RPE cell structure and stress. (We previously reported that translocation of α-catenin from cell membranes into the cytosol indicates RPE cell stress.) The remaining flatmounts were stained for ZO-1 and Iba-1 to assess the RPE cell size and shape, and inflammatory responses. Results: In vivo measures revealed that induction of the I307N Rho degeneration decreased retinal and visual function, decreased the thickness of the retina and photoreceptor layers, and increased the number of blue autofluorescence spots at the level of the photoreceptor-RPE interface. Post-mortem analyses showed that induction caused loss of photoreceptors in the central retinal region, and increased TUNEL labeling in the outer nuclear layer (ONL). The RPE was disrupted 1 week after induction, with changes in cell size and shape accompanied by increased α-catenin translocation and Iba-1 staining. These outcomes were partially but statistically significantly prevented in the exercised mice. The exercised mice that underwent induced I307N Rho degeneration exhibited retinal function and visual function measures that were statistically indistinguishable from that of the uninduced mice, and compared to the unexercised induced mice, had thicker retina and photoreceptor layers, and decreased numbers of subretinal autofluorescent spots. Post-mortem, the retina sections from the exercised mice that had undergone induced I307N Rho degeneration exhibited numbers of photoreceptors that were statistically indistinguishable from those of uninduced mice. Similarly, exercise largely precluded a degeneration-induced increase in TUNEL-positive cells in the ONL. Finally, the RPE of the exercised mice appeared normal, with a regular cell shape and size, and little to no alpha-catenin translocation or Iba-1 immunosignal. Conclusions: Voluntary wheel running partially protected against retinal degeneration and inflammation, and RPE disruption in a model of inducible adRP. This is the first report of exercise protection in an adult adRP animal model. It is also the first report of an RPE phenotype in the I307N Rho mouse. These findings add to a growing literature reporting that modest whole-body exercise is protective across a wide range of models of retinal damage and disease, and further highlights the potential for this accessible and inexpensive therapeutic intervention in the ophthalmic clinic.

Structural dysconnectivity of key cognitive and emotional hubs in young people at high genetic risk for bipolar disorder.

Emerging evidence suggests that psychiatric disorders are associated with disturbances in structural brain networks. Little is known, however, about brain networks in those at high risk (HR) of bipolar disorder (BD), with such disturbances carrying substantial predictive and etiological value. Whole-brain tractography was performed on diffusion-weighted images acquired from 84 unaffected HR individuals with at least one first-degree relative with BD, 38 young patients with BD and 96 matched controls (CNs) with no family history of mental illness. We studied structural connectivity differences between these groups, with a focus on highly connected hubs and networks involving emotional centres. HR participants showed lower structural connectivity in two lateralised sub-networks centred on bilateral inferior frontal gyri and left insular cortex, as well as increased connectivity in a right lateralised limbic sub-network compared with CN subjects. BD was associated with weaker connectivity in a small right-sided sub-network involving connections between fronto-temporal and temporal areas. Although these sub-networks preferentially involved structural hubs, the integrity of the highly connected structural backbone was preserved in both groups. Weaker structural brain networks involving key emotional centres occur in young people at genetic risk of BD and those with established BD. In contrast to other psychiatric disorders such as schizophrenia, the structural core of the brain remains intact, despite the local involvement of network hubs. These results add to our understanding of the neurobiological correlates of BD and provide predictions for outcomes in young people at high genetic risk for BD.

Initial Assessment of Lactate as Mediator of Exercise-Induced Retinal Protection.

Physical exercise is protective in rodent models of retinal injury and disease. Data suggest that this is in part mediated by brain-derived neurotrophic factor (BDNF) signal transduction. It has been hypothesized that exercised-induced neuroprotection may be mediated by increases in circulating lactate that in turn alter BDNF secretion. We therefore tested whether mice undergoing a treadmill running regimen previously shown to be protective in a mouse model of retinal degeneration (RD) have increased serum levels of lactate. Lactate levels in exercised and non-exercised mice were statistically indistinguishable. A role for circulating lactate in exercise-induced retinal protection is unsupported.

The effects of ethosuximide on aversive instrumental learning in adult rats.

Antiepileptic medications are the frontline treatment for seizure conditions but are not without cognitive side effects. Previously, our laboratory reported learning deficits in phenytoin-, carbamazepine-, valproic acid-, and felbamate-treated rats. In this experiment, the effects found in ethosuximide (ETH)-treated rats have been compared with those in water-treated controls (controls) using the same instrumental training tasks. Rats treated with ETH did not display any performance deficits in any of the conditions tested relative to controls. These animals showed more rapid acquisition of the avoidance response than the control animals but only when they had prior experience in the appetitive condition. Of the drugs tested to date with these learning paradigms, ETH is the only one that did not impair performance relative to controls in any condition tested. Moreover, in comparison with rats treated with valproic acid, the only other available compound commonly recommended for the treatment of absence seizures, ETH-treated rats show substantially higher performance.

The effects of felbamate on appetitive and aversive instrumental learning in adult rats.

Antiepileptic medications are the frontline treatment for seizure conditions but are not without cognitive side effects. Previously, our laboratory reported learning deficits in phenytoin-, carbamazepine-, and valproate-treated rats. In the present experiment, the effects of felbamate (FBM) have been compared to water-treated controls (controls) using the same instrumental training tasks employed here. Rats treated with FBM displayed a deficit in acquiring a tone-signaled avoidance response, relative to controls, but this was true only if they had no prior appetitive experience. Terminal avoidance behavior was equivalent to healthy controls. In contrast, the FBM-treated rats showed enhanced acquisition of the avoidance response relative to controls when given the benefit of prior experience in the appetitive condition. Relative to animals treated with phenytoin, carbamazepine, or valproate, FBM-treated rats showed the lowest overall pattern of deficits using these instrumental learning tasks. While FBM treatment has been severely restricted because of rather low risks of serious medical side effects, we suggest that the risks are not substantially higher than those shown to exist for phenytoin, carbamazepine, or valproate. As psychologists, we further suggest that negative cognitive deficits associated with these various drugs, along with their quality-of-life costs, are of relevance in the design of treatment strategies for individuals with seizure disorders.

HuR promotes the molecular signature and phenotype of activated microglia: Implications for amyotrophic lateral sclerosis and other neurodegenerative diseases.

In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), chronic activation of microglia contributes to disease progression. Activated microglia produce cytokines, chemokines, and other factors that normally serve to clear infection or damaged tissue either directly or through the recruitment of other immune cells. The molecular program driving this phenotype is classically linked to the transcription factor NF-κB and characterized by the upregulation of proinflammatory factors such as IL-1ß, TNF-α, and IL-6. Here, we investigated the role of HuR, an RNA-binding protein that regulates gene expression through posttranscriptional pathways, on the molecular and cellular phenotypes of activated microglia. We performed RNA sequencing of HuR-silenced microglia and found significant attenuation of lipopolysaccharide-induced IL-1ß and TNF-α inflammatory pathways and other factors that promote microglial migration and invasion. RNA kinetics and luciferase reporter studies suggested that the attenuation was related to altered promoter activity rather than a change in RNA stability. HuR-silenced microglia showed reduced migration, invasion, and chemotactic properties but maintained viability. MMP-12, a target exquisitely sensitive to HuR knockdown, participates in the migration/invasion phenotype. HuR is abundantly detected in the cytoplasmic compartment of activated microglia from ALS spinal cords consistent with its increased activity. Microglia from ALS-associated mutant SOD1 mice demonstrated higher migration/invasion properties which can be blocked with HuR inhibition. These findings underscore an important role for HuR in sculpting the molecular signature and phenotype of activated microglia, and as a possible therapeutic target in ALS and other neurodegenerative diseases.

Doxycycline improves clinical outcomes during cystic fibrosis exacerbations.

Matrix metalloprotease-9 (MMP-9) plays a role in progression of cystic fibrosis, and doxycycline can reduce MMP-9 in vitro Here, we explore the effect of doxycycline during cystic fibrosis exacerbation treatment on MMP-9 related readouts and clinical end-points.This randomised, double-blind, placebo-controlled study enrolled hospitalised patients with cystic fibrosis undergoing exacerbation. In total, 20 participants were given doxycycline and 19 participants were given placebo over an 8-day period during hospitalisation. Biospecimens were collected at the beginning and the end of the study period. Primary end-points were total MMP-9 levels in the sputum and safety/tolerability. Secondary end-points included change in lung function, time to next exacerbation, and markers of MMP-9-related protease activity (active MMP-9 and TIMP-1). Nonparametric testing was used for within-group and between-group analyses.Doxycycline was well tolerated, with no treatment discontinuations or serious adverse events. Doxycycline reduced total sputum MMP-9 levels by 63.2% (p<0.05), and was also associated with a 56.5% reduction in active MMP-9 levels (p<0.05), a 1.6-fold increase in sputum TIMP-1 (p<0.05), improvement in forced expiratory volume in 1 s (p<0.05), and an increase in time to next exacerbation (p<0.01).Adjunctive use of doxycycline improved dysregulated MMP-9 levels in sputum, along with biomarkers consistent with a reduced proteolytic pulmonary environment. Improvement in clinical outcome measures suggests an important therapeutic benefit of doxycycline for individuals with cystic fibrosis.

Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes.

Proteases are important regulators of pulmonary remodeling and airway inflammation. Recently, we have characterized the enzyme prolyl endopeptidase (PE), a serine peptidase, as a critical protease in the generation of the neutrophil chemoattractant tripeptide Pro-Gly-Pro (PGP) from collagen. However, PE has been characterized as a cytosolic enzyme, and the mechanism mediating PE release extracellularly remains unknown. We examined the role of exosomes derived from airway epithelia as a mechanism for PE release and the potential extracellular signals that regulate the release of these exosomes. We demonstrate a specific regulatory pathway of exosome release from airway epithelia and identify PE as novel exosome cargo. LPS stimulation of airway epithelial cells induces release of PE-containing exosomes, which is significantly attenuated by small interfering RNA depletion of Toll-like receptor 4 (TLR4). These differences were recapitulated upon intratracheal LPS administration in mice competent versus deficient for TLR4 signaling. Finally, sputum samples from subjects with cystic fibrosis colonized with Pseudomonas aeruginosa demonstrate elevated exosome content and increased PE levels. This TLR4-based mechanism highlights the first report of nonstochastic release of exosomes in the lung and couples TLR4 activation with matrikine generation. The increased quantity of these proteolytic exosomes in the airways of subjects with chronic lung disease highlights a new mechanism of injury and inflammation in the pathogenesis of pulmonary disorders.

Interhemispheric white matter integrity in young people with bipolar disorder and at high genetic risk.

BACKGROUND: White matter (WM) impairments have been reported in patients with bipolar disorder (BD) and those at high familial risk of developing BD. However, the distribution of these impairments has not been well characterized. Few studies have examined WM integrity in young people early in the course of illness and in individuals at familial risk who have not yet passed the peak age of onset. METHOD: WM integrity was examined in 63 BD subjects, 150 high-risk (HR) individuals and 111 participants with no family history of mental illness (CON). All subjects were aged 12 to 30 years. RESULTS: This young BD group had significantly lower fractional anisotropy within the genu of the corpus callosum (CC) compared with the CON and HR groups. Moreover, the abnormality in the genu of the CC was also present in HR participants with recurrent major depressive disorder (MDD) (n = 16) compared with CON participants. CONCLUSIONS: Our findings provide important validation of interhemispheric abnormalities in BD patients. The novel finding in HR subjects with recurrent MDD - a group at particular risk of future hypo/manic episodes - suggests that this may potentially represent a trait marker for BD, though this will need to be confirmed in longitudinal follow-up studies.

Are there subtypes of bipolar depression?

OBJECTIVE: To investigate for subtypes of bipolar depression using latent class analysis (LCA). METHOD: Participants were recruited through a bipolar disorder (BD) clinic. LCA was undertaken using: (i) symptoms reported on the SCID-IV for the most severe lifetime depressive episode; (ii) lifetime illness features such as age at first depressive and hypo/manic episodes; and (iii) family history of BD and unipolar depression. To explore the validity of any demonstrated 'classes', clinical, demographic and treatment correlates were investigated. RESULTS: A total of 243 BD subjects (170 with BD-I and 73 with BD-II) were included. For the combined sample, we found two robust LCA solutions, with two and three classes respectively. There were no consistent solutions when the BD-I and BD-II samples were considered separately. Subjects in class 2 of the three-class solution (characterised by anxiety, insomnia, reduced appetite/weight loss, irritability, psychomotor retardation, suicidal ideation, guilt, worthlessness and evening worsening) were significantly more likely to be in receipt of government financial support, suggesting a particularly malign pattern of symptoms. CONCLUSION: Our study suggests the existence of two or three distinct classes of bipolar depression and a strong association with functional outcome.

Exercise and Cyclic Light Preconditioning Protect Against Light-Induced Retinal Degeneration and Evoke Similar Gene Expression Patterns.

To compare patterns of gene expression following preconditioning cyclic light rearing versus preconditioning aerobic exercise. BALB/C mice were preconditioned either by rearing in 800 lx 12:12 h cyclic light for 8 days or by running on treadmills for 9 days, exposed to toxic levels of light to cause light-induced retinal degeneration (LIRD), then sacrificed and retinal tissue harvested. Subsets of mice were maintained for an additional 2 weeks and for assessment of retinal function by electroretinogram (ERG). Both preconditioning protocols partially but significantly preserved retinal function and morphology and induced similar leukemia inhibitory factor (LIF) gene expression pattern. The data demonstrate that exercise preconditioning and cyclic light preconditioning protect photoreceptors against LIRD and evoke a similar pattern of retinal LIF gene expression. It may be that similar stress response pathways mediate the protection provided by the two preconditioning modalities.

Reconciling homeostatic and use-dependent plasticity in the context of somatosensory deprivation.

The concept of homeostatic plasticity postulates that neurons maintain relatively stable rates of firing despite changing inputs. Homeostatic and use-dependent plasticity mechanisms operate concurrently, although they have different requirements for induction. Depriving central somatosensory neurons of their primary activating inputs reduces activity and results in compensatory changes that favor excitation. Both a reduction of GABAergic inhibition and increase in glutamatergic excitatory transmission are observed in input-deprived cortex. Topographic reorganization of the adult somatosensory cortex is likely driven by both homeostatic and use-dependent mechanisms. Plasticity is induced by changes in the strengths of synaptic inputs, as well as changes in temporal correlation of neuronal activity. However, there is less certainty regarding the in vivo contribution of homeostatic mechanisms as in vitro experiments rely on manipulations that create states that do not normally occur in the living nervous system. Homeostatic plasticity seems to occur, but more in vivo research is needed to determine mechanisms. In vitro research is also needed but should better conform to conditions that might occur naturally in vivo.

Perceptions and experiences of health professionals when supporting adults with stroke to engage in physical activity.

Background Understanding health professional perceptions and experiences when supporting post-stroke physical activity may assist with development of strategies targeting low physical activity observed in this group. The aims of this study were to explore health professionals' perceptions and experiences of post-stroke physical activity, the barriers they experience and potential facilitators when supporting people with stroke to be active. Methods Ten focus groups were conducted with 57 health professionals (physiotherapists, occupational therapists, nurses, exercise physiologists, psychologists and sports scientists) and allied health students. Data were analysed via inductive thematic analysis. Results Health professionals were reluctant to recommend moderate intensity physical activity. Barriers included: (1) post-stroke barriers being varied and individual; (2) resources being under pressure and (3) physical activity goals falling through the cracks. Suggested facilitators included: (1) clearly defined roles, processes and environments which encourage activity; (2) funding for more staff; (3) improving health professional skills and confidence and (4) using internal motivation and social supports after stroke. Conclusions Post-stroke physical activity is a complex goal. Varied and individual barriers require tailored solutions. Health professionals report insufficient time, resources and skills to address these individual barriers as well as limited pathways to access physical activity support. Resource-efficient interventions and care models that allow routine strategies targeting post-stroke physical activity are required.

The Impact of Time to Anterior Cruciate Ligament Reconstruction on Return to Duty Among Active Duty Military Personnel.

INTRODUCTION: After an anterior cruciate ligament (ACL) injury, service members often undergo ACL reconstruction (ACLR) to restore knee stability, which is critical for performing physically demanding and unconventional military-specific tasks. Despite advancements in surgical techniques and rehabilitation protocols, a large portion of service members will not fully return to duty (RTD) post-ACLR and will receive a permanent profile restriction (PP) or undergo a medical evaluation board (MEB). The timing of ACLR is a modifiable factor that can potentially impact RTD and remains underexplored in this population. This study aimed to assess the relationship between the timing of ACLR and its impact on RTD and meniscal procedures performed at index ACLR. METHODS: This retrospective observational study was conducted among active duty military personnel who underwent primary ACLR at Madigan Army Medical Center between October 1, 2016, and December 31, 2022. The primary outcome was the number of RTD, PP, or MEB outcomes. Secondary outcomes included the incidence and type of meniscal procedure performed at index ACLR. Kruskal-Wallis analyses were employed to assess the relationships between time to ACLR and RTD, as well as the incidence and type of meniscal procedure performed. After separating time to ACLR into four distinct time-based groups (0-3 months, 3-6 months, 6-12 months, and >12 months), a chi-squared test with post hoc analysis via Dunn's test with Bonferroni correction was conducted to identify a time interval from injury to ACLR that impacted RTD. RESULTS: Initial analysis to assess the relationship between time to ACLR and outcome (RTD, PP, or MEB) were significant (P = .02). Subsequent analyses performed between 4 distinct time-based groups (0-3 months, 3-6 months, 6-12 months, and >12 months) were also significant (P = .03). Pairwise comparisons revealed an 80% rate of RTD in the 0-3 month group compared to a 53% RTD rate in 3-6 month group (P = .006). However, comparisons between the 3-6 month and 6-12 month group (P = .68) and between the 6-12 month and greater than 12 month groups were not significant (P = .80).Additionally, time to ACLR significantly differed between service members who did not undergo any concurrent meniscal procedure to those who had a meniscal debridement (P = .002), and to those who underwent meniscal repair (P = .02). There was no significant difference in time to ACLR between those who underwent debridement versus repair (P = .22). Patients without any meniscal procedure had an average surgery time of 175 days, compared to 240 days for those undergoing meniscal repair and 295 days for those with meniscal debridement. CONCLUSION: The findings from this novel study suggest that ACLR within 3 months after injury can improve the likelihood of RTD without limitations. The timing of ACLR can also impact the incidence and type of meniscal procedures, as patients who did not undergo any concomitant meniscal procedures underwent ACLR within 6 months after injury. This study offers valuable insight into the importance of earlier ACLR among service members to improve RTD rates and decrease additional concomitant meniscal procedures.

Pentosan Polysulfate Sodium Causes Diminished Function and Subtle Morphological Changes in Retina and RPE of Mice.

Purpose: There are numerous reports of a distinctive maculopathy in adults exposed to pentosan polysulfate sodium (PPS), a drug prescribed to treat bladder discomfort associated with interstitial cystitis. We tested whether PPS treatment of mice injures RPE or retina to provide insight into the etiology of the human condition. Methods: Mice were fed PPS-supplemented chow over 14 months. RPE and retinal function was assessed by electroretinography (ERG) regularly. Following euthanasia, one eye was used for sagittal sectioning and histology, the contralateral for RPE flatmounting. ZO-1 positive RPE cell borders were imaged using confocal microscopy and cell morphology was analyzed using CellProfiler. Results: After 10 months of PPS treatment, we observed diminution of mean scotopic c-wave amplitudes. By 11 months, we additionally observed diminutions of mean scotopic a- and b-wave amplitudes. Analysis of flatmounts revealed altered RPE cell morphology and morphometrics in PPS-treated mice, including increased mean en face cell area and geometric eccentricity, decreased RPE cell solidity and extent, and cytosolic translocation of alpha-catenin, all markers of RPE cell stress. Sex and regional differences were seen in RPE flatmount measures. Shortened photoreceptor outer segments were also observed. Conclusions: PPS treatment reduced RPE and later retina function as measured by ERG, consistent with a primary RPE injury. Post-mortem analysis revealed extensive RPE pleomorphism and polymegathism and modest photoreceptor changes. We conclude that PPS treatment of mice causes slowly progressing RPE and photoreceptor damage and thus may provide a useful model for some retinal pathologies.