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.

Anatomical Diversity of the Adult Corticospinal Tract Revealed by Single-Cell Transcriptional Profiling.

The corticospinal tract (CST) forms a central part of the voluntary motor apparatus in all mammals. Thus, injury, disease, and subsequent degeneration within this pathway result in chronic irreversible functional deficits. Current strategies to repair the damaged CST are suboptimal in part because of underexplored molecular heterogeneity within the adult tract. Here, we combine spinal retrograde CST tracing with single-cell RNA sequencing (scRNAseq) in adult male and female mice to index corticospinal neuron (CSN) subtypes that differentially innervate the forelimb and hindlimb. We exploit publicly available datasets to confer anatomic specialization among CSNs and show that CSNs segregate not only along the forelimb and hindlimb axis but also by supraspinal axon collateralization. These anatomically defined transcriptional data allow us to use machine learning tools to build classifiers that discriminate between CSNs and cortical layer 2/3 and nonspinally terminating layer 5 neurons in M1 and separately identify limb-specific CSNs. Using these tools, CSN subtypes can be differentially identified to study postnatal patterning of the CST in vivo, leveraged to screen for novel limb-specific axon growth survival and growth activators in vitro, and ultimately exploited to repair the damaged CST after injury and disease.SIGNIFICANCE STATEMENT Therapeutic interventions designed to repair the damaged CST after spinal cord injury have remained functionally suboptimal in part because of an incomplete understanding of the molecular heterogeneity among subclasses of CSNs. Here, we combine spinal retrograde labeling with scRNAseq and annotate a CSN index by the termination pattern of their primary axon in the cervical or lumbar spinal cord and supraspinal collateral terminal fields. Using machine learning we have confirmed the veracity of our CSN gene lists to train classifiers to identify CSNs among all classes of neurons in primary motor cortex to study the development, patterning, homeostasis, and response to injury and disease, and ultimately target streamlined repair strategies to this critical motor pathway.

PAK1 inhibition with Romidepsin attenuates H-reflex hyperexcitability after spinal cord injury.

Hyperreflexia associated with spasticity is a prevalent neurological condition characterized by excessive and exaggerated reflex responses to stimuli. Hyperreflexia can be caused by several diseases including multiple sclerosis, stroke and spinal cord injury (SCI). Although we have previously identified the contribution of the RAC1-PAK1 pathway underlying spinal hyperreflexia with SCI-induced spasticity, a feasible druggable target has not been validated. To assess the utility of targeting PAK1 to attenuate H-reflex hyperexcitability, we administered Romidepsin, a clinically available PAK1 inhibitor, in Thy1-YFP reporter mice. We performed longitudinal EMG studies with a study design that allowed us to assess pathological H-reflex changes and drug intervention effects over time, before and after contusive SCI. As expected, our results show a significant loss of rate-dependent depression - an indication of hyperreflexia and spasticity - 1 month following SCI as compared with baseline, uninjured controls (or before injury). Romidepsin treatment reduced signs of hyperreflexia in comparison with control cohorts and in pre- and post-drug intervention in SCI animals. Neuroanatomical study further confirmed drug response, as romidepsin treatment also reduced the presence of SCI-induced dendritic spine dysgenesis on α-motor neurons. Taken together, our findings extend previous work demonstrating the utility of targeting PAK1 activity in SCI-induced spasticity and support the novel use of romidepsin as an effective tool for managing spasticity. KEY POINTS: PAK1 plays a role in contributing to the development of spinal cord injury (SCI)-induced spasticity by contributing to dendritic spine dysgenesis. In this study, we explored the preclinical utility of inhibiting PAK1 to reduce spasticity and dendritic spine dysgenesis in an SCI mouse model. Romidepsin is a PAK1 inhibitor approved in the US in 2009 for the treatment of cutaneous T-cell lymphoma. Here we show that romidepsin treatment after SCI reduced SCI-induced H-reflex hyperexcitability and abnormal α-motor neuron spine morphology. This study provides compelling evidence that romidepsin may be a promising therapeutic approach for attenuating SCI-induced spasticity.

Periventricular nodular heterotopia in patients with a prenatal diagnosis of myelomeningocele/myeloschisis: associations with seizures and neurodevelopmental outcomes during early childhood.

PURPOSE: Historically, the presence of gray matter heterotopia was a concern for adverse postnatal neurocognitive status in patients undergoing fetal closure of open spinal dysraphism. The purpose of this study was to evaluate neurodevelopmental outcomes and the onset of seizures during early childhood in patients with a prenatal diagnosis of myelomeningocele/myeloschisis (MMC) and periventricular nodular heterotopia (PVNH). METHODS: All patients evaluated at the Center for Fetal Diagnosis and Treatment with a diagnosis of MMC between June 2016 to March 2023 were identified. PVNH was determined from prenatal and/or postnatal MRI. The Bayley Scales of Infant and Toddler Development (edition III or IV) were used for neurodevelopmental assessments. Patients were screened for seizures/epilepsy. RESULTS: Of 497 patients evaluated with a prenatal diagnosis of MMC, 99 were found to have PVNH on prenatal MRI, of which 35 had confirmed PVNH on postnatal imaging. From the 497 patients, 398 initially did not exhibit heterotopia on prenatal MRI, but 47 of these then had confirmed postnatal PVNH. The presence of PVNH was not a significant risk factor for postnatal seizures in early childhood. The average neurodevelopmental scores were not significantly different among heterotopia groups for cognitive, language, and motor domains. CONCLUSION: The presence of PVNH in patients with a prenatal diagnosis of MMC does not indicate an increased risk for neurodevelopmental delay at 1 year of age. We did not demonstrate an association with seizures/epilepsy. These findings can aid clinicians in prenatal consultation regarding fetal repair of open spinal dysraphism. Long-term follow-up is required to discern the true association between PVNH seen on prenatal imaging and postnatal seizures/epilepsy and neurodevelopmental outcomes.

A Qualitative Evidence Synthesis of Patient and Provider Attitudes Toward Audio-Only Telemental Health Care.

Background: Audio-only (phone) telemental health care can increase access to care, but its lack of nonverbal information may negatively impact care quality as compared to video or in-person visits. The objective of this work was to understand patient and provider attitudes toward phone care via a review of qualitative research. Methods: A qualitative evidence synthesis was conducted of peer-reviewed qualitative research published between 2013 and 2023. Studies were required to include qualitative data regarding patient and/or provider attitudes toward audio-only telemental health care. Results pertinent to phone care were extracted and underwent coding followed by theme identification. Results: We identified 2,065 abstracts and 29 articles were ultimately included in the synthesis; 27 of these studies were conducted during the COVID-19 pandemic. Five themes described benefits of phone care, nine described drawbacks, and three themes were neutral. Phone care was seen as easy to use, particularly for briefer check-ins or as a back-up option if video calls failed, and some patients preferred the privacy of not being seen. However, the loss of visual information during phone visits was considered particularly challenging in the treatment of more complex or severe patients; providers questioned whether they were able to provide high quality care, and patients reported feeling less supported and understood by their providers. Conclusions: The relative benefits and drawbacks of audio-only telemental health care must be carefully weighed against the options of video or in-person treatment based on patient needs and severity. Future work should continue to examine patient and provider attitudes toward phone care as the mental health landscape evolves postpandemic.

Inositol Polyphosphate-5-Phosphatase K (Inpp5k) Enhances Sprouting of Corticospinal Tract Axons after CNS Trauma.

Failure of CNS neurons to mount a significant growth response after trauma contributes to chronic functional deficits after spinal cord injury. Activator and repressor screening of embryonic cortical neurons and retinal ganglion cells in vitro and transcriptional profiling of developing CNS neurons harvested in vivo have identified several candidates that stimulate robust axon growth in vitro and in vivo Building on these studies, we sought to identify novel axon growth activators induced in the complex adult CNS environment in vivo We transcriptionally profiled intact sprouting adult corticospinal neurons (CSNs) after contralateral pyramidotomy (PyX) in nogo receptor-1 knock-out mice and found that intact CSNs were enriched in genes in the 3-phosphoinositide degradation pathway, including six 5-phosphatases. We explored whether inositol polyphosphate-5-phosphatase K (Inpp5k) could enhance corticospinal tract (CST) axon growth in preclinical models of acute and chronic CNS trauma. Overexpression of Inpp5k in intact adult CSNs in male and female mice enhanced the sprouting of intact CST terminals after PyX and cortical stroke and sprouting of CST axons after acute and chronic severe thoracic spinal contusion. We show that Inpp5k stimulates axon growth in part by elevating the density of active cofilin in labile growth cones, thus stimulating actin polymerization and enhancing microtubule protrusion into distal filopodia. We identify Inpp5k as a novel CST growth activator capable of driving compensatory axon growth in multiple complex CNS injury environments and underscores the veracity of using in vivo transcriptional screening to identify the next generation of cell-autonomous factors capable of repairing the damaged CNS.SIGNIFICANCE STATEMENT Neurologic recovery is limited after spinal cord injury as CNS neurons are incapable of self-repair post-trauma. In vitro screening strategies exploit the intrinsically high growth capacity of embryonic CNS neurons to identify novel axon growth activators. While promising candidates have been shown to stimulate axon growth in vivo, concomitant functional recovery remains incomplete. We identified Inpp5k as a novel axon growth activator using transcriptional profiling of intact adult corticospinal tract (CST) neurons that had initiated a growth response after pyramidotomy in plasticity sensitized nogo receptor-1-null mice. Here, we show that Inpp5k overexpression can stimulate CST axon growth after pyramidotomy, stroke, and acute and chronic contusion injuries. These data support in vivo screening approaches to identify novel axon growth activators.

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 one-year study of human milk oligosaccharide profiles in the milk of healthy UK mothers and their relationship to maternal FUT2 genotype.

Human milk oligosaccharides (HMOs) are indigestible carbohydrates with prebiotic, pathogen decoy and immunomodulatory activities that are theorized to substantially impact infant health. The objective of this study was to monitor HMO concentrations over 1 year to develop a long-term longitudinal dataset. HMO concentrations in the breast milk of healthy lactating mothers of the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) were measured at birth, 2 weeks, 6 weeks, 3 months, 6 months and 12 months postpartum. HMO quantification was conducted by high-performance anion-exchange chromatography with pulsed amperometric detection using a newly validated "dilute-and-shoot" method. This technique minimizes sample losses and expedites throughput, making it particularly suitable for the analysis of large sample sets. Varying patterns of individual HMO concentrations were observed with changes in lactation timepoint and maternal secretor status, with the most prominent temporal changes occurring during the first 3 months. These data provide valuable information for the development of human milk banks in view of targeted distribution of donor milk based on infant age. Maternal FUT2 genotype was determined based on identification at single-nucleotide polymorphism rs516246 and compared with the genotype expected based on phenotypic markers in the HMO profile. Surprisingly, two mothers genotyped as secretors produced milk that displayed very low levels of 2'-fucosylated moieties. This unexpected discrepancy between genotype and phenotype suggests that differential enzyme expression may cause substantial variation in HMO profiles between genotypically similar mothers, and current genotypic methods of secretor status determination may require validation with HMO markers from milk analysis.

A quality improvement project to address the challenges surrounding zoledronic acid use in children.

INTRODUCTION: Zoledronic acid (ZA) is an intravenous bisphosphonate used to treat pediatric osteoporosis. Adverse events including hypocalcemia and acute phase reaction (APR) are common following first-infusion. The purpose of this report is to describe implementation of a ZA clinical practice guideline and the subsequent process changes to improve adherence to aspects of the protocol related to safety and efficacy. METHODS: Quality assurance was evaluated by chart review over a 5-year period to compare the prevalence of hypocalcemia and APR to published data. A quality improvement (QI) initiative consisting of process changes including the addition of an endocrine RN to coordinate infusions and a shift to patient/family self-scheduling of infusions was conducted. The effect of the interventions on safety (completion of pre- and post-infusion bloodwork) and efficacy (receipt of all prescribed infusions) outcomes was evaluated. RESULTS: Seventy-two patients received 244 infusions over the period. The frequency of hypocalcemia (22%) and APR (31%) was consistent with prior reports. 99% of patients received pre-infusion bloodwork, 78% received post-first-infusion bloodwork, and 47% received all prescribed infusions. QI initiatives increased the percentage of patients receiving post-first-infusion bloodwork from 67 to 79% and those receiving all infusions from 62 to 74%, but fell short of the goal of 90%. CONCLUSIONS: The implementation of a standardized protocol for ZA use in children was successful in confirming patient eligibility with pre-infusion bloodwork but failed to ensure that patients obtained post-first-infusion bloodwork and received all prescribed infusions. Further efforts to systematize the management of children on ZA are needed.

Newlywed Couples' Own and Partner Sexual Disgust Sensitivities Interact to Predict Their Marital Satisfaction Through Their Sexual Satisfaction.

Sex is integral to maintaining a satisfying long-term romantic relationship such as marriage. It is thus important to identify the factors that promote sexual satisfaction in these relationships. To this end, we examined the extent to which a crucial evolved individual difference-sexual disgust sensitivity-impacts people's sexual satisfaction and relationship satisfaction. Using a two-year longitudinal study of 102 newlywed couples (204 individuals), we demonstrated that, rather than exerting main effects, the interaction of both couple members' sexual disgust sensitivities was indirectly associated with marital satisfaction through sexual satisfaction. People whose partners' sexual disgust sensitivities were relatively similar (versus dissimilar) to their own maintained higher levels of sexual satisfaction across the first two years of marriage, which was associated with similarly elevated marital satisfaction. Not only do these findings highlight the importance of integrating evolutionary perspectives and relationship science, they underscore the value of conducting dyadic research to examine the unique intersection of both couple members' characteristics for people's relationship outcomes.

Pericytes improve locomotor recovery after spinal cord injury in male and female neonatal rats.

OBJECTIVE: It is not known how activation of the hypoxia-inducible factor (HIF) pathway in pericytes, cells of the microvascular wall, influences new capillary growth. We tested the hypothesis that HIF-activated pericytes promote angiogenesis in a neonatal model of spinal cord injury (SCI). METHODS: Human placental pericytes stimulated with cobalt chloride and naïve pericytes were injected into the site of a thoracic hemi-section of the spinal cord in rat pups on postnatal day three (P3). Hindlimb motor recovery and Doppler blood flow perfusion at the site of transection were measured on P10. Immunohistochemistry was used to visualize vessel and neurofilament density for quantification. RESULTS: Injection of HIF-activated pericytes resulted in greater vascular density in males but did not result in improved motor function for males or females. Injection of non-HIF-activated pericytes resulted improved motor function recovery in both sexes (males, 2.722 ± 0.31-fold score improvement; females, 3.824 ± 0.58-fold score improvement, P < .05) but produced no significant changes in vessel density. CONCLUSIONS: HIF-activated pericytes promote vascular density in males post-SCI. Acute delivery of non-HIF-activated pericytes at the site of injury can improve motor recovery post-SCI.

Separate transcriptionally regulated pathways specify distinct classes of sister dendrites in a nociceptive neuron.

The dendritic processes of nociceptive neurons transduce external signals into neurochemical cues that alert the organism to potentially damaging stimuli. The receptive field for each sensory neuron is defined by its dendritic arbor, but the mechanisms that shape dendritic architecture are incompletely understood. Using the model nociceptor, the PVD neuron in C. elegans, we determined that two types of PVD lateral branches project along the dorsal/ventral axis to generate the PVD dendritic arbor: (1) Pioneer dendrites that adhere to the epidermis, and (2) Commissural dendrites that fasciculate with circumferential motor neuron processes. Previous reports have shown that the LIM homeodomain transcription factor MEC-3 is required for all higher order PVD branching and that one of its targets, the claudin-like membrane protein HPO-30, preferentially promotes outgrowth of pioneer branches. Here, we show that another MEC-3 target, the conserved TFIIA-like zinc finger transcription factor EGL-46, adopts the alternative role of specifying commissural dendrites. The known EGL-46 binding partner, the TEAD transcription factor EGL-44, is also required for PVD commissural branch outgrowth. Double mutants of hpo-30 and egl-44 show strong enhancement of the lateral branching defect with decreased numbers of both pioneer and commissural dendrites. Thus, HPO-30/Claudin and EGL-46/EGL-44 function downstream of MEC-3 and in parallel acting pathways to direct outgrowth of two distinct classes of PVD dendritic branches.

Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function.

Cellular senescence is emerging as a key mechanism of age-related vascular endothelial dysfunction, but evidence in healthy humans is lacking. Moreover, the influence of lifestyle factors such as habitual exercise on endothelial cell (EC) senescence is unknown. We tested the hypothesis that EC senescence increases with sedentary, but not physically active, aging and is associated with vascular endothelial dysfunction. Protein expression (quantitative immunofluorescence) of p53, a transcription factor related to increased cellular senescence, and the cyclin-dependent kinase inhibitors p21 and p16 were 116%, 119%, and 128% greater (all P < 0.05), respectively, in ECs obtained from antecubital veins of older sedentary (60 ± 1 yr, n = 12) versus young sedentary (22 ± 1 yr, n = 9) adults. These age-related differences were not present (all P > 0.05) in venous ECs from older exercising adults (57 ± 1 yr, n = 13). Furthermore, venous EC protein levels of p53 (r = -0.49, P = 0.003), p21 (r = -0.38, P = 0.03), and p16 (r = -0.58, P = 0.002) were inversely associated with vascular endothelial function (brachial artery flow-mediated dilation). Similarly, protein expression of p53 and p21 was 26% and 23% higher (both P < 0.05), respectively, in ECs sampled from brachial arteries of healthy older sedentary (63 ± 1 yr, n = 18) versus young sedentary (25 ± 1 yr, n = 9) adults; age-related changes in arterial EC p53 and p21 expression were not observed (P > 0.05) in older habitually exercising adults (59 ± 1 yr, n = 14). These data indicate that EC senescence is associated with sedentary aging and is linked to endothelial dysfunction. Moreover, these data suggest that prevention of EC senescence may be one mechanism by which aerobic exercise protects against endothelial dysfunction with age.NEW & NOTEWORTHY Our study provides novel evidence in humans of increased endothelial cell senescence with sedentary aging, which is associated with impaired vascular endothelial function. Furthermore, our data suggest an absence of age-related increases in endothelial cell senescence in older exercising adults, which is linked with preserved vascular endothelial function.

Determination of neutrophil CD64 expression as a prognostic biomarker in patients with community-acquired pneumonia.

The expression of CD64 in neutrophils (nCD64) has shown utility in the diagnosis of sepsis. The aim of this study was to assess the usefulness of nCD64 expression to identify patients with community-acquired pneumonia (CAP) at risk of a poor outcome. A prospective study of nCD64 expression (determined by flow cytometry) in patients with CAP was performed. The sensitivity/specificity of nCD64 in predicting poor outcome [defined as intensive care unit (ICU) admission and/or clinical deterioration after arrival at the emergency department] was calculated. Eighty-three adults with CAP were included; 14.5 % had septic shock, 19.3 % required ICU admission, and 10.8 % presented clinical deterioration after admission. The mean of the median fluorescence intensity (MFI) of nCD64 expression was 1140 (±1097). Patients with nCD64 expression ≥2700 MFI had more clinical deterioration (36.4 vs. 7.2 %, p = 0.015) and more ICU admission (45.5 vs. 14.5 %, p = 0.028). To identify clinical deterioration and ICU admission, nCD64 expression showed a sensitivity of 44.4 and 33.3 % and a specificity of 90.1 and 90.8 %, respectively. The addition of nCD64 expression to the Pneumonia Severity Index and CURB-65 severity scores did not improve the accuracy of predicting these outcomes. Although nCD64 expression is associated with an increased risk of ICU admission or clinical deterioration after admission, its accuracy in predicting these poor outcomes is modest and does not significantly improve the predictive ability of the PSI and CURB-65 severity scores.

Maternal behavior influences development of a reflexive action pattern in the newborn rat.

This study examined the effect of maternal behavior on the expression and postnatal development of a reflexive behavior in rat pups. In neonatal rats, the leg extension response (LER) is a bilateral hyperextension of the hindlimbs in response to maternal anogenital licking (AGL). Past research has found that intranasal application of zinc sulfate (ZnSO4 ) to the dam induces hyponosmia, thereby reducing the incidence of AGL. In this study, pregnant dams received intranasal application of air (control), distilled water (control), or ZnSO4 on the day before birth and every other day thereafter until postnatal day 9 (P9). The LER was experimentally evoked in pups, using a vibrotactile device, at P1, P5, or P10. Pups born to ZnSO4 -treated dams showed significantly shorter bilateral LER durations and significantly smaller ankle angles than pups born to control dams. Reduction of overall maternal AGL approached significance, and afternoon AGL was significantly reduced. These data suggest that maternal behavior influenced development of the LER in rat pups, demonstrating the influence of maternal care on behavioral development during the perinatal period.

Higher oesophageal temperature at rest and during exercise in humans with patent foramen ovale.

Respiratory system cooling occurs via convective and evaporative heat loss, so right-to-left shunted blood flow through a patent foramen ovale (PFO) would not be cooled. Accordingly, we hypothesized that PFO+ subjects would have a higher core temperature than PFO- subjects due, in part, to absence of respiratory system cooling of the shunted blood and that this effect would be dependent upon the estimated PFO size and inspired air temperature. Subjects were screened for the presence and size of a PFO using saline contrast echocardiography. Thirty well-matched males (15 PFO-, 8 large PFO+, 7 small PFO+) completed cycle ergometer exercise trials on three separate days. During Trial 1, subjects completed a V̇(O2max) test. For Trials 2 and 3, randomized, subjects completed four 2.5 min stages at 25, 50, 75 and 90% of the maximum workload achieved during Trial 1, breathing either ambient air (20.6 ± 1.0°C) or cold air (1.9 ± 3.5°C). PFO+ subjects had a higher oesophageal temperature (T(oesoph)) (P < 0.05) than PFO- subjects on Trial 1. During exercise breathing cold and dry air, PFO+ subjects achieved a higher T(oesoph) than PFO- subjects (P < 0.05). Subjects with a large PFO, but not those with a small PFO, had a higher T(oesoph) than PFO- subjects (P < 0.05) during Trial 1 and increased T(oesoph) breathing cold and dry air. These data suggest that the presence and size of a PFO are associated with T(oesoph) in healthy humans but this is explained only partially by absence of respiratory system cooling of shunted blood.

Developmental plasticity of coordinated action patterns in the perinatal rat.

Some of the most simple, stereotyped, reflexive, and spinal-mediated motor behaviors expressed by animals display a level of flexibility and plasticity that is not always recognized. We discuss several examples of how coordinated action patterns have been shown to be flexible and adaptive in response to sensory feedback. We focus on interlimb and intralimb coordination during the expression of two action patterns (stepping and the leg extension response) in newborn rats, as well as interlimb motor learning. We also discuss the idea that the spinal cord is a major site for supporting plasticity in the developing motor system. An implication of this research is that normally occurring sensory stimulation during the perinatal period influences the typical development and expression of action patterns, and that exploiting the developmental plasticity of the motor system may lead to improved strategies for promoting recovery of function in human infants with motor disorders.

Age-associated Epstein-Barr virus-specific T cell responses in seropositive healthy adults.

Epstein-Barr virus (EBV) is present in 95% of the world's adult population. The immune response participates in immune vigilance and persistent infection control, and this condition is maintained by both a good quality (functionality) and quantity of specific T cells throughout life. In the present study, we evaluated EBV-specific CD4(+) and CD8(+) T lymphocyte responses in seropositive healthy individuals younger and older than 50 years of age. The assessment comprised the frequency, phenotype, functionality and clonotypic distribution of T lymphocytes. We found that in both age groups a similar EBV-specific T cell response was found, with overlapping numbers of tumour necrosis factor (TNF)-α(+) T lymphocytes (CD4(+) and CD8(+)) within the memory and effector cell compartments, in addition to monofunctional and multi-functional T cells producing interleukin (IL)-2 and/or interferon (IFN)-γ. However, individuals aged more than 50 years showed significantly higher frequencies of IL-2-producing CD4(+) T lymphocytes in association with greater production of soluble IFN-γ, TNF-α and IL-6 than subjects younger than 50 years. A polyclonal T cell receptor (TCR)-variable beta region (Vß) repertoire exists in both age groups under basal conditions and in response to EBV; the major TCR families found in TNF-α(+) /CD4(+) T lymphocytes were Vß1, Vß2, Vß17 and Vß22 in both age groups, and the major TCR family in TNF-α(+) /CD8(+) T cells was Vß13·1 for individuals younger than 50 years and Vß9 for individuals aged more than 50 years. Our findings suggest that the EBV-specific T cell response (using a polyclonal stimulation model) is distributed throughout several T cell differentiation compartments in an age-independent manner and includes both monofunctional and multi-functional T lymphocytes.

Jail Characteristics and Availability of Opioid Treatment Services: Results from a Nationally Representative Survey.

The current wave of the opioid epidemic has contributed to a record number of drug-related overdoses and a significant proportion of people who experience opioid use disorder are admitted to local jails. These correctional facilities serve as the principal entry point to the criminal justice system as nearly every person who is taken into custody is admitted to a local detention center. Although jails are recognized as primary intervention points for people who may require treatment for opioid use disorder, services in these facilities remain deficient. The absence of jail-based treatment has become a pressing concern as the number of drug-related deaths in custody continues to rise and the risk of post-release overdose also remains high. The present study draws on the opioid-related module of the 2019 Bureau of Justice Statistics' Census of Jails to assess the relationships between the characteristics of 2588 local detention centers and the availability of treatment services. These specific approaches included screening for opioid use disorder, providing medication to manage withdrawal symptoms, administering medication for opioid use disorder (MOUD), providing overdose reversal medication at the time of release, and linking people with community-based care following release from the detention center. The results demonstrate facilities located in the Northeast, larger jails, those in urban areas, and detention centers with higher turnover rates are significantly more likely to provide a wider variety of opioid treatment services. These findings have important implications for the prioritization of policies and the allocation of resources to support the adoption of opioid treatment services in local jails.