Neuropathic pain is a chronic disease state resulting from injury to the nervous system. This type of pain often responds poorly to standard treatments and occasionally may get worse instead of ...better over time. Patients who experience neuropathic pain report sensitivity to cold and mechanical stimuli. Since the nociceptive system of African naked mole-rats contains unique adaptations that result in insensitivity to some pain types, we investigated whether naked mole-rats may be resilient to sensitivity following nerve injury. Using the spared nerve injury model of neuropathic pain, we showed that sensitivity to mechanical stimuli developed similarly in mice and naked mole-rats. However, naked mole-rats lacked sensitivity to mild cold stimulation after nerve injury, while mice developed robust cold sensitivity. We pursued this response deficit by testing behavior to activators of transient receptor potential (TRP) receptors involved in detecting cold in naïve animals. Following mustard oil, a TRPA1 activator, naked mole-rats responded similarly to mice. Conversely, icilin, a TRPM8 agonist, did not evoke pain behavior in naked mole-rats when compared with mice. Finally, we used RNAscope to probe for TRPA1 and TRPM8 messenger RNA expression in dorsal root ganglia of both species. We found increased TRPA1 messenger RNA, but decreased TRPM8 punctae in naked mole-rats when compared with mice. Our findings likely reflect species differences due to evolutionary environmental responses that are not easily explained by differences in receptor expression between the species.
The social decision-making network (SDMN) is a conserved neural circuit that modulates a range of social behaviors via context-specific patterns of activation that may be controlled in part by ...oxytocinergic signaling. We have previously characterized oxytocin's (OT) influence on prosociality in the naked mole-rat, a eusocial mammalian species, and its altered neural distribution between animals of differing social status. Here, we asked two questions: (1) do patterns of activation in the SDMN vary by social context and (2) is functional connectivity of the SDMN altered by OT manipulation? Adult subordinate naked mole-rats were exposed to one of three types of stimuli (three behavioral paradigms: familiar adult conspecific, unfamiliar adult conspecific, or familiar pups) while manipulating OT (three manipulations: saline, OT, or OT antagonist). Immediate early gene c-Fos activity was quantified using immunohistochemistry across SDMN regions. Network analyses indicated that the SDMN is conserved in naked mole-rats and functions in a context-dependent manner. Specific brain regions were recruited with each behavioral paradigm suggesting a role for the nucleus accumbens in social valence and sociosexual interaction, the prefrontal cortex in assessing/establishing social dominance, and the hippocampus in pup recognition. Furthermore, while OT manipulation was generally disruptive to coordinated neural activity, the specific effects were context-dependent supporting the hypothesis that oxytocinergic signaling promotes context appropriate social behaviors by modulating co-ordinated activity of the SDMN.
Regional changes to cortical thickness in individuals with neurodegenerative and cerebrovascular diseases (CVD) can be estimated using specialized neuroimaging software. However, the presence of ...cerebral small vessel disease, focal atrophy, and cortico-subcortical stroke lesions, pose significant challenges that increase the likelihood of misclassification errors and segmentation failures.
The main goal of this study was to examine a correction procedure developed for enhancing FreeSurfer's (FS's) cortical thickness estimation tool, particularly when applied to the most challenging MRI obtained from participants with chronic stroke and CVD, with varying degrees of neurovascular lesions and brain atrophy.
In 155 CVD participants enrolled in the Ontario Neurodegenerative Disease Research Initiative (ONDRI), FS outputs were compared between a fully automated, unmodified procedure and a corrected procedure that accounted for potential sources of error due to atrophy and neurovascular lesions. Quality control (QC) measures were obtained from both procedures. Association between cortical thickness and global cognitive status as assessed by the Montreal Cognitive Assessment (MoCA) score was also investigated from both procedures.
Corrected procedures increased "Acceptable" QC ratings from 18 to 76% for the cortical ribbon and from 38 to 92% for tissue segmentation. Corrected procedures reduced "Fail" ratings from 11 to 0% for the cortical ribbon and 62 to 8% for tissue segmentation. FS-based segmentation of T1-weighted white matter hypointensities were significantly greater in the corrected procedure (5.8 mL vs. 15.9 mL,
< 0.001). The unmodified procedure yielded no significant associations with global cognitive status, whereas the corrected procedure yielded positive associations between MoCA total score and clusters of cortical thickness in the left superior parietal (
= 0.018) and left insula (
= 0.04) regions. Further analyses with the corrected cortical thickness results and MoCA subscores showed a positive association between left superior parietal cortical thickness and Attention (
< 0.001).
These findings suggest that correction procedures which account for brain atrophy and neurovascular lesions can significantly improve FS's segmentation results and reduce failure rates, thus maximizing power by preventing the loss of our important study participants. Future work will examine relationships between cortical thickness, cerebral small vessel disease, and cognitive dysfunction due to neurodegenerative disease in the ONDRI study.
IntroductionChronic low back pain (CLBP) is a common condition and source of significant suffering, disability and healthcare costs. Current physiotherapy treatment is moderately effective. Combining ...theory-based psychological methods with physiotherapy could improve outcomes for people with CLBP. The primary aim of this randomised controlled trial (RCT) is to evaluate the efficacy of Physiotherapy informed by Acceptance and Commitment Therapy (PACT) on functioning in patients with CLBP.Methods and analysisThe PACT trial is a two-armed, parallel-group, multicentre RCT to assess the efficacy of PACT in comparison with usual physiotherapy care (UC). 240 patients referred to physiotherapy with CLBP will be recruited from three National Health Service (NHS) hospitals trusts. Inclusion criteria are: age ≥18 years, CLBP ≥12-week duration, scoring ≥3 points on the Roland-Morris Disability Questionnaire (RMDQ) and adequate understanding of spoken and written English to participate. Patients will be randomised to PACT or UC (120 per arm stratified by centre) by an independent randomisation service and followed up at 3 and 12 months post randomisation. The sample size of 240 will provide adequate power to detect a standardised mean difference of 0.40 in the primary outcome (RMDQ; 5% significance, 80% power) assuming attrition of 20%. Analysis will be by intention to treat conducted by the trial statistician, blind to treatment group, following a prespecified analysis plan. Estimates of treatment effect at the follow-up assessments will use an intention-to-treat framework, implemented using a linear mixed-effects model.Ethics and disseminationThis trial has full ethical approval (14/SC/0277). It will be disseminated via peer-reviewed publications and conference presentations. The results will enable clinicians, patients and health service managers to make informed decisions regarding the efficacy of PACT for patients with CLBP.Trial registration numberISRCTN95392287; Pre-results.
The transcription factor Pax5 is essential for B cell commitment in the mouse, where it represses lineage-inappropriate gene expression while simultaneously activating the B cell gene expression ...program. In this study we have performed a global gene expression screen of wild-type and Pax5-deficient pro-B cells in an attempt to identify the crucial Pax5 targets in early B lymphopoiesis. These studies have identified 109 Pax5 targets comprising 61% activated and 39% repressed genes. Interestingly, Pax5 directly regulates the genes encoding a number of transcription factors that are required at the pre-B cell stage of differentiation, including Irf8, Spib, and Ikzf3 (Aiolos), suggesting that a key function of Pax5 is to activate secondary transcription factors that further reinforce the B cell program. Pax5 is also required for the expression of many genes known to be involved in adhesion and signaling, indicating that Pax5 modulates the homing and or migration properties of B cell progenitors. Finally, Pax5 also represses a cohort of genes that are involved in multiple biological processes, many of which are not typically associated with B cells. These include the repression of the adhesion molecule Embigin, which is expressed in bone marrow progenitors, T cells, and myeloid cells but is specifically repressed by Pax5 in B cells.
The neuropeptide oxytocin (OT) influences prosocial behavior(s), aggression, and stress responsiveness, and these diverse effects are regulated in a species- and context-specific manner. The naked ...mole-rat (Heterocephalus glaber) is a unique species with which to study context-dependent effects of OT, exhibiting a strict social hierarchy with behavioral specialization within the subordinate caste: soldiers are aggressive and defend colonies against unfamiliar conspecifics while workers are prosocial and contribute to in-colony behaviors such as pup care. To determine if OT is involved in subcaste-specific behaviors, we compared behavioral responses between workers and soldiers of both sexes during a modified resident/intruder paradigm, and quantified activation of OT neurons in the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON) using the immediate-early-gene marker c-fos co-localized with OT neurons. Resident workers and soldiers were age-matched with unfamiliar worker stimulus animals as intruders, and encounters were videorecorded and scored for aggressive behaviors. Colony-matched controls were left in their home colony for the duration of the encounters. Brains were extracted and cell counts were conducted for OT immunoreactive (ir), c-fos-ir, and percentage of OT-c-fos double-labeled cells. Results indicate that resident workers were less aggressive but showed greater OT neural activity than soldiers. Furthermore, a linear model including social treatment, cortisol, and subcaste revealed that subcaste was the only significant predictor of OT-c-fos double-labeled cells in the PVN. These data suggest that in naked mole-rats OT promotes prosocial behaviors rather than aggression and that even within subordinates status exerts robust effects on brain and behavior.
•We compared behavior and oxytocin neural activity between naked mole-rat sub-castes.•Soldiers were more aggressive than workers during a resident/intruder paradigm.•Workers exhibited greater oxytocin neural activity than soldiers in this paradigm.•Sub-caste is a significant predictor of oxytocin neural activity.
Introduction: The pandemic has been difficult on physicians, with two fifths of doctors in one survey reporting that their mental health is now worse than before the pandemic. It is likely that a ...significant proportion of these physicians are parents of children necessitating childcare, as approximately 32% of the US workforce has someone in their household under the age of 14. We sought to study the impact of the coronavirus 2019 (COVID-19) pandemic on physician parents in academia. Our goal was to investigate the intersection of professional and personal challenges, as well as perceived impact on domestic life and professional development secondary to the COVID-19 pandemic.
Methods: Using Survey Monkey, we developed a 37-question survey to address the aim of this study. Questions were grouped into four categories: demographics; impact on childcare; impact on care; and impact on mental health/wellness. Most of the questions were multiple choice with a few fill-in-the-blank options to allow participants to provide additional information related to their experiences as physicians during the pandemic. A link to the survey was disseminated via email to physicians at our home institution, Rush University Medical Center (Chicago), via our own intra- and interdepartmental communications, We used private social media accounts such as Facebook physician groups to reach out to physicians at other academic medical centers. Survey responses were voluntary and collected anonymously over an eight-week period, without identifiable data. Inclusion criteria included any physician identifying themselves as working full or full or part time in an academic facility in the US and caregivers for children <18 years.
Results: Survey respondents were mostly female (83.2%), practicing in the Midwest (61.2%), and ranked as assistant professor (59.5%). The majority of respondents had two children (65.1%) who were <11 years in age (85.6%). Most respondents worked full time with 72.8% working over 50% clinically. Childcare was disrupted for 171 of 232 respondents (73.7%); 62.9% struggled with balancing work with childcare; 81.9% worried often or very often about fulfilling their responsibilities. A vast majority, 210 of 232 respondents (90.5%) had some degree of concern about feeling overburdened by their roles. More than half (57.3%) worried that their professional advancement was impacted by the pandemic, and 53.9% considered making adjustments to their clinical workload/. Over half (51.6%) thought that increased domestic responsibilities impacted their professional advancement .
Conclusion: In the survey, which was completed primarily by early-career women physicians practicing in a variety of specialties and geographic regions, we noted that childcare disruption amidst the pandemic was extremely prevalent. The majority of respondents reported full-time equivalent work; thus, it is reasonable to assume that significant workloads and limitations in remote work in combination with childcare constraints resulted in significant burden. A large number felt the challenges were negatively impacting their professional development and felt overburdened by their various roles.
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