Clemastine enhances exercise-induced motor improvement in hypoxic ischemic rats.

Neonatal hypoxic ischemia (HI) occurs owing to reduced cerebral oxygen levels and perfusion during the perinatal period. Brain injury after HI triggers neurological manifestations such as motor impairment, and the improvement of impaired brain function remains challenging. Recent studies suggest that cortical myelination plays a role in motor learning, but its involvement in motor improvement after HI injury is not well understood. This study aimed to investigate the impact of myelination on motor improvement following neonatal HI injury. We employed a modified Rice-Vannucci model; the right common carotid artery of postnatal day 7 (P7) Wistar rats was isolated and divided, and the rats were then exposed to hypoxic condition (90 min, 8 % O2). A total of 101 rats (66 males) were divided into four groups: trained-HI (n = 38), trained-Sham (n = 16), untrained-HI (n = 31), and untrained-Sham (n = 16). The trained groups underwent rotarod-based exercise training from P22 to P41 (3 days per week). Structural analysis using magnetic resonance imaging and immunohistochemistry (n = 6 per group) revealed increased fractional anisotropy and myelin density in the primary somatosensory cortex of the trained-HI group. We further evaluated the effect of myelination promotion on rotarod performance by administering clemastine, a myelination-promoting drug, via daily intraperitoneal injections. Clemastine did not enhance motor improvement in untrained-HI rats. However, clemastine-administered trained-HI rats (n = 7) exhibited significantly improved motor performance compared to both saline-administered trained-HI rats (n = 11) and clemastine-administered untrained-HI rats (n = 7). These findings suggest that myelination may be a key mechanism in motor improvement after HI injury and that combining exercise training with clemastine administration could be an effective therapeutic strategy for motor improvement following HI injury.

Dietary habits and genetic susceptibility: correlations between nutritional intake and genetic risks for schizophrenia and bipolar disorder.

Dietary habits may impact the prevention and management of schizophrenia (SCZ) and bipolar disorder (BD), and genetic and environmental factors can influence both these habits and these disorders. This study investigated the effects of genetic predispositions to SCZ and BD on current dietary habits among older adults with lifestyle-related diseases, potentially offering insights for preventive mental health strategies. A cohort of 730 older patients who were diagnosed with or suspected of having lifestyle-related diseases was assessed for eight current dietary categories: miso soup, Japanese tea, green and yellow vegetables, light-colored vegetables, fruits, pickles, meats, and soybeans. Polygenic risk scores (PRSs) for the risk of SCZ and BD, including BD types I and II, the shared risk of SCZ and BD, and the differentiation of SCZ from BD, were calculated utilizing data from large-scale genome-wide association studies (GWASs). Our findings revealed that PRSs for SCZ and BD risk significantly influenced specific dietary habits, particularly decreased consumption of nutrient-rich foods such as light-colored vegetables (SCZ, R2 = 0.0096, p = 3.54 × 10-3; BD, R2 = 0.0074, p = 9.09 × 10-3) and soybeans (SCZ, R2 = 0.0061, p = 0.019; BD, R2 = 0.014, p = 8.38 × 10-4). Notable differences in dietary effects were observed between PRSs for BD I and BD II, with a more pronounced impact associated with BD I (e.g., light-colored vegetables, BD I, R2 = 0.015, p = 3.11 × 10-4; BD II, p > 0.05). Moreover, shared genetic factors for SCZ and BD were correlated with lower intakes of miso soup (R2 = 0.013, p = 1.21 × 10-3), Japanese tea (R2 = 0.0092, p = 5.59 × 10-3), light-colored vegetables (R2 = 0.010, p = 2.92 × 10-3), and soybeans (R2 = 0.014, p = 3.13 × 10-4). No significant correlations were found between PRSs for differentiating SCZ from BD and any dietary patterns (p > 6.25 × 10-3). Genetic risks shared by individuals with SCZ and BD may influence dietary choices in older adults, emphasizing the potential for dietary modifications as part of comprehensive strategies for the prevention of the SCZ and BD onset, as well as for the treatment of individuals at risk of or diagnosed with SCZ and BD.

Characterization of cancer survivors clustered by subjective and objective cognitive function scores.

BACKGROUND: Cancer-related cognitive impairment (CRCI) is a prevalent condition that significantly impacts the quality of life of individuals who receive cancer treatment. Clinical management of CRCI presents challenges due to the absence of a standardized assessment. This study identified clinically relevant phenotypic clusters of CRCI based on subjective and objective cognitive function scores. METHODS: In this cross-sectional study, participants were clustered using the VARCLUS™ based on subjective cognitive impairment assessed through the PROMIS® version 1.0 short-form subscales of cognitive abilities and cognitive concerns and the CANTAB Cambridge Cognition® scores, which included measures of visuospatial working memory capacity, visual episodic memory, new learning, working memory, executive function, and sustained attention. Each cluster's characteristics were described using demographics, physical and psychosocial factors (physical function, affect, optimism, and social support), and psychoneurological symptoms (anxiety, depression, fatigue, neuropathic pain, and sleep disturbance). RESULTS: We obtained five clusters from a total of 414 participants, where 99% were female, and 93% were self-reported white. Clusters 4 and 5 showed the highest PROMIS® cognitive abilities and the lowest measures of cognitive concern, while Clusters 1 and 2 showed the lowest cognitive abilities and the highest cognitive concerns. Clusters 4 and 5 had higher education, income, employment, and higher scores in physical function, positive affect, optimism, and social support. Additionally, individuals in these clusters were less prone to experience severe cancer-related psychoneurological symptoms. CONCLUSION: Our clustering approach, combining subjective and objective cognitive function information, shows promise in identifying phenotypes that hold clinical relevance for categorizing patient presentation of CRCI and facilitating individualized management strategies.

Cancer-Related Cognitive Impairment Associated with APOE rs7412 and BDNF rs6265 in Breast Cancer Survivors.

OBJECTIVES: Cancer-related cognitive impairment (CRCI) is a highly prevalent and debilitating symptom reported by breast cancer survivors (BCS). The etiology of CRCI remains unclear, leading to poor symptom management. Building from prior studies, BCS with the C/C genotype of apolipoprotein E (APOE) rs7412 and the T/T genotype of brain-derived neurotrophic factor (BDNF) rs6265 were hypothesized to experience more severe CRCI. Therefore, we investigated the relationships between the severity of CRCI and polymorphisms of APOE and BDNF among BCS. METHODS: This was a subanalysis of data from a larger descriptive, correlational, and cross-sectional study. Subjective and objective CRCI were measured using the Patient-Reported Outcomes Measurement Information System and CANTAB Cambridge Cognitive assessment, respectively. Buccal swab samples were collected to evaluate the single nucleotide polymorphisms. Multivariable generalized linear regression models were used to analyze data. RESULTS: APOE rs7412 and BDNF rs6265 were significantly associated with lower self-reported cognitive abilities in a total of 353 BCS. Age was positively associated with self-reported cognitive scores, indicating that younger BCS perceived lower cognitive abilities. Individuals carrying genotype of C/T for APOE with the C/C or C/T for BDNF showed positive associations with cognitive abilities. CONCLUSIONS: Younger BCS with the C/C genotype for APOE rs7412 and the T/T genotype for BDNF rs6265 may be at risk for CRCI. Knowledge regarding predictive markers for CRCI symptoms is essential for precision symptom management. Further investigation with a longitudinal and translational design is necessary to explore the etiologies for CRCI. IMPLICATIONS FOR NURSING PRACTICE: Integrating genetic phenotyping into routine clinical practice will provide nurses with unique opportunities to understand individual susceptibilities, and how symptoms may trigger other symptoms. Further, findings from these innovative investigations will provide symptom interventionists and implementation scientists with critical data to optimize individualized strategies for symptom prevention, detection, and management.

Mechanistic insights into behavioral clusters associated with cancer-related systemic inflammatory response.

PURPOSE OF REVIEW: This focused, narrative review mostly describes our team's investigations into the potential inflammatory mechanisms that contribute to the development of cancer-related gastrointestinal (GI) mucositis and its associated symptoms. This review summarizes details of our clinical and preclinical findings to test the role of inflammation in the development and occurrence of these cancer-related conditions. RECENT FINDINGS: GI mucositis (GIM) is a common, distressing condition reported by cancer patients. GIM is often clustered with other behaviors including fatigue, pain, anorexia, depression, and diarrhea. It is hypothesized that there is a common biologic mechanism underpinning this symptom cluster. Our multi-platform investigations revealed that GIM and its associated cluster of behaviors may be triggered by local inflammation spreading systemically causing pro-inflammatory-mediated toxicities, leading to alterations in immune, metabolic, and nervous system functions and activities. For example, behavioral toxicities related to local irradiation for non-metastatic cancer may be triggered by mGluR5 activation influencing prolonged T cell as well as NF-κB transcription factor activities. Thus, interventions targeting inflammation and associated pathways may be a reasonable strategy to alleviate GIM and its symptom cluster. SUMMARY: GIM may be a sign of a broader systemic inflammatory response triggered by cancer or its treatment. Addressing GIM and its associated symptoms primarily involves supportive care strategies focused on relieving symptoms, promoting healing, and preventing complications.

Associations of brain-derived neurotrophic factor rs6265 polymorphism and cognitive function in breast cancer survivors from a cross-sectional study.

BACKGROUND: Breast cancer survivors (BCS) often complain of cancer-related cognitive impairment (CRCI) during and even months after completing primary cancer treatments, particularly chemotherapy. The etiology of CRCI is unknown, but associations of CRCI with germline genetic polymorphisms have been reported, including Brain-Derived Neurotrophic Factor (BDNF) rs6265 polymorphism. The current study investigated the associations of specific BDNF rs6265 with CRCI. METHODS: Cancer-related cognitive impairment was assessed using subjective reports of cognitive symptoms (the version 1.0, 8-item short-forms of the Patient-Reported Outcomes Measurement Information System®) and computerized objective cognitive function scores (CANTAB®). BDNF rs6265 genotypes were determined from buccal swabs. The associations of specific BDNF rs6265 with CRCI were examined by either one-way analysis of variance or the Kruskal-Wallis test followed by post hoc tests and rank-based regression analysis. RESULTS: We examined 356 female BCS. The mean (SD) age was 55.6 (9.8) years old, the median (IQR) years since cancer diagnosis were 4.0 (6.0), and 331 (92.7%) were self-described as White. BCS carrying the Met/Met genotype showed poorer results on 'visual episodic memory and new learning' and 'spatial working memory and executive function.' This relationship was observed regardless of prior chemotherapy. CONCLUSION: Our findings suggest that carrying the BDNF rs6265 Met/Met genotype increases the risk for CRCI in BCS. These results are foundational in nature and provide important information to identify mechanisms underpinning CRCI.

Family Wellbeing and Sexual Health of Patients Receiving Treatment for Prostate Cancer.

Purpose: Prostate cancer and its treatment may affect patients' sexual function and social wellbeing. This study investigated the relationship between social/family wellbeing and sexual health in patients with prostate cancer. Additionally, the moderating effect of clinical characteristics on this relationship was also explored. Patients and Methods: This is a descriptive correlational study using baseline data of a longitudinal study enrolling 137 patients with prostate cancer. Sexual Function (SF) and Sexual Function Distress (SFD) data were collected using the Symptom Index questionnaire. Demographic data were obtained during study intake and clinical data were obtained from chart review. Bivariate correlation determined the correlations among continuous demographic/clinical data, social/family wellbeing, and sexual health. Moderated regression analysis determined the moderating effects of clinical characteristics on the relationship of social/family wellbeing and sexual health. Results: Moderate positive correlation was found between social/family wellbeing and SF, whereas a weak negative correlation was noted between social/family wellbeing and SFD. Depression was significantly correlated with social/family wellbeing and SFD. Both sexual health domains were significantly correlated with Gleason score. A significant difference was noted in the social/family wellbeing and both SF and SFD in participants receiving androgen deprivation therapy (ADT) compared to those not receiving ADT. Concomitant ADT use was the only clinical characteristic found to be a significant moderator of the relationship between social/family wellbeing and SFD, but none of the clinical characteristics was found to have a moderating effect on the relationship of social/family wellbeing and SF. Among patients who were not receiving ADT, high social/family wellbeing was associated with low SFD. Patients who were receiving ADT reported slightly higher SFD despite having higher social/family wellbeing. Conclusion: Ensuring sexual health in patients with prostate cancer requires a comprehensive approach to address factors contributing to sexual health such as side effects of treatment and family wellbeing.

Community-Based Wound Care Programs for Unhoused Individuals.

Wound care management for unhoused individuals is challenging due to the lack of healthcare infrastructure to handle the unique needs of this population. Therefore, we aimed to obtain insights for best practices and to establish a care clinic that is low threshold, community-based and meets the needs of unhoused people. We employed two approaches: (1) conduct a targeted narrative review of the literature of existing or proposed community-based program models that can address the wound care needs of unhoused individuals, and (2) assess cost-effectiveness and describe the results of a survey administered to unhoused clients and their health care providers at a community-based wound care program in Honolulu, Hawai'i. The literature search and screening yielded 11 articles relevant to the topic. Per the literature, existing community-based healthcare programs were successful when: (1) wound care services were incorporated into a broader social/health program, (2) cost-effective, and (3) comprehensive services were provided. Survey results in Honolulu found that the wound care program matched the needs of the targeted population and was cost-effective. Difficulty in following clients until wound closure and the sustainability of the program, particularly the lack of insurance reimbursement for street-based services, were perceived challenges. Additionally, the lack of insurance reimbursement for street-based wound care services continues to impact sustainability. Community-based programs can be successful in addressing the wound care needs of unhoused individuals if they address complex fundamental issues. This paper highlights existing gaps in logistics and policies that must be addressed to meet the specific medical needs of these vulnerable individuals.

Brain-Derived Neurotrophic Factor rs6265 polymorphism is associated with severe cancer-related fatigue and neuropathic pain in female cancer survivors.

PURPOSE: This study examined the relationships between a single-nucleotide polymorphism (SNP) of brain-derived neurotrophic factor (BDNF) rs6265 and psychoneurological (PN) symptoms in female cancer survivors. METHODS: This secondary analysis examined 393 study participants. In addition to demographic variables, self-reported PN symptom scores (anxiety, bodily pain, depression, fatigue, neuropathic pain, and sleep disturbance) were collected using the Patient-Reported Outcomes Measurement Information System and 36-Item Short-Form Health Survey. Buccal swab samples were collected to obtain genotypes for BDNF rs6265 (Val/Val, Val/Met, or Met/Met). The PN symptom scores were compared across genotypes, and the relationships were examined using a regression model. We also explored correlations between different symptoms within each genotype. RESULTS: Participants with the Met/Met genotype reported significantly worse cancer-related fatigue and neuropathic pain, which was confirmed by rank-based regression analysis. In addition, cancer-related fatigue was correlated with other PN symptoms, particularly depression. These correlations were stronger in study participants with the Met/Met genotype than those with other genotypes. CONCLUSION: Our study suggests that female cancer survivors with the Met/Met genotype of BDNF rs6265 are likely to experience worse cancer-related fatigue and neuropathic pain and that cancer-related fatigue is a good predictor of co-occurring PN symptoms in this population. IMPLICATIONS FOR CANCER SURVIVORS: Our findings advance the scientific community's understanding of cancer-related PN symptoms experienced by female cancer survivors, especially the unique role of BDNF rs6265 polymorphism in these symptoms. Our findings offer valuable insights for clinical practice that the symptom experience among female cancer survivors may vary based on BDNF genotypes.

Anatomical Analysis of Transient Potential Vanilloid Receptor 1 (Trpv1+) and Mu-Opioid Receptor (Oprm1+) Co-expression in Rat Dorsal Root Ganglion Neurons.

Primary afferent neurons of the dorsal root ganglia (DRG) transduce peripheral nociceptive signals and transmit them to the spinal cord. These neurons also mediate analgesic control of the nociceptive inputs, particularly through the µ-opioid receptor (encoded by Oprm1). While opioid receptors are found throughout the neuraxis and in the spinal cord tissue itself, intrathecal administration of µ-opioid agonists also acts directly on nociceptive nerve terminals in the dorsal spinal cord resulting in marked analgesia. Additionally, selective chemoaxotomy of cells expressing the TRPV1 channel, a nonselective calcium-permeable ion channel that transduces thermal and inflammatory pain, yields profound pain relief in rats, canines, and humans. However, the relationship between Oprm1 and Trpv1 expressing DRG neurons has not been precisely determined. The present study examines rat DRG neurons using high resolution multiplex fluorescent in situ hybridization to visualize molecular co-expression. Neurons positive for Trpv1 exhibited varying levels of expression for Trpv1 and co-expression of other excitatory and inhibitory ion channels or receptors. A subpopulation of densely labeled Trpv1+ neurons did not co-express Oprm1. In contrast, a population of less densely labeled Trpv1+ neurons did co-express Oprm1. This finding suggests that the medium/low Trpv1 expressing neurons represent a specific set of DRG neurons subserving the opponent processes of both transducing and inhibiting nociceptive inputs. Additionally, the medium/low Trpv1 expressing neurons co-expressed other markers implicated in pathological pain states, such as Trpa1 and Trpm8, which are involved in chemical nociception and cold allodynia, respectively, as well as Scn11a, whose mutations are implicated in familial episodic pain. Conversely, none of the Trpv1+ neurons co-expressed Spp1, which codes for osteopontin, a marker for large diameter proprioceptive neurons, validating that nociception and proprioception are governed by separate neuronal populations. Our findings support the hypothesis that the population of Trpv1 and Oprm1 coexpressing neurons may explain the remarkable efficacy of opioid drugs administered at the level of the DRG-spinal synapse, and that this subpopulation of Trpv1+ neurons is responsible for registering tissue damage.

Early and Late Transcriptional Changes in Blood, Neural, and Colon Tissues in Rat Models of Stress-Induced and Comorbid Pain Hypersensitivity Reveal Regulatory Roles in Neurological Disease.

Background: Irritable bowel syndrome (IBS) and temporomandibular disorder (TMD) are two chronic pain conditions that frequently overlap in the same individual, more commonly in women. Stress is a significant risk factor, exacerbating or triggering one or both conditions. However, the mechanisms underlying IBS-TMD co-morbidity are mostly unknown. Aim: To detect both specific and common stress-induced visceral hypersensitivity (SIH) and comorbid TMD-IBS pain hypersensitivity (CPH) genetic signatures over time. Method: Twenty-four female rats were randomly assigned to one of three experimental groups: naïve, SIH, and CPH (orofacial pain plus stress). RNA was extracted from blood, colon, spinal cord, and dorsal root ganglion 1 or 7 weeks after the stress paradigm. We combined differential gene expression and co-expression network analyses to define both SIH and CPH expression profiles across tissues and time. Results: The transcriptomic profile in blood and colon showed increased expression of genes enriched in inflammatory and neurological biological processes in CPH compared to SIH rats, both at 1 and 7 weeks after stress. In lumbosacral spinal tissue, both SIH and CPH rats compared to naïve revealed decreased expression of genes related to synaptic activity and increased expression of genes enriched in "angiogenesis," "Neurotrophin," and "PI3K-Akt" pathways. Compared to SIH, CPH rats showed increased expression of angiogenesis-related genes 1 week after exposure to stress, while 7 weeks post-stress the expression of these genes was higher in SIH rats. In dorsal root ganglia (DRG), CPH rats showed decreased expression of immune response genes at week 1 and inhibition of nerve myelination genes at 7 weeks compared to naïve. For all tissues, we observed higher expression of genes involved in ATP production in SIH compared to CPH at 1 week and this was reversed 7 weeks after the induction of stress. Conclusion: Our study highlights an increased inflammatory response in CPH compared to SIH rats in the blood and colon. DRG and spinal transcriptomic profiles of both CPH and SIH rats showed inhibition of synaptic activity along with activation of angiogenesis. Targeting these biological processes may lead to a more profound understanding of the mechanisms underlying IBS-TMD comorbidities and new diagnostic and therapeutic strategies.

Psychosocial interventions for community-dwelling individuals with schizophrenia: study protocol for a systematic review and meta-analysis.

INTRODUCTION: Despite the recent global mental health movement of the transition from hospital-centred to integrated community-based services, comprehensive evidence of psychosocial interventions focusing on community-dwelling individuals with schizophrenia is still lacking. To overcome this gap in the current knowledge, we will conduct a systematic review and meta-analysis to assess the efficacy of all types of psychosocial interventions for community-dwelling (non-hospitalised) individuals with schizophrenia when compared with non-active control conditions (eg, treatment as usual). METHODS AND ANALYSIS: This study protocol has been developed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. By March 2022, the following sources will have been searched, without restrictions for language or publication period: Embase, PubMed, PsycINFO, CINAHL, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. We will also try to identify other potentially eligible studies by searching the reference lists of included studies, other relevant systematic reviews and grey literature. All relevant randomised controlled trials from both high-income and low-income to middle-income countries will be allowed. Two independent reviewers will conduct the selection/screening of studies, data extraction and methodological quality assessment of included studies. The primary outcomes are quality of life and psychiatric hospital admission. Standard pairwise meta-analyses with a random-effects model will be conducted. Subgroup and sensitivity analyses will be performed to assess the robustness of the findings. Risk of bias will be assessed with the Revised Cochrane Risk-of-Bias Tool for Randomised Trials. The Grades of Recommendation Assessment, Development and Evaluation approach will be used to assess the quality of evidence. ETHICS AND DISSEMINATION: Ethics approval is not required for this study. The study findings will be disseminated through conference presentations as well as peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42021266187.

Longitudinal peripheral tissue RNA-Seq transcriptomic profiling, hyperalgesia, and wound healing in the rat plantar surgical incision model.

Postoperative pain and delayed healing in surgical wounds, which require complex management strategies have understudied complicated mechanisms. Here we investigated temporal changes in behavior, tissue structure, and transcriptomic profiles in a rat model of a surgical incision, using hyperalgesic behavioral tests, histological analyses, and next-generation RNA sequencing, respectively. The most rapidly (1 hour) expressed genes were the chemokines, Cxcl1 and Cxcl2. Consequently, infiltrating leukocytes were abundantly observed starting at 6 and peaking at 24 hours after incising which was supported by histological analysis and appearance of the neutrophil markers, S100a8 and S100a9. At this time, hyperalgesia was at a peak and overall transcriptional activity was most highly activated. At the 1-day timepoint, Nppb, coding for natriuretic peptide precursor B, was the most strongly upregulated gene and was localized by in situ hybridization to the epidermal keratinocytes at the margins of the incision. Nppb was basically unaffected in a peripheral inflammation model transcriptomic dataset. At the late phase of wound healing, five secreted, incision-specific peptidases, Mmp2, Aebp1, Mmp23, Adamts7, and Adamtsl1, showed increased expression, supporting the idea of a sustained tissue remodeling process. Transcripts that are specifically upregulated at each timepoint in the incision model may be potential candidates for either biomarkers or therapeutic targets for wound pain and wound healing. This study incorporates the examination of longitudinal temporal molecular responses, corresponding anatomical localization, and hyperalgesic behavioral alterations in the surgical incision model that together provide important and novel foundational knowledge to understand mechanisms of wound pain and wound healing.

Concurrent validity of biofilm detection by wound blotting on hard-to-heal wounds.

OBJECTIVE: Wound biofilms delay healing of hard-to-heal wounds. Convenient biofilm identification tools for clinical settings are currently not available, hindering biofilm-based wound management. Wound blotting with biofilm staining is a potential tool for biofilm detection, owing to its convenience. Although predictive validity of wound blotting has been established, it is necessary to confirm its concurrent validity. Furthermore, current staining systems employing ruthenium red have some disadvantages for clinical use. This study aimed to evaluate the usability of alcian blue as a substitute for ruthenium red. METHOD: Both in vitro and in vivo clinical samples were used to investigate validity and usability. RESULTS: The in vitro study showed that proteins and extracellular DNA in biofilms did not affect staining ability of ruthenium red and alcian blue in the detection of biofilms. In the in vivo study, using a wound biofilm model with Pseudomonas aeruginosa, the staining sensitivity of ruthenium red was 88.9% and 100% for alcian blue, with correlation coefficients of signal intensities with native polyacrylamide gel electrophoresis (PAGE) of r=0.67 (p=0.035) and r=0.67 (p=0.036) for ruthenium red and alcian blue, respectively. Results from clinical samples were r=0.75 (p=0.001) for ruthenium red and r=0.77 (p<0.001) for alcian blue. The sensitivities of wound blotting staining by ruthenium red and alcian blue were very high and had a good correlation with native PAGE analysis. CONCLUSION: Because the alcian blue procedure is more convenient than the ruthenium red procedure, wound blotting with alcian blue staining would be a promising tool to guide clinicians in delivering biofilm-based wound management.

The Persistent Pain Transcriptome: Identification of Cells and Molecules Activated by Hyperalgesia.

During persistent pain, the dorsal spinal cord responds to painful inputs from the site of injury, but the molecular modulatory processes have not been comprehensively examined. Using transcriptomics and multiplex in situ hybridization, we identified the most highly regulated receptors and signaling molecules in rat dorsal spinal cord in peripheral inflammatory and post-surgical incisional pain models. We examined a time course of the response including acute (2 hours) and longer term (2 day) time points after peripheral injury representing the early onset and instantiation of hyperalgesic processes. From this analysis, we identify a key population of superficial dorsal spinal cord neurons marked by somatotopic upregulation of the opioid neuropeptide precursor prodynorphin, and 2 receptors: the neurokinin 1 receptor, and anaplastic lymphoma kinase. These alterations occur specifically in the glutamatergic subpopulation of superficial dynorphinergic neurons. In addition to specific neuronal gene regulation, both models showed induction of broad transcriptional signatures for tissue remodeling, synaptic rearrangement, and immune signaling defined by complement and interferon induction. These signatures were predominantly induced ipsilateral to tissue injury, implying linkage to primary afferent drive. We present a comprehensive set of gene regulatory events across 2 models that can be targeted for the development of non-opioid analgesics. PERSPECTIVE: The deadly impact of the opioid crisis and the need to replace morphine and other opioids in clinical practice is well recognized. Embedded within this research is an overarching goal of obtaining foundational knowledge from transcriptomics to search for non-opioid analgesic targets. Developing such analgesics would address unmet clinical needs.

Molecular Pathways Linking Oxylipins to Nociception in Rats.

Oxylipins are lipid peroxidation products that participate in nociceptive, inflammatory, and vascular responses to injury. Effects of oxylipins depend on tissue-specific differences in accumulation of precursor polyunsaturated fatty acids and the expression of specific enzymes to transform the precursors. The study of oxylipins in nociception has presented technical challenges leading to critical knowledge gaps in the way these molecules operate in nociception. We applied a systems-based approach to characterize oxylipin precursor fatty acids, and expression of genes coding for proteins involved in biosynthesis, transport, signaling and inactivation of pro- and antinociceptive oxylipins in pain circuit tissues. We further linked these pathways to nociception by demonstrating intraplantar carrageenan injection induced gene expression changes in oxylipin biosynthetic pathways. We determined functional-biochemical relevance of the proposed pathways in rat hind paw and dorsal spinal cord by measuring basal and stimulated levels of oxylipins throughout the time-course of carrageenan-induced inflammation. Finally, when oxylipins were administered by intradermal injection we observed modulation of nociceptive thermal hypersensitivity, providing a functional-behavioral link between oxylipins, their molecular biosynthetic pathways, and involvement in pain and nociception. Together, these findings advance our understanding of molecular lipidomic systems linking oxylipins and their precursors to nociceptive and inflammatory signaling pathways in rats. PERSPECTIVE: We applied a systems approach to characterize molecular pathways linking precursor lipids and oxylipins to nociceptive signaling. This systematic, quantitative evaluation of the molecular pathways linking oxylipins to nociception provides a framework for future basic and clinical research investigating the role of oxylipins in pain.

Longitudinal Transcriptomic Profiling in Carrageenan-Induced Rat Hind Paw Peripheral Inflammation and Hyperalgesia Reveals Progressive Recruitment of Innate Immune System Components.

Pain is a common but potentially debilitating symptom, often requiring complex management strategies. To understand the molecular dynamics of peripheral inflammation and nociceptive pain, we investigated longitudinal changes in behavior, tissue structure, and transcriptomic profiles in the rat carrageenan-induced peripheral inflammation model. Sequential changes in the number of differentially expressed genes are consistent with temporal recruitment of key leukocyte populations, mainly neutrophils and macrophages with each wave being preceded by upregulation of the cell-specific chemoattractants, Cxcl1 and Cxcl2, and Ccl2 and Ccl7, respectively. We defined 12 temporal gene clusters based on expression pattern. Within the patterns we extracted genes comprising the inflammatory secretome and others related to nociceptive tissue remodeling and to sensory perception of pain. Structural tissue changes, involving upregulation of multiple collagens occurred as soon as 1-hour postinjection, consistent with inflammatory tissue remodeling. Inflammatory expression profiling revealed a broad-spectrum, temporally orchestrated molecular and cellular recruitment process. The results provide numerous potential targets for modulation of pain and inflammation. PERSPECTIVE: This study investigates the highly orchestrated biological response during tissue inflammation with precise assessment of molecular dynamics at the transcriptional level. The results identify transcriptional changes that define an evolving inflammatory state in rats. This study provides foundational data for identifying markers of, and potential treatments for, inflammation and pain in patients.

Wound Pain and Wound Healing Biomarkers From Wound Exudate: A Scoping Review.

PURPOSE: Effective management of wound pain is essential for optimal wound healing. Nevertheless, the outcomes of wound pain interventions are based on subjective measures, which can prove problematic in patients with cognitive impairment. Identification of biomarkers associated with wound pain and wound healing can be used to more objectively estimate wound pain and contribute to the development of precise management options to reduce wound pain and promote wound healing. This scoping review aimed to identify wound pain and wound healing biomarkers from wound exudates and to describe different wound collection methods to identify these biomarkers. METHODS: We searched the literature (PROSPERO database registration number: CRD42018103843) via a scoping review. SEARCH STRATEGY: The PubMed database was searched for articles that explored relationships between cutaneous wound pain, wound healing, and biomolecules. Inclusion criteria were articles that reported original data, used adult human samples, and were published in English. FINDINGS: Twenty-one articles were retrieved: 17 investigated molecules from wound exudate associated with wound healing status, and 4 reported molecules associated with wound pain. The most frequently observed wound pain biomarkers were proinflammatory cytokines; the most frequently observed wound healing biomarkers were proteases including those in the matrix metalloproteinase family. Six wound exudate collection methods were identified to extract potential wound pain and wound healing biomarkers from wound exudate. IMPLICATIONS: The results can guide future wound exudate research to validate these wound pain and wound healing biomarkers and to develop therapies targeting these biomarkers to reduce wound pain and promote wound healing.

Recording and reconstruction of volumetric magnetic hologram using multilayer medium with heat dissipation layers.

Hologram memory is a strong candidate for optical storage due to its high recording density and high data transfer rate. We have studied and engineered a magnetic hologram memory medium using a stable magnetic garnet as recording material. To record a deep and clear magnetic hologram, it is important to control the heat diffusion generated during recording. Numerical simulation suggested that a multilayer structure with transparent heat-dissipation layers would be effective to address this. We fabricated a multilayer magnetic medium for a collinear magnetic hologram. This medium exhibited a diffraction efficiency as high as that of the single layered one, and errorless recording and reconstruction was achieved with the magnetic assist technique.

Measurement of mechanical withdrawal threshold on full-thickness cutaneous wounds in rats using the von Frey test.

OBJECTIVE: A method for measuring mechanical withdrawal threshold of full-thickness cutaneous wound pain in animal models is lacking. This study aimed to confirm the validity and reactivity of the von Frey test in full-thickness cutaneous wounds in rats. METHOD: A 1.5cm-diameter wound was established on the dorsal areas of male Sprague-Dawley rats and subcutaneously injected with either morphine hydrochloride (5.0mg/kg) or indomethacin (2.5mg/kg) with a 27-gauge needle on day three post-wounding. On day five post-wounding, an injection of morphine hydrochloride, indomethacin or lambda-carrageenan (1.0%) into the granulation tissue was also administered. The withdrawal threshold of mechanical stimulation of the wound edge was compared in each group before treatment with injection and at two, four, eight and 24 hours after injection. RESULTS: A total of 40 rats were used in the study. Since more severe inflammation in and around the wound was induced on day three post-wounding than that of day five, the withdrawal threshold measured on day three post-wounding was significantly lower than that of day five. The decrease of the withdrawal threshold was depressed by morphine hydrochloride and indomethacin treatment on day three post-wounding. While there was no significant difference between the changes in the withdrawal threshold after indomethacin treatment on day five post-wounding, we observed an increased withdrawal threshold after morphine hydrochloride treatment and decreased withdrawal threshold after lambda-carrageenan treatment on day five post-wounding. CONCLUSION: The results suggest that the von Frey test can be applied to measure the mechanical withdrawal threshold of full-thickness dorsal wounds in rats.