Chronic Decrements in Energy in Women with Breast Cancer are Associated with Cytokine Gene Polymorphisms.

OBJECTIVES: Decrements in energy were found in 67% of women who underwent breast cancer surgery. However, no information is available on chronic decrements in energy and associations with inflammation. Purposes were to identify latent classes of patients with distinct average energy profiles from prior to through 12 months after breast cancer surgery; evaluate for differences in demographic and clinical characteristics between the two extreme average energy classes; and evaluate for polymorphisms for cytokine genes associated with membership in the Low energy class. METHODS: Women (n = 397) completed assessments of energy prior to and for 12 months following breast cancer surgery. Growth mixture modeling was used to identify classes of patients with distinct average energy profiles. Eighty-two single nucleotide polymorphisms (SNPs) among 15 cytokine genes were evaluated. RESULTS: Three distinct energy profiles were identified (ie, Low [27.0%], Moderate [54.4%], Changing [18.6%]). Data from patients in the Low and Moderate energy classes were used in the candidate gene analyses. Five SNPs and one haplotype in six different genes remained significant in logistic regression analyses (ie, interleukin [IL]-1ß rs1143623, IL1 receptor 1 rs3917332 IL4 rs2243263, IL6 HapA1 [that consisted of rs1800795, rs2069830, rs2069840, rs1554606, rs2069845, rs2069849, and rs2069861], nuclear factor kappa beta subunit 1 rs170731, tumor necrosis factor rs1799964). For several SNPs for IL6, expression quantitative trait locis were identified in subcutaneous and visceral adipose tissue and thyroid tissue. In addition, skeletal muscle was identified as an expression quantitative trait loci for nuclear factor kappa beta subunit 1. CONCLUSIONS: Findings suggest that cytokine genes are involved in the mechanisms that underlie chronic decrements in energy in women following breast cancer surgery. Given the roles of subcutaneous and visceral adipose and thyroid tissues in metabolism and energy balance, the findings related to IL6 suggest that these polymorphisms may have a functional role in the development and maintenance of chronic decrements in energy.

Morphine acts in vitro to directly prime nociceptors.

Hyperalgesic priming is a preclinical model of the transition from acute to chronic pain characterized by a leftward shift in the dose-response curve for and marked prolongation of prostaglandin E2 (PGE2)-induced mechanical hyperalgesia, in vivo. In vitro, priming in nociceptors is characterized by a leftward shift in the concentration dependence for PGE2-induced nociceptor sensitization. In the present in vitro study we tested the hypothesis that a mu-opioid receptor (MOR) agonist opioid analgesic, morphine, can produce priming by its direct action on nociceptors. We report that treatment of nociceptors with morphine, in vitro, produces a leftward shift in the concentration dependence for PGE2-induced nociceptor sensitization. Our findings support the suggestion that opioids act directly on nociceptors to induce priming.

A novel anti-pruritic: Topical co-administration of high molecular weight hyaluronan (HMWH) with protamine, a transdermal transport enhancer.

Pruritis, the sensation of itch, is produced by multiple substances, exogenous and endogenous, that sensitizes specialized sensory neurons (pruriceptors and pruri-nociceptors). Unfortunately, many patients with acute and chronic pruritis obtain only partial relief when treated with currently available treatment modalities. We recently demonstrated that the topical application of high molecular weight hyaluronan (HMWH), when combined with vehicles containing transdermal transport enhancers, produce potent long-lasting reversal of nociceptor sensitization associated with inflammatory and neuropathic pain. In the present experiments we tested the hypothesis that the topical formulation of HMWH with protamine, a transdermal transport enhancer, can also attenuate pruritis. We report that this topical formulation of HMWH markedly attenuates scratching behavior at the nape of the neck induced by serotonin (5-hydroxytryptamine, 5-HT), in male and female rats. Our results support the hypothesis that topical HMWH in a transdermal transport enhancer vehicle is a strong anti-pruritic.

Neurodegenerative disease pathways are perturbed in patients with cancer who self-report cognitive changes and anxiety: A pathway impact analysis.

BACKGROUND: Cancer-related cognitive impairment (CRCI) and anxiety co-occur in patients with cancer. Little is known about mechanisms for the co-occurrence of these two symptoms. The purposes of this secondary analysis were to evaluate for perturbed pathways associated with the co-occurrence of self-reported CRCI and anxiety in patients with low versus high levels of these two symptoms and to identify potential mechanisms for the co-occurrence of CRCI and anxiety using biological processes common across any perturbed neurodegenerative disease pathways. METHODS: Patients completed the Attentional Function Index and the Spielberger State-Trait Anxiety Inventory six times over two cycles of chemotherapy. Based on findings from a previous latent profile analysis, patients were grouped into none versus both high levels of these symptoms. Gene expression was quantified, and pathway impact analyses were performed. Signaling pathways for evaluation were defined with the Kyoto Encyclopedia of Genes and Genomes database. RESULTS: A total of 451 patients had data available for analysis. Approximately 85.0% of patients were in the none class and 15.0% were in the both high class. Pathway impact analyses identified five perturbed pathways related to neurodegenerative diseases (i.e., amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, prion disease, and pathways of neurodegeneration-multiple diseases). Apoptosis, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum stress were common biological processes across these pathways. CONCLUSIONS: This study is the first to describe perturbations in neurodegenerative disease pathways associated with CRCI and anxiety in patients receiving chemotherapy. These findings provide new insights into potential targets for the development of mechanistically based interventions.

Stress and Coping in Patients With Cancer With Depression and Sleep Disturbance.

OBJECTIVES: To evaluate for differences in global, cancer-specific, and cumulative life stress, as well as resilience and use of various coping strategies among five groups (no depression or sleep disturbance, no depression and moderate sleep disturbance, subsyndromal depression and very high sleep disturbance, moderate depression and moderate sleep disturbance [Both Moderate]; and high depression and very high sleep disturbance [Both High]). SAMPLE & SETTING: Patients (N = 1,331) receiving chemotherapy were recruited from outpatient oncology clinics. METHODS & VARIABLES: Measures of global, cancer-specific, and cumulative life stress, resilience, and coping were obtained. Differences were evaluated using parametric and nonparametric tests. RESULTS: Global and cancer-specific stress scores increased as joint profiles worsened. Both Moderate and Both High classes had cancer-specific stress scores suggestive of post-traumatic stress. Both Moderate and Both High classes reported higher occurrence rates for several stressful life events and higher use of disengagement coping. Both Moderate and Both High classes had resilience scores below the normative score for the United States. IMPLICATIONS FOR NURSING: Clinicians need to screen vulnerable patients for post-traumatic stress disorder and implement interventions to reduce stress.

TrkB-mediated neuroprotection in female hippocampal neurons is autonomous, estrogen receptor alpha-dependent, and eliminated by testosterone: a proposed model for sex differences in neonatal hippocampal neuronal injury.

BACKGROUND: Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of learning disabilities and memory deficits in children. In both human and animal studies, female neonate brains are less susceptible to HI than male brains. Phosphorylation of the nerve growth factor receptor TrkB has been shown to provide sex-specific neuroprotection following in vivo HI in female mice in an estrogen receptor alpha (ERα)-dependent manner. However, the molecular and cellular mechanisms conferring sex-specific neonatal neuroprotection remain incompletely understood. Here, we test whether female neonatal hippocampal neurons express autonomous neuroprotective properties and assess the ability of testosterone (T) to alter this phenotype. METHODS: We cultured sexed hippocampal neurons from ERα+/+ and ERα-/- mice and subjected them to 4 h oxygen glucose deprivation and 24 h reoxygenation (4-OGD/24-REOX). Sexed hippocampal neurons were treated either with vehicle control (VC) or the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) following in vitro ischemia. End points at 24 h REOX were TrkB phosphorylation (p-TrkB) and neuronal survival assessed by immunohistochemistry. In addition, in vitro ischemia-mediated ERα gene expression in hippocampal neurons were investigated following testosterone (T) pre-treatment and TrkB antagonist therapy via q-RTPCR. Multifactorial analysis of variance was conducted to test for significant differences between experimental conditions. RESULTS: Under normoxic conditions, administration of 3 µM 7,8-DHF resulted an ERα-dependent increase in p-TrkB immunoexpression that was higher in female, as compared to male neurons. Following 4-OGD/24-REOX, p-TrkB expression increased 20% in both male and female ERα+/+ neurons. However, with 3 µM 7,8-DHF treatment p-TrkB expression increased further in female neurons by 2.81 ± 0.79-fold and was ERα dependent. 4-OGD/24-REOX resulted in a 56% increase in cell death, but only female cells were rescued with 3 µM 7,8-DHF, again in an ERα dependent manner. Following 4-OGD/3-REOX, ERα mRNA increased ~ 3 fold in female neurons. This increase was blocked with either the TrkB antagonist ANA-12 or pre-treatment with T. Pre-treatment with T also blocked the 7,8-DHF- dependent sex-specific neuronal survival in female neurons following 4-OGD/24-REOX. CONCLUSIONS: OGD/REOX results in sex-dependent TrkB phosphorylation in female neurons that increases further with 7,8-DHF treatment. TrkB phosphorylation by 7,8-DHF increased ERα mRNA expression and promoted cell survival preferentially in female hippocampal neurons. The sex-dependent neuroprotective actions of 7,8-DHF were blocked by either ANA-12 or by T pre-treatment. These results are consistent with a model for a female-specific neuroprotective pathway in hippocampal neurons in response to hypoxia. The pathway is activated by 7,8-DHF, mediated by TrkB phosphorylation, dependent on ERα and blocked by pre-exposure to T.

Self-Reported Cancer-Related Cognitive Impairment in Patients With Breast Cancer Is Associated With Potassium Channel Gene Polymorphisms.

OBJECTIVES: To evaluate for associations of polymorphisms for potassium channel genes in patients with breast cancer who were classified as having high or low-moderate levels of cancer-related cognitive impairment (CRCI). SAMPLE & SETTING: 397 women who were scheduled to undergo surgery for breast cancer on one breast were recruited from breast care centers located in a comprehensive cancer center, two public hospitals, and four community practices. METHODS & VARIABLES: CRCI was assessed using the Attentional Function Index prior to and for six months after surgery. The attentional function classes were identified using growth mixture modeling. RESULTS: Differences between patients in the high versus low-moderate attentional function classes were evaluated. Six single nucleotide polymorphisms for potassium channel genes were associated with low-moderate class membership. IMPLICATIONS FOR NURSING: The results contribute to knowledge of the mechanisms for CRCI. These findings may lead to the identification of high-risk patients and the development of novel therapeutics.

Increases in stress and adverse childhood experiences are associated with the co-occurrence of anxiety and depression in oncology patients.

PURPOSE: Identify subgroups of patients with distinct joint anxiety AND depression profiles and evaluate for differences in demographic and clinical characteristics, as well as stress, resilience, and coping. DESIGN: Longitudinal study. PARTICIPANTS: Patients (n = 1328) receiving chemotherapy. METHODS: Measures of state anxiety and depression were done six times over two cycles of chemotherapy. All of the other measures were completed prior to second or third cycle of chemotherapy. Latent profile analysis was used to identify the distinct joint anxiety and depression profiles. FINDINGS: Three classes were identified (i.e. Low Anxiety and Low Depression (57.5%); Moderate Anxiety and Moderate Depression (33.7%), High Anxiety and High Depression (8.8%)). For all of the stress measures, a dose response effect was seen among the profiles. Two worst profiles reported higher occurrence rates for a number of adverse childhood experiences. IMPLICATIONS FOR PROVIDERS: Patients need referrals for stress reduction techniques and mental health and social services.

Stress Exposures Contribute to Worse Joint Morning and Evening Fatigue Profiles in Patients With Cancer During Chemotherapy.

OBJECTIVES: To evaluate differences among stress, resilience, and coping strategies related to morning and evening fatigue profiles (both low, low morning and moderate evening, both moderate, and both high). SAMPLE & SETTING: Data were collected from 1,334 adult patients with cancer receiving chemotherapy. METHODS & VARIABLES: Morning and evening fatigue severity were rated over two cycles of chemotherapy using the Lee Fatigue Scale. Latent profile analysis was used to identify patient subgroups with distinct joint morning and evening profiles. Data were collected on global, cancer-specific, and cumulative life stress; resilience; and coping strategies. Differences among the latent classes were evaluated using parametric and nonparametric tests. RESULTS: Compared to the other three classes, the both high class reported the highest stress scores, highest occurrence of and effects from a variety of stressful life events, lowest resilience scores, and higher use of disengagement coping strategies. The both high class met the criteria for subsyndromal post-traumatic stress disorder. IMPLICATIONS FOR NURSING: When patients report high levels of fatigue, detailed assessments of stress are warranted to provide tailored interventions.

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain.

The primary cilium, a 1-3 µm long hair-like structure protruding from the surface of almost all cells in the vertebrate body, is critical for neuronal development and also functions in the adult. As the migratory neural crest settles into dorsal root ganglia (DRG) sensory neurons elaborate a single primary cilium at their soma that is maintained into adult stages. While it is not known if primary cilia are expressed in nociceptors, or their potential function in the mature DRG neuron, recent studies have shown a role for Hedgehog, whose signaling demonstrates a dependence on primary cilia, in nociceptor sensitization. Here we report the expression of primary cilia in rat and mouse nociceptors, where they modulate mechanical nociceptive threshold, and contribute to inflammatory and neuropathic pain. When siRNA targeting Ift88, a primary cilium-specific intraflagellar transport (IFT) protein required for ciliary integrity, was administered by intrathecal injection, in the rat, it resulted in loss of Ift88 mRNA in DRG, and primary cilia in neuronal cell bodies, which was associated with an increase in mechanical nociceptive threshold, and abrogation of hyperalgesia induced by the pronociceptive inflammatory mediator, prostaglandin E2, and painful peripheral neuropathy induced by a neurotoxic chemotherapy drug, paclitaxel. To provide further support for the role of the primary cilium in nociceptor function we also administered siRNA for another IFT protein, Ift52. Ift52 siRNA results in loss of Ift52 in DRG and abrogates paclitaxel-induced painful peripheral neuropathy. Attenuation of Hedgehog-induced hyperalgesia by Ift88 knockdown supports a role for the primary cilium in the hyperalgesia induced by Hedgehog, and attenuation of paclitaxel chemotherapy-induced neuropathy (CIPN) by cyclopamine, which attenuates Hedgehog signaling, suggests a role of Hedgehog in CIPN. Our findings support a role of nociceptor primary cilia in the control of mechanical nociceptive threshold and in inflammatory and neuropathic pain, the latter, at least in part, Hedgehog dependent.

Perturbations in inflammatory pathways are associated with shortness of breath profiles in oncology patients receiving chemotherapy.

PURPOSE: One plausible mechanistic hypothesis is the potential contribution of inflammatory mechanisms to shortness of breath. This study was aimed to evaluate for associations between the occurrence of shortness of breath and perturbations in inflammatory pathways. METHODS: Patients with cancer reported the occurrence of shortness of breath six times over two cycles of chemotherapy. Latent class analysis was used to identify subgroups of patients with distinct shortness of breath occurrence profiles (i.e., none (70.5%), decreasing (8.2%), increasing (7.8%), high (13.5%)). Using an extreme phenotype approach, whole transcriptome differential gene expression and pathway impact analyses were performed to evaluate for perturbed signaling pathways associated with shortness of breath between the none and high classes. Two independent samples (RNA-sequencing (n = 293) and microarray (n = 295) methodologies) were evaluated. Fisher's combined probability method was used to combine these results to obtain a global test of the null hypothesis. In addition, an unweighted knowledge network was created using the specific pathway maps to evaluate for interconnections among these pathways. RESULTS: Twenty-nine Kyoto Encyclopedia of Genes and Genomes inflammatory signaling pathways were perturbed. The mitogen-activated protein kinase signaling pathway node had the highest closeness, betweenness, and degree scores. In addition, five common respiratory disease-related pathways, that may share mechanisms with cancer-related shortness of breath, were perturbed. CONCLUSIONS: Findings provide preliminary support for the hypothesis that inflammation contribute to the occurrence of shortness of breath in patients with cancer. In addition, the mechanisms that underlie shortness of breath in oncology patients may be similar to other respiratory diseases.

Common and distinct risk factors that influence more severe and distressing shortness of breath profiles in oncology outpatients.

BACKGROUND: Shortness of breath occurs in 10%-70% of oncology patients. Very little is known about interindividual variability in its severity and distress and associated risk factors. Using latent profile analyses (LPAs), purpose was to identify subgroups of patients with distinct severity and distress profiles for shortness of breath as single symptom dimensions. In addition, a joint LPA was done using patients' severity AND distress ratings. For each of the three LPAs, differences among the shortness of breath classes in demographic, clinical, symptom, stress, and resilience characteristics were evaluated. METHODS: Patients completed ratings of severity and distress from shortness of breath a total of six times over two cycles of chemotherapy. All of the other measures were completed at enrollment (i.e., prior to the second or third cycle of chemotherapy). Separate LPAs were done using ratings of severity and distress, as well as a joint analysis using severity AND distress ratings. Differences among the latent classes were evaluated using parametric and nonparametric tests. RESULTS: For severity, two classes were identified (Slight to Moderate [91.6%] and Moderate to Severe [8.4%]). For distress, two classes were identified (A Little Bit to Somewhat [83.9%] and Somewhat to Quite a Bit [16.1%]). For the joint LPA, two classes were identified (Lower Severity and Distress [79.9%] and Higher Severity and Distress [20.1%]). While distinct risk factors were associated with each of the LPAs, across the three LPAs, the common risk factors associated with membership in the worse class included: a past or current history of smoking, poorer functional status, and higher comorbidity burden. In addition, these patients had a higher symptom burden and higher levels of cancer-specific stress. CONCLUSIONS: Clinicians can use the information provided in this study to identify high-risk patients and develop individualized interventions.

Identification Of A Higher Risk Lymphedema Phenotype And Associations With Cytokine Gene Polymorphisms.

CONTEXT: Breast cancer-related lymphedema (BCRL) is chronic condition that occurs in 5% to 75% of women following treatment for breast cancer. However, little is known about the risk factors and mechanisms associated with a worse BCRL profile. OBJECTIVES: Identify distinct BCRL profiles in women with the condition (i.e., lower vs. higher risk phenotype) and evaluate for associations with pro- and anti-inflammatory genes. METHODS: Latent class profile analysis (LCPA) was used to identify the BCRL profiles using phenotypic characteristics evaluated prior to surgery. Candidate gene analyses were done to identify cytokine genes associated with the two BCRL profiles. RESULTS: Of the 155 patients evaluated, 35.5% (n = 55) were in the Lower and 64.5% (n = 100) were in the Higher Risk classes. Risk factors for membership in the Higher class included: lower functional status, having sentinel lymph node biopsy, axillary lymph node dissection, mastectomy, higher number of positive lymph nodes, and receipt of chemotherapy. Polymorphisms for interleukin (IL)1-beta and IL6 were associated with membership in the Higher Risk class. CONCLUSION: The readily available and clinically relevant phenotypic characteristics associated with a worse BCRL profile can be used by clinicians to identify higher risk patients. If confirmed, these characteristics can be tested in predictive risk models. In addition, the candidate gene findings may guide the development of mechanistically-based interventions to decrease the risk of BCRL.

Stability and consistency of symptom clusters in younger versus older patients receiving chemotherapy.

BACKGROUND: By 2035, the number of newly diagnosed cancer cases will double and over 50% will be in older adults. Given this rapidly growing demographic, a need exists to understand how age influences oncology patients' symptom burden. The study purposes were to evaluate for differences in the occurrence, severity, and distress of 38 symptoms in younger (< 60 years) versus older (≥ 60 years) oncology patients undergoing chemotherapy and to evaluate for differences in the stability and consistency of symptom clusters across the two age groups. METHODS: A total of 1329 patients were dichotomized into the younger and older groups. Patients completed demographic and clinical questionnaires prior to the initiation of their second or third cycle of chemotherapy. A modified version of Memorial Symptom Assessment Scale was used to evaluate the occurrence, severity, and distress of 38 common symptoms associated with cancer and its treatment. Differences between the two age groups in demographic and clinical characteristics and ratings of occurrence, severity, and distress for the 38 symptoms were evaluated using parametric and nonparametric tests. Exploratory factor analyses were done within each age group to identify symptom clusters using symptom occurrence rates. RESULTS: Compared to the younger group (14.8 (± 7.0)), older adults reported a lower mean number of symptoms (12.9 (± 7.2)). Older patients experienced lower occurrence rates for almost 50% of the symptoms. Regarding symptom clusters, an eight-factor solution was selected for both age groups. Across the two age groups, the eight symptom clusters (i.e., physical and cognitive fatigue, respiratory, psychological, hormonal, chemotherapy-related toxicity, weight gain, gastrointestinal, epithelial) were stable. However, symptoms within the physical and cognitive, chemotherapy-related toxicity, and gastrointestinal clusters were not consistent across the age groups. CONCLUSIONS: To be able to provide tailored and effective symptom management interventions to older oncology patients, routine assessments of the core symptoms unique to the symptom clusters identified for this group warrants consideration. The underlying mechanism(s) for these inconsistencies in symptom burden is an important focus for future studies.

TrkB-mediated sustained neuroprotection is sex-specific and Erα-dependent in adult mice following neonatal hypoxia ischemia.

BACKGROUND: Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of life-long neurological morbidities that result in learning and memory impairments. Evidence suggests that male neonates are more susceptible to the detrimental effects of HI, yet the mechanisms mediating these sex-specific responses to neural injury in neonates remain poorly understood. We previously tested the effects of treatment with a small molecule agonist of the tyrosine kinase B receptor (TrkB), 7,8-dihydroxyflavone (DHF) following neonatal HI and determined that females, but not males exhibit increased phosphorylation of TrkB and reduced apoptosis in their hippocampi. Moreover, these female-specific effects of the TrkB agonist were found to be dependent upon the expression of Erα. These findings demonstrated that TrkB activation in the presence of Erα comprises one pathway by which neuroprotection may be conferred in a female-specific manner. The goal of this study was to determine the role of Erα-dependent TrkB-mediated neuroprotection in memory and anxiety in young adult mice exposed to HI during the neonatal period. METHODS: In this study, we used a unilateral hypoxic ischemic (HI) mouse model. Erα+/+ or Erα-/- mice were subjected to HI on postnatal day (P) 9 and mice were treated with either vehicle control or the TrkB agonist, DHF, for 7 days following HI. When mice reached young adulthood, we used the novel object recognition, novel object location and open field tests to assess long-term memory and anxiety-like behavior. The brains were then assessed for tissue damage using immunohistochemistry. RESULTS: Neonatal DHF treatment prevented HI-induced decrements in recognition and location memory in adulthood in females, but not in males. This protective effect was absent in female mice lacking Erα. The female-specific improved recognition and location memory outcomes in adulthood conferred by DHF therapy after neonatal HI tended to be or were Erα-dependent, respectively. Interestingly, DHF triggered anxiety-like behavior in both sexes only in the mice that lacked Erα. When we assessed the severity of injury, we found that DHF therapy did not decrease the percent tissue loss in proportion to functional recovery. We additionally observed that the presence of Erα significantly reduced overall HI-associated mortality in both sexes. CONCLUSIONS: These observations provide evidence for a therapeutic role for DHF in which TrkB-mediated sustained recovery of recognition and location memories in females are Erα-associated and dependent, respectively. However, the beneficial effects of DHF therapy did not include reduction of gross tissue loss but may be derived from the enhanced functioning of residual tissues in a cell-specific manner.

Periods of low oxygen delivery and blood flow to the brains of newborns are known to cause life-long impairments to their cognitive ability as adults. Interestingly, male newborns are more susceptible to this injury than females. The mechanisms causing this sex difference are poorly understood. Here we test the role of the nerve growth factor receptor tyrosine kinase B (TrkB) in providing long-term neuroprotection following neonatal hypoxia­ischemia (HI) in mice. We have previously shown that when mice are treated with the TrkB agonist 7,8-dihydroxyflavone (DHF) in the days following neonatal HI, the result is short-term neuroprotection only in females and this protection is dependent on the presence of the estrogen receptor alpha receptor ([Formula: see text]). In this study, we extend these observations by subjecting mice either with or without [Formula: see text] to HI. Some of the mice were then treated with DHF immediately after HI. As adults, we performed tests to assess the mice's memory and anxiety-like behavior. At the end of these tests, we assessed the brains for tissue loss. Our results show that as adults the DHF treatment following HI in neonatal mice preserved memory only in females and this effect was dependent on the presence of [Formula: see text]. In addition, DHF therapy triggered anxiety-like behavior in mice lacking [Formula: see text]. We also show that this neuroprotection is not dependent on preservation of brain tissue following the injury. These results provide insight into the mechanisms behind the female resistance to hypoxic ischemic episodes as newborns.

Isolectin B4 (IB4)-conjugated streptavidin for the selective knockdown of proteins in IB4-positive (+) nociceptors.

In vivo analysis of protein function in nociceptor subpopulations using antisense oligonucleotides and short interfering RNAs is limited by their non-selective cellular uptake. To address the need for selective transfection methods, we covalently linked isolectin B4 (IB4) to streptavidin and analyzed whether it could be used to study protein function in IB4(+)-nociceptors. Rats treated intrathecally with IB4-conjugated streptavidin complexed with biotinylated antisense oligonucleotides for protein kinase C epsilon (PKCε) mRNA were found to have: (a) less PKCε in dorsal root ganglia (DRG), (b) reduced PKCε expression in IB4(+) but not IB4(-) DRG neurons, and (c) fewer transcripts of the PKCε gene in the DRG. This knockdown in PKCε expression in IB4(+) DRG neurons is sufficient to reverse hyperalgesic priming, a rodent model of chronic pain that is dependent on PKCε in IB4(+)-nociceptors. These results establish that IB4-streptavidin can be used to study protein function in a defined subpopulation of nociceptive C-fiber afferents.

Higher Levels of Multiple Types of Stress Are Associated With Worse State Anxiety and Morning Fatigue Profiles in Patients Receiving Chemotherapy.

BACKGROUND: Anxiety and fatigue are common problems in patients receiving chemotherapy. Unrelieved stress is a potential cause for the co-occurrence of these symptoms. OBJECTIVES: The aims of this study were to identify subgroups of patients with distinct state anxiety and morning fatigue profiles and evaluate for differences among these subgroups in demographic and clinical characteristics, as well as measures of global, cancer-specific, and cumulative life stress and resilience and coping. METHODS: Patients (n = 1335) completed measures of state anxiety and morning fatigue 6 times over 2 cycles of chemotherapy. All of the other measures were completed prior to the second or third cycle of chemotherapy. Latent profile analysis was used to identify the state anxiety and morning fatigue profiles. RESULTS: Three distinct joint profiles were identified: Low Anxiety and Low Morning Fatigue (59%), Moderate Anxiety and Moderate Morning Fatigue (33.4%), and High Anxiety and High Morning Fatigue (7.6%). Patients in the 2 highest classes were younger, were less likely to be married/partnered, and had a higher comorbidity burden. All of the stress scores demonstrated a dose-response effect (ie, as anxiety and morning fatigue profiles worsened, stress increased). Patients in the 2 highest classes reported higher rates of emotional abuse, physical neglect, physical abuse, and sexual harassment. CONCLUSIONS: More than 40% of these patients experienced moderate to high levels of both anxiety and morning fatigue. Higher levels of all 3 types of stress were associated with the 2 highest profiles. IMPLICATIONS FOR PRACTICE: Clinicians need to perform comprehensive evaluations of patients' levels of stress and recommend referrals to psychosocial services.

Worse Depression Profiles Are Associated With Higher Symptom Burden and Poorer Quality of Life in Patients With Gynecologic Cancer.

BACKGROUND: Depression is a pervasive symptom in patients with gynecological cancer undergoing chemotherapy. OBJECTIVES: Purposes were to identify subgroups of patients with distinct depression profiles and evaluate for differences in demographic and clinical characteristics, severity of common symptoms, and quality of life (QOL) outcomes among these subgroups. METHODS: Patients with gynecological cancer (n = 231) completed the Center for Epidemiologic Studies-Depression Scale 6 times over 2 cycles of chemotherapy. All of the other measures were completed prior to the second or third cycle of chemotherapy. Latent profile analysis was done to identify the distinct depression profiles. Differences were evaluated using parametric and nonparametric tests. RESULTS: Three distinct profiles were identified: low (60.1%), high (35.1%), and very high (4.8%). Compared with low class, the other 2 classes had lower functional status and were more likely to self-report a diagnosis of depression. Patients in the 2 worse profiles reported a higher comorbidity burden, higher levels of trait and state anxiety, sleep disturbance, and fatigue, as well as lower levels of cognitive function and poorer QOL. State and trait anxiety, evening fatigue, and sleep disturbance scores exhibit a "dose-response effect" (ie, as the depression profile worsened, the severity of these symptoms increased). CONCLUSIONS: Almost 40% of our sample experienced high or very high levels of depression across 2 cycles of chemotherapy. IMPLICATIONS FOR PRACTICE: Clinicians can use the identified risk factors to identify high patients risk and provide tailored psychological interventions aimed to decrease symptom burden and prevent decrements in QOL.

Increased Stress Is Associated With Severe Pain and Decrements in Cognitive Function in Patients Receiving Chemotherapy.

OBJECTIVES: Purposes were to identify subgroups of adult oncology patients (n = 1342) with distinct joint profiles of worst pain and cognitive function (CF) and evaluate for differences in demographic and clinical characteristics, as well as the severity of three distinct types of stress, resilience, and coping. DATA SOURCES: Measures of pain and CF were evaluated six times over two cycles of chemotherapy. The other measures of demographic and clinical characteristics, stress, resilience, and coping were completed at enrollment (ie, prior to the second or third cycle of chemotherapy). RESULTS: Using latent profile analysis, four distinct profiles were identified (ie, no pain + moderate CF [27.6%], moderate pain + high CF [22.4%] moderate pain and moderate CF [32.4%, both moderate], severe pain and low CF [17.5%, both severe]). Both moderate and both severe classes reported higher global, cancer-specific, and cumulative life stress, lower levels of resilience, and greater use of disengagement coping strategies. The Both severe class had higher occurrence rates for a number of adverse childhood experiences (ie, family violence in childhood, physical abuse at <16 years, forced sex at <16 years). Risk factors associated with membership in the two worst profiles included: being female, having a lower annual income, having a higher comorbidity burden, and having a poorer functional status. CONCLUSION: Findings suggest that 72.4% of the patients reported pain scores in the moderate to severe range and 77.6% reported low to moderate levels of CF. Clinicians need to assess for both symptoms and various types of stress on a routine basis.

Sensitization of human and rat nociceptors by low dose morphine is toll-like receptor 4-dependent.

While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4. And, sub-analgesic doses of several opioids have been shown to induce hyperalgesia in rodents by their action as TLR4 agonists. In the present in vitro patch-clamp electrophysiology experiments, we demonstrate that low dose morphine directly sensitizes human as well as rodent dorsal root ganglion (DRG) neurons, an effect of this opioid analgesic that is antagonized by LPS-RS Ultrapure, a selective TLR4 antagonist. We found that low concentration (100 nM) of morphine reduced rheobase in human (by 36%) and rat (by 26%) putative C-type nociceptors, an effect of morphine that was markedly attenuated by preincubation with LPS-RS Ultrapure. Our findings support the suggestion that in humans, as in rodents, OIH is mediated by the direct action of opioids at TLR4 on nociceptors.