Perceived Barriers to Pap Screening Influence Adherence to Screening Recommendations Among Black Women.

Objectives: The aim of this study was to determine the Health Belief Model (HBM) constructs associated with Pap screening adherence among a sample of African American and sub-Saharan African immigrant women in the United States. Methods: A descriptive cross-sectional study was conducted via an online survey. Participants were recruited from central Kentucky counties. Ninety-one eligible women participated (mean age 38 ± 12 years), 49.5% identified as African American. Twenty-nine percent indicated never being screened or not being up-to-date. Self-reported demographic data, HBM constructs for Pap screening, and Pap screening history were collected. Bivariate and logistic regressions were performed. Results: There was a significant negative association between perceived barriers and being up-to-date. For every one-point increase in perceived barriers, the odds of being up-to-date decreased by 81%, (p = 0.004; CI: 0.06-0.60), findings from further evaluation of the barrier construct showed that barriers significantly associated with screening include items related to lack of knowledge about where to get a Pap screening, lack of time to attend the screening, screening-associated shame and pain, negligence, and age. There were no other significant HBM constructs associated with up-to-date Pap screening status. There was no difference in perceived barriers between African American and sub-Saharan African women. Conclusions: Despite public health efforts to decrease screening barriers, a perception of barriers exists among Black women. Continued efforts to address screening barriers as well as the perception of barriers are warranted among Black women.

The relationship of health activation with risk of future cardiovascular disease among rural family caregivers of patients with chronic illnesses.

BACKGROUND: Family caregivers are at higher risk for developing cardiovascular disease (CVD) than non-caregivers. This risk is worse for those who live in rural compared to urban areas. Health activation, an indicator of engagement in self-care, is predictive of health outcomes and CVD risk in several populations. However, it is not known whether health activation is associated with CVD risk in rural caregivers of patients with chronic illnesses nor is it clear whether sex moderates any association. OBJECTIVES: Our aims were to determine (1) whether health activation independently predicts 10-year CVD risk; and (2) whether sex interacts with health activation in the prediction of 10-year CVD risk among rural family caregivers (N = 247) of patients with chronic illnesses. METHODS: Health activation was measured using the Patient Activation Measure. The predicted 10-year risk of CVD was assessed using the Framingham Risk Score. Data were analyzed using nonlinear regression analysis. RESULTS: Higher levels of health activation were significantly associated with decreased risk of developing CVD (p < 0.028). There was no interaction of sex with health activation on future CVD risk. However, male caregivers had greater risk of developing CVD in the next 10 years than female caregivers (p < 0.001). CONCLUSIONS: We demonstrated the importance of health activation to future CVD risk in rural family caregivers of patients with chronic illnesses. We also demonstrated that despite the higher risk of future CVD among male, the degree of association between health activation and CVD risk did not differ by sex.

Perceived Control, Functional Status, Depressive Symptoms, and Anxiety: Mediating and Moderating Influences on Health-Related Quality of Life in Patients With Heart Failure.

BACKGROUND: Health-related quality of life (HRQoL) is poor in patients with heart failure. Psychological (ie, depressive symptoms [DS], anxiety, and perceived control) and physical (ie, functional status) factors are associated with HRQoL. The dynamic relationships among these variables and their impact on HRQoL remain unclear, limiting the ability to design effective interventions. PURPOSE: Our aim was to evaluate a moderated mediation model, in which the association between perceived control and HRQoL was hypothesized to be mediated by DS and anxiety in the presence of a moderator, functional status. METHODS: Patients (N = 426) with heart failure completed the Control Attitudes Scale-Revised to measure perceived control, Duke Activity Status Index for functional status, Patient Health Questionnaire-9 for DS, Brief Symptom Inventory for anxiety, and Minnesota Living with Heart Failure Questionnaire for HRQoL. We performed a moderated parallel mediation analysis. RESULTS: Higher levels of perceived control were associated with better HRQoL through lower levels of anxiety and DS in the presence of functional status (index of moderated mediation for DS, b = 0.029; 95% confidence interval, 0.016-0.045; for anxiety: b = 0.009, 95% confidence interval, 0.002-0.018). The effect of perceived control on psychological symptoms was stronger at low and moderate functional statuses; however, this effect diminished with increasing functional status. CONCLUSION: Functional status moderated the indirect effects of perceived control on HRQoL through DS and anxiety in patients with heart failure. Efforts to improve HRQoL by targeting perceived control may be more effective when considering DS and anxiety in patients with low to moderate levels of functional status.

Diet Quality Mediates the Relationship Between Chronic Stress and Inflammation in Patients With Metabolic Syndrome.

BACKGROUND: Chronic stress is associated with promotion of inflammation and development of metabolic syndrome, as well as deterioration of diet quality. Inflammation can be modified by changes in dietary intake. OBJECTIVE: The aim of this study was to test the hypothesis that diet quality mediates the relationship of chronic stress with inflammation in patients with metabolic syndrome. METHODS: Participants with metabolic syndrome (n = 73, 62 ± 12 years old, 71% female) completed questionnaires on chronic stress (Perceived Stress Scale-10) and diet quality (Healthy Eating Index-2020). The Perceived Stress Scale-10 was dichotomized. The Healthy Eating Index-2020 score was used as a continuous variable, and higher scores indicate better diet quality. Inflammation was assessed using plasma high-sensitivity C-reactive protein (log-transformed). We used PROCESS in SPSS to test the hypothesis. RESULTS: Patients in the higher stress group had lower Healthy Eating Index-2020 scores (worse diet quality) than those in the lower stress group (57 ± 13 vs 64 ± 10, P = .01). Diet quality mediated the relationship between chronic stress and inflammation (indirect effect, 0.211; 95% bootstrap confidence interval, 0.006-0.496). Higher stress was associated with lower diet quality (effect, -7.152; 95% confidence interval, -13.168 to -1.137) that was associated with increased inflammation (effect, -0.030; 95% confidence interval, -0.052 to -0.007). CONCLUSIONS: Our findings show the important role of diet quality in the relationship of chronic stress with inflammation in patients with metabolic syndrome. Healthcare providers should encourage patients with higher stress to improve diet quality, which can decrease inflammation.

Psychometric Properties of the Advance Care Planning Engagement Survey-9 in Cardiovascular and Metabolic Diseases.

The purpose of this study was to test the reliability and validity of the Advance Care Planning Engagement Survey-9 Korean version in patients with cardiovascular diseases or metabolic syndrome. In this cross-sectional study, data on advance care planning engagement, registration of advance directives and the intention, and sociodemographic characteristics were collected from 105 patients (mean age, 66.3 years) at 4 medical institutions. Cronbach α was used to test the reliability. Confirmatory factor analysis and independent t tests were used to test the validity. Cronbach α s for the total scale and the self-efficacy and readiness dimensions were .93, .82, and .97, respectively. In confirmatory factor analysis with 2 factors, all indices of model fit were acceptable: comparative fit index, 0.995; Tucker-Lewis index, 0.989; standardized root-mean-square residual, 0.024; root-mean-square error of approximation, 0.059; and factor loadings > 0.65. Patients who registered advance directives ( P < .001) or had the intention ( P < .001) had higher scores of the Advance Care Planning Engagement Survey-9 Korean version than their counterparts. The findings demonstrate that the Advance Care Planning Engagement Survey-9 Korean version was a reliable and valid instrument. Health care providers, including nurses, can use this instrument to assess and manage advance care planning engagement in Korean patients with cardiovascular diseases or metabolic syndrome.

Relationships of multidimensional factors to self-management in patients with diabetes: A Cross-sectional, correlational study.

Poor self-management in patients with diabetes is a consistent issue, leading to diabetes complications. The purpose of this study was to examine the relationships of demographic, cognitive, psychological, social, and physiological factors to self-management in patients with diabetes. In this cross-sectional, correlational study, data were collected from 98 patients through REDCap in 2023. Multiple regression analysis was used to address the study purpose. In the sample, adherence to adequate self-management was poor. Knowledge, self-efficacy, and body mass index (BMI) were associated with overall diabetes self-management. Self-efficacy and BMI were associated with diet and exercise. Knowledge and self-efficacy were associated with blood glucose testing. No factors were associated with smoking and foot care. In conclusion, different factors were associated with different types of self-management, but BMI and self-efficacy were associated with most types of self-management. Clinicians and researchers can target BMI, self-efficacy, and knowledge to improve self-management in patients with diabetes.

Examining Food Security, Choices and Barriers among Community Supported Agriculture participants during COVID- 19 in Kentucky.

The coronavirus disease (COVID-19) pandemic is challenging food security. Our study's purpose was to examine relationships among food security status, eating patterns and perceived barriers to food choices among shareholders (N= 209) in a Community Supported Agriculture (CSA) program during stay-at-home restrictions due to the pandemic. The food insecure group (n= 33) reported lower consumption of fruits/vegetables, whole grains and greater consumption of fast foods and more barriers to food choices compared to the food secure group (p<.05). A low food insecure proportion (16%) among the CSA participants suggests a potential role of a CSA program to prevent food insecurity.

The moderating effect of attitudes in the relationship between knowledge and self-efficacy in palliative care among nurses: A cross-sectional, correlational study.

Provision of palliative care to patients with advanced chronic diseases or old populations is suboptimal, which results in unnecessary suffering of and burden to patients, caregivers, and society. Low self-efficacy in palliative care among nurses is a factor affecting suboptimal utilization of palliative care. Poor knowledge is a factor affecting low self-efficacy in palliative care of nurses. Attitudes may contribute to the relationship between knowledge and self-efficacy in palliative care, but these relationships have been rarely examined in nurses. This study aimed to determine whether nurses' attitudes moderate the relationship between knowledge and self-efficacy in palliative care. In a cross-sectional, correlational study, online or offline survey on self-efficacy, knowledge, attitudes, and covariates was conducted from 282 nurses in South Korea. PROCESS v4.1 for SPSS was used to address the study aim. Higher levels of knowledge (p = .048) and attitudes (p < .001), and the interaction term of knowledge and attitudes (p = .025) were significantly associated with higher levels of self-efficacy (F = 6.12, p < .001, R2 = .152), indicating the moderating effects of attitudes. The relationships between higher levels of knowledge and self-efficacy were significant only in nurses with highly and moderately positive attitudes (R2 change = .016, F = 5.11, p = .025), but not nurses with lack of positive attitudes. Our results supported the moderating role of nurses' attitudes in the relationship between knowledge and self-efficacy. To improve self-efficacy in palliative care in nurses, improvement in knowledge and facilitation of positive attitudes are needed.

Effects of Meditation Intervention on Self-management in Adult Patients With Type 2 Diabetes: A Systematic Literature Review and Meta-analysis.

BACKGROUND: Diabetes complications are prevalent and cause adverse effects on the physical, psychological, and economic status of adult patients with type 2 diabetes. Meditation may positively affect self-management and, in turn, reduce diabetes complications. However, the systematic examination of the effects of meditation without additional components on self-management in this population have been rarely examined. PURPOSE: The aim of this study was to examine the effects of meditation interventions on self-management (ie, control of glucose, blood pressure, cholesterol, and obesity and self-management) among adult patients with type 2 diabetes in randomized controlled trials. METHODS: In this systematic review and meta-analysis, 6 electronic databases were searched using major keywords of meditation , diabetes , and self-management during March 2022. RESULTS: Eight studies (9 articles) using mindfulness-based meditation were included. The meta-analysis showed that meditation improved hemoglobin A 1c (effect size = -0.75; 95% confidence interval, -1.30 to -0.21; P = .007) but not fasting blood glucose. Only a few studies examined meditation effects on other types of self-management (eg, blood pressure, body mass index, cholesterol, diet, exercise, foot care, and monitoring of blood glucose), and the effects were inconsistent. In 1 study, meditation improved diabetes self-management. CONCLUSIONS: Mindfulness-based meditation reduced hemoglobin A 1c levels in adult patients with type 2 diabetes but did not consistently improve other types of self-management in a few studies examined. This may imply the need for additional intervention components to improve different types of self-management. Further studies are needed to examine the effects of different types of meditations with additional components on different types of self-management.

Mediation by Fatalism of the Association Between Symptom Burden and Self-care Management in Patients With Heart Failure.

BACKGROUND: Clinicians and researchers often assume that symptom burden is associated with self-care management (SCM) in patients with heart failure (HF). However, that association is often not borne out in simple regression analyses and may be because another variable mediates the association. Fatalism is an appropriate candidate for mediation and is the belief that circumstances are predetermined without opportunity for control by individuals. OBJECTIVE: Our objective was to determine whether fatalism mediated the relationship of symptom burden with SCM among adults with HF. METHODS: We conducted a secondary analysis (N = 95) from a clinical trial. We used Self-care of HF Index to measure SCM, the Memorial Symptom Assessment Scale-HF for symptom burden, and the Cardiovascular Disease Fatalism Instrument to measure fatalism. We used the PROCESS macro to evaluate mediation. RESULTS: Symptom burden was not directly associated with SCM (effect coefficient [C'] = 0.0805; 95% confidence interval, -0.048 to 0.209; P = .217). There was, however, an indirect pathway between symptom burden and SCM through fatalism (ab = -0.040; 95% confidence interval, -0.097 to -0.002). Those with higher symptom burden were more fatalistic (a = 0.004, P = .015), and greater fatalism was associated with worse SCM (b = -9.132, P = .007). CONCLUSION: Symptom burden, not directly associated with SCM, is associated through the mediator of fatalism. Interventions to improve SCM should include strategies to mitigate fatalistic views. Self-care management interventions should focus on promoting internal locus of control or increasing perceptions of perceived control to decrease fatalism and improve engagement in self-care.

Age- and sex-matched comparison of diet quality in patients with heart failure to similarly aged healthy older adults.

The aims of this study were to (1) compare diet quality between patients with heart failure (HF) and age- and sex-matched community-dwelling healthy older adults and (2) determine whether having HF was associated with a lower Healthy Eating Index-2015 (HEI-2015) score and risk of micronutrient deficiency. The HEI-2015 and macro- and micronutrient intakes of patients with HF were compared with healthy older adults (N 102; 55-92 years old; 53 % female). A paired t-test or Wilcoxon singed-rank test, McNemar's test, and conditional logistic regression were used to assess the association between diet quality and HF status. Median values for HEI-2015 and the number of micronutrient deficiency were used to dichotomise into groups in the conditional logistic regression. There was no significant between-group difference in the HEI-2015 total score (P 0⋅059), whereas the whole grain component was lower in patients with HF than in healthy older adults (3⋅1 ± 3⋅5 v. 4⋅5 ± 3⋅1, P 0⋅037; respectively). Total caloric intake was lower in patients with HF than in healthy older adults (1683 ± 595 v. 2104 ± 670 kcal; P < 0⋅001). Patients with HF had a higher average number of micronutrient deficiencies than healthy older adults (4[2, 6] v. 1[0, 4], respectively, P < 0⋅001). Patients with HF had four times higher odds of being in a high micronutrient deficiency group than healthy older adults, controlling for socio-demographics and body mass index (adjusted odds ratio [95 % confidence interval]: 4⋅04[1⋅06, 15⋅41]). Our findings demonstrate that diet quality measured by nutritional intake identifies patients with HF with lower caloric intake and higher micronutrient deficiencies compared with age- and sex-matched healthy older adults.

COVID-19 and the impact on rural and black church Congregants: Results of the C-M-C project.

The COVID-19 pandemic has had devastating effects on Black and rural populations with a mortality rate among Blacks three times that of Whites and both rural and Black populations experiencing limited access to COVID-19 resources. The primary purpose of this study was to explore the health, financial, and psychological impact of COVID-19 among rural White Appalachian and Black nonrural central Kentucky church congregants. Secondarily we sought to examine the association between sociodemographics and behaviors, attitudes, and beliefs regarding COVID-19 and intent to vaccinate. We used a cross sectional survey design developed with the constructs of the Health Belief and Theory of Planned Behavior models. The majority of the 942 respondents were ≥36 years. A total of 54% were from central Kentucky, while 47.5% were from Appalachia. Among all participants, the pandemic worsened anxiety and depression and delayed access to medical care. There were no associations between sociodemographics and practicing COVID-19 prevention behaviors. Appalachian region was associated with financial burden and delay in medical care (p = 0.03). Appalachian respondents had lower perceived benefit and attitude for COVID-19 prevention behaviors (p = 0.004 and <0.001, respectively). Among all respondents, the perceived risk of contracting COVID was high (54%), yet 33.2% indicated unlikeliness to receive the COVID-19 vaccine if offered. The COVID-19 pandemic had a differential impact on White rural and Black nonrural populations. Nurses and public health officials should assess knowledge and explore patient's attitudes regarding COVID-19 prevention behaviors, as well as advocate for public health resources to reduce the differential impact of COVID-19 on these at-risk populations.

Self-care strategies and interventions needed in patients with heart failure: from patient perspectives-a qualitative study.

AIMS: Most patients with heart failure (HF) have symptoms. Poor self-care has been associated with the development or worsening symptoms. Thus, to improve HF symptoms, it may be critical to understand self-care and interventions targeting improvements in HF symptoms needed from patients' perspectives. To explore patients' perceptions of self-care strategies of individual symptoms, HF symptom improvement, and interventions needed to improve HF symptoms in patients with HF. METHODS AND RESULTS: Qualitative data were collected from 20 patients with HF using a semi-structured open-ended interview guide. Data were analysed using content analysis. Five themes appeared: (i) use of a variety of strategies with some knowledge deficit and inefficiency, (ii) uncertainty in symptom improvement, (iii) consideration of several possible self-care strategies, (iv) use of situation-specific strategies in seeking treatment, and (v) willingness to receive comprehensive and realistic interventions. Patients used a variety of self-care strategies, including taking medication, reducing activities, and changing diet and position, but many reported having a lack of knowledge and multiple HF symptoms. Several patients were uncertain whether symptoms could be improved, but all patients reported that they would participate in comprehensive and realistic intervention sessions to gain knowledge about their symptoms and management strategies, and to receive emotional support from healthcare providers and peer patients. CONCLUSION: Patients with HF used several self-care strategies with the hope of symptom improvements but were uncertain about the effectiveness. More effective, comprehensive, and realistic interventions need to be delivered to patients with HF to enhance their ability to manage their symptoms.

A Comparison of Diet Quality of Patients With Heart Failure and Their Family Caregivers.

BACKGROUND: Patients with heart failure (HF) and their family caregivers usually consume similar diets, but there is a lack of evidence about diet quality of patients with HF and their family caregivers. OBJECTIVE: The specific aim of this study was to compare diet quality of patients with HF with that of their family caregivers. METHODS: In this cross-sectional study, 40 patients with HF and their 40 family caregivers completed a VioScreen Food Frequency Questionnaire from which Healthy Eating Index-2010 (HEI) diet quality scores (consisting of the total HEI score and 12 component scores) were calculated. RESULTS: None of the 40 patient-caregiver dyads had a high diet quality score (ie, total HEI > 80), whereas 21% of participants had poor diet scores (ie, total HEI ≤ 50). There were no differences in total HEI scores (58.5 vs 59.4, P = .58) or the 12 component scores of the HEI within dyad members. Mean scores of 6 of the 12 components (ie, total fruit, greens and beans, total protein foods, seafood and plant proteins, fatty acids, empty calories) for both members of the HF dyad were lower than the national average. Interestingly, scores for the sodium component were similarly low in patients and caregivers (4.1 vs 3.4, P = .24), indicating high sodium intake. CONCLUSION: Both patients and caregivers consume poor-quality diets that are high in sodium. These findings suggest that nutrition interventions to improve diet quality for patients with HF need to be targeted at the family as a unit.

Inflammatory properties of diet mediate the effect of depressive symptoms on Framingham risk score in men and women: Results from the National Health and Nutrition Examination Survey (2007-2014).

Depression is common in patients with cardiovascular disease (CVD) and associated with inflammation. Inflammation contributes to the development of CVD and can be modulated by diet. However, the role of inflammatory properties of diet in the relationship between depressive symptoms and CVD risk is not well understood. We hypothesized that the inflammatory properties of diet mediate the relationship between depressive symptoms and CVD risk in men and women. Cross-sectional data collected by the National Health and Nutrition Examination Survey (2007-2014) were used for the study. Depressive symptoms scores, inflammatory properties of diet, and CVD risk were measured by the Patient Health Questionnaire-9 (PHQ-9), the Dietary Inflammatory Index (DII), and the Framingham risk score (FRS), respectively. Generalized linear models were used for the mediation analysis. There were significant differences in the proportions of men and women in the depressed group (PHQ-9 ≥ 10; 5.24 ±â€¯0.65% vs 9.36 ±â€¯0.87%, P < .001) and high CVD risk group (FRS >20%; 16.47 ±â€¯0.79% vs 6.03 ±â€¯0.32%, P < .001). The DII partially mediated the relationship between depressive symptoms and CVD risk in men (indirect effect: 0.06, P = .010) but fully mediated the relationship between depressive symptoms and CVD risk in women (indirect effect: 0.10, P < .001). These findings confirmed our hypothesis that inflammatory properties of diet at least partially mediate the relationship between depressive symptoms and CVD risk in men and women. Our findings suggest that interventions designed to reduce depressive symptoms should contain strategies to reduce pro-inflammatory and increase anti-inflammatory properties of diet to decrease CVD risk.

Symptom Perception, Evaluation, Response to Symptom, and Delayed Care Seeking in Patients With Acute Heart Failure: An Observational Study.

BACKGROUND: Exacerbation of heart failure (HF) requires early intervention to prevent hospital admission and to reduce mortality. Early care seeking requires that patients perceive symptoms, accurately evaluate perceived symptoms, and respond appropriately. How perception, evaluation, and response to symptoms are associated with delay in seeking care for worsening symptoms has rarely been studied. OBJECTIVE: The aims of this study were to investigate the associations of perception of symptoms, evaluation of symptoms, and response to symptoms with delayed care seeking in patients with HF and to identify factors associated with delayed care seeking. METHODS: Patients admitted for acute exacerbation of HF were enrolled in this cross-sectional observational study. We used structured interviews, questionnaires, and medical record review to collect data. Factors related to delayed care seeking were identified using nonlinear regression. RESULTS: Analysis was performed in 109 patients with HF. The median delay time was 124 hours. Delayed care seeking was associated with younger age and perception of fatigue, whereas evaluation of and response to symptoms were not associated with delay. CONCLUSIONS: Few characteristics of the symptom experience are associated with delayed care seeking among patients with HF who experience an exacerbation of symptoms. Further research is needed to determine why early care seeking is difficult among patients with HF.

DGAT2 Mutation in a Family with Autosomal-Dominant Early-Onset Axonal Charcot-Marie-Tooth Disease.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and is a genetically and clinically heterogeneous disorder. We examined a Korean family in which two individuals had an autosomal-dominant axonal CMT with early-onset, sensory ataxia, tremor, and slow disease progression. Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O-acyltransferase 2 (DGAT2) gene. DGAT2 encodes an endoplasmic reticulum-mitochondrial-associated membrane protein, acyl-CoA:diacylglycerol acyltransferase, which catalyzes the final step of the triglyceride (TG) biosynthesis pathway. The patient showed consistently decreased serum TG levels, and overexpression of the mutant DGAT2 significantly inhibited the proliferation of mouse motor neuron cells. Moreover, the variant form of human DGAT2 inhibited the axonal branching in the peripheral nervous system of zebrafish. We suggest that mutation of DGAT2 is the novel underlying cause of an autosomal-dominant axonal CMT2 neuropathy. This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies.

Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia.

Abnormal aggregation of α-synuclein and sustained microglial activation are important contributors to the pathogenic processes of Parkinson's disease. However, the relationship between disease-associated protein aggregation and microglia-mediated neuroinflammation remains unknown. Here, using a combination of in silico, in vitro and in vivo approaches, we show that extracellular α-synuclein released from neuronal cells is an endogenous agonist for Toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia. The TLR2 ligand activity of α-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric α-synuclein and TLR2 in microglia suggests that both of these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases.

Microglial activation of the NLRP3 inflammasome by the priming signals derived from macrophages infected with mycobacteria.

The inflammasome is a multimolecular complex that orchestrates the activation of proinflammatory caspases and interleukin (IL)-1ß, which is generally increased in the cerebrospinal fluids of patients with tuberculous meningitis. However, it has not been clarified whether mycobacteria can activate the inflammasome and induce IL-1ß maturation in microglia. In this study, we found that the priming of primary murine microglial cells with conditioned media from cultures of macrophages infected with Mycobacterium tuberculosis (Mtb) led to robust activation of caspase-1 and IL-1ß secretion after Mtb stimulation. Potassium efflux and the lysosomal proteases cathepsin B and cathepsin L were required for the Mtb-induced caspase-1 activation and maturation of IL-1ß production in primed microglia. Mtb-induced IL-1ß maturation was also found to depend on the nucleotide binding and oligomerization of domain-like receptor family pyrin domain containing 3 protein (NLRP3) and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), as well as the generation of mitochondrial reactive oxygen species (ROS). Notably, the priming of microglia with tumor necrosis factor-α or oncostatin M resulted in caspase-1 cleavage and IL-1ß secretion in response to Mtb. Moreover, dexamethasone, as an adjunctive therapy for patients of tuberculous meningitis, significantly reduced the Mtb-induced maturation of IL-1ß through inhibition of mitochondrial ROS generation. Collectively, these data suggest that Mtb stimulation induces activation of the microglial NLRP3 inflammasome (composed of NLRP3, ASC, and cysteine protease caspase-1) through microglia-leukocyte interactions as a priming signal, and that dexamethasone decreases inflammasome activation through inhibition of ROS of mitochondrial origin.

IKK-ß-mediated myeloid cell activation exacerbates inflammation and inhibits recovery after spinal cord injury.

Traumatic spinal cord injury (SCI) is followed by massive infiltration and activation of myeloid cells such as neutrophils and macrophages, but the functions of these cells are controversial. In this study, our objective was to elucidate the in vivo role of a signaling pathway involved in activation of these innate immune cells in SCI using myeloid cell-specific IκB kinase (IKK)-ß conditional knockout (ikkßΔmye) mice. In these mice, the ikkß gene has been specifically deleted from myeloid cells, compromising their in vivo IKK/NF-κB-dependent activation. We found that ikkßΔmye mice had significantly reduced neutrophil and macrophage infiltrations after SCI compared to ikkß(+/+) controls. SCI-induced proinflammatory gene expression was also reduced in ikkßΔmye mice. Reduced neuroinflammation in ikkßΔmye mice was accompanied by attenuated neuronal loss and behavioral deficits in motor activity. In addition, the SCI-induced expression of CXC ligand 1 was reduced in ikkßΔmye mice, which may be responsible for the reduced neutrophil infiltration in these mice. Our data demonstrate that IKK-ß-dependent myeloid cell activation potentiates neuroinflammation and neuronal damage after SCI.