Exacerbation Outcomes Research Articles

Bronchiectasis-COPD Overlap Syndrome (BCOS) among the Nepalese Patients: Emerging disease from a developing country

Background and objective: There is no clearly specified diagnostic criteria to identify BCOS in Nepalese context. So this first, observational cross-sectional study was conducted to determine the current situation, main clinical practices, and features of BCOS in Nepalese patients, exploring its clinical trajectory and severity. Methods: This is a hospital based descriptive cross-sectional study conducted, where patients presenting with respiratory symptoms complex were subsequently enrolled by purposive sampling. Descriptive Statistics was calculated using Absolute and Relative Frequencies for categorical variables and mean and standard deviation for numerical ones. P-value of <0.05 was considered significant. Results: Out of 236 patients of Respiratory Symptoms Complex, prevalence of BCOS was 22.03%. 57.7% were males with mean age of 67.8 years. Among BCOS cohorts, 92.3% were smokers and 73 % had significant exposure to indoor air pollution. 63.5% of the patients had past history of tuberculosis and cardio-metabolic co-morbidities were seen in 34.6% of the patients. The most frequent symptoms were cough and shortness of breath and the commonest sign was bilateral basal coarse crackles. Frequent exacerbations were present in 25% of the patients and PFT revealed obstructive pattern in 71% of the BCOS patients with a mean FACED score of 3.94±1.62. Conclusion: Among the patients presenting with Respiratory symptom complex in Nepal, BCOS is common and is more prevalent in elderly male, having a high co-morbidities, usually following a course of slowly progressive breathlessness, with higher incidence of exacerbation and poorer functional outcome.

Long- versus short-duration systemic corticosteroid regimens for acute exacerbations of COPD: A systematic review and meta-analysis of randomized trials and cohort studies.

While systemic corticosteroids quicken patient recovery during acute exacerbations of COPD, they also have many adverse effects. The optimal duration of corticosteroid administration remains uncertain. We performed a systematic review and meta-analysis to compare patient outcomes between short- (≤7 days) and long- (>7 days) corticosteroid regimens in adults with acute exacerbations of COPD. MEDLINE, EMBASE, CENTRAL, and hand searches were used to identify eligible studies. Risk of bias was assessed using the Cochrane RoB 2.0 tool and ROBINS-I. Data were summarized as ORs (odds ratios) or MDs (mean differences) whenever possible and qualitatively described otherwise. A total of 11532 participants from eight RCTs and three retrospective cohort studies were included, with 1296 from seven RCTs and two cohort studies eligible for meta-analyses. Heterogeneity was present in the methodology and settings of the studies. The OR (using short duration as the treatment arm) for mortality was 0.76 (95% CI = 0.40-1.44, n = 1055). The MD for hospital length-of-stay was -0.91 days (95% CI = -1.81--0.02 days, n = 421). The OR for re-exacerbations was 1.31 (95% CI = 0.90-1.90, n = 552). The OR for hyperglycemia was 0.90 (95% CI = 0.60-1.33, n = 423). The OR for infection incidence was 0.96 (95% CI = 0.59-1.156, n = 389). The MD for one-second forced expiratory volume change was -18.40 mL (95% CI = -111.80-75.01 mL, n = 161). The RCTs generally had low or unclear risks of bias, while the cohort studies had serious or moderate risks of bias. Our meta-analyses were affected by imprecision due to insufficient data. Some heterogeneity was present in the results, suggesting population, setting, and treatment details are potential prognostic factors. Our evidence suggests that short-duration treatments are not worse than long-duration treatments in moderate/severe exacerbations and may lead to considerably better outcomes in milder exacerbations. This supports the current GOLD guidelines. Trial registration: Our protocol is registered in PROSPERO: CRD42023374410.

The association between blood eosinophils and clinical outcome of acute exacerbations of chronic obstructive pulmonary disease: A systematic review and meta-analysis

ObjectivesStudies have shown an association between eosinophilia and clinical outcomes in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, contradictory findings exist. Our study aims to systematically evaluate the association between elevated peripheral blood eosinophils and clinical outcome of patients with AECOPD. MethodsAn electronic search was conducted for relevant studies published from database inception to February 28, 2023, on PubMed, EMBASE, Cochrane Library, and Web of Science. The analysis covered studies on the correlation between EOS AECOPD and mortality, hospital stay duration, readmission and hospitalization rates, and invasive mechanical ventilation. Where applicable, relative risk (RR) and weighted mean difference (WMD) were extracted, pooled, and assessed using meta-analysis. Sensitivity analysis was performed to explore the source of heterogeneity. ResultsFifteen high-quality studies including 14 cohort studies and one case-control study were included in the meta-analysis. Compared with non-eosinophilic AECOPD patients, those with eosinophilic AECOPD had a lower risk of mortality (RR = 0.65, 95 % confidence interval [CI] 0.54, 0.77, P < 0.001), shorter length of hospital stay (WMD = −1.56, 95%CI -2.16, −0.96, P < 0.001), and higher readmission rate (RR = 1.07, 95%CI 1.01,1.13, P = 0.029). No difference was found concerning the rate of hospitalization and invasive mechanical ventilation between the two groups. ConclusionIndividuals diagnosed with eosinophilic AECOPD had a reduced mortality rate, a truncated period of hospitalization, and an insubstantial increase in the probability of readmission relative to their non-eosinophilic AECOPD counterparts. The level of eosinophils in blood has been shown to serve as a potential predictive biomarker for AECOPD patients.

Efficacy of sodium-glucose cotransporter 2 inhibitors on cardiorenal outcomes in older patients: a systematic review and meta-analysis

Abstract Background Recent randomized controlled trials (RCTs) showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiorenal outcomes in patients with increased risks of cardiovascular diseases. However, only limited data from subgroup analyses are available for older patients. Methods A systematic review was performed by searching PubMed, Cochran Central, and Embase through February 2023 for RCTs of SGLT2 inhibitors that were performed in adults and large (≥500 participants per group). Hazard ratios (HRs) and relative risk estimates in older subgroups ≥ 65 years were extracted from each study and were pooled using a random-effects meta-analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The secondary outcomes were heart failure exacerbation, adverse renal outcomes, and a composite outcome of cardiovascular death or heart failure exacerbation. Results This study included 10 RCTs. SGLT2 inhibitors decreased the primary outcome but it did not reach statistical significance in older subgroups (HR, 0.86; 95% CI, 0.73-0.1.00, p = 0.06). Whereas SGLT2 inhibitors were associated with decreased risks of heart failure exacerbation (HR, 0.76; 95% CI, 0.67-0.87), adverse renal outcome (HR, 0.58; 95% CI, 0.43-0.77), and a composite outcome of cardiovascular death or heart failure exacerbation (HR, 0.76; 95% CI, 0.70-0.83). Conclusions SGLT2 inhibitors were associated with improved cardiovascular outcomes in older patients. Further therapeutic data and sufficient long-term safety data are warranted in this population.

Sex differences for the efficacy of sodium-glucose cotransporter 2 inhibitors on cardiorenal outcomes: a systematic review and meta-analysis

Abstract Background It is unclear if sex differences affect the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors to improve cardiorenal outcomes in patients with increased risks of cardiovascular diseases. Methods A systematic review was performed by searching PubMed, Cochran Central, and Embase through February 2023 for randomized controlled trials (RCTs) of SGLT2 inhibitors that were performed in adults and large (≥500 participants per group). Hazard ratios (HRs) and relative risk estimates in subgroups stratified by sex were extracted from each study and were pooled using a random-effects meta-analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The secondary outcomes were heart failure exacerbation, adverse renal outcomes, and a composite outcome of cardiovascular death or heart failure exacerbation. Results This study included 10 RCTs. SGLT2 inhibitors were associated with decreased risks of the primary outcome (Female and male in total: HR, 0.80; 95% CI, 0.67-0.96, Female: HR, 0.71; 95% CI, 0.51-0.98, Male: HR, 0.90; 95% CI, 0.83-0.97). SGLT2 inhibitors were associated with decreased risks of heart failure exacerbation (Female: HR, 0.80; 95% CI, 0.69-0.94, Male: HR, 0.78; 95% CI, 0.69-0.87), adverse renal outcomes (Female: HR, 0.65; 95% CI, 0.48-0.88, Male: HR, 0.58; 95% CI, 0.46-0.72), and a composite outcome of cardiovascular death or heart failure exacerbation (Female: HR, 0.75; 95% CI, 0.67-0.84, Male: HR, 0.78; 95% CI, 0.72-0.85). There were no significant subgroup differences by sex for all outcomes (p&amp;gt;0.05). Conclusions SGLT2 inhibitor was associated with decreased risks of cardiorenal outcomes similarly in both sexes.

104 Effect of acute systemic corticosteroids on clinical outcomes in cystic fibrosis pulmonary exacerbations

104 Effect of acute systemic corticosteroids on clinical outcomes in cystic fibrosis pulmonary exacerbations

Sedating antihistamine treatment with promethazine in patients with severe COPD with and without asthma: death and severe exacerbations in a nationwide register study

ABSTRACT Background Sedating antihistamines such as promethazine are used as anxiolytics and hypnotic agents for patients with chronic obstructive pulmonary disease (COPD) with and without asthma despite limited knowledge of its effects and side effects. We evaluated if treatment with promethazine had a lower risk of harmful outcome. Methods Nationwide retrospective cohort study of Danish specialist diagnosed outpatients with COPD treated with promethazine or an active comparator (melatonin). Patients with collection of promethazine or melatonin were propensity score matched 1:1. The primary outcome was a composite of severe COPD exacerbations and death from all causes analyzed by Cox proportional hazards regression. We performed an interaction analysis for comorbid asthma. Results In our registry of 56,523 patients with COPD, 5,661 collected promethazine (n = 3,723) or melatonin (n = 1,938). A cohort of 3,290 promethazine- or melatonin-treated patients matched 1:1 was available for the primary analysis. Within 1-year patients treated with promethazine were at higher risk of the primary outcome than matched controls with a Hazard Ratio (HR) of 1.42 (CI 1.27–1.58, p < 0.0001). Similarly, the risk of death was higher for promethazine-treated patients (HR 1.53, CI 1.32–1.77, p < 0.0001). An interaction analysis for comorbid asthma showed no interaction between comorbid asthma and the likelihood of a primary outcome when collecting promethazine (p = 0.19). Adjusted Cox analysis on the entire population indicated a further increased risk with more promethazine (HR for primary outcome among patients collecting ≥ 400 promethazine tablets/year=2.15, CI 1.94–2.38, p<0.0001). Conclusions Promethazine-treated patients with COPD had a concerning excess risk of a composite outcome of severe exacerbations and death from all causes compared to melatonin.

Association of GLP-1 Receptor Agonists with Chronic Obstructive Pulmonary Disease Exacerbations among Patients with Type 2 Diabetes.

Rationale: Patients with chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D) have worse clinical outcomes compared with patients without metabolic dysregulation. GLP-1 (glucagon-like peptide 1) receptor agonists (GLP-1RAs) reduce asthma exacerbation risk and improve FVC in patients with COPD. Objectives: To determine whether GLP-1RA use is associated with reduced COPD exacerbation rates, and severe and moderate exacerbation risk, compared with other T2D therapies. Methods: A retrospective, observational, electronic health records-based study was conducted using an active comparator, new-user design of 1,642 patients with COPD in a U.S. health system from 2012 to 2022. The COPD cohort was identified using a previously validated machine learning algorithm that includes a natural language processing tool. Exposures were defined as prescriptions for GLP-1RAs (reference group), DPP-4 (dipeptidyl peptidase 4) inhibitors (DPP-4is), SGLT2 (sodium-glucose cotransporter 2) inhibitors, or sulfonylureas. Measurements and Main Results: Unadjusted COPD exacerbation counts were lower in GLP-1RA users. Adjusted exacerbation rates were significantly higher in DPP-4i (incidence rate ratio, 1.48 [95% confidence interval, 1.08-2.04]; P = 0.02) and sulfonylurea (incidence rate ratio, 2.09 [95% confidence interval, 1.62-2.69]; P < 0.0001) users compared with GLP-1RA users. GLP-1RA use was also associated with significantly reduced risk of severe exacerbations compared with DPP-4i and sulfonylurea use, and of moderate exacerbations compared with sulfonylurea use. After adjustment for clinical covariates, moderate exacerbation risk was also lower in GLP-1RA users compared with DPP-4i users. No statistically significant difference in exacerbation outcomes was seen between GLP-1RA and SGLT2 inhibitor users. Conclusions: Prospective studies of COPD exacerbations in patients with comorbid T2D are warranted. Additional research may elucidate the mechanisms underlying these observed associations with T2D medications.

Can we apply biomarkers in the management of non-steroidal anti-inflammatory drug exacerbated respiratory disease?

Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is characterized by adult-onset asthma, chronic rhinosinusitis with nasal polyps (CRSwNPs), and aspirin/NSAID hypersensitivity, presenting recurrent asthma exacerbation and poor clinical outcomes. Patients with NERD have heterogeneous clinical phenotypes/endotypes, and the management of NERD remains challenging. Dysregulation of arachidonic acid (AA) metabolism and persistent eosinophilic airway inflammation are the major pathogenic mechanisms in the upper and lower airways of NERD. To date, increased levels of urinary leukotriene E4 (uLTE4) [a terminal metabolite of the lipoxygenase (LOX) pathway] have been the most relevant biomarker for NERD. It is demonstrated that mast cells, platelets, and epithelial cells can amplify upper and lower airway inflammation in NERD, and several potential biomarkers based on these complicated and heterogeneous mechanisms have been suggested. This review summarizes potential biomarkers for application in the management of NERD.

Emergency ultrasound of respiratory muscles: a promising tool for determining the outcomes of COPD exacerbations.

The respiratory muscles of patients with chronic obstructive pulmonary disease (COPD) exhibit structural and functional changes that can be evaluated and monitored by ultrasonography. This single-center, prospective study was conducted in the emergency department (ED) of a tertiary care hospital over an eight-month period (September 2020-May 2021). Diaphragmatic excursions, end-expiratory thickness, and thickening fractions, as well as right and left intercostal muscle thicknesses, of all adult subjects manifesting COPD exacerbation, were assessed. The data were analyzed regarding ward/intensive care unit (ICU) hospitalization or discharge from the ED, mortality, and readmission within 15 days. Sixty-three subjects were recruited for the study. Diaphragmatic excursion, end-expiratory diaphragmatic thickness, and intercostal muscle thickness measurements were significantly different between the ward, ICU, and discharge groups (p < 0.001) but lower in the deceased subjects (all p < 0.05). The diaphragmatic excursion value of 3.25 cm was the threshold value measured for distinguishing discharge from ED, and 1.82 cm was measured for admission to the ICU, both with 100% sensitivity and selectivity (AUC = 1). Diaphragmatic excursion, diaphragmatic end-expiratory thickness, and right and left intercostal muscle thicknesses vary in the prognosis of subjects presenting with COPD exacerbation.

Effect of angiotensin II on irradiation exacerbated decompression sickness

In some complicated situations, decompression sickness (DCS) combined with other injuries, such as irradiation, will seriously endanger life safety. However, it is still unclear whether irradiation will increase the incidence of DCS. This study was designed to investigate the damage effects of irradiation on decompression injury and the underlying mechanism. Sprague–Dawley rats were exposed to irradiation followed by hyperbaric decompressing and the mortality and decompression symptoms were observed. Lung tissue and bronchoalveolar lavage fluid were collected to detect the lung lesion, inflammation response, activity of the angiotensin system, oxidative stress, and relative signal pathway by multiple methods, including Q-PCR, western blot, and ELISA. As a result, pre-exposure to radiation significantly exacerbated disease outcomes and lung lesions of DCS. Mechanically, the up-regulation of angiotensin-converting enzyme expression and angiotensin II levels was responsible for the exacerbated DCS and lung lesions caused by predisposing irradiation exposure. Oxidative stress and PI3K/AKT signal pathway activation in pulmonary tissue were enhanced after irradiation plus decompression treatment. In conclusion, our results suggested that irradiation could exacerbate lung injury and the outcomes of DCS by activating the angiotensin system, which included eliciting oxidative stress and activation of the PI3K/AKT signal pathway.

A population-based study of the burden of severe asthma in Alberta, Canada

RATIONALE A comprehensive understanding of the burden of illness and management strategies for severe asthma (SA), especially by disease control, is lacking in Canada. OBJECTIVES The objectives of this study were to describe treatments, exacerbation outcomes and healthcare resource utilization (HCRU) for patients with controlled and uncontrolled SA in Alberta, Canada. METHODS A retrospective cohort of SA patients 12+ years (April 1, 2011 to March 31, 2020) was identified from administrative health data, based on medication dispensed for controlling asthma symptoms, stratified by disease control at index. Treatment patterns were analyzed for incident SA patients. Annualized exacerbation incidence rate ratios (IRR) were estimated throughout follow-up and stratified by disease control at index. Asthma-specific HCRU and direct costs were calculated. RESULTS The study cohort included 74,134 patients (12.4% of eligible asthma patients) of whom 71,099 (95.5%) were classified as controlled and 3,035 (4.1%) as uncontrolled at index. Inhaled corticosteroid + long-acting beta agonist (ICS + LABA) was the most frequent first-line therapy among incident SA patients (n = 53,084), received by 42.7% of patients. A minority received >2 lines of therapy; few received triple therapy. The uncontrolled (at index) versus controlled (at index) cohort had a 5.5 times higher exacerbation rate (IRR: 5.5, 95% CI: 5.1–5.8; p < 0.001), higher HCRU, and higher associated annual costs (mean [SD]: $3,799 [$6,668] uncontrolled vs $1,339 [$2,515] controlled). CONCLUSIONS SA, whether controlled or uncontrolled at index, was associated with ongoing exacerbations and HCRU despite treatment intensification that identified patients as having SA. Some treatment patterns appeared misaligned with guidelines, suggesting potential need for better recognition of asthma severity and escalating therapies.

Role of hyperglycemia in cystic fibrosis pulmonary exacerbations

BackgroundHyperglycemia could affect treatment response during cystic fibrosis (CF) exacerbations. We aimed to evaluate the prevalence and associations of hyperglycemia with exacerbation outcomes. We also evaluated feasibility of continuous glucose monitoring (CGM) during exacerbations. MethodsThe STOP2 study assessed efficacy and safety of different durations of intravenous antibiotics for CF exacerbations. We conducted a secondary data analysis of random glucose levels measured as part of clinical care during exacerbations. A small subset of participants also underwent CGM per research protocol. The associations between hyperglycemia, defined as random glucose ≥140 mg/dL, and changes in weight and lung function with exacerbation treatment were evaluated with linear regression after adjustment for confounding variables. ResultsGlucose levels were available for 182 STOP2 participants of mean (SD) age 31.6 (10.8) years, baseline percent predicted (pp) FEV1 53.6 (22.5); 37% had CF related diabetes and 27% were on insulin. Hyperglycemia was detected in 44% of participants. Adjusted mean difference (95% CI) was 1.34% (-1.39, 4.08) (p = 0.336) for change in ppFEV1 and 0.33 kg (-0.11, 0.78) (p = 0.145) for change in weight between hyperglycemic and non-hyperglycemic groups. Ten participants not on antidiabetic agents in the 4 weeks prior to enrollment underwent CGM; mean (SD) time spent >140 mg/dL was 24.6% (12.5) with 9/10 participants spending >4.5% time >140 mg/dL. ConclusionsHyperglycemia identified with random glucose is prevalent during CF exacerbations but not associated with changes in lung function or weight with exacerbation treatment. CGM is feasible and may provide a useful tool for hyperglycemia monitoring during exacerbations.

Acute Exacerbations of Interstitial Lung Diseases: Focus on Biomarkers.

Interstitial lung diseases (ILDs) are a large group of pulmonary disorders characterized histologically by the cardinal involvement of the pulmonary interstitium. The prototype of ILDs is idiopathic pulmonary fibrosis (IPF), an incurable disease characterized by progressive distortion and loss of normal lung architecture through unchecked collagen deposition. Acute exacerbations are dramatic events during the clinical course of ILDs, associated with high morbidity and mortality. Infections, microaspiration, and advanced lung disease might be involved in the pathogenesis of acute exacerbations. Despite clinical scores, the prediction of the onset and outcome of acute exacerbations is still inaccurate. Biomarkers are necessary to characterize acute exacerbations better. We review the evidence for alveolar epithelial cell, fibropoliferation, and immunity molecules as potential biomarkers for acute exacerbations of interstitial lung disease.

P096 Effect of acute systemic corticosteroids on clinical outcomes in cystic fibrosis pulmonary exacerbations

P096 Effect of acute systemic corticosteroids on clinical outcomes in cystic fibrosis pulmonary exacerbations

Unsupervised machine learning identifies symptoms of indigestion as a predictor of acute decompensation and adverse cardiac events in patients with heart failure presenting to the emergency department

BackgroundPatients with known heart failure (HF) present to emergency departments (ED) with a plethora of symptoms. Although symptom clusters have been suggested as prognostic features, accurately triaging HF patients is a longstanding challenge. ObjectivesWe sought to use machine learning to identify subtle phenotypes of patient symptoms and evaluate their diagnostic and prognostic value among HF patients seeking emergency care. MethodsThis was a secondary analysis of a prospective cohort study of consecutive patients seen in the ED for chest pain or equivalent symptoms. Independent reviewers extracted clinical data from charts, including nine categories of subjective symptoms reported during initial evaluation. The diagnostic outcome was acute HF exacerbation and prognostic outcome was 30-day major adverse cardiac events (MACE). Outcomes were adjudicated by two independent reviewers. K-means clustering was used to derive latent patient symptom clusters, and their associations with outcomes were assessed using multivariate logistic regression. ResultsSample included 438 patients (age 65±14 years; 45% female, 49% Black, 18% HF exacerbation, 32% MACE). K-means clustering identified three presentation phenotypes: patients with dyspnea only (Cluster A, 40%); patients with indigestion, with or without dyspnea (Cluster B, 23%); patients with neither dyspnea nor indigestion (Cluster C, 37%). Compared to Cluster C, indigestion was a significant predictor of acute HF exacerbation (OR=1.8, 95%CI=1.0–3.4) and 30-day MACE (OR=1.8, 95%CI=1.0–3.1), independent of age, sex, race, and other comorbidities. ConclusionIndigestion symptoms in patients with known HF signify excess risk of adverse events, suggesting that these patients should be triaged as high-risk during initial ED evaluation.

The effects of childhood maltreatment on adolescent non-suicidal self-injury behavior: mediating role of impulsivity.

Non-suicidal self-injury (NSSI) severely challenges mental health in adolescents. Childhood maltreatment experience acts as high-risk factor for adolescents to engage in NSSI behaviors. On the other hand, impulsivity or loss of control sets the threshold for NSSI execution. Here we examined the effects of childhood maltreatment on adolescent NSSI-related clinical outcomes and the potential role of impulsivity. We assessed the clinical data of 160 hospitalized NSSI adolescents and recruited 64 age-matched healthy subjects as a control group. The clinical symptoms of NSSI are expressed by the NSSI frequency, depression, and anxiety measured by the Ottawa Self-Injury Inventory, the Beck Depression Inventory, and the Beck Anxiety Inventory. Childhood maltreatment and impulsivity were assessed with Childhood Trauma Questionnaire and Barratt Impulsiveness Scale. The results showed that when compared to HC group, NSSI group is more likely to experience childhood maltreatment. Notably, NSSI group with Childhood maltreatment accompanies higher trait impulsivity and exacerbated clinical outcomes, such as NSSI frequency, depression and anxiety symptoms. Mediation analyses indicated that the association between childhood maltreatment and NSSI-related clinical outcomes was partially explained by impulsivity. We found that NSSI adolescents have a higher proportion of childhood maltreatment. Impulsivity plays a mediating role between childhood maltreatment and NSSI behaviors.

Neutrophil-derived cathelicidin promotes cerebral angiogenesis after ischemic stroke.

Neutrophils play critical roles in the evolving of brain injuries following ischemic stroke. However, how they impact the brain repair in the late phase after stroke remain uncertain. Using a prospective clinical stroke patient cohort, we found significantly increased cathelicidin antimicrobial peptide (CAMP) in the peripheral blood of stroke patients compared to that of healthy controls. While in the mouse stroke model, CAMP was present in the peripheral blood, brain ischemic core and significantly increased at day 1, 3, 7, 14 after middle cerebral artery occlusion (MCAO). CAMP-/- mice exhibited significantly increased infarct volume, exacerbated neurological outcome, reduced cerebral endothelial cell proliferation and vascular density at 7 and 14 days after MCAO. Using bEND3 cells subjected to oxygen-glucose deprivation (OGD), we found significantly increased angiogenesis-related gene expression with the treatment of recombinant CAMP peptide (rCAMP) after reoxygenation. Intracerebroventricular injection (ICV) of AZD-5069, the antagonist of CAMP receptor CXCR2, or knockdown of CXCR2 by shCXCR2 recombinant adeno-associated virus (rAAV) impeded angiogenesis and neurological recovery after MCAO. Administration of rCAMP promoted endothelial proliferation and angiogenesis and attenuated neurological deficits 14 days after MCAO. In conclusion, neutrophil derived CAMP represents an important mediator that could promote post-stroke angiogenesis and neurological recovery in the late phase after stroke.

Ablation of Argonaute 2 in Schwann cells accelerates the progression of diabetic peripheral neuropathy.

Schwann cells (SCs) form myelin and provide metabolic support for axons, and are essential for normal nerve function. Identification of key molecules specific to SCs and nerve fibers may provide new therapeutic targets for diabetic peripheral neuropathy (DPN). Argonaute2 (Ago2) is a key molecular player that mediates the activity of miRNA-guided mRNA cleavage and miRNA stability. Our study found that Ago2 knockout (Ago2-KO) in proteolipid protein (PLP) lineage SCs in mice resulted in a significant reduction of nerve conduction velocities and impairments of thermal and mechanical sensitivities. Histopathological data revealed that Ago2-KO significantly induced demyelination and neurodegeneration. When DPN was induced in both wild-type and Ago2-KO mice, Ago2-KO mice exhibited further decreased myelin thickness and exacerbated neurological outcomes compared with wild-type mice. Deep sequencing analysis of Ago2 immunoprecipitated complexes showed that deregulated miR-206 in Ago2-KO mice is highly related to mitochondrial function. In vitro data showed that knockdown of miR-200 induced mitochondrial dysfunction and apoptosis in SCs. Together, our data suggest that Ago2 in SCs is essential to maintain peripheral nerve function while ablation of Ago2 in SCs exacerbates SC dysfunction and neuronal degeneration in DPN. These findings provide new insight into the molecular mechanisms of DPN.

Development of skeletal muscle fibrosis in a rodent model of cancer cachexia.

Cachexia is characterized by losses in lean body mass and its progression results in worsened quality of life and exacerbated outcomes in cancer patients. However, the role and impact of fibrosis during the early stages and development of cachexia in under-investigated. The purpose of this study was to determine if fibrosis occurs during cachexia development, and to evaluate this in both sexes. Female and male C57BL6/J mice were injected with phosphate-buffered saline or Lewis Lung Carcinoma (LLC) at 8-week of age, and tumors were allowed to develop for 1, 2, 3, or 4 weeks. 3wk and 4wk female tumor-bearing mice displayed a dichotomy in tumor growth and were reassigned to high tumor (HT) and low tumor (LT) groups. In vitro analyses were also performed on cocultured C2C12 and 3T3 cells exposed to LLC conditioned media. Immunohistochemistry and quantitative polymerase chain reaction (qPCR) analysis were used to investigate fibrosis and fibrosis-related signaling in skeletal muscle. Collagen deposition in skeletal muscle was increased in the 1wk, LT, and HT groups in female mice. However, collagen deposition was only increased in the 4wk group in male mice. In general, female mice displayed earlier alterations in extracellular matrix (ECM)-related genes beginning at 1wk post-LLC injection. Whereas this was not seen in males. While overall tumor burden is tightly correlated to cachexia development in both sexes, fibrotic development is not. Male mice did not exhibit early-stage alterations in ECM-related genes contrary to what was noted in female mice.