bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intrapericardial Exosome Therapy Dampens Cardiac Injury via Activating Foxo3
Authors: Zhu Dashuai , Liu Shuo , Huang Ke , Wang Zhenzhen , Hu Shiqi , Li Junlang , Li Zhenhua , Cheng Ke 
Published: October 2022

Background:
Mesenchymal stem cell (MSC)-derived exosomes are well recognized immunomodulating agents for cardiac repair, while the detailed mechanisms remain elusive. The Pericardial drainage pathway provides the heart with immunosurveillance and establishes a simplified model for studying the mechanisms underlying the immunomodulating effects of therapeutic exosomes.

Methods:
Myocardial infarction (MI) models with and without pericardiectomy (corresponding to Tomy MI and NonTomy MI) were established to study the functions of pericardial drainage pathway in immune activation of cardiac-draining mediastinal lymph node (MLN). Using the NonTomy MI model, MSC exosomes or vehicle PBS was intrapericardially injected for MI treatment. Via cell sorting and RNA-seq (RNA-sequencing) analysis, the differentially expressed genes were acquired for integrated pathway analysis to identify responsible mechanisms. Further, through functional knockdown/inhibition studies, application of cytokines and neutralizing antibodies, western blot, flow cytometry, and cytokine array, the molecular mechanisms were studied. In addition, the therapeutic efficacy of intrapericardially injected exosomes for MI treatment was evaluated through functional and histological analyses.

Results:

We show that the pericardial draining pathway promoted immune activation in the MLN following MI. Intrapericardially injected exosomes accumulated in the MLN and induced regulatory T cell differentiation to promote cardiac repair. Mechanistically, uptake of exosomes by major histocompatibility complex (MHC)-II
+
antigen-presenting cells (APCs) induced Foxo3 activation via the protein phosphatase (PP)-2A/p-Akt/forkhead box O3 (Foxo3) pathway. Foxo3 dominated APC cytokines (IL-10, IL-33, and IL-34) expression and built up a regulatory T cell (Treg)-inducing niche in the MLN. The differentiation of Tregs as well as their cardiac deployment were elevated, which contributed to cardiac inflammation resolution and cardiac repair.

Conclusions:
This study reveals a novel mechanism underlying the immunomodulation effects of MSC exosomes and provides a promising candidate (PP2A/p-Akt/Foxo3 signaling pathway) with a favorable delivery route (intrapericardial injection) for cardiac repair.
Effect of 3, 2-Drug Combinations of Antihypertensive Therapies on Blood Pressure Variability in Black African Patients: Secondary Analyses of the CREOLE Trial
Authors: Ojji Dike B. , Cornelius Victoria , Partington Giles , Francis Veronica , Pandie Shahiemah , Smythe Wynand , Hickman Nicky , Barasa Felix , Damasceno Albertino , Dzudie Anastase , Jones Erika , Ingabire Prossie Merab , Mondo Charles , Ogah Okechukwu , Ogola Elijah , Sani Mahmoud U. , Shedul Gabriel Lamkur , Shedul Grace , Rayner Brian , Sliwa Karen , Poulter Neil ,   for CREOLE Investigators
Published: October 2022

Background:
The effect of 3 commonly recommended combinations of anti-hypertensive agents—amlodipine plus hydrochlorothiazide (calcium channel blocker [CCB]+thiazide), amlodipine plus perindopril (CCB+ACE [angiotensin-converting enzyme]-inhibitor), and perindopril plus hydrochlorothiazide (ACE-inhibitor+thiazide) on blood pressure variability (V) are unknown.

Methods:
We calculated the blood pressure variability (BPV) in 405 patients (130, 146, and 129 randomized to ACE-inhibitor+thiazide, CCB+thiazide, and CCB+ACE-inhibitor, respectively) who underwent ambulatory blood pressure monitoring after 6 months of treatment in the Comparisons of Three Combinations Therapies in Lowering Blood Pressure in Black Africans trial (CREOLE) of Black African patients. BPV was calculated using the SD of 30-minute interval values for 24-hour ambulatory BPs and for confirmation using the coefficient of variation. Linear mixed model regression was used to calculate mean differences in BPV between treatment arms. Within-clinic BPV was also calculated from the mean SD and coefficient of variation of 3 readings at clinic visits.

Results:
Baseline distributions of age, sex, and blood pressure parameters were similar across treatment groups. Participants were predominately male (62.2%) with mean age 50.4 years. Those taking CCB+thiazide had significantly reduced ambulatory systolic and diastolic BPV compared with those taking ACE-inhibitor+thiazide. The CCB+thiazide and CCB+ACE-inhibitor groups showed similar BPV. Similar patterns of BPV were apparent among groups using within-clinic blood pressures and when assessed by coefficient of variation.

Conclusions:
Compared with CCB-containing combinations, ACE-inhibitor plus thiazide was associated with higher levels, generally significant, of ambulatory and within-clinic systolic and diastolic BPV. These results supplement the differential ambulatory blood pressure–lowering effects of these therapies in the CREOLE trial.
ARRB2 (β-Arrestin-2) Deficiency Alters Fluid Homeostasis and Blood Pressure Regulation
Authors: Mathieu Natalia M. , Nakagawa Pablo , Grobe Connie C. , Reho John J. , Brozoski Daniel T. , Lu Ko-Ting , Wackman Kelsey K. , Ritter McKenzie L. , Segar Jeffrey L. , Grobe Justin L. , Sigmund Curt D. 
Published: October 2022

Background:
GPCRs (G protein–coupled receptors) are implicated in blood pressure (BP) and fluid intake regulation. There is a developing concept that these effects are mediated by both canonical G protein signaling and noncanonical β-arrestin mediated signaling, but the contributions of each remain largely unexplored. Here, we hypothesized that β-arrestin contributes to fluid homeostasis and blood pressure (BP) regulation in deoxycorticosterone acetate (DOCA) salt hypertension, a prototypical model of salt-sensitive hypertension.

Methods:

Global β-arrestin1 (
Arrb1
) and β-arrestin2 (
Arrb2
) knockout mice were employed to evaluate drinking behavior, and BP was evaluated in
Arrb2
-knockout mice. Age- and sex-matched C57BL/6 mice served as controls. We measured intake of water and different sodium chloride solutions and BP employing a 2-bottle choice paradigm with and without DOCA.

Results:

Without DOCA (baseline),
Arrb2
-knockout mice exhibited a significant elevation in saline intake with no change in water intake. With DOCA treatment,
Arrb2
-knockout mice exhibited a significant increase in both saline and water intake. Although
Arrb2
-knockout mice exhibited hypernatremia at baseline conditions, we did not find significant changes in total body sodium stores or sodium palatability. In a separate cohort, BP was measured via telemetry in
Arrb2
-knockout and C57BL/6 mice with and without DOCA.
Arrb2
-knockout did not exhibit significant differences in BP before DOCA treatment when provided water alone, or when provided a choice of water and saline. However,
Arrb2
-knockout exhibited an increased pressor response to DOCA-salt.

Conclusions:
These findings suggest that in salt-sensitive hypertension, ARRB2, but not ARRB1 (β-arrestin 1), might counterbalance the canonical signaling of GPCRs.
Circuit analysis of the Drosophila brain using connectivity-based neuronal classification reveals organization of key communication pathways
Authors: Mehta Ketan , Goldin Rebecca F. , Ascoli Giorgio A. 
Published: October 2022

Abstract
We present a functionally relevant, quantitative characterization of the neural circuitry of Drosophila melanogaster at the mesoscopic level of neuron types as classified exclusively based on potential network connectivity. Starting from a large neuron-to-neuron brain-wide connectome of the fruit fly, we use stochastic block modeling and spectral graph clustering to group neurons together into a common “cell class” if they connect to neurons of other classes according to the same probability distributions. We then characterize the connectivity-based cell classes with standard neuronal biomarkers, including neurotransmitters, developmental birthtimes, morphological features, spatial embedding, and functional anatomy. Mutual information indicates that connectivity-based classification reveals aspects of neurons that are not adequately captured by traditional classification schemes. Next, using graph theoretic and random walk analyses to identify neuron classes as hubs, sources, or destinations, we detect pathways and patterns of directional connectivity that potentially underpin specific functional interactions in the Drosophila brain. We uncover a core of highly interconnected dopaminergic cell classes functioning as the backbone communication pathway for multisensory integration. Additional predicted pathways pertain to the facilitation of circadian rhythmic activity, spatial orientation, fight-or-flight response, and olfactory learning. Our analysis provides experimentally testable hypotheses critically deconstructing complex brain function from organized connectomic architecture.
Rabies prevention and control practices and associated factors among dog owners in Chiro, West Hararghe, Ethiopia
Authors: Ahmed Mohammed Jemal , Dirirsa Gebisa , Mengistu Dechasa Adare , Demena Melake , Geremew Abraham 
Published: October 2022

Background: Rabies is among the most deadly and fatal diseases of all human diseases, once clinical symptoms appear. In developing countries, including Ethiopia, rabies prevention and control practices is not adequate. The study aimed to assess knowledge, attitude, and practices toward rabies prevention and control and identified factors associated with prevention and control practices. Methods: A community-based cross-sectional study was conducted from July 30 to August 30, 2021. A total of 326 dog-owner households were selected from the total number of 6500 dog-owner households using a simple random sampling method. Pretested and structured questionnaire were used to collect the data. The sections of the questionnaire includes socio-demographic, knowledge, attitude, and practice toward rabies prevention practices, and health and personal-related characteristics of the participants. The data was analyzed using SPSS version 24. Bivariate and multivariable logistic regression were used to determine the association variables. Finally, a p-value of less than 0.05 was considered as a cut-off point for statistical significance. Results: Of 326 households involved in the study, 52.8% of the participants were found to have poor rabies prevention and control practices. More than half (52.1%) of the respondents had good knowledge of rabies prevention and control practices, and 49.1% had a positive attitude. Only 28.2% of the respondents reported a history of dog bites. Factors associated with good rabies prevention and control practices were; having good knowledge of human rabies virus [(Adjusted Odd Ratio (AOR) = 2.41 (95% CI: 2.25−4.83)], having good attitude on prevention and control [AOR = 2.06 (95% CI: 1.95–3.82)], having only one dog per household [AOR = 2.46 (95% CI: 1.25–4.83)], availability of vet clinic within 30 min distance from residents [AOR = 9.32 (95% CI: 4.19–20.70)], and getting health information from Mass media [AOR = 3.68(95% CI: 1.74–7.77)] or Health workers [AOR = 3.16 (95% CI: 1.60–6.23)]. Conclusions: More than half (52.1%) of the participants had poor rabies prevention and control practices. Improving rabies prevention and control practices through improving the knowledge and attitude of the community is important to protect public health.
Neuromuscular Control During Stair Descent and Artificial Tibial Translation After Acute ACL Rupture
Authors: Blasimann Angela , Busch Aglaja , Henle Philipp , Bruhn Sven , Vissers Dirk , Baur Heiner 
Published: October 2022

Background: Anterior cruciate ligament (ACL) rupture has direct effect on passive and active knee stability and, specifically, stretch-reflex excitability. Purpose/Hypothesis: The purpose of this study was to investigate neuromuscular activity in patients with an acute ACL deficit (ACL-D group) compared with a matched control group with an intact ACL (ACL-I group) during stair descent and artificially induced anterior tibial translation. It was hypothesized that neuromuscular control would be impaired in the ACL-D group. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Surface electromyographic (EMG) activity of the vastus medialis (VM), vastus lateralis (VL), biceps femoris (BF), and semitendinosus (ST) muscles was recorded bilaterally in 15 patients with ACL-D (mean, 13.8 days [range, 7-21 days] since injury) and 15 controls with ACL-I during stair descent and artificially induced anterior tibial translation. The movements of stair descent were divided into preactivity, weight acceptance, and push-off phases. Reflex activity during anterior tibial translation was split into preactivity and short, medium, and late latency responses. Walking on a treadmill was used for submaximal EMG normalization. Kruskal-Wallis test and post hoc analyses with Dunn-Bonferroni correction were used to compare normalized root mean square values for each muscle, limb, movement, and reflex phase between the ACL-D and ACL-I groups. Results: During the preactivity phase of stair descent, the hamstrings of the involved leg of the ACL-D group showed 33% to 51% less activity compared with the matched leg and contralateral leg of the ACL-I group ( P < .05). During the weight acceptance and push-off phases, the VL revealed a significant reduction (approximately 40%) in the involved leg of the ACL-D group compared with the ACL-I group. At short latency, the BF and ST of the involved leg of the ACL-D group showed a significant increase in EMG activity compared with the uninvolved leg of the ACL-I group, by a factor of 2.2 to 4.6. Conclusion: In the acute phase after an ACL rupture, neuromuscular alterations were found mainly in the hamstrings of both limbs during stair descent and reflex activity. The potential role of prehabilitation needs to be further studied.
Combined Margin Convergence Repair and Subacromial Balloon Spacer for the Treatment of Massive Rotator Cuff Tears
Authors: Sivasundaram Lakshmanan , Hevesi Mario , Berlinberg Elyse J. , Patel Harsh H. , Verma Nikhil N. , Forsythe Brian 
Published: October 2022

Background: Current joint-sparing treatment options for massive, irreparable rotator cuff tears aim to prevent superior migration of the humeral head and maintain the subacromial space. Although options such as superior capsular reconstruction and posterosuperior tendon transfer may appropriately restore function and reduce pain, these procedures harbor significant comorbidity and intense postoperative rehabilitation. Recently, studies have demonstrated excellent results from a subacromial balloon spacer composed of a biocompatible copolymer that degrades over the 12 months following implantation. This spacer enables a more anatomic position of the humeral head to restore normal shoulder biomechanics. Indications: The subacromial balloon spacer is primarily indicated in patients with massive, irreparable rotator cuff tears who demonstrate proximal humeral migration. Contraindications include subscapularis or teres minor tendon tears, deltoid dysfunction, and pseudoparalysis. Technique Description: Standard arthroscopic portals are established, and a diagnostic arthroscopy is performed to assess the glenohumeral joint space and subscapularis tendon. A subacromial bursectomy is performed without proceeding medial to the superior glenoid rim. The subacromial space is measured utilizing an arthroscopic measurement probe to ensure that the selected spacer will lie slightly medial to the glenoid. The rotator cuff is then reapproximated from the lateral to medial aspect of the tear and repaired via a side-to-side manner with high strength, nonabsorbable tape, and a self-capturing suture device. Following repair, the deployment device is inserted through the lateral portal, placed slightly medial to the glenoid, and inflated with saline. Results: Utilization of the described subacromial balloon augmentation provides significant pain relief by restoring glenohumeral biomechanics, improvements in range of motion, and an enhancement in quality of life. Discussion: This case report and video review of a technique for utilizing a subacromial balloon spacer demonstrates an effective, simple, and safe treatment for massive, irreparable rotator cuff tears. Positive results rely on appropriate inflation and secure fixation. Recent clinical trial data suggest that functional outcomes for the subacromial balloon spacer are noninferior to that of partial rotator cuff repair. These promising results suggest that the subacromial balloon spacer may prove an essential tool for joint-preserving surgery following massive, irreparable rotator cuff tears.
Effect of adaptive servo-ventilation for central sleep apnoea in systolic heart failure on muscle sympathetic nerve activity: a SERVE-HF randomised ancillary study
Authors: Tamisier Renaud , Pépin Jean-Louis , Woehrle Holger , Salvat Muriel , Barone-Rochette Gilles , Rocca Cécile , Vettorazzi Eik , Teschler Helmut , Cowie Martin , Lévy Patrick 
Published: October 2022

BackgroundAdaptive servo-ventilation (ASV) effectively suppresses central sleep apnoea (CSA) but has been associated with increased all-cause and cardiovascular mortality in chronic heart failure patients with reduced ventricular ejection fraction (HFrEF). All-cause and, especially, cardiovascular mortality in chronic heart failure is highly correlated with sympathetic tone. This analysis of SERVE-HF data investigated the effect of ASV on sympathetic tone in patients with HFrEF and CSA.MethodsHFrEF patients in the SERVE-HF trial (left ventricular ejection fraction (LVEF) ≤45%, apnoea–hypopnoea index (AHI) ≥15 events·h−1with predominant CSA) were randomly assigned to receive guideline-based heart failure treatment alone (controls) or plus ASV. For this analysis, the primary outcome was change in muscle sympathetic nerve activity (MSNA) at 3-month follow-up. The effects of baseline MSNA and change in MSNA over time on mortality in the main study were also assessed.Results40 patients with HFrEF were included in this analysis (age 71.3±11.7 years, LVEF 34.2±7.7%, 57.5% in New York Heart Association (NYHA) Functional Class II, 42.5% in NYHA Functional Class III, AHI 35.2±11 events·h−1). Sympathetic tone evolution during follow-up did not differ between groups (controls: 47.6±8.3 bursts·min−1at baseline to 44.6±11.2 bursts·min−1; ASV group: 43.0±9.0 bursts·min−1at baseline to 42.74±9.45 bursts·min−1). The reduction in sympathetic tone was associated with significantly increased cardiovascular mortality in the ASV group, whereas in the control group reduced sympathetic tone appeared to be protective.ConclusionsSuppression of CSA with ASV did not seem to have a significant effect on chronic heart failure-related sympathetic activation. Simultaneous suppression of CSA and reduction in MSNA was associated with increased cardiovascular mortality.
Apnoea–hypopnoea index of 5 events·h−1as a metabolomic threshold in patients with sleep complaints
Authors: Kiens Ott , Taalberg Egon , Ivanova Viktoria , Veeväli Ketlin , Laurits Triin , Tamm Ragne , Ottas Aigar , Kilk Kalle , Soomets Ursel , Altraja Alan 
Published: October 2022

BackgroundThe apnoea–hypopnoea index (AHI) forms the basis for severity of obstructive sleep apnoea (OSA), a condition expected to reprogramme metabolic pathways in humans. We aimed to identify the AHI breakpoint from which the majority of significant changes in the systemic metabolome of patients with sleep complaints occur.MethodsIn a prospective observational study on symptomatic individuals, who underwent polysomnography for the diagnosis of OSA, profiles of 187 metabolites including amino acids, biogenic amines, acylcarnitines, lysophosphatidylcholines, phosphatidylcholines and sphingomyelins were analysed with liquid chromatography mass spectrometry in peripheral blood drawn at three different time points overnight. Comparisons of rank-transformed data using a general linear model for repeated measures after dichotomising the study group at different AHI levels were applied to define the best cut-off based on Cohen's f.Results65 subjects were recruited with a median AHI of 15.6 events·h−1. The mean Cohen's f over the metabolites was highest (0.161) at an AHI level of 5 events·h−1representing the metabolomic threshold. Of the particular between-group differences, eight phosphatidylcholines, nine acylcarnitines and one amino acid (threonine) had significantly lower concentrations in the individuals with an AHI level equal to or above the metabolomic threshold. The metabolomic changes at AHI levels defining moderate and severe OSA were smaller than at an AHI of 5 events·h−1.ConclusionsThe metabolomic threshold for patients with sleep complaints described in this report for the first time coincides with the AHI threshold required to confirm the diagnosis of OSA.
Prime-boost, double-dose influenza vaccine immunity in COPD: a pilot observational study
Authors: Anderson Gary P. , Irving Louis B. , Jarnicki Andrew , Kedzierska Katherine , Koutsakos Marios , Kent Stephen , Hurt Aeron C. , Wheatley Adam K. , Nguyen Thi H.O. , Snape Natale , Upham John W. 
Published: October 2022

BackgroundCOPD patients are more susceptible to viral respiratory infections and their sequelae, and have intrinsically weaker immune responses to vaccinations against influenza and other pathogens. Prime-boost, double-dose immunisation has been suggested as a general strategy to overcome weak humoral response to vaccines, such as seasonal influenza vaccination, in susceptible populations with weak immunity. However, this strategy, which may also provide fundamental insights into the nature of weakened immunity, has not been formally studied in COPD.MethodsWe conducted an open-label study of seasonal influenza vaccination in 33 vaccine-experienced COPD patients recruited from established cohorts (mean age 70 (95% CI 66.9–73.2) years; mean forced expiratory volume in 1 s/forced vital capacity ratio 53.4% (95% CI 48.0–58.8%)). Patients received two sequential standard doses of the 2018 quadrivalent influenza vaccine (15 μg haemagglutinin per strain) in a prime-boost schedule 28 days apart. We measured strain-specific antibody titres, an accepted surrogate of likely efficacy, and induction of strain-specific B-cell responses following the prime and boost immunisations.ResultsWhereas priming immunisation induced the expected increase in strain-specific antibody titres, a second booster dose was strikingly ineffective at further increasing antibody titres. Similarly, priming immunisation induced strain-specific B-cells, but a second booster dose did not further enhance the B-cell response. Poor antibody responses were associated with male gender and cumulative cigarette exposure.ConclusionsPrime-boost, double-dose immunisation does not further improve influenza vaccine immunogenicity in previously vaccinated COPD patients. These findings underscore the need to design more effective vaccine strategies for COPD patients for influenza.