Sham Control Research Articles

Placebo response to sham electroacupuncture in patients with chronic functional constipation: A secondary analysis.

Chronic severe functional constipation is a common disease that requires novel and effective treatment strategies. Acupuncture might constitute a promising therapeutic approach for chronic constipation, but it reportedly engenders an enhanced placebo response. Herein, we aimed to determine the magnitude of the placebo responses to electroacupuncture for constipation and identify its influencing factors. In this secondary analysis of a multicenter randomized trial, patients were randomized to a sham electroacupuncture group, which was administered for 8 weeks in 24 sessions of superficial needling at nonacupoints. The placebo response rates were assessed using three responder criteria: ≥3 complete spontaneous bowel movements per week (CSBMs/week), overall CSBM, and sustained CSBM. Logistic regression with backward selection method was employed to identify the potential factors that affected the placebo response. Overall, 539 patients were included in the study. The placebo response rate was 10.58%, 9.46%, and 9.09% according to the three aforementioned criteria, respectively. Those who exhibited more CSBMs/week at baseline were more likely to respond to sham electroacupuncture. Among patients with more than one CSBM per week at baseline, the response rates for achieving the criteria of ≥3 CSBMs per week, overall CSBM, and sustained CSBM were 25.40%, 30.16%, and 22.22%. Electroacupuncture did not demonstrate a large placebo response in functional constipation treatment. The number of CSBMs at baseline may be a moderator of the placebo response to sham electroacupuncture. Thus, superficial needling sham acupuncture may be considered an ideal sham control for clinical trials of chronic constipation.

Effect of His Bundle Pacing on Abnormal Myocardial Fatty Acid and Glucose Metabolism Induced by Right Ventricular Pacing.

Metabolic disorder is noted for pacing-induced cardiomyopathy. The benefits of His bundle pacing over right ventricular (RV) pacing in preventing pacing-induced cardiomyopathy from a metabolic perspective are yet to be fully understood. Three pig groups were established for this study: sham control, RV pacing (RV pacing for 6 months), and His pacing (RV pacing for 6 months, followed by His bundle pacing for 3 months). Complete atrioventricular block was created in the last 2 groups. Left ventricular function and dyssynchrony were assessed via echocardiography, while proteins linked to metabolism, endoplasmic reticulum stress, and inflammation in left ventricular myocardium were examined. The RV pacing group had significantly more left ventricular mechanical dyssynchrony compared with the other groups. The RV pacing group exhibited triglyceride and diacylglycerol accumulation in cardiomyocytes and higher expression of binding immunoglobulin protein and tumor necrosis factor-α than the other groups. Additionally, the expression of CD36 was activated, while the expression of hormone-sensitive lipase was downregulated in the RV pacing group compared with the His pacing and sham control groups. Furthermore, the expressions of GLUT4 and pyruvate dehydrogenase were higher in the RV pacing group than the sham control and His pacing groups. Notably, the abnormal fatty acid and glucose metabolic pathways in the left ventricular myocardium during RV pacing could be corrected by His bundle pacing. His bundle pacing can mitigate the abnormal metabolism disorders, endoplasmic reticulum stress, and inflammation induced during RV pacing and may contribute to the superiority of conduction system pacing over RV pacing in reducing heart failure hospitalization.

Integrated multi-omic analysis identifies fatty acid binding protein 4 as a biomarker and therapeutic target of ischemia–reperfusion injury in steatotic liver transplantation

Background and aimsDue to a lack of donor grafts, steatotic livers are used more often for liver transplantation (LT). However, steatotic donor livers are more sensitive to ischemia–reperfusion (IR) injury and have a worse prognosis after LT. Efforts to optimize steatotic liver grafts by identifying injury targets and interventions have become a hot issue.MethodsMouse LT models were established, and 4D label-free proteome sequencing was performed for four groups: normal control (NC) SHAM, high-fat (HF) SHAM, NC LT, and HF LT to screen molecular targets for aggravating liver injury in steatotic LT. Expression detection of molecular targets was performed based on liver specimens from 110 donors to verify its impact on the overall survival of recipients. Pharmacological intervention using small-molecule inhibitors on an injury-related target was used to evaluate the therapeutic effect. Transcriptomics and metabolomics were performed to explore the regulatory network and further integrated bioinformatics analysis and multiplex immunofluorescence were adopted to assess the regulation of pathways and organelles.ResultsHF LT group represented worse liver function compared with NC LT group, including more apoptotic hepatocytes (P < 0.01) and higher serum transaminase (P < 0.05). Proteomic results revealed that the mitochondrial membrane, endocytosis, and oxidative phosphorylation pathways were upregulated in HF LT group. Fatty acid binding protein 4 (FABP4) was identified as a hypoxia-inducible protein (fold change > 2 and P < 0.05) that sensitized mice to IR injury in steatotic LT. The overall survival of recipients using liver grafts with high expression of FABP4 was significantly worse than low expression of FABP4 (68.5 vs. 87.3%, P < 0.05). Adoption of FABP4 inhibitor could protect the steatotic liver from IR injury during transplantation, including reducing hepatocyte apoptosis, reducing serum transaminase (P < 0.05), and alleviating oxidative stress damage (P < 0.01). According to integrated transcriptomics and metabolomics analysis, cAMP signaling pathway was enriched following FABP4 inhibitor use. The activation of cAMP signaling pathway was validated. Microscopy and immunofluorescence staining results suggested that FABP4 inhibitors could regulate mitochondrial membrane homeostasis in steatotic LT.ConclusionsFABP4 was identified as a hypoxia-inducible protein that sensitized steatotic liver grafts to IR injury. The FABP4 inhibitor, BMS-309403, could activate of cAMP signaling pathway thereby modulating mitochondrial membrane homeostasis, reducing oxidative stress injury in steatotic donors.Graphical

A nine-month repeat-dose intravaginal ring (Ovaprene) irritation study in sheep

ObjectivesOvaprene is a novel, investigational, intravaginal hormone-free monthly ring contraceptive designed for use in women of reproductive age to be worn over multiple weeks (one menstrual cycle). The objective of this work was to evaluate the safety of Ovaprene during a nine-month repeat-dose sheep study. Study designIn addition to traditional safety endpoints such as histopathological evaluation of the sheep female reproductive tract, vaginal fluids were collected and tested for released iron over time. Also, the amount of iron in the rings was assessed following removal, and serum iron levels were measured. There were four sheep in each group (Ovaprene group and sham group). ResultsThere were no macroscopic clinical findings. There was minimal to mild, mixed or mononuclear cell infiltration present in all levels of vagina (cranial, mid, and caudal) from all animals including sham controls based on post-study necropsy. The female reproductive tract from animals treated with the Ovaprene ring was comparable to the sham controls. The concentrations of serum iron in sheep treated with Ovaprene ring were similar compared to a sham treated animal. The average amount of ferrous gluconate released from Ovaprene over the 29-day period of use was 175 mg of the approximately 512 mg nominally loaded into the rings. ConclusionsOverall, the Ovaprene devices were well-tolerated in female sheep. ImplicationsThis study should support a chronic (e.g., one year) contraceptive efficacy study in women.

Peritoneal sepsis caused by Escherichia coli triggers brainstem inflammation and alters the function of sympatho-respiratory control circuits

BackgroundSepsis has a high mortality rate due to multiple organ failure. However, the influence of peripheral inflammation on brainstem autonomic and respiratory circuits in sepsis is poorly understood. Our working hypothesis is that peripheral inflammation affects central autonomic circuits and consequently contributes to multiorgan failure in sepsis.MethodsIn an Escherichia coli (E. coli)–fibrin clot model of peritonitis, we first recorded ventilatory patterns using plethysmography before and 24 h after fibrin clot implantation. To assess whether peritonitis was associated with brainstem neuro-inflammation, we measured cytokine and chemokine levels in Luminex assays. To determine the effect of E. coli peritonitis on brainstem function, we assessed sympatho-respiratory nerve activities at baseline and during brief (20 s) hypoxemic ischemia challenges using in situ-perfused brainstem preparations (PBPs) from sham or infected rats. PBPs lack peripheral organs and blood, but generate vascular tone and in vivo rhythmic activities in thoracic sympathetic (tSNA), phrenic and vagal nerves.ResultsRespiratory frequency was greater (p < 0.001) at 24 h post-infection with E. coli than in the sham control. However, breath-by-breath variability and total protein in the BALF did not differ. IL-1β (p < 0.05), IL-6 (p < 0.05) and IL-17 (p < 0.04) concentrations were greater in the brainstem of infected rats. In the PBP, integrated tSNA (p < 0.05) and perfusion pressure were greater (p < 0.001), indicating a neural-mediated pathophysiological high sympathetic drive. Moreover, respiratory frequency was greater (p < 0.001) in PBPs from infected rats than from sham rats. Normalized phase durations of inspiration and expiration were greater (p < 0.009, p < 0.015, respectively), but the post-inspiratory phase (p < 0.007) and the breath-by-breath variability (p < 0.001) were less compared to sham PBPs. Hypoxemic ischemia triggered a biphasic response, respiratory augmentation followed by depression. PBPs from infected rats had weaker respiratory augmentation (p < 0.001) and depression (p < 0.001) than PBPs from sham rats. In contrast, tSNA in E. coli-treated PBPs was enhanced throughout the entire response to hypoxemic ischemia (p < 0.01), consistent with sympathetic hyperactivity.ConclusionWe show that peripheral sepsis caused brainstem inflammation and impaired sympatho-respiratory motor control in a single day after infection. We conclude that central sympathetic hyperactivity may impact vital organ systems in sepsis.

Slow waves during deep sleep support cardiac function

Introduction The role of sleep in cardiovascular health, particularly the impact of deep non-rapid eye movement (NREM) sleep, is gaining interest in the prevention of cardiovascular diseases (Grandner et al., 2016). Essentially slow waves, prominent brain oscillations during deep sleep, seem to represent an important cardiovascular recovery process for the human body. However, to date, the specific mechanisms through which sleep affects cardiovascular function and whether slow waves accelerate recovery remain elusive. Methods Here, we explored the role of slow waves in promoting cardiovascular function. In this randomized, cross-over trial involving 18 healthy male participants (Huwiler et al., 2023), we investigated how experimentally enhancing slow waves via auditory stimulation (Huwiler et al., 2022) impacts cardiovascular dynamics during sleep and next-day cardiac function, assessed via an echocardiography. All participants underwent three experimental nights including two conditions for slow wave enhancement and one SHAM control condition while brain oscillatory, blood pressure, and cardiac dynamics were continuously measured during sleep. Results Using a linear mixed-effect model approach, we found auditory stimulation to significantly increase slow wave activity (F(2, 33.095) = 11.397, p &lt; 0.001) during times of stimulation. This slow wave enhancement coincided with a dynamic cardiovascular activation, indicated through short increases in blood pressure and a biphasic heart rate response. After sleep, we found a significant increase in general longitudinal strain (F(2, 34) = 81.17, p &lt; 0.001), an increase in left-ventricular ejection fraction (F(2, 34) = 4.55, p = 0.018), and a decrease in E/e’ ratio (F(2, 34) = 3.38, p = 0.046) for both slow wave stimulation conditions compared to SHAM. Discussion/Conclusion We show that slow wave stimulation induces a cardiovascular activation response possibly related to increasing cardiovascular stability during sleep (De Zambotti et al., 2016). Moreover, we demonstrate that slow wave stimulation enhances left-ventricular systolic and diastolic function, both together indicating improved cardiac function. Altogether, this points towards the functional involvement of slow waves in promoting cardiovascular health. Therefore, sleep slow wave stimulation may be considered a potential supplementary method in treating cardiovascular diseases involving decreased left-ventricular function. Furthermore, our findings hint that enhancing slow waves could potentially optimize post-exercise recovery processes and increase cardiovascular well-being.

(061) Analysis of BMP4 and GREM1 as Targets of SHH Signaling and Downstream Regulators of the Collagen Axis in the Penis

Abstract Introduction Cavernous nerve (CN) injury caused by prostatectomy and diabetes, initiates a remodeling process (smooth muscle apoptosis and increased collagen) in the corpora cavernosa of the penis of patients and animal models that is an underlying cause of erectile dysfunction (ED). The Sonic hedgehog (SHH) pathway plays an essential role in the response of the penis to denervation, as collagen increases with SHH inhibition and decreases with SHH treatment. Part of the mechanism of how SHH impacts collagen may involve bone morphogenetic protein four (BMP4) and GREMLIN (GREM1). Microarray analysis identified increased GREM1 (BMP4 antagonist) in corpora cavernosa of ED patients and SHH is a regulator of GREM1 in the limb bud. Objective We will examine the relationship between SHH, BMP4, GREM1 and collagen in penis of ED patients and rat models of CN injury, SHH inhibition, and SHH, BMP4 and GREM1 treatment. Methods Corpora cavernosa of Peyronie’s (control), prostatectomy and diabetic ED patients was obtained (n=26). Adult Sprague Dawley rats (n=90) underwent either: 1. CN crush (1-7 days) or sham control, 2. CN injury and BMP4, GREM1 or MSA (control) protein treatment via Affi-Gel beads or peptide amphiphile (PA) for 14 days, 3. 5E1 SHH inhibitor, IgG and PBS (controls), or SHH protein treatment for 2-4 days. Immunohistochemical and western analysis for BMP-4 and GREM1, and collagen analysis by hydroxyproline and trichrome stain were performed. Results BMP4 and GREM1 proteins were identified in corpora cavernosal smooth muscle of prostatectomy, diabetic and Peyronie’s patients, and in rat penis, sympathetic nerve fibers, perineurium, blood vessels, and urethra. Collagen decreased 25.4% in rats with CN injury and BMP4 PA treatment (p=0.02) and increased 61.3% with CN injury and GREM1 treatment (p=0.005). Trichrome showed increased collagen in rats treated with GREM1. BMP4 increased smooth muscle. Western identified increased BMP4 and GREM1 in corpora cavernosa of prostatectomy and diabetic patients, and after CN injury (1-2 days) in our rat model. Localization of BMP4 and GREM1 changed with SHH inhibition. SHH treatment increased BMP4 and GREM1. Aging did not impact BMP4 and GREM1 localization. Conclusions BMP4 and GREM1 are downstream targets of SHH that impact collagen and may be useful in collaboration with SHH to prevent penile remodeling and ED. Better understanding of penile remodeling and how fibrosis occurs is essential for development of novel therapies for ED. Disclosure No.

(066) Targets of SHH Signaling, BMP4 and GREM1, are Downstream Regulators of Smooth Muscle in the Penis

Abstract Introduction A key aspect of erectile dysfunction (ED) development is loss of innervation to the penis. The cavernous nerve (CN) is frequently damaged in prostatectomy and diabetic patients with ED, initiating changes in penile morphology including an acute and intense phase of apoptosis in penile smooth muscle followed by increasing collagen and fibrosis. This remodeling process alters penile architecture so that there is less smooth muscle in the corpora cavernosa, and what remains is less compliant/able to relax in response to normal neurotransmitter signaling, and ED results. Thus, novel therapies are needed which target the underlying remodeling process. We have shown previously that Sonic hedgehog (SHH) is a critical regulator of penile smooth muscle, and that SHH protein treatment suppresses penile remodeling after CN injury through an unknown mechanism. Objective We examine if part of the mechanism of how SHH preserves smooth muscle after CN injury involves bone morphogenetic protein 4 (BMP4) and GREMLIN (GREM1). Methods Primary cultures of smooth muscle cells were established from patients who had prostatectomy, diabetes, hypertension and Peyronie’s (control, n=18). Cultures were characterized by immunohistochemical analysis (IHC) for ACTA2, CD31, P4HB and nNOS. Smooth muscle cell growth was quantified in response to BMP4 and GREM1. Adult Sprague Dawley rats that were uninjured or underwent CN crush injury, were treated with BMP4, GREM1 or MSA (control) proteins via Affi-Gel beads (n=16) or peptide amphiphile (PA, n=26) for 3 and 14 days, and trichrome stain was performed. Sprague Dawley rats underwent CN injury (n=9) and SHH PA treatment for 1, 2 and 4 days (n=9) and western was performed assaying for BMP4 and GREM1 proteins in comparison to sham (n=3) controls. Adult Sprague Dawley rats were treated with 5E1 SHH inhibitor (n=6) or IgG (control, n=6) for 2 and 4 days, and BMP4 and GREM1 localization were examined by IHC. Statistics were performed by ANOVA with Scheffe’s posthoc test. Results Patient primary smooth muscle cultures were established. BMP-4 increased patient smooth muscle cell growth and GREM1 decreased growth. In rats BMP4 treatment via Aff-Gel beads and PA increased smooth muscle growth at 3 and 14 days of treatment. GREM1 treatment caused collagen and smooth muscle growth at 3 days, which switched to primarily collagen at 14 days. CN injury increased BMP4 and GREM1. SHH PA altered western band size suggesting alternative cleavage and range of signaling. SHH inhibition in rats changed BMP4 and GREM1 localization. Conclusions BMP4 treatment increases smooth muscle in patient cultures and in our rat model. BMP4 and GREM1 mediate a switch from smooth muscle to collagen induction. SHH treatment alters BMP4 and GREM1 localization and range of signaling, which can affect penile morphology. Whether GREM1 directly effects collagen induction or acts strictly through inhibition of BMP4 is unknown and requires further study. Part of the mechanism of how SHH regulates corpora cavernosal smooth muscle, involves BMP4 and GREM1. Understanding how SHH PA impacts penile morphology after CN injury will aid development of ED therapies. Disclosure No.

Evaluation of Adjuvant Effect of Cytosine-Guanosine-Oligodeoxynucleotide in Meat-Type Chickens Coadministered In Ovo with Herpesvirus of Turkey Vaccine.

Herpesvirus of turkey (HVT) increases activation of T cells in 1-day-old chickens when administered in ovo. This study evaluated whether adding cytosine-guanosine oligodeoxynucleotides (CpG ODNs) to the HVT vaccine could enhance the adjuvant effect of HVT. We used a CpG ODN dose of 10 μg per egg. The experimental groups were (1) diluent-only control (sham), (2) HVT, (3) HVT+CpG ODN, (4) HVT+non-CpG ODN, (5) CpG ODN, and (6) non-CpG ODN control. Cellular response evaluation included measuring the frequencies of macrophages (KUL01+MHC-II+), gamma delta T cells (γδTCR+MHC-II+), CD4+, and CD8+ T cell subsets, including double-positive (DP) cells. In addition, CD4+ and CD8+ T cell activation was evaluated by measuring the cellular expression of major histocompatibility complex class II (MHC-II), CD44 or CD28 costimulatory molecules. An adjuvant effect was considered when HVT+CpG ODN, but not HVT+non CpG ODN, or CpG ODN, or non-CpG ODN, induced significantly increased effects on any of the immune parameters examined when compared with HVT. The findings showed that (1) HVT vaccination induced significantly higher frequencies of γδ+MHC-II+ and CD4+CD28+ T cells when compared with sham chickens. Frequencies of DP and CD4+CD28+ T cells in HVT-administered birds were significantly higher than those observed in the non-CpG ODN group. (2) Groups receiving HVT+CpG ODN or CpG ODN alone were found to have significantly increased frequencies of activated CD4+ and CD8+ T cells, when compared with HVT. Our results show that CpG ODN administration in ovo with or without HVT significantly increased frequencies of activated CD4+ and CD8+ T cells.

Abstract WP321: Novel Therapeutic Potential of Intestinal Organoids Secretomes for Cerebrovascular Stroke

Background: Our recent studies show that transplants of intestine epithelial stem cells (IESCs) promote acute and long term recovery after stroke in middle-aged rats. To improve the translational potential of this therapy, we investigated whether injections of the IESC conditioned media (CM) would be similarly effective in improving acute and chronic stroke outcomes. Methods: Conditioned media was collected intestinal organoids culture from young animals and processed for proteomic and tropic factors analysis. CM efficacy was tested in middle-aged male and female rats assigned to the following groups: Control (sham), stroke+vehicle injection, or stroke+IESC-CM treatment. Middle cerebral artery occlusion (MCAo) was induced by Endothelin-1 (vasoconstrictor). Conditioned media was injected ip (CMip) 4h/24h/48h after stroke. In the acute phase, infarct volume, sensorimotor function and serum levels of the gut permeability markers were measured 4d post stroke. Long term (4 weeks after stroke) depressive-like behavior was assessed by the Social Interaction test, and cognitive performance by the Novel object Recognition test and Barnes maze test. Results: Proteomic analysis of CM showed elevated levels of small peptide growth factors ad large matrix molecules. IESC-CMip treatment significantly improved acute stroke outcomes and reduced gut permeability in middle-aged hosts of either sex. In long term study, vehicle-treated MCAo animals showed depressive-like behaviors compared to their pre-stroke behaviors. In contrast, stroke animals that received IESC secretome were no different from their pre stroke performance and were similar sham (no-stroke) animals. In cognition assesments. MCAo+vehicle animals showed poor ability to discriminate the novel object and displayed impaired learning and recall on the Barnes maze. MCAo animals that received IESC secretome did not show significant improved during the Barnes learning trials, but retrieval (memory recall) performance was improved and significantly different from the vehicle group. Conclusion: Overall, these data show that IESC secretome derived from a healthy young animal can significantly improve acute stroke outcomes and specific aspects of cognitive performance.

Brilaroxazine lipogel displays antipsoriatic activity in imiquimod-induced mouse model.

Dopamine (D) and serotonin (5-HT) pathways contribute to psoriasis pathobiology. Disruptions incite increased inflammatory mediators, keratinocyte activation and deterioration, and worsening symptoms. Brilaroxazine (RP5063), which displays potent high binding affinity to D2/3/4 and 5-HT1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology. An imiquimod-induced psoriatic mouse model (BALB/c) evaluated brilaroxazine's activity in a topical liposomal-aqueous gel (Lipogel) formulation. Two of the three groups (n=6 per) underwent induction with 5% imiquimod, and one group received topical brilaroxazine Lipogel (Days 1-11). Assessments included (1) Psoriasis Area and Severity Index (PASI) scores (Days 1-12), skin histology for Baker score based on H&E stained tissue (Day 12), and serum blood collection for serum cytokine analysis (Day 12). One-way ANOVA followed by post hoc Dunnett's t-test evaluated significance (p<0.05). Imiquimod-induced animal Baker scores were higher versus Sham non-induced control's results (p<0.001). Brilaroxazine Lipogel had significantly (p=0.003) lower Baker scores versus the induced Psoriasis group. Brilaroxazine PASI scores were lower (p=0.03) versus the induced Psoriasis group (Days3-12), with the greatest effect in the last 3 days. The induced Psoriasis group showed higher Ki-67 and TGF-β levels versus non-induced Sham controls (p=0.001). The brilaroxazine Lipogel group displayed lower levels of these cytokines versus the induced Psoriasis group, Ki-67 (p=0.001) and TGF-β (p=0.008), and no difference in TNF-α levels versus Sham non-induced controls. Brilaroxazine Lipogel displayed significant activity in imiquimod-induced psoriatic animals, offering a novel therapeutic strategy.

Alleviation of radiation combined skin injury in rat model by topical application of ascorbate formulation

Purpose This research endeavor was undertaken to elucidate the impact of an innovative ascorbate formulation on the regeneration process of full-thickness excision wounds in a rat model exposed to whole-body gamma irradiation, replicating conditions akin to combat or radiation emergency scenarios. Materials and Methods We established a comprehensive rat model by optimizing whole body γ-radiation doses (5–9 Gy) and full-thickness excision wound sizes (1–3 cm2) to mimic radiation combined injury (RCI). The developed RCI model was used to explore the healing potential of ascorbate formulation. The study includes various treatment groups (i.e., sham control, radiation alone, wound alone, radiation + wound, and radiation + wound + formulation). The ascorbate formulation was applied twice daily, with a 12-hour gap between each application, starting 1 hour after the initiation of the wound. The healing potential of the formulation in the RCI context was evaluated over 14 days through hematological, molecular, and histological parameters. Results The combination of a 5 Gy radiation dose and a 1 cm2 wound was identified as the optimal setting to develop the RCI model for subsequent studies. The formulation was used topically immediately following RCI, and then twice daily until complete healing. Treatment with the ascorbate formulation yielded noteworthy outcomes and led to a substantial reduction (p < .05) in the wound area, accelerated epithelialization periods, and an increased wound contraction rate. The formulation’s localized healing response improved organ weights, normalized blood parameters, and enhanced hematopoietic and immune systems. A gene expression study revealed the treatment up-regulated TGF-β and FGF, and down-regulated PDGF-α, TNF-α, IL-1β, IL-6, MIP-1α, and MCP-1 (p < .05). Histopathological assessments supported the formulation’s effectiveness in restoring cellular architecture and promoting tissue regeneration. Conclusion Topical application of the ascorbate formulation in RCI resulted in a significant improvement in delayed wound healing, leading to accelerated wound closure by mitigating the expression of inflammatory responses.

Does training improve users' mental models about adaptive cruise control?

While Advanced Driver Assistance Systems (ADAS) promise safety benefits to drivers, there is evidence to suggest that drivers are unaware or uninformed about their vehicles’ systems and thus have poor mental models about the systems. Previous studies suggest that training improves drivers’ mental models, although some studies report limited impacts. This study investigated the relationship between training and drivers’ mental models about Adaptive Cruise Control (ACC), compared the impact of two different training approaches on drivers’ mental models, and examined the relationship between driver knowledge and trust regarding ADAS technologies. This study was conducted online, and participants were randomly and equally assigned to one of three training groups – owner’s manual (text-based); state diagram visualization; or sham (control). Surveys measured their trust and mental models about ACC before and after training. The results found that the text-based group outperformed the visualization group and the control group in terms of post-training overall mental model scores, but these differences were not statistically significant. No correlation between post-training mental model scores and overall trust scores was found. This study provides evidence that training improves users’ mental models about technology and finds that different training platforms or paradigms may affect learning differently.

Effects on pain of kinesiology tape in patients with plantar fasciitis: a randomized controlled study

Purpose. Plantar fasciitis is the most frequent cause of heel pain. Custom-made plantar supports are a common treatment solution, while the application of kinesiology tape (KT) can be an effective measure to alleviate pain. The objective was to evaluate the effects of KT on the pain of patients with plantar fasciitis. Methods. Randomized controlled trial including participants with plantar fasciitis. There was an experimental group (n = 17), whose participants underwent a KT treatment, and a control (sham tape) group (n = 17). The pain, measured with a visual analog scale (VAS), was the primary outcome and was assessed daily until the fifth day of wearing the tape and 24 h after removing it. Inferential statistics looked for time, group, and time per group differences with CI at 95%. Results. The greatest between-group VAS difference was 3.5 points, and occurred at the 2-day follow-up assessment. Then, pain differences decreased over time until the last assessment point. Statistically significant time, group, and time*group differences were found with p < 0.001. Conclusion. This study supports that KT is effective in reducing pain in the short term in patients with plantar fasciitis, and more effective than a sham intervention with tape.

Male versus female inflammatory response after brain death model followed by ex vivo lung perfusion

BackgroundEx vivo lung perfusion (EVLP) is a useful tool for assessing lung grafts quality before transplantation. Studies indicate that donor sex is as an important factor for transplant outcome, as females present higher inflammatory response to brain death (BD) than males. Here, we investigated sex differences in the lungs of rats subjected to BD followed by EVLP.MethodsMale and female Wistar rats were subjected to BD, and as controls sham animals. Arterial blood was sampled for gas analysis. Heart–lung blocks were kept in cold storage (1 h) and normothermic EVLP carried out (4 h), meanwhile ventilation parameters were recorded. Perfusate was sampled for gas analysis and IL-1β levels. Leukocyte infiltration, myeloperoxidase presence, IL-1β gene expression, and long-term release in lung culture (explant) were evaluated.ResultsBrain dead females presented a low lung function after BD, compared to BD-males; however, at the end of the EVLP period oxygenation capacity decreased in all BD groups. Overall, ventilation parameters were maintained in all groups. After EVLP lung infiltrate was higher in brain dead females, with higher neutrophil content, and accompanied by high IL-1β levels, with increased gene expression and concentration in the culture medium (explant) 24 h after EVLP. Female rats presented higher lung inflammation after BD than male rats. Despite maintaining lung function and ventilation mechanics parameters for 4 h, EVLP was not able to alter this profile.ConclusionIn this context, further studies should focus on therapeutic measures to control inflammation in donor or during EVLP to increase lung quality.

Exclusive Enteral Nutrition Beneficially Modulates Gut Microbiome in a Preclinical Model of Crohn's-like Colitis.

Exclusive enteral nutrition (EEN) is an established dietary treatment for Crohn's disease (CD) by alleviating inflammation and inducing remission. However, the mechanisms of action of EEN are incompletely understood. As CD is associated with gut microbiome dysbiosis, we investigated the effect of EEN on the microbiome in a rat model of CD-like colitis. The rat model of CD-like colitis was established by an intracolonic instillation of TNBS at 65 mg/kg in 250 µL of 40% ethanol. Sham control rats were instilled with saline. Rats were fed ad libitum with either regular pellet food or EEN treatment with a clear liquid diet (Ensure). Rats were euthanized at 7 days. Fecal pellets were collected from the distal colon for 16S rRNA sequencing analysis of gut microbiota. In addition, colon tissues were taken for histological and molecular analyses in all the groups of rats. EEN administration to TNBS-induced CD rats significantly improved the body weight change, inflammation scores, and disease activity index. The mRNA expression of IL-17A and interferon-γ was significantly increased in the colonic tissue in TNBS rats when fed with regular food. However, EEN treatment significantly attenuated the increase in IL-17A and interferon-γ in TNBS rats. Our 16S rRNA sequencing analysis found that gut microbiota diversity and compositions were significantly altered in TNBS rats, compared to controls. However, EEN treatment improved alpha diversity and increased certain beneficial bacteria such as Lactobacillus and Dubosiella and decreased bacteria such as Bacteroides and Enterorhabdus in CD-like rats, compared to CD-like rats with the regular pellet diet. In conclusion, EEN treatment increases the diversity of gut microbiota and the composition of certain beneficial bacteria. These effects may contribute to the reduced inflammation by EEN in the rat model of CD-like colitis.

Contribution of the medial entorhinal cortex to performance on the Traveling Salesperson Problem in rats

In order to successfully navigate through space, animals must rely on multiple cognitive processes, including orientation in space, memory of object locations, and navigational decisions based on that information. Although highly-controlled behavioral tasks are valuable for isolating and targeting specific processes, they risk producing a narrow understanding of complex behavior in natural contexts. The Traveling Salesperson Problem (TSP) is an optimization problem that can be used to study naturalistic foraging behaviors, in which subjects select routes between multiple baited targets. Foraging is a spontaneous, yet complex, behavior, involving decision-making, attention, course planning, and memory. Previous research found that hippocampal lesions in rats impaired TSP task performance, particularly on measures of spatial memory. Although traditional laboratory tests have shown the medial entorhinal cortex (MEC) to play an important role in spatial memory, if and how the MEC is involved in finding efficient solutions to the TSP remains unknown. In the current study, rats were trained on the TSP, learning to retrieve bait from targets in a variety of spatial configurations. After recovering from either an MEC lesion or control sham surgery, the rats were tested on eight new configurations. Our results showed that, similar to rats with hippocampal lesions, MEC-lesioned rats were impaired on measures of spatial memory, but not spatial decision-making, with greatest impairments on configurations requiring a global navigational strategy for selecting the optimal route. These findings suggest that the MEC is important for effective spatial navigation, especially when global cue processing is required.

The effects of the cholinergic system on carrageenan-induced arthritis

The cholinergic system has been found to make an anti-inflammatory effect through the cholinergic anti-inflammatory pathway (CAIP), which suppresses the production of pro-inflammatory cytokines by secreting acetylcholine, a major neurotransmitter. However, no studies have been conducted on the effects of CAIP on joint pain and inflammation. In this study, we investigated the effects of muscarinic acetylcholine receptors (mAChRs) in knee arthritis. To examine pain behavioral changes, atropine (or saline for sham control) was pretreated in the joint cavity of rats at 1 % carrageenan + 5, 10, and 30 μL and the dynamic weight-bearing evaluation was performed. Synovial membranes were collected and cyclooxygenase-2 (COX-2) and interleukin-1β (IL-1β) were measured using a western blot. Hematoxylin and eosin staining was performed. Compared to that of the sham group, the weight-bearing of the affected knee joint significantly increased in the 1 % carrageenan + 10 μL atropine group (p < 0.05). However, no significant changes were observed in the 1 % carrageenan + 5 and 30 μL atropine groups. COX-2 and IL-1β and the number of inflammatory cells in synovial membrane significantly increased with 1 % carrageenan + 10 μL of atropine (p < 0.05). These results suggest that cholinergic system is involved in knee joint pain and inflammation and that mAChRs are potential therapeutic targets for knee joint arthritis.

Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation.

Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction. We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function. Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; P<0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; P=0.03 versus reperfusion alone and P<0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle. We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.

Increasing striatal dopamine release through repeated bouts of theta burst transcranial magnetic stimulation of the left dorsolateral prefrontal cortex. A 18F-desmethoxyfallypride positron emission tomography study.

Transcranial Magnetic Stimulation (TMS) can modulate fronto-striatal connectivity in the human brain. Here Positron Emission Tomography (PET) and neuro-navigated TMS were combined to investigate the dynamics of the fronto-striatal connectivity in the human brain. Employing 18F-DesmethoxyFallypride (DMFP) - a Dopamine receptor-antagonist - the release of endogenous dopamine in the striatum in response to time-spaced repeated bouts of excitatory, intermittent theta burst stimulation (iTBS) of the Left-Dorsolateral Prefrontal Cortex (L-DLPFC) was measured. 23 healthy participants underwent two PET sessions, each one with four blocks of iTBS separated by 30 minutes: sham (control) and verum (90% of individual resting motor threshold). Receptor Binding Ratios were collected for sham and verum sessions across 37 time frames (about 130 minutes) in striatal sub-regions (Caudate nucleus and Putamen). Verum iTBS increased the dopamine release in striatal sub-regions, relative to sham iTBS. Dopamine levels in the verum session increased progressively across the time frames until frame number 28 (approximately 85 minutes after the start of the session and after three iTBS bouts) and then essentially remained unchanged until the end of the session. Results suggest that the short-timed iTBS protocol performed in time-spaced blocks can effectively induce a dynamic dose dependent increase in dopaminergic fronto-striatal connectivity. This scheme could provide an alternative to unpleasant and distressing, long stimulation protocols in experimental and therapeutic settings. Specifically, it was demonstrated that three repeated bouts of iTBS, spaced by short intervals, achieve larger effects than one single stimulation. This finding has implications for the planning of therapeutic interventions, for example, treatment of major depression.