Effects of Noise Electrical Stimulation on Proprioception, Force Control, and Corticomuscular Functional Connectivity

Sensory afferent inputs play an important role in neuromuscular functions. Subsensory level noise electrical stimulation enhances the sensitivity of peripheral sensory system and improves lower extremity motor function. The current study aimed to investigate the immediate effects of noise electrical stimulation on proprioceptive senses and grip force control, and whether there are associated neural activities in the central nervous system. Fourteen healthy adults participated in 2 experiments on 2 different days. In day 1, participants performed grip force and joint proprioceptive tasks with and without (sham) noise electrical stimulation. In day 2, participants performed grip force steady hold task before and after 30-min noise electrical stimulation. Noise stimulation was applied with surface electrodes secured along the course of the median nerve and proximal to the coronoid fossa EEG power spectrum density of bilateral sensorimotor cortex and coherence between EEG and finger flexor EMG were calculated and compared. Wilcoxon Signed-Rank Tests were used to compare the differences of proprioception, force control, EEG power spectrum density and EEG-EMG coherence between noise electrical stimulation and sham conditions. The significance level (alpha) was set at 0.05. Our study found that noise stimulation with optimal intensity could improve both force and joint proprioceptive senses. Furthermore, individuals with higher gamma coherence showed better force proprioceptive sense improvement with 30-min noise electrical stimulation. These observations indicate the potential clinical benefits of noise stimulation on individuals with impaired proprioceptive senses and the characteristics of individuals who might benefit from noise stimulation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Preservation of vascular endothelial glycocalyx and barrier by activation of adenosine A2A receptor (A2AR) improved renal dysfunction in cirrhotic rats

Cirrhosis-related hepatic and renal endothelial dysfunction is characterized by macrophage-endothelium adhesion-mediated inflammation, glycocalyx/barrier damage, and impaired vasodilation. Activation of adenosine A2A receptor (A2AR) protects cirrhotic rats from impairment of hepatic microcirculation post hepatectomy. This study evaluates the effects of A2AR activation on the cirrhosis-related hepatic and renal endothelial dysfunction in biliary cirrhotic rats receiving two weeks of A2AR agonist PSB0777 [bile duct ligated (BDL)+PSB0777] treatment.Endothelial dysfunction in cirrhotic liver, renal vessels, and kidney is characterized by downregulation of the A2AR expressions, decreased vascular endothelial vasodilatory (p-eNOS)/anti-inflammatory (IL-10/IL-10R)/barrier [VE-cadherin (CDH5) and β-catenin (CTNNB1)]/glycocalyx [syndecan-1 (SDC1) and hyaluronan synthase-2 (HAS2)] markers, and increased leukocyte-endothelium adhesion molecules (F4/80, CD68, ICAM-1, and VCAM-1). In BDL rats, PSB0777 treatment improves hepatic and renal endothelial dysfunction, ameliorates portal hypertension, and attenuates renal hypoperfusion by restoring of the vascular endothelial anti-inflammatory, barrier, glycocalyx markers and vasodilatory response as well as inhibiting the leukocyte-endothelium adhesion. In an in vitro study, conditioned medium (CM) of bone marrow-derived macrophage (BMDM) of BDL rats [BMDM-CM (BDL)] induced barrier/glycocalyx damage, which was reversed by the PSB0777 pre-treatment. The A2AR agonist is a potential agent that can simultaneously correct cirrhosis-related hepatic and renal endothelial dysfunction, portal hypertension, renal hypoperfusion, and renal dysfunction

A Ten-Year Retrospective Cohort Study on Neck Collar Immobilization in Trauma Patients with Head and Neck Injuries

Background and Objectives: In the context of prehospital care, spinal immobilization is commonly employed to maintain cervical stability in head and neck injury patients. However, its use in cases of unclear consciousness or major trauma patients is often precautionary, pending the exclusion of unstable spinal injuries through appropriate diagnostic imaging. The impact of prehospital C-spinal immobilization in these specific patient populations remains uncertain. Materials and Methods: We conducted a retrospective cohort study at Taipei Tzu Chi Hospital from January 2009 to May 2019, focusing on trauma patients suspected of head and neck injuries. The primary outcome assessed was in-hospital mortality. We employed multivariable logistic regression to investigate the relationship between prehospital C-spine immobilization and outcomes, while adjusting for various factors such as age, gender, type of traumatic brain injury, Injury Severity Score (ISS), Revised Trauma Score (RTS), and activation of trauma team. Results: Our analysis encompassed 2733 patients. Among these, patients in the unclear consciousness group (GCS ≤ 8) who underwent C-spine immobilization exhibited a higher mortality rate than those without immobilization. However, there was no statistically significant difference in mortality among patients with alert consciousness (GCS > 8). Multivariable logistic regression analysis revealed that advanced age (age ≥ 65), unclear consciousness (GCS ≤ 8), major traumatic injuries (ISS ≥ 16 and RTS ≤ 7), and the use of neck collars for immobilization (adjusted OR: 1.850, 95% CI: 1.240–2.760, p = 0.003) were significantly associated with an increased risk of mortality. Subgroup analysis indicated that C-spine immobilization was significantly linked to an elevated risk of mortality in older adults (age ≥ 65), patients with unclear consciousness (GCS ≤ 8), those with major traumatic injuries (ISS ≥ 16 and RTS ≤ 7), and individuals in shock (shock index > 1). Conclusions: While our findings do not advocate for the complete abandonment of neck collars in all suspected head and neck injury patients, our study suggests that prehospital cervical and spinal immobilization should be applied more selectively in certain head and neck injury populations. This approach is particularly relevant for older individuals (age ≥ 65), those with unclear consciousness (GCS ≤ 8), individuals experiencing major traumatic injuries (ISS ≥ 16 or RTS ≤ 7), and patients in a state of shock (shock index ≥ 1). Our study employs a retrospective cohort design, which may introduce selection bias. Therefore, in the future, there is a need for confirmation of our results through a two-arm randomized controlled trial (RCT) arises, as this design is considered ideal for addressing this issue

Obeticholic acid treatment ameliorates the cardiac dysfunction in NASH mice.

BackgroundSuppression of cardiac iinflammasome, which can be inhibited by Farnesoid X receptor (FXR) agonist, can ameliorate cardiac inflammation and fibrosis. Increased cardiac inflammasome decrease the abundance of regulatory T (Treg) cells and exacerbate cardiac dysfunction. Interaction between cardiomyocytes and Treg cells is involved in the development of nonalcoholic steatohepatitis (NASH)-related cardiac dysfunction.AimsThis study evaluates whether the FXR agonist obeticholic acid (OCA) treatment improves NASH-associated cardiac dysfunction.MethodsThe in vivo and in vitro mechanisms and effects of two weeks of OCA treatment on inflammasome and Treg dysregulation-related cardiac dysfunction in NASH mice (NASH-OCA) at systemic, tissue and cellular levels were investigated.ResultsThe OCA treatment suppressed the serum and cardiac inflammasome levels, reduced the cardiac infiltrated CD3+ T cells, increased the cardiac Treg-represented anti-inflammatory cytokines (IL-10/IL-10R) and improved cardiac inflammation, fibrosis and function [decreased left ventricle (LV) mass and increased fractional shortening (FS)] in NASH-OCA mice. The percentages of OCA-decreased cardiac fibrosis and OCA-increased FS were positively correlated with the percentage of OCA-increased levels of cardiac FXR and IL-10/IL-10R. In the Treg cells from NASH-OCA mice spleen, in comparison with the Treg cells of the NASH group, higher intracellular FXR but lower inflammasome levels, and more proliferative/active and less apoptotic cells were observed. Incubation of H9c2 cardiomyoblasts with Treg-NASHcm [supernatant of Treg from NASH mice as condition medium (cm)], increased inflammasome levels, decreased the proliferative/active cells, suppressed the intracellular FXR, and downregulated differentiation/contraction marker. The Treg-NASHcm-induced hypocontractility of H9c2 can be attenuated by co-incubation with OCA, and the OCA-related effects were abolished by siIL-10R pretreatment.ConclusionsChronic FXR activation with OCA is a potential strategy for activating IL-10/IL-10R signalling, reversing cardiac regulatory T cell dysfunction, and improving inflammasome-mediated NASH-related cardiac dysfunction

Obeticholic acid treatment ameliorates the cardiac dysfunction in NASH mice

Background Suppression of cardiac iinflammasome, which can be inhibited by Farnesoid X receptor (FXR) agonist, can ameliorate cardiac inflammation and fibrosis. Increased cardiac inflammasome decrease the abundance of regulatory T (Treg) cells and exacerbate cardiac dysfunction. Interaction between cardiomyocytes and Treg cells is involved in the development of nonalcoholic steatohepatitis (NASH)-related cardiac dysfunction. Aims This study evaluates whether the FXR agonist obeticholic acid (OCA) treatment improves NASH-associated cardiac dysfunction. Methods The in vivo and in vitro mechanisms and effects of two weeks of OCA treatment on inflammasome and Treg dysregulation-related cardiac dysfunction in NASH mice (NASH-OCA) at systemic, tissue and cellular levels were investigated. Results The OCA treatment suppressed the serum and cardiac inflammasome levels, reduced the cardiac infiltrated CD3+ T cells, increased the cardiac Treg-represented anti-inflammatory cytokines (IL-10/IL-10R) and improved cardiac inflammation, fibrosis and function [decreased left ventricle (LV) mass and increased fractional shortening (FS)] in NASH-OCA mice. The percentages of OCA-decreased cardiac fibrosis and OCA-increased FS were positively correlated with the percentage of OCA-increased levels of cardiac FXR and IL-10/IL-10R. In the Treg cells from NASH-OCA mice spleen, in comparison with the Treg cells of the NASH group, higher intracellular FXR but lower inflammasome levels, and more proliferative/active and less apoptotic cells were observed. Incubation of H9c2 cardiomyoblasts with Treg-NASHcm [supernatant of Treg from NASH mice as condition medium (cm)], increased inflammasome levels, decreased the proliferative/active cells, suppressed the intracellular FXR, and downregulated differentiation/contraction marker. The Treg-NASHcm-induced hypocontractility of H9c2 can be attenuated by co-incubation with OCA, and the OCA-related effects were abolished by siIL-10R pretreatment. Conclusions Chronic FXR activation with OCA is a potential strategy for activating IL-10/IL-10R signalling, reversing cardiac regulatory T cell dysfunction, and improving inflammasome-mediated NASH-related cardiac dysfunction

A Novel pH-Tunable Secondary Conformation Containing Mixed Micellar System in Anticancer Treatment

In this study, for the first time, we precisely assembled the poly-&gamma;-benzyl-l-glutamate and an amphiphilic copolymer d-&alpha;-tocopherol polyethylene glycol succinate into a mixed micellar system for the embedment of the anticancer drug doxorubicin. Importantly, the intracellular drug-releasing behaviors could be controlled by changing the secondary structures of poly-&gamma;-benzyl-l-glutamate via the precise regulation of the buffer&rsquo;s pH value. Under neutral conditions, the micellar architectures were stabilized by both &alpha;-helix secondary structures and the microcrystalline structures. Under acidic conditions (pH 4.0), the interior structures transformed into a coil state with a disordered alignment, inducing the release of the loaded drug. A remarkable cytotoxicity of the Dox-loaded mixed micelles was exhibited toward human lung cancer cells in vitro. The internalizing capability into the cancer cells, as well as the intracellular drug-releasing behaviors, were also identified and observed. The secondary structures containing Dox-loaded mixed micelles had an outstanding antitumor efficacy in human lung cancer A549 cells-bearing nude mice, while little toxicities occurred or interfered with the hepatic or renal functions after the treatments. Thus, these pH-tunable &alpha;-helix-containing mixed micelles are innovative and promising for controlled intracellular anticancer drug delivery

Non-Selective Beta-Blockers Decrease Infection, Acute Kidney Injury Episodes, and Ameliorate Sarcopenic Changes in Patients with Cirrhosis: A Propensity-Score Matching Tertiary-Center Cohort Study

Background: Cirrhotic complications resulting from portal hypertension can be considerably reduced by non-selective beta-blockers (NSBBs); however, scarce studies have investigated therapeutic agents for other complications. We aimed to investigate the effects of NSBBs on common cirrhotic complications of infection, acute kidney injury (AKI), chronic renal function declination, and sarcopenic changes. Methods: Medical records of hospitalization for cirrhosis with at least a 4-year follow-up were analyzed and selected using propensity-score matching (PSM). Generalized estimating equation (GEE) was applied to assess the association of NSBBs with infection requiring hospitalization and AKI. Chronic renal function declination was evaluated by slope of regression lines derived from reciprocal of the serum creatinine level. The covariates of CT-measured skeletal muscle index (SMI) alterations were analyzed by generalized linear mixed model. Results: Among the 4946 reviewed individuals, 166 (83 NSBB group, 83 non-NSBB group) were eligible. Using GEE, Charlson comorbidity index, Child-Pugh score and non-NSBB were risk factors for infection; non-NSBB group revealed a robust trend toward AKI, showed no significant difference with chronic renal function declination of NSBB group, and was negatively associated with SMI alteration. Conclusion: Chronic NSBB use lowered the episodes of infection requiring hospitalization and AKIs, whereas non-NSBB was associated with sarcopenic changes