The immune system plays a critical role in fighting cancer. Research shows that immune activity can be affected by one’s emotional state, and that patient’s mood can impact the success of cancer ...therapy. Although, studies primarily focused on the effects of stress on immunity, a growing body of evidence indicates that positive emotions can also affect immunity. One of the brain circuits associated with positive affect is the brain’s reward system. Here we show that activation of the brain’s reward system can stimulate the anti-tumor immune response and significantly attenuate tumor development. We used pharmacogenetics (DREADDs) to activate the dopaminergic neurons in the ventral tegmental area (VTA), the central component of the brain’s reward system. We found that repeated VTA activation in tumor-bearing mice (Lewis lung carcinoma; LLC) significantly reduced the tumor weight by 36 percent. We attribute this effect to changes in the anti-tumor immune response. Specifically, we found that VTA activation decreased the abundance and activity of CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs), known to suppress anti-tumor immune response. We further demonstrate that these effects were mediated, at least in part, via the sympathetic nervous system (SNS). Taken together, our data indicates that the reward system can affect tumor progression by enhancing the anti-tumor immune response. These findings introduce a potential mechanism whereby positive emotions can impact the organism’s ability to fight cancer.
A systematic analysis of clinical trials was performed in order to assess the effectiveness and risks of bilateral renal denervation (RDN) in patients with chronic heart failure with reduced ejection ...fraction (HFrEF).
A systematic review was conducted of all clinical trials exploring the effectiveness of RDN in patients with HF who had reduced (<50%) EF. Primary outcomes were NYHA class, 6-min walk test, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, left ventricular ejection fraction (LVEF) and other cardiac parameters including left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), and left atrium diameter (LAD). Secondary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), glomerular filtration rate (GFR), and creatinine.
Seven studies were included in this analysis. From baseline to 6 months after RDN, the pooled mean NYHA class was decreased (mean difference MD, -0.9; 95% confidence interval CI, -1.6 to -0.2; P = 0.018), the mean 6-min walk test was increased (MD, 79.5 m; 95% CI, 26.9 to 132.1; P = 0.003), and the average NT-proBNP level was decreased (MD, -520.6 pg/mL; 95% CI, -1128.4 to 87.2; P = 0.093). Bilateral RDN increased the LVEF (MD, 5.7%; 95% CI, 1.6 to 9.6; P = 0.004), decreased the LVESD (MD, -0.4 cm; 95% CI, -0.5 to -0.2; P < 0.001), decreased the LVEDD (MD, -0.5 cm; 95% CI, -0.6 to -0.3; P < 0.001), and decreased the LAD (MD, -0.4 cm; 95% CI, -0.8 to 0; P = 0.045). In addition, RDN significantly decreased systolic BP (MD, -9.4 mmHg; 95% CI, -16.3 to -2.4; P = 0.008) and diastolic BP (MD, -4.9 mmHg; 95% CI, -9.5 to -0.4; P = 0.033), and decreased HR (MD, -4.5 bpm; 95% CI, -8.2to -0.9; P = 0.015). RDN did not significantly change GFR (MD, 7.9; 95% CI, -5.0 to 20.8; P = 0.230), or serum creatinine levels (MD, -7.2; 95% CI, -23.7 to 9.4; P = 0.397).
Bilateral RDN appears safe and well-tolerated in patients with HF. RDN improved the signs and symptoms of HF and slightly decreased systolic and diastolic BP without affecting renal function in the clinical trials performed to date.
Chronic heart failure, Renal denervation, Sympatho-excitation.
Macrophages (MΦs) are prevalent innate immune cells, present throughout human bodily tissues where they orchestrate innate and adaptive immune responses to maintain cellular homeostasis. MΦs have the ...capacity to display a wide array of functional phenotypes due to different microenvironmental cues, particularly soluble bacterial secretory products. Recent evidence has emerged demonstrating that metabolism supports MΦ function and plasticity, in addition to energy and biomolecular precursor production. In this study, 1D 1H-NMR-based metabolomics was used to identify the metabolic pathways that are differentially altered following primary human monocyte-derived MΦ exposure to P. aeruginosa planktonic- and biofilm-conditioned media (PCM and BCM). Metabolic profiling of PCM- and BCM-exposed MΦs indicated a significant increase in glycolytic metabolism, purine biosynthesis, and inositol phosphate metabolism. In addition, these metabolic patterns suggested that BCM-exposed MΦs exhibit a hyperinflammatory metabolic profile with reduced glycerol metabolism and elevated catabolism of lactate and amino acids, relative to PCM-exposed MΦs. Altogether, our study reveals novel findings concerning the metabolic modulation of human MΦs after exposure to secretory microbial products and contributes additional knowledge to the field of immunometabolism in MΦs.
The ability to quickly diagnose hemorrhagic shock is critical for favorable patient outcomes. Therefore, it is important to understand the time course and involvement of the various physiological ...mechanisms that are active during volume loss and that have the ability to stave off hemodynamic collapse. This review provides new insights about the physiology that underlies blood loss and shock in humans through the development of a simulated model of hemorrhage using lower body negative pressure. In this review, we present controlled experimental results through utilization of the lower body negative pressure human hemorrhage model that provide novel insights on the integration of physiological mechanisms critical to the compensation for volume loss. We provide data obtained from more than 250 human experiments to classify human subjects into two distinct groups: those who have a high tolerance and can compensate well for reduced central blood volume (e.g. hemorrhage) and those with low tolerance with poor capacity to compensate.We include the conceptual introduction of arterial pressure and cerebral blood flow oscillations, reflex-mediated autonomic and neuroendocrine responses, and respiration that function to protect adequate tissue oxygenation through adjustments in cardiac output and peripheral vascular resistance. Finally, unique time course data are presented that describe mechanistic events associated with the rapid onset of hemodynamic failure (i.e. decompensatory shock).
Impact Statement
Hemorrhage is the leading cause of death in both civilian and military trauma. The work submitted in this review is important because it advances the understanding of mechanisms that contribute to the total integrated physiological compensations for inadequate tissue oxygenation (i.e. shock) that arise from hemorrhage. Unlike an animal model, we introduce the utilization of lower body negative pressure as a noninvasive model that allows for the study of progressive reductions in central blood volume similar to those reported during actual hemorrhage in conscious humans to the onset of hemodynamic decompensation (i.e. early phase of decompensatory shock), and is repeatable in the same subject. Understanding the fundamental underlying physiology of human hemorrhage helps to test paradigms of critical care medicine, and identify and develop novel clinical practices and technologies for advanced diagnostics and therapeutics in patients with life-threatening blood loss.
Prospective cohort study.
For acute traumatic spinal cord injury (ATSCI), this study aimed to determine differences in outcomes between patient groups stratified by admission time (⩽24 vs >24 h) to ...the Spinal Injury Unit (SIU) and by the nature of the admission (direct admission to the SIU vs indirect admission via another hospital). We also aimed to measure the effect on time to admission of a 'non-refusal' policy that triggered immediate acceptance of ATSCI cases to the SIU.
New South Wales, Australia.
Study population was all adult SCI patients admitted to the Prince of Wales SIU from 1 January 2001 to 31 December 2012. Patients admitted with chronic-stage SCI or with incomplete data for the duration of their stay were excluded. Comparison of outcomes was made between groups according to the setting of admission. Time to admission before and after initiation (2009) of the 'non-refusal' policy was compared. The prevalence of complications, lengths of stay (LOSs) and time to admission were compared by Mann-Whitney non-parametric methods. Count modelling was used to control for confounders of age and gender.
A total of 460 cases were identified and 76 were excluded. The early group had fewer pressure areas (41.8% vs 63.2%; P<0.001) and shorter LOS (136 vs 172 days; P<0.001) than the late group. The direct group had fewer pressure areas (35.2% vs 54.9%, P<0.001), deep vein thrombosis (9.9% vs 24.6%, P=0.003) and shorter LOS (124 vs 158 days, P=0.007) than those admitted indirectly. Time to admission was reduced after introduction of the 'non-refusal' policy (1.53 vs 0.63 days; P=0.001).
Early and direct admission to SIU reduced complication rates and LOS. A non-refusal policy reduced time to admission.
Summary Background In 2005, a scoring system (CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index) was developed for patients with cutaneous lupus erythematosus (CLE) to assess ...disease ‘activity’ and ‘damage’. However, the CLASI does not give an accurate assessment of the severity in all disease subtypes.
Objectives The main objective of this study was to analyse critically the included parameters of the CLASI and to revise the activity and damage score taking into account various clinical features of the different subtypes of CLE. The revised CLASI (RCLASI) was also validated for use in clinical trials.
Patients and methods A RCLASI was designed with regard to the anatomical region (i.e. face, chest, arms) and morphological aspects (i.e. erythema, scaling/hyperkeratosis, oedema/infiltration, scarring/atrophy) of skin lesions and evaluated by nine dermatologists who scored 12 patients with different subtypes of CLE to estimate inter‐ and intrarater reliability.
Results Reliability studies demonstrated an intraclass correlation coefficient (ICC) for an inter‐rater reliability of 0·89 for the activity score 95% confidence interval (CI) 0·79–0·96 and of 0·79 for the damage score (95% CI 0·62–0·92). The ICC for intrarater reliability for the activity score was 0·92 (95% CI 0·89–0·95) and the ICC for the damage score was 0·95 (95% CI 0·92–0·98).
Conclusions In the present study, a RCLASI was developed by experts, and reliability studies supported the validity and applicability of the revised scoring instrument for CLE. Thus, the RCLASI is a valuable instrument in multicentre studies and for the clinical evaluation of activity and damage in different disease subtypes.
People with end-stage kidney disease receiving peritoneal dialysis (PD) are generally physically inactive and frail. Exercise studies in PD are scarce and currently there are no PD exercise programs ...in the United States. The primary objective of this study was to test the feasibility of a combined resistance and cardiovascular exercise program for PD patients under the care of a dedicated home dialysis center in the United States.
Parallel randomized controlled feasibility study.
PD patients were recruited from a single center and randomly assigned to the intervention (exercise; n = 18) or control (nonexercise; n = 18) group.
The intervention group received monthly exercise physiologist consultation, exercise prescription (resistance and aerobic exercise program using exercise bands), and 4 exercise support telephone calls over 12 weeks. The control group received standard care.
The primary outcome was study feasibility as measured by eligibility rates, recruitment rates, retention rates, adherence rates, adverse events, and sustained exercise rates. Secondary outcome measures were changes in physical function (sit-to-stand test, timed-up-and-go test, and pinch-strength tests) and patient-reported outcome measures.
From a single center with 75 PD patients, 57 (76%) were deemed eligible, resulting in a recruitment rate of 36 (63%) patients. Participants were randomly assigned into 2 groups of 18 (1:1). 10 patients discontinued the study (5 in each arm), resulting in 26 (72%) patients, 13 in each arm, completing the study. 10 of 13 (77%) intervention patients were adherent to the exercise program. A t test analysis of covariance found a difference between the treatment groups for the timed-up-and-go test (P = 0.04) and appetite (P = 0.04). No serious adverse events caused by the exercise program were reported.
Single center, no blinded assessors.
A resistance and cardiovascular exercise program appears feasible and safe for PD patients. We recommend that providers of PD therapy consider including exercise programs coordinated by exercise professionals to reduce the physical deterioration of PD patients.
None.
NCT03980795.
Display omitted
The morphogenesis of dendritic spines, the major sites of excitatory synaptic transmission in the brain, is important in synaptic development and plasticity. We have identified an ephrinB-EphB ...receptor
trans-synaptic signaling pathway which regulates the morphogenesis and maturation of dendritic spines in hippocampal neurons. Activation of the EphB receptor induces translocation of the Rho-GEF kalirin to synapses and activation of Rac1 and its effector PAK. Overexpression of dominant-negative EphB receptor, catalytically inactive kalirin, or dominant-negative Rac1, or inhibition of PAK eliminates ephrin-induced spine development. This novel signal transduction pathway may be critical for the regulation of the actin cytoskeleton controlling spine morphogenesis during development and plasticity.
Background
Idiopathic Parkinson's disease (IPD) is characterized by the clinical motor symptoms of hypokinesia, rigidity, and tremor. Apart from these motor symptoms, cognitive deficits often occur ...in IPD. The positive effect of cholinesterase inhibitors on cognitive deficits in IPD and findings of earlier molecular imaging studies suggest that the cholinergic system plays an important role in the origin of cognitive decline in IPD.
Methods
Twenty‐five non‐demented patients with IPD underwent a 5‐123Iiodo‐3‐2(S)‐2‐azetidinylmethoxypyridine (5‐I‐A‐85380) SPECT to visualize α4β2 nicotinic acetylcholine receptors (nAchR) and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) battery to identify domains of cognitive dysfunction.
Results
In the CERAD, the IPD patients exhibited deficits in non‐verbal memory, attention, psychomotor velocity, visuoconstructive ability, and executive functions. After Bonferroni correction for multiple comparisons, we found significant correlations between performance of the CERAD subtests Boston Naming Test (a specific test for visual perception and for detection of word‐finding difficulties) and Word List Intrusions (a specific test for learning capacity and memory for language information) vs binding of α4β2 nAchR in cortical (the right superior parietal lobule) and subcortical areas (the left thalamus, the left posterior subcortical region, and the right posterior subcortical region).
Conclusions
These significant correlations between the results of the CERAD subtests and the cerebral α4β2 nAchR density, as assessed by 5‐I‐A‐85380 SPECT, indicate that cerebral cholinergic pathways are relevant to cognitive processing in IPD.
PDF
