Abstract
In mammalians, serotonin (5-HT) has critical roles in the central nervous system (CNS), including mood stability, pain tolerance, or sleep patterns. However, the vast majority of serotonin ...is produced by intestinal enterochromaffin cells of the gastrointestinal tract and circulating blood platelets, also acting outside of the CNS. Serotonin effects are mediated through its interaction with 5-HT receptors (5-HTRs), a superfamily with a repertoire of at least fourteen well-characterized members. 5-HT
7
receptors are the last 5-HTR member to be identified, with well-defined functions in the nervous, gastrointestinal, and vascular systems. The effects of serotonin on the immune response are less well understood. Mast cells are known to produce serotonin, while T cells, dendritic cells, monocytes, macrophages and microglia express 5-HT
7
receptor. Here, we review the known roles of 5-HT
7
receptors in the immune system, as well as their potential therapeutic implication in inflammatory and immune-mediated disorders.
Apart from mental, motor and sensory functions, the human central nervous system (CNS) regulates a plethora of homeostatic (autonomic and hormonal) bodily functions. These functions are dependent on ...specialized neuronal networks. To ensure connectivity of these networks, they are continuously refined and supported by glial cells that outnumber neurons by, according to some accounts, an order of magnitude. Among glial cells, microglia - the brain resident macrophages - plays a crucial role in maintaining neuronal networks. However, in their concomitant role as brain immune cells microglia also engage in inflammatory signaling that may disrupt neuronal networks. Here, we review novel insights for molecular pathways involved in the protective functions of microglia and other immune cells in response to systemic signals and stimuli.
Recent evidence suggests that aging and systemic disease push individual microglia toward proinflammatory phenotypes compromising the connectivity of neuronal networks, resulting in neuropsychiatric disease. Furthermore, cells (self as well as the microbiome) outside the CNS have been shown to affect neuronal function.
These recent findings have critical implications for mental health, particularly of an aging population, in particular for the development of novel immunomodulatory therapies for brain disease.
The coronavirus disease 2019 (COVID-19) is a systemic entity that frequently implies neurologic features at presentation and complications during the disease course. We aimed to describe the ...characteristics and predictors for developing in-hospital neurologic manifestations in a large cohort of hospitalized patients with COVID-19 in Mexico City.
We analyzed records from consecutive adult patients hospitalized from March 15 to June 30, 2020, with moderate to severe COVID-19 confirmed by reverse transcription real-time polymerase chain reaction (rtRT-PCR) for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neurologic syndromes were actively searched by a standardized structured questionnaire and physical examination, confirmed by neuroimaging, neurophysiology of laboratory analyses, as applicable.
We studied 1,072 cases (65% men, mean age 53.2±13 years), 71 patients had pre-existing neurologic diseases (diabetic neuropathy: 17, epilepsy: 15, history of ischemic stroke: eight, migraine: six, multiple sclerosis: one, Parkinson disease: one), and 163 (15.2%) developed a new neurologic complication. Headache (41.7%), myalgia (38.5%), dysgeusia (8%), and anosmia (7%) were the most common neurologic symptoms at hospital presentation. Delirium (13.1%), objective limb weakness (5.1%), and delayed recovery of mental status after sedation withdrawal (2.5%), were the most common new neurologic syndromes. Age, headache at presentation, preexisting neurologic disease, invasive mechanical ventilation, and neutrophil/lymphocyte ratio ≥9 were independent predictors of new in-hospital neurologic complications.
Even after excluding initial clinical features and pre-existing comorbidities, new neurologic complications in hospitalized patients with COVID-19 are frequent and can be predicted from clinical information at hospital admission.
Background:
Prospective longitudinal studies evaluating the relevance of “Metabolically Healthy but Obese” (MHO) phenotype at risk for type 2 diabetes mellitus (T2D) and cardiovascular diseases are ...few and results are contradictory.
Methods:
As a representative of the general population, 1051 individuals were evaluated in 1997–1998 and re-evaluated after 6 years and 11 years. Subjects without known T2D were given an oral glucose tolerance test. Anthropometric and biochemical variables were measured. Four sets of criteria were considered to define MHO subjects besides body mass index ≥30 kg/m2: A: Homeostatic Model of Assessment-Insulin Resistance Index (HOMA-IR) <90th percentile; B: HOMA-IR <90th percentile, high-density lipoprotein cholesterol >40 mg/dL in men and high-density lipoprotein cholesterol >50 mg/dL in women, triglycerides <150 mg/dL, fasting glucose <110 mg/dL, and blood pressure ≤140/90 mm Hg; C: HOMA-IR <90th percentile, triglycerides <150 mg/dL, fasting glucose <110 mg/dL, and blood pressure ≤140/90 mm Hg; D: HOMA-IR <90th percentile, triglycerides <150 mg/dL, and fasting glucose <110 mg/dL. Subjects with T2D at baseline were excluded from the calculations of incidence of T2D.
Results:
The baseline prevalence of MHO phenotype varied between 3.0% and 16.9%, depending on the set of criteria chosen. Metabolically nonhealthy obese subjects were at highest risk for becoming diabetic after 11 years of follow-up (odds ratio = 8.20; 95% confidence interval = 2.72–24.72; P < .0001). In MHO subjects the risk for becoming diabetic was lower than in metabolically nonhealthy obese subjects, but this risk remained significant (odds ratio = 3.13; 95% confidence interval = 1.07–9.17; P = .02). In subjects who lost weight during the study, the association between MHO phenotype and T2D incidence disappeared, even after adjusting for HOMA-IR.
Conclusions:
The results suggest that MHO is a dynamic concept that should be taken into account over time. As a clinical entity, it may be questionable.
Abstract Inflammatory conditions characterized by excessive immune cell activation and cytokine release, are associated with bidirectional immune system-brain communication, underlying sickness ...behavior and other physiological responses. The vagus nerve has an important role in this communication by conveying sensory information to the brain, and brain-derived immunoregulatory signals that suppress peripheral cytokine levels and inflammation. Brain muscarinic acetylcholine receptor (mAChR)-mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of centrally-acting mAChR agonists is unexplored. To provide insight we used the centrally-acting M1 mAChR agonist xanomeline, previously developed in the context of Alzheimer’s disease and schizophrenia. Intraperitoneal administration of xanomeline significantly suppressed serum and splenic TNF levels, alleviated sickness behavior, and increased survival during lethal murine endotoxemia. The anti-inflammatory effects of xanomeline were brain mAChR-mediated and required intact vagus nerve and splenic nerve signaling. The anti-inflammatory efficacy of xanomeline was retained for at least 20 h, associated with alterations in splenic lymphocyte, and dendritic cell proportions, and decreased splenocyte responsiveness to endotoxin. These results highlight an important role of the M1 mAChR in a neural circuitry to spleen in which brain cholinergic activation lowers peripheral pro-inflammatory cytokines to levels favoring survival. The therapeutic efficacy of xanomeline was also manifested by significantly improved survival in preclinical settings of severe sepsis. These findings are of interest for strategizing novel therapeutic approaches in inflammatory diseases.
•Brain metastases are associated with minor overall survival in breast cancer.•The hormone receptor positive is the most common breast cancer subtype.•Current guidelines do not recommend a routine ...assessment of brain metastases.•A model with clinical variables showed adequate capacity to predict brain metastases in patients with breast cancer.
Breast cancer is a leading cause of cancer-related deaths in females, and the hormone receptor-positive subtype is the most frequent. Breast cancer is a common source of brain metastases; therefore, we aimed to generate a brain metastases prediction model in females with hormone receptor-positive breast cancer.
The primary cohort included 3,682 females with hormone receptor-positive breast cancer treated at a single center from May 2009 to May 2020. Patients were randomly divided into a training dataset (n = 2,455) and a validation dataset (n = 1,227). In the training dataset, simple logistic regression analyses were used to measure associations between variables and the diagnosis of brain metastases and to build multivariable models. The model with better calibration and discrimination capacity was tested in the validation dataset to measure its predictive performance.
The variables incorporated in the model included age, tumor size, axillary lymph node status, clinical stage at diagnosis, HER2 expression, Ki-67 proliferation index, and the modified Scarff-Bloom-Richardson grade. The area under the curve was 0.81 (95 % CI 0.75–0.86), p < 0.001 in the validation dataset. The study presents a guide for the clinical use of the model.
A brain metastases prediction model in females with hormone receptor-positive breast cancer helps assess the individual risk of brain metastases.
Background
Autonomic dysfunction is a hallmark feature of hereditary ATTR amyloidosis. The aim of this study was to summarize the characteristics and natural history of autonomic dysfunction in ...patients with hereditary ATTR amyloidosis.
Methods
A systematic review of the natural history and clinical trials of patients with ATTR amyloidosis was performed. Alternative surrogate markers of autonomic function were analyzed to understand the prevalence and outcome of autonomic dysfunction.
Results
Patients with early-onset disease displayed autonomic dysfunction more distinctively than those with late-onset disease. The nutritional status and some autonomic items in the quality-of-life questionnaires were used to assess the indirect progression of autonomic dysfunction in most studies. Gastrointestinal symptoms and orthostatic hypotension were resent earlier than urogenital complications. Once symptoms were present, their evolution was equivalent to the progression of the motor and sensory neuropathy impairment.
Conclusion
The development of autonomic dysfunction impacts morbidity, disease progression, and mortality in patients with hereditary ATTR amyloidosis.
Oxygen therapy, using supraphysiological concentrations of oxygen (hyperoxia), is routinely administered to patients who require respiratory support including mechanical ventilation (MV). However, ...prolonged exposure to hyperoxia results in acute lung injury (ALI) and accumulation of high mobility group box 1 (HMGB1) in the airways. We previously showed that airway HMGB1 mediates hyperoxia-induced lung injury in a mouse model of ALI. Cholinergic signaling through the α7 nicotinic acetylcholine receptor (α7nAChR) attenuates several inflammatory conditions. The aim of this study was to determine whether 3-(2,4 dimethoxy-benzylidene)-anabaseine dihydrochloride, GTS-21, an α7nAChR partial agonist, inhibits hyperoxia-induced HMGB1 accumulation in the airways and circulation, and consequently attenuates inflammatory lung injury.
Mice were exposed to hyperoxia (≥99% O
) for 3 days and treated concurrently with GTS-21 (0.04, 0.4 and 4 mg/kg, i.p.) or the control vehicle, saline.
The systemic administration of GTS-21 (4 mg/kg) significantly decreased levels of HMGB1 in the airways and the serum. Moreover, GTS-21 (4 mg/kg) significantly reduced hyperoxia-induced acute inflammatory lung injury, as indicated by the decreased total protein content in the airways, reduced infiltration of inflammatory monocytes/macrophages and neutrophils into the lung tissue and airways, and improved lung injury histopathology.
Our results indicate that GTS-21 can attenuate hyperoxia-induced ALI by inhibiting extracellular HMGB1-mediated inflammatory responses. This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy.
A physically active life-style plays an independent role in the protection against type 2 diabetes and cardiovascular diseases. Irisin, a novel exercise-induced myokine, activates thermogenesis in ...rodents through increasing beige fat cells abundance within white fat. We aimed to investigate circulating irisin levels in association with the degree of physical activity and various metabolic parameters in humans.
Circulating irisin levels (ELISA) and metabolic parameters were analyzed in 428 subjects (195 men/233 women). Participants were classified according to their self-reported physical activity and to their area of residence.
Circulating irisin levels were higher in active than in sedentary subjects (p = 0.006). Rural inhabitants showed higher circulating irisin levels than urban subjects (p < 0.0001). The increase in irisin levels related to an active lifestyle was only observed in rural citizens (p = 0.014). Among sedentary participants, irisin levels were positively associated with metabolic risk factors (BMI, fasting insulin, HOMA and fasting triglycerides). The area of residence (β = - 0.592, p = < 0.0001) contributed independently to circulating irisin levels variance after controlling for age, gender, BMI, HOMAIR, triglycerides and physical activity.
In sedentary participants, circulating irisin levels were positively associated with parameters related to an increased cardiometabolic risk. The present study confirmed that an active lifestyle increases circulating irisin levels, but only among subjects living in a rural environment. Area of residence might be a determinant of irisin levels.
Objective It has been proposed that a mild form of acquired resistance to thyroid hormone may occur in the general population. Its clinical significance remains largely unknown. The objective of the ...study was to explore whether a newly described thyroid hormone resistance index is associated with the risk of mortality in a sample of community-dwelling euthyroid subjects representative of the adult population of Spain. Design Longitudinal observational study including 3750 individuals, free of thyroid disease, TPO antibodies-negative (<50 IU/mL) and with TSH levels within the euthyroid range (≥0.5 and ≤5.0 mUI/mL) participating in the nationwide study Di@bet.es (2008–2010). Methods We used the Thyroid Feedback Quantile-based Index (TFQI) as a marker of resistance to thyroid hormone. The study population was grouped into categories according to their TFQI values at baseline. Fatal events were ascertained from the national death registry (end of follow-up December 2016). Results A total of 231 deaths were recorded during an average follow-up of 7.3 years. Compared with the category with the highest sensitivity to free thyroxine (TFQI ≤ p5) (reference), the relative risk of mortality in the categories with TFQI > p5 and ≤p25; >p25 and ≤p50; >p50 and ≤p75; >p75 and ≤p95 and >p95 were 1.01, (0.47–2.19), 1.42 (0.68–2.97), 1.54 (0.74–3.22), 1.47 (0.70–3.11) and 2.61 (1.16–5.89), respectively (P for trend 0.003). The association remained significant after multivariate adjustment of the data (P for trend 0.017). Conclusions A thyroid hormone resistance index focused on deviations of the average pituitary response to thyroid hormones may be associated with all-cause mortality independently of other conventional risk factors and comorbidities.
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