OBJECTIVEThe coronavirus disease 2019 (COVID-19) has spread worldwide since December 2019. Neurologic symptoms have been reported as part of the clinical spectrum of the disease. We aimed to ...determine whether neurologic manifestations are common in hospitalized patients with COVID-19 and to describe their main characteristics.
METHODSWe systematically reviewed all patients diagnosed with COVID-19 admitted to the hospital in a Spanish population during March 2020. Demographic characteristics, systemic and neurologic clinical manifestations, and complementary tests were analyzed.
RESULTSOf 841 patients hospitalized with COVID-19 (mean age 66.4 years, 56.2% men), 57.4% developed some form of neurologic symptom. Nonspecific symptoms such as myalgias (17.2%), headache (14.1%), and dizziness (6.1%) were present mostly in the early stages of infection. Anosmia (4.9%) and dysgeusia (6.2%) tended to occur early (60% as the first clinical manifestation) and were more frequent in less severe cases. Disorders of consciousness occurred commonly (19.6%), mostly in older patients and in severe and advanced COVID-19 stages. Myopathy (3.1%), dysautonomia (2.5%), cerebrovascular diseases (1.7%), seizures (0.7%), movement disorders (0.7%), encephalitis (n = 1), Guillain-Barré syndrome (n = 1), and optic neuritis (n = 1) were also reported, but less frequent. Neurologic complications were the main cause of death in 4.1% of all deceased study participants.
CONCLUSIONSNeurologic manifestations are common in hospitalized patients with COVID-19. In our series, more than half of patients presented some form of neurologic symptom. Clinicians need to maintain close neurologic surveillance for prompt recognition of these complications. The mechanisms and consequences of severe acute respiratory syndrome coronavirus type 2 neurologic involvement require further studies.
The epithelial-to-mesenchymal transition (EMT) is a biological process in which a non-motile epithelial cell changes to a mesenchymal state with invasive capacities. However, the EMT program is ...involved in both physiological and pathological processes. Cancer-associated EMT is known to contribute to increase invasiveness and metastasis, resistance to therapies, and generation of cell populations with stem cell-like characteristics and therefore is deeply involved in tumor progression. This process is finely orchestrated by multiple signaling pathways and regulatory transcriptional networks. The hallmark of EMT is the loss of epithelial surface markers, mainly E-cadherin, and the acquisition of mesenchymal phenotype. These events can be mediated by EMT transcription factors which can cooperate with several enzymes to repress the E-cadherin expression and regulate EMT at the epigenetic and post-translational level. A growing body of evidence indicates that cancer cells can reside in various phenotypic states along the EMT spectrum, where cells can jointly retain epithelial traits with mesenchymal ones. This type of phenotypic plasticity endows cancer cells with tumor-initiating potential. The identification of the signaling pathways and modulators that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
Academic literature and practitioners acknowledge that there is a need to improve efficiency and service quality in the healthcare industry. In Spain, osteoporotic fractures represent a great cost in ...socio-economic and morbi-mortality terms, hip fracture being the surgical pathology with the second highest consumption of resources. The research questions that govern this study concern the use of Lean principles to identify waste, and an evaluation of the application of an innovative approach in the hip fracture surgery process. A research design based on a case study and action research was developed. Findings relate to (i) the identification of the main types of waste or muda (being the most frequent delay, transportation, over-processing and defects); (ii) the analysis of existing processes based on a Lean approach (identifying opportunities for improvement as a reduction of the number of steps and participants, improving communication, automation, standardization, etc.); and (iii) the application of an innovative process based on the Lean approach and action research in the healthcare industry. This research provides insights for academia, practitioners, management, and society: waste identification and process redesign helps to continue the improvement of operations, increase efficiency, reduce costs, and enhance services, providing benefits to patients, families, hospital employees, and the healthcare system.
Background
Cachexia is a metabolic syndrome that affects up to 50–80% of cancer patients. The pathophysiology is characterized by a variable combination of reduced food intake and abnormal ...metabolism, including systemic inflammation and negative protein and energy balance. Despite its high clinical significance, defined diagnostic criteria and established therapeutic strategies are lacking. The ‘omics’ technologies provide a global view of biological systems. We hypothesize that blood‐based metabolomics might identify findings in cachectic patients that could provide clues to gain knowledge on its pathophysiology, and eventually postulate new therapeutic strategies.
Methods
This is a cross‐sectional observational study in two cohorts of cancer patients, with and without cachexia. Patients were consecutively recruited from routine clinical practice of a General Oncology Department at ‘12 de Octubre’ University Hospital. Selected clinical and biochemical features were collected. Blood metabolite fingerprinting was performed using three analytical platforms, gas chromatography coupled to mass spectrometry (GC–MS), capillary electrophoresis coupled to mass spectrometry (CE–MS), and liquid chromatography coupled to mass spectrometry (LC–MS). Besides, we performed pathway‐based metabolite analyses to obtain more information on biological functions.
Results
A total of 15 subjects were included in this study, 8 cachectic and 7 non‐cachectic patients. Metabolomic analyses were able to correctly classify their samples in 80% (GC–MS), 97% (CE–MS), 96% LC–MS (positive mode), and 89% LC–MS (negative mode) of the cases. The most prominent metabolic alteration in plasma of cachectic patients was the decrease of amino acids and derivatives especially arginine, tryptophan, indolelactic acid, and threonine, with 0.4‐fold change (FC) compared with non‐cachectic patients, along with the reduction of glycerophospholipids mainly lysophosphatidylcholines(O‐16:0) and lysophosphatidylcholines(20:3) sn‐1, FC = 0.1 and sphingolipids SM(d30:0), FC = 0.5. The metabolite with the highest increase was cortisol (FC = 1.6). Such alterations suggest a role of the following metabolic pathways in the pathophysiology of cancer cachexia: arginine and proline metabolism; alanine, aspartate, and glutamate metabolism; phenylalanine metabolism; lysine degradation; aminoacyl‐tRNA biosynthesis; fatty acid elongation in mitochondria; tricarboxylic acids cycle; among others.
Conclusions
These findings suggest that plasma amino acids and lipids profiling has great potential to find the mechanisms involved in the pathogenesis of cachexia. Metabolic profiling of plasma from cancer patients show differences between cachexia and non‐cachexia in amino acids and lipids that might be related to mechanisms involved in its pathophysiology. A better understanding of these mechanisms might identify novel therapeutic approaches to palliate this unmet medical condition.
Emerging evidence suggests that the hypocretinergic system is involved in addictive behavior. In this study, we investigated the role of these hypothalamic neuropeptides in anxiety-like responses of ...nicotine and stress-induced reinstatement of nicotine-seeking behavior. Acute nicotine (0.8 mg/kg, s.c.) induced anxiogenic-like effects in the elevated plus-maze and activated the paraventricular nucleus of the hypothalamus (PVN) as revealed by c-Fos expression. Pretreatment with the hypocretin receptor 1 (Hcrtr-1) antagonist SB334867 or preprohypocretin gene deletion blocked both nicotine effects. In the PVN, SB334867 also prevented the activation of corticotrophin releasing factor (CRF) and arginine-vasopressin (AVP) neurons, which expressed Hcrtr-1. In addition, an increase of the percentage of c-Fos-positive hypocretin cells in the perifornical and dorsomedial hypothalamic (PFA/DMH) areas was found after nicotine (0.8 mg/kg, s.c.) administration. Intracerebroventricular infusion of hypocretin-1 (Hcrt-1) (0.75 nmol/1 mul) or footshock stress reinstated a previously extinguished nicotine-seeking behavior. The effects of Hcrt-1 were blocked by SB334867, but not by the CRF1 receptor antagonist antalarmin. Moreover, SB334867 did not block CRF-dependent footshock-induced reinstatement of nicotine-seeking while antalarmin was effective in preventing this nicotine motivational response. Therefore, the Hcrt system interacts with CRF and AVP neurons in the PVN and modulates the anxiogenic-like effects of nicotine whereas Hcrt and CRF play a different role in the reinstatement of nicotine-seeking. Indeed, Hcrt-1 reinstates nicotine-seeking through a mechanism independent of CRF activation whereas CRF mediates the reinstatement induced by stress.
As the mechanism that links obstructive sleep apnea (OSA) with the regulation of inflammatory response is not well known, it is important to understand the inflammasome activation, mainly of NLRP3 ...(nucleotide-binding oligomerization domain-like receptor 3).
To assess the NLRP3 activity in patients with severe OSA and to identify its role in the systemic inflammatory response of patients with OSA.
We analyzed the NLRP3 activity as well as key components of the inflammasome cascade, such as adaptor molecule apoptosis-associated speck-like protein, caspase-1, Gasdermin D, IL-1β, IL-18, and tissue factor, in monocytes and plasma from patients with severe OSA and control subjects without sleep apnea. We explored the association of the different key markers with inflammatory comorbidities.
Monocytes from patients with severe OSA presented higher NLRP3 activity than those from control subjects, which directly correlated with the apnea-hypopnea index and hypoxemic indices. NLRP3 overactivity triggered inflammatory cytokines (IL-1β and IL-18) via caspase-1 and increased Gasdermin D, allowing for tissue factor to be released.
models confirmed that monocytes increase NLRP3 signaling under intermittent hypoxia in a hypoxia-inducible factor-1α-dependent manner, and/or in combination with plasma from patients with OSA. Plasma concentrations of tissue factor were higher in patients with OSA with systemic inflammatory comorbidities than in those without them.
In patients with severe OSA, NLRP3 activation might be a linking mechanism between intermittent hypoxia and other OSA-induced immediate changes with the development of systemic inflammatory response.
Carbon dots (CDs) due to their unique optical features, chemical stability and low environmental hazard are applied in different fields such as metal ion sensing, photo-catalysis, bio-imaging and ...tribology, among others. The aims of the present research were to obtain CDs from vegetable wastes (tea and grapes) as carbon sources and to explore their potential properties as radical scavengers. CDs from glutathione/citric acid (GCDs) were synthetized for comparison purposes. The CDs were investigated for their chemical structure, morphology, optical and electronical properties. The antioxidant activity has been explored by DPPH and Folin-Ciocelteau assays in aqueous media. Due to their solubility in oil, the CDs prepared from tea wastes and GCDs were assayed as antioxidants in a mineral oil lubricant by potentiometric determination of the peroxide value. CDs from tea wastes and GCDs exhibited good antioxidant properties both in aqueous and oil media. Possible mechanisms, such as C-addition to double bonds, H-abstraction and SOMO-CDs conduction band interaction, were proposed for the CDs radical scavenging activity. CDs from natural sources open new application pathways as antioxidant green additives.
Introduction
Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. ...Recently, the adhesion receptor P-selectin glycoprotein-1 (PSGL 1) has been identified as a novel immune checkpoint, which are recognized major hallmarks in several types of cancer and have revolutionized cancer therapy.
Methods
The expression of PSGL-1 and its ligands VISTA and SIGLEC-5 was assessed in the leucocytes of OSA patients and control subjects exploring the role of intermittent hypoxia (IH) using
in vitro
models. In addition, PSGL-1 impact on T-cells function was evaluated by
ex vivo
models.
Results
Data showed PSGL-1 expression is upregulated in the T-lymphocytes from patients with severe OSA, indicating a relevant role of hypoxemia mediated by intermittent hypoxia. Besides, results suggest an inhibitory role of PSGL-1 on T-cell proliferation capacity. Finally, the expression of SIGLEC-5 but not VISTA was increased in monocytes from OSA patients, suggesting a regulatory role of intermittent hypoxia.
Discussion
In conclusion, PSGL-1 might constitute an additional immune checkpoint leading to T-cell dysfunction in OSA patients, contributing to the disruption of immune surveillance, which might provide biological plausibility to the higher incidence and aggressiveness of several tumors in these patients.
Midkine (MDK) might mediate the proangiogenic effect of intermittent hypoxia (IH) in patients with obstructive sleep apnea (OSA) and cutaneous melanoma (CM). We compare circulating MDK in CM patients ...with and without OSA, and their relationship with tumor aggressiveness, while exploring in vitro effects of soluble MDK on human lymphatic endothelial (HLEC) and melanoma cell proliferation. In 360 CM patients, sleep studies and MDK serum level measurements were performed. The effect of MDK on cell proliferation was assessed using HLEC and melanoma cell lines with patient sera under both normoxia and IH. MDK levels were higher in severe OSA compared to mild OSA or non‐OSA patients, whereas no differences in VEGF levels emerged. In OSA patients, MDK levels correlated with nocturnal hypoxemia and CM mitotic rate. In vitro, MDK promotes HLEC proliferation under IH conditions. Moreover, cultures of the human melanoma cell line C81‐61 with sera from patients with the highest MDK levels promoted tumor cell proliferation, which was attenuated after the addition of MDK antibody. These responses were enhanced by IH exposures. In conclusion, in CM patients, OSA severity is associated with higher MDK levels, which, appear to enhance both the lymphangiogenesis as the intrinsic aggressiveness of CM tumor cells.
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