Differential expression of biomarkers in saliva related to SARS-CoV-2 infection in patients with mild, moderate and severe COVID-19.

BACKGROUND: Severe COVID-19 is a disease characterized by profound dysregulation of the innate immune system. There is a need to identify highly reliable prognostic biomarkers that can be rapidly assessed in body fluids for early identification of patients at higher risk for hospitalization and/or death. This study aimed to assess whether differential gene expression of immune response molecules and cellular enzymes, detected in saliva samples of COVID-19 patients, occurs according to disease severity staging. METHODS: In this cross-sectional study, subjects with a COVID-19 diagnosis were classified as having mild, moderate, or severe disease based on clinical features. Transcripts of genes encoding 6 biomarkers, IL-1ß, IL-6, IL-10, C-reactive protein, IDO1 and ACE2, were measured by RT‒qPCR in saliva samples of patients and COVID-19-free individuals. RESULTS: The gene expression levels of all 6 biomarkers in saliva were significantly increased in severe disease patients compared to mild/moderate disease patients and healthy controls. A significant strong inverse relationship between oxemia and the level of expression of the 6 biomarkers (Spearman's correlation coefficient between -0.692 and -0.757; p < 0.001) was found. CONCLUSIONS: Biomarker gene expression determined in saliva samples still needs to be validated as a potentially valuable predictor of severe clinical outcomes early at the onset of COVID-19 symptoms.

Methodology of the INVestigating traIning assoCiated blasT pAthology (INVICTA) study.

BACKGROUND: Subconcussive blast exposure during military training has been the subject of both anecdotal concerns and reports in the medical literature, but prior studies have often been small and have used inconsistent methods. METHODS: This paper presents the methodology employed in INVestigating traIning assoCiated blasT pAthology (INVICTA) to assess a wide range of aspects of brain function, including immediate and delayed recall, gait and balance, audiologic and oculomotor function, cerebral blood flow, brain electrical activity and neuroimaging and blood biomarkers. RESULTS: A number of the methods employed in INVICTA are relatively easy to reproducibly utilize, and can be completed efficiently, while other measures require greater technical expertise, take longer to complete, or may have logistical challenges. CONCLUSIONS: This presentation of methods used to assess the impact of blast exposure on the brain is intended to facilitate greater uniformity of data collection in this setting, which would enable comparison between different types of blast exposure and environmental circumstances, as well as to facilitate meta-analyses and syntheses across studies.

Non-tuberculous mycobacteria immunopathogenesis: Closer than they appear. a prime of innate immunity trade-off and NTM ways into virulence.

INTRODUCTION: The growing incidence of non-tuberculous mycobacteria (NTM) and changes in epidemiological factors have indicated that immune dysregulation may be associated with the emergence of NTM. Minireview entails to acknowledge complex interaction and new ways NTM are evolving around diverse immune status. METHODS: In order to perform this review, we selected peer reviewed, NLM database articles under the terms NTM, mycobacterium complex 'AND' -Host- immune response, immunity regulation, Disease, Single Nucleotide Polymorphism (SNP´s), and -pathogen- followed by a snow ball rolling basis search on immune components and NTM related with diseases distribution. RESULTS: The universal exposure and diversity of NTM are well-documented; however, hospitals seldom establish vigilant control of water quality or immunodeficiencies for patients with NTM infections. Depending on the chemical structures and immune mechanisms presented by various NTM varieties, they can trigger different effects in dendritic and natural killer cells, which release interleukin (IL)-17, tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and rIL-1B. The T helper (Th)2-acquired immune response is responsible for autoimmune responses in patients with NTM infections, and, quite disturbingly, immunocompetent patients have been reported to suffer from NTM infections. CONCLUSION: New technologies and a comprehensive view has taught us; to acknowledge metabolic/immune determinants and trade-offs along transit through mutualism-parasite continuous.

Marine Seagrass Extract of Thalassia testudinum Suppresses Colorectal Tumor Growth, Motility and Angiogenesis by Autophagic Stress and Immunogenic Cell Death Pathways.

Marine plants have become an inexhaustible reservoir of new phytopharmaceuticals for cancer treatment. We demonstrate in vitro/in vivo antitumor efficacy of a standardized polyphenol extract from the marine angiosperm Thalassia testudinum (TTE) in colon tumor cell lines (RKO, SW480, and CT26) and a syngeneic allograft murine colorectal cancer model. MTT assays revealed a dose-dependent decrease of cell viability of RKO, CT26, and SW480 cells upon TTE treatment with IC50 values of, respectively, 175, 115, and 60 µg/mL. Furthermore, TTE significantly prevented basal and bFGF-induced angiogenesis in the chicken chorioallantoic membrane angiogenesis assay. In addition, TTE suppressed bFGF-induced migration of endothelial cells in a wound closure assay. Finally, TTE treatment abrogated CT26 colorectal cancer growth and increased overall organism survival in a syngeneic murine allograft model. Corresponding transcriptome profiling and pathway analysis allowed for the identification of the mechanism of action for the antitumor effects of TTE. In line with our in vitro/in vivo results, TTE treatment triggers ATF4-P53-NFκB specific gene expression and autophagy stress pathways. This results in suppression of colon cancer cell growth, cell motility, and angiogenesis pathways in vitro and in addition promotes antitumor immunogenic cell death in vivo.

Mangiferin: Possible uses in the prevention and treatment of mixed osteoarthritic pain.

Osteoarthritis (OA) pain has been proposed to be a mixed pain state, because in some patients, central nervous system factors are superimposed upon the more traditional peripheral factors. In addition, a considerable amount of preclinical and clinical evidence has shown that, accompanying the central neuroplasticity changes and partially driven by a peripheral nociceptive input, a real neuropathic component occurs that are particularly linked to disease severity and progression. Hence, innovative strategies targeting neuroprotection and particularly neuroinflammation to prevent and treat OA pain could be introduced. Mangiferin (MG) is a glucosylxanthone that is broadly distributed in higher plants, such as Mangifera indica L. Previous studies have documented its analgesic, anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory properties. In this paper, we propose its potential utility as a multitargeted compound for mixed OA pain, even in the context of multimodal pharmacotherapy. This hypothesis is supported by three main aspects: the cumulus of preclinical evidence around this xanthone, some preliminary clinical results using formulations containing MG in clinical musculoskeletal or neuropathic pain, and by speculations regarding its possible mechanism of action according to recent advances in OA pain knowledge.

Semi-synthetic sapogenin exerts neuroprotective effects by skewing the brain ischemia reperfusion transcriptome towards inflammatory resolution.

Stroke represents one of the first causes of mortality and morbidity worldwide. We evaluated the therapeutic potential of a novel semi-synthetic spirosteroid sapogenin derivative "S15" in a transient middle cerebral artery occlusion (tMCAO) focal ischemia model in rat. S15-treated rats had significantly reduced infarct volumes and improved neurological functions at 24h post-reperfusion, compared with ischemia. Corresponding gene expression changes in brain were characterized by mRNA sequencing and qPCR approaches. Next, we applied geneset, pathway and transcription factor motif enrichment analysis to identify relevant signaling networks responsible for neuronal damage upon ischemia-reperfusion or neuroprotection upon pretreatment with S15. As expected, ischemia-reperfusion brain damage strongly modulates transcriptional programs associated with immune responses, increased differentiation of immune cells as well as reduced (cat)ion transport and synaptic activity. Interestingly, S15-dependent neuroprotection regulates inflammation-associated genes involved in phagosome specific resolution of tissue damage, chemotaxis and anti-inflammatory alternative activation of microglia. Altogether our transcriptome wide RNA sequencing and integrated pathway analysis provides new clues in the neuroprotective properties of a novel spirosteroid S15 or neuronal damage in rat brains subjected to ischemia, which opens new perspectives for successful treatment of stroke.

In Vitro Neuroprotective and Anti-Inflammatory Activities of Natural and Semi-Synthetic Spirosteroid Analogues.

Two spirosteroid analogues were synthesized and evaluated for their in vitro neuroprotective activities in PC12 cells, against glutamate-induced excitotoxicity and mitochondrial damage in glucose deprivation conditions, as well as their anti-inflammatory potential in LPS/IFNγ-stimulated microglia primary cultures. We also evaluated the in vitro anti-excitotoxic and anti-inflammatory activities of natural and endogenous steroids. Our results show that the plant-derived steroid solasodine decreased PC12 glutamate-induced excitotoxicity, but not the cell death induced by mitochondrial damage and glucose deprivation. Among the two synthetic spirosteroid analogues, only the (25R)-5α-spirostan-3,6-one (S15) protected PC12 against ischemia-related in vitro models and inhibited NO production, as well as the release of IL-1ß by stimulated primary microglia. These findings provide further insights into the role of specific modifications of the A and B rings of sapogenins for their neuroprotective potential.

A Jurassic ceratosaur from China helps clarify avian digital homologies.

Theropods have traditionally been assumed to have lost manual digits from the lateral side inward, which differs from the bilateral reduction pattern seen in other tetrapod groups. This unusual reduction pattern is clearly present in basal theropods, and has also been inferred in non-avian tetanurans based on identification of their three digits as the medial ones of the hand (I-II-III). This contradicts the many developmental studies indicating II-III-IV identities for the three manual digits of the only extant tetanurans, the birds. Here we report a new basal ceratosaur from the Oxfordian stage of the Jurassic period of China (156-161 million years ago), representing the first known Asian ceratosaur and the only known beaked, herbivorous Jurassic theropod. Most significantly, this taxon possesses a strongly reduced manual digit I, documenting a complex pattern of digital reduction within the Theropoda. Comparisons among theropod hands show that the three manual digits of basal tetanurans are similar in many metacarpal features to digits II-III-IV, but in phalangeal features to digits I-II-III, of more basal theropods. Given II-III-IV identities in avians, the simplest interpretation is that these identities were shared by all tetanurans. The transition to tetanurans involved complex changes in the hand including a shift in digit identities, with ceratosaurs displaying an intermediate condition.

[Resistance to antibiotic: A serious global problem]. / La resistencia a los antibióticos: Un grave problema global.

An important piece of improvement in public health standards, medicine achievements, and development is based on the impressive effect of vaccines and antibiotics on infectious diseases. However, the last three or so decades have witnessed how an unsound use of antibiotics has resulted in antibiotic multi-resistant clones in hospitals and community environments. It also has been said that antibiotic research and the development pipeline has crashed, leading to no new antibiotic molecules to be tested at a time of treatment failure, manifest with unacceptable frequency as an increased economic and human cost in lives. Like the name of the series, antibiotic resistance is a global problem with clear evolutionary roots and a broad local impact. In that sense, this review explores the interaction among resistant mechanisms, underlying motives of expansion and actual trends in antibiotic resistance upgrade to limit the problem. Conceivably, only the involvement of players at every level, and coordinated actions accordingly constitute the necessary elements for effectively intervention.

Wavefront-coding technique for inexpensive and robust retinal imaging.

We propose a hybrid optical-digital imaging system that can provide high-resolution retinal images without wavefront sensing or correction of the spatial and dynamic variations of eye aberrations. A methodology based on wavefront coding is implemented in a fundus camera in order to obtain a high-quality image of retinal detail. Wavefront-coded systems rely simply on the use of a cubic-phase plate in the pupil of the optical system. The phase element is intended to blur images in such a way that invariance to optical aberrations is achieved. The blur is then removed by image postprocessing. Thus, the system can provide high-resolution retinal images, avoiding all the optics needed to sense and correct ocular aberration, i.e., wavefront sensors and deformable mirrors.

Antihyperalgesic effects of an aqueous stem bark extract of Mangifera indica L.: role of mangiferin isolated from the extract.

This study aimed to assess the effects of a Mangifera indica stem bark extract (MSBE) and mangiferin (MG) on pain-related acute behaviors in the formalin 5% test. Rats received repeated oral MSBE (125-500 mg/kg) once daily for 7 days before formalin injection. Other four groups with the same treatments were performed in order to study the effect of MSBE on the formalin-induced long-term secondary mechano-hyperalgesia at 7 days after the injury by means of the pin-prick method. Additional groups received a single oral MSBE dose (250 mg/kg) plus ascorbic acid (1 mg/kg, i.p.). Also, repeated oral MG doses (12.5-50 mg/kg) during 7 days were administered. MSBE decreased licking/biting and flinching behaviors only in phase II and reduced the long-term formalin injury-induced secondary chronic mechano-hyperalgesia. The combination of MSBE plus ascorbic acid produced a reinforcement of this effect for flinching behavior, advising that antioxidant mechanisms are involved, at least in part, in these actions. Chronic administration of MG reproduced the effects of MSBE. For the first time, the antihyperalgesic effects of MSBE and MG in formalin 5% test, a recommended concentration for studying the antinociceptive activity of nitric oxide-related and N-methyl-d-aspartate-related compounds, were reported. These results could represent an important contribution to explain the analgesic ethnobotanical effects recognized to M. indica and other species containing MG.

Combination of Mangifera indica L. extract supplementation plus methotrexate in rheumatoid arthritis patients: a pilot study.

The purpose of the present study was to evaluate the possible therapeutic effects and the safety of Mangifera indica extract (Vimang tablets, 300 mg) combined with methotrexate (MTX) on reducing disease activity in rheumatoid arthritis (RA). Twenty patients with active RA underwent a year of treatment with MTX (12.5 mg/week) associated to non-steroidal anti-inflammatory drugs (NSAIDs) and/or prednisone (5-10 mg/day) were randomly allocated to the experimental group (n=10), that received the extract supplementation (900 mg/day) or preceding usual treatment (n=10) during 180 days. RA activity was evaluated using the tender and swollen joint counts, erythrocyte sedimentation rate, disease activity score-28 (DAS 28), visual analogue scale (VAS) and health assessment questionnaire (HAQ). Treatment's efficacy was demonstrated with ACR criteria. Only the patients of MTX-Vimang group revealed statistically significant improvement in DAS 28 parameters with respect baseline data but no differences were observed between groups. ACR improvements amounted 80% only in MTX-Vimang group at the 90 days (p<0.001). In MTX-Vimang group, 100% of patients decreased NSAIDs administration (p<0.01) and 70% of those eradicated gastrointestinal side effects (p<0.01) ensuing of the preceding treatment. Other adverse effects were not reported.

Enrichment of carbon dioxide in the atmosphere increases the capsaicinoids content in Habanero peppers (Capsicum chinense Jacq.).

BACKGROUND: The effects of the increase of atmospheric CO2 on agricultural productivity have been mainly analyzed through its impact on biomass yield, and little attention has been directed to quality traits, such as nutritional or organoleptic attributes. For this study, plants of hot Habanero pepper (Capsicum chinense Jacq.) were grown in growth chambers under three different CO2 levels: 380 (normal atmospheric value), 760 and 1140 µmol mol(-1), and their effects on pod yield, size, color and pungency, were monitored. RESULTS: The total number of pods per plant increased by 88.5% at the highest CO2 , in comparison to plants grown at normal CO2 conditions. Pod size and yield per plant also increased when plants were grown at the highest CO2 concentration (partial pressure). Furthermore, total capsaicinoids contents in ripe peppers under a high CO2 atmosphere were 27% higher than those from plants under lower concentrations, but it was not the case for immature pods. CONCLUSION: These data suggest that the increase of atmospheric CO2 could modify specific routes of secondary metabolism as well as others desirable traits, thus affecting the quality of Capsicum pepper products.

Identification of peptides presented through the MHC-II of dendritic cells stimulated with Mycobacterium avium.

Mycobacterium avium (M. avium) represents a species of concern, because of its ability to modulate the host's innate immune response, and therefore influence trajectory of adaptative immunity. Since eradicative response against mycobacteria, and M. tuberculosis/M. avium, relies on peptides actively presented on a Major Histocompatibility complex-II (MHC-II) context, we assessed paradoxical stimulation of Dendritic Cell resulting on immature immunophenotype characterized by membrane minor increase of MHC-II and CD40 despite of high expression of the pro-inflammatory tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in supernatants. Identification of M. avium leucine rich peptides forming short α-helices shutting down Type 1T helper (Th1), contribute to the understanding of immune evasion of an increasingly prevalent pathogen, and may provide a basis for future immunotherapy to infectious and non-infectious disease.

Induced Systemic Resistance in the Bacillus spp.-Capsicum chinense Jacq.-PepGMV Interaction, Elicited by Defense-Related Gene Expression.

Induced systemic resistance (ISR) is a mechanism involved in the plant defense response against pathogens. Certain members of the Bacillus genus are able to promote the ISR by maintaining a healthy photosynthetic apparatus, which prepares the plant for future stress situations. The goal of the present study was to analyze the effect of the inoculation of Bacillus on the expression of genes involved in plant responses to pathogens, as a part of the ISR, during the interaction of Capsicum chinense infected with PepGMV. The effects of the inoculation of the Bacillus strains in pepper plants infected with PepGMV were evaluated by observing the accumulation of viral DNA and the visible symptoms of pepper plants during a time-course experiment in greenhouse and in in vitro experiments. The relative expression of the defense genes CcNPR1, CcPR10, and CcCOI1 were also evaluated. The results showed that the plants inoculated with Bacillus subtilis K47, Bacillus cereus K46, and Bacillus sp. M9 had a reduction in the PepGMV viral titer, and the symptoms in these plants were less severe compared to the plants infected with PepGMV and non-inoculated with Bacillus. Additionally, an increase in the transcript levels of CcNPR1, CcPR10, and CcCOI1 was observed in plants inoculated with Bacillus strains. Our results suggest that the inoculation of Bacillus strains interferes with the viral replication, through the increase in the transcription of pathogenesis-related genes, which is reflected in a lowered plant symptomatology and an improved yield in the greenhouse, regardless of PepGMV infection status.

Cat Coat Color, Personality Traits and the Cat-Owner Relationship Scale: A Study with Cat Owners in Mexico.

Studies regarding the cat-owner bond are quite rare, and several aspects merit more research, including personality trait differences in cats related to coat color and the cat-owner relationship. The objectives of the study were to describe, from the perspective of their owners, the personality traits of cats based on their coat colors and to evaluate the relationships among the Cat Owner Relationship Scale (CORS), its subscales and the traits of cats. Therefore, the CORS was translated into Spanish, and its psychometric properties were assessed. For the personality traits of cats, participants answered a 7-point Likert scale indicating the extent to which they agreed with the following characteristics in describing their cats: active, aloof, bold, calm, friendly, intolerant, shy, stubborn, tolerant and trainable. 211 cat owners living in Mexico participated. Owners perceived their cats as being bold and friendly. Gray cats had the highest score for being as shy, aloof and intolerant, while orange cats had the highest scores for being trainable, friendly and calm. Tabbies the highest for bold and active, tricolor cats for stubborn, and bicolor cats for tolerant. The 3 CORS subscales had adequate psychometric properties when evaluated separately. Cat-owner interaction was positively correlated with an active and friendly personality and negatively correlated with aloofness. Emotional closeness was positively correlated with an active, bold and friendly personality, and perceived cost was negatively correlated with boldness.

Phytochemical characterisation and in vivo antilithiatic activity of the stems of Caesalpinia bahamensis (Brasilete).

The aim of this work was to identify the main chemical constituents and to evaluate the antilithiatic activity of the aqueous and hydroalcoholic extracts of stems of Caesalpinia bahamensis Lam. Fractionation and isolation of constituents from the hydroalcoholic extract was carried out by flash chromatography and semi-preparative liquid chromatography. The antilithiatic activity of the aqueous and hydroalcoholic extracts was evaluated in Wistar rats, where kidney stones were induced by ethylene glycol and ammonium chloride. Creatinine, calcium, and oxalate levels were evaluated and histological analysis was carried out. The homoisoflavonoids protosappanin B, 10-methyl-protosappanin B and brazilin were isolated and the antilithiatic activity of the aqueous and hydroalcoholic extracts was demonstrated by the reduction of the concentration of calcium and oxalate in urine compared to the lithiasis group. It was corroborated by histological analysis. Brazilin and protosappanin B were proposed as chemical markers for this plant species.

CT-guided versus MR-guided radiotherapy: Impact on gastrointestinal sparing in adrenal stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: To quantify the indication for adaptive, gated breath-hold (BH) MR-guided radiotherapy (MRgRTBH) versus BH or free-breathing (FB) CT-based image-guided radiotherapy (CT-IGRT) for the ablative treatment of adrenal malignancies. MATERIALS AND METHODS: Twenty adrenal patients underwent adaptive IMRT MRgRTBH to a median dose of 50 Gy/5 fractions. Each patient was replanned for VMAT CT-IGRTBH and CT-IGRTFB on a c-arm linac. Only CT-IGRTFB used an ITV, summed from GTVs of all phases of the 4DCT respiratory evaluation. All used the same 5 mm GTV/ITV to PTV expansion. Metrics evaluated included: target volume and coverage, conformality, mean ipsilateral kidney and 0.5 cc gastrointestinal organ-at-risk (OAR) doses (D0.5cc). Adaptive dose for MRgRTBH and predicted dose (i.e., initial plan re-calculated on anatomy of the day) was performed for CT-IGRTBH and MRgRTBH to assess frequency of OAR violations and coverage reductions for each fraction. RESULTS: The more common VMAT CT-IGRTFB, with its significantly larger target volumes, proved inferior to MRgRTBH in mean PTV and ITV/GTV coverage, as well as small bowel D0.5cc. Conversely, VMAT CT-IGRTBH delivered a dosimetrically superior initial plan in terms of statistically significant (p ≤ 0.02) improvements in target coverage, conformality and D0.5cc to the large bowel, duodenum and mean ipsilateral kidney compared to IMRT MRgRTBH. However, non-adaptive CT-IGRTBH had a 71.8% frequency of predicted indications for adaptation and was 2.8 times more likely to experience a coverage reduction in PTV D95% than predicted for MRgRTBH. CONCLUSION: Breath-hold VMAT radiotherapy provides superior target coverage and conformality over MRgRTBH, but the ability of MRgRTBH to safely provide ablative doses to adrenal lesions near mobile luminal OAR through adaptation and direct, real-time motion tracking is unmatched.

A strong protective action of guttiferone-A, a naturally occurring prenylated benzophenone, against iron-induced neuronal cell damage.

Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with several reported pharmacological actions. We have assessed the protective action of GA on iron-induced neuronal cell damage by employing the PC12 cell line and primary culture of rat cortical neurons (PCRCN). A strong protection by GA, assessed by the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carbox-anilide (XTT) assay, was revealed, with IC(50) values <1 µM. GA also inhibited Fe(3+)-ascorbate reduction, iron-induced oxidative degradation of 2-deoxiribose, and iron-induced lipid peroxidation in rat brain homogenate, as well as stimulated oxygen consumption by Fe(2+) autoxidation. Absorption spectra and cyclic voltammograms of GA-Fe(2+)/Fe(3+) complexes suggest the formation of a transient charge transfer complex between Fe(2+) and GA, accelerating Fe(2+) oxidation. The more stable Fe(3+) complex with GA would be unable to participate in Fenton-Haber Weiss-type reactions and the propagation phase of lipid peroxidation. The results show a potential of GA against neuronal diseases associated with iron-induced oxidative stress.

The role of stress transactional theory on the development of fibromyalgia: a structural equation model.

INTRODUCTION: The aim of this paper is to evaluate the efficacy of a model based on the Lazarus & Folkman's transactional theory of stress to explain perceived stress and symptoms in a sample of people with fibromyalgia. METHODS: The design was an open, cross-sectional, uncontrolled study. Subjects were contacted through internet. A self-administered questionnaire was used that contained each of the variables included in the model. To perform the statistical analysis we used structural equation models. RESULTS: We evaluated 165 people who reported to have fibromyalgia diagnosis, 93.9% were female. According to PHQ-15 categories, used to measure symptoms, 83% of the participants were in the highest level of somatic symptom severity. FIQ was used to evaluate fibromyalgia impact, its maximum score is 100 points; taking into account mean and standard deviation, the samples are severely affected by fibromyalgia. We estimated five structural models; fifth model confirmed that some personal and social resources (self-esteem, self-efficacy, social support) perform as predictors of perceived stress level explaining 53% of its variance. This perceived stress was predictor of a latent variable indicated by symptoms and FIQ, and it explained 31% of its variance. Goodness of fit index was adequate. CONCLUSIONS: The study suggests the important role that perceived stress has in the fibromyalgia impact and the symptoms severity. This model can help to adequate and establish targets for the psychological treatments included in multidisciplinary programs for this disorder.