Miracle-dz/UniFAR-FTUs huggingface dataset:
Ischemic Heart Disease Pathophysiology Paradigms Overview: From Plaque Activation to Microvascular Dysfunction

Ischemic heart disease still represents a large burden on individuals and health care resources worldwide. By conventions, it is equated with atherosclerotic plaque due to flow-limiting obstruction in large–medium sized coronary arteries. However, clinical, angiographic and autoptic findings suggest a multifaceted pathophysiology for ischemic heart disease and just some cases are caused by severe or complicated atherosclerotic plaques. Currently there is no well-defined assessment of ischemic heart disease pathophysiology that satisfies all the observations and sometimes the underlying mechanism to everyday ischemic heart disease ward cases is misleading. In order to better examine this complicated disease and to provide future perspectives, it is important to know and analyze the pathophysiological mechanisms that underline it, because ischemic heart disease is not always determined by atherosclerotic plaque complication. Therefore, in order to have a more complete comprehension of ischemic heart disease we propose an overview of the available pathophysiological paradigms, from plaque activation to microvascular dysfunction.
Effects of Strength vs. Plyometric Training on Change of Direction Performance in Experienced Soccer Players

The purpose of this study was to compare how 6 weeks of strength- vs. plyometric training, which were matched upon direction of motion and workload, influences change of direction (COD) performance. Twenty-one experienced male soccer players (age: 22.2 ± 2.7) were pair-matched into a strength- (n = 10) and a plyometric (n = 11) training group. CODs of 45°, 90°, 135° and 180° performed from either a 4 m or 20 m approach distance were compared before and after intervention. Results showed no significant difference between groups. Significant effects were only found within the plyometric training group (−3.2% to −4.6%) in 90°, 135° and 180° CODs from 4 m and a 180° COD from a 20 m approach distance. Individual changes in COD performances showed that with the 4 m approach at least 55% and 81% of the strength and plyometric training group, respectively, improved COD performance, while with the 20 m approach at least 66% of both groups improved performance. This study showed that the plyometric training program can improve most CODs, with angles over 90°, although this is dependent on the distance approaching the COD. Considering the limited time of implementing physical conditioning, in addition to regular soccer practice in most soccer environments, the current plyometric training program can be advantageous in improving CODs at maximal intensity.
Development of Chlorhexidine Digluconate and Lippia sidoides Essential Oil Loaded in Microemulsion for Disinfection of Dental Root Canals: Substantivity Profile and Antimicrobial Activity

The dental intracanal disinfection is crucial to achieve the success of endodontic treatment, avoiding the maintenance of endodontic infections. Chlorhexidine digluconate can act as an irrigating agent for it. However, it can cause tissue irritation in high concentrations. Therefore, combinations with other antimicrobial agents and more efficient therapeutic alternatives are studied, which make it possible to administer drugs more safely and with minimal adverse effects. Thus, the objective of this study was the development of a microemulsion containing chlorhexidine digluconate and essential oil of Lippia sidoides to be used for disinfection of dental root canals and to evaluate its profile of substantivity and antimicrobial activity. The microemulsions were obtained through phase diagrams, using the spontaneous formation method. We completed a physical-chemical characterization and evaluate the stability of the microemulsions, in addition to the substantivity profile in a bovine root dentin model, and in vitro antibacterial effect on Enterococcus faecalis. A method for quantifying chlorhexidine was developed using UV-Vis spectroscopy. The microemulsions showed acid pH, conductivity above 1.3 μScm−1, and dispersion index similar to water. The microemulsions showed antimicrobial inhibition halos similar to the commercial gel conventionally used, but with four times more substantivity to dentinal tissues. Microemulsions were obtained as a therapeutic alternative to formulations available on the market, presenting themselves as a system with great potential for the administration of drugs for disinfection of root canals.
Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial

Objectives Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. Methods 18 patients with SLE and with musculoskeletal pain ≥4 on a 10 cm Visual Analogue Scale were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient’s therapy. Potential biomarkers were evaluated. Results taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. Conclusion taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted.
Chronic Active Epstein–Barr Virus Infection: Is It Immunodeficiency, Malignancy, or Both?

Simple Summary Chronic active Epstein–Barr virus (EBV) infection (CAEBV) is a rare syndrome of unknown etiology characterized by prolonged infectious mononucleosis-like symptoms and proliferation of EBV-infected T and/or natural killer cells. CAEBV has been primarily reported in East Asia and Latin America, suggesting a genetic predisposition in its pathogenesis. The clinical course of CAEBV is heterogeneous ranging from an indolent and occasionally self-limiting disease to an aggressive and fatal condition, but its prognosis is generally poor. This heterogeneous clinical picture does not suggest a simple etiology for the syndrome. Clinicopathological investigations of CAEBV suggest that it has aspects of both malignant neoplasm and immunodeficiency. This article summarizes the latest findings on CAEBV and discusses critical unsolved questions regarding its pathogenesis and disease concept. Abstract Chronic active Epstein–Barr virus (EBV) infection (CAEBV) is a rare syndrome characterized by prolonged infectious mononucleosis-like symptoms and elevated peripheral blood EBV DNA load in apparently immunocompetent persons. CAEBV has been primarily reported in East Asia and Latin America, suggesting a genetic predisposition in its pathogenesis. In most cases of CAEBV, EBV induces proliferation of its unusual host cells, T or natural killer (NK) cells. The clinical course of CAEBV is heterogeneous; some patients show an indolent course, remaining in a stable condition for years, whereas others show an aggressive course with a fatal outcome due to hemophagocytic lymphohistiocytosis, multiple organ failure, or progression to leukemia/lymphoma. The pathogenesis of CAEBV is unclear and clinicopathological investigations suggest that it has aspects of both malignant neoplasm and immunodeficiency. Recent genetic analyses of both viral and host genomes in CAEBV patients have led to discoveries that are improving our understanding of the nature of this syndrome. This article summarizes the latest findings on CAEBV and discusses critical unsolved questions regarding its pathogenesis and disease concept.
MiR‐223‐3p inhibits rTp17‐induced inflammasome activation and pyroptosis by targeting NLRP3

The incidence of syphilis caused by Treponema pallidum subsp pallidum (T pallidum) infection is accompanied by inflammatory injuries of vascular endothelial cells. Studies have revealed that T pallidum infection could induce inflammasome activation and pyroptosis in macrophages. MicroRNA‐223‐3p (miR‐223‐3p) was reported to be a negative regulator in inflammatory diseases. The present study aimed to explore whether miR‐223‐3p regulates T pallidum‐induced inflammasome activation and pyroptosis in vascular endothelial cells, and determine the mechanisms which underlie this process. MiR‐223‐3p levels in syphilis and control samples were determined. The biological function of miR‐223‐3p in the NLRP3 inflammasome and pyroptosis was evaluated in T pallidum‐infected human umbilical vein endothelial cells (HUVECs). We observed a dramatic decrease in miR‐223‐3p levels in syphilis patients (n = 20) when compared to healthy controls (n = 20). Moreover, miR‐223‐3p showed a notable inhibitory effect on recombinant Tp17 (rTP17)‐induced caspase‐1 activation, resulting in decrease in IL‐1β production and pyroptosis, which was accompanied by the release of lactate dehydrogenase (LDH) in HUVECs. Additionally, the dual‐luciferase assay confirmed that NLRP3 is a direct target of miR‐223‐3p. Moreover, NLRP3 overexpression or knockdown largely blocked the effects of miR‐223‐3p on T pallidum‐induced inflammasome activation and pyroptosis in HUVECs. Most importantly, a notable negative correlation was observed between miR‐223‐3p and NLRP3, caspase‐1, and IL‐1β, respectively, in the serum of syphilis patients and healthy controls. Taken together, our results reveal that miR‐223‐3p targets NLRP3 to suppress inflammasome activation and pyroptosis in T pallidum‐infected endothelial cells, implying that miR‐223‐3p could be a potential target for syphilis patients.
Does anxiety moderate the effectiveness of mirtazapine in patients with treatment-resistant depression? A secondary analysis of the MIR trial

Background: There is a lack of evidence to guide treatment of comorbid depression and anxiety. Preliminary evidence suggests mirtazapine may be effective in treating patients with both depression and anxiety symptoms. Methods: We undertook a secondary analysis of mirtazapine (MIR): a placebo-controlled trial of the addition of mirtazapine to a selective serotonin reuptake inhibitor or serotonin–norepinephrine reuptake inhibitor in treatment-resistant depression (TRD) in primary care. We subdivided participants into three groups by baseline generalized anxiety disorder score (GAD-7): severe (GAD-7 ⩾ 16), moderate (GAD-7 = 11–15), no/mild (GAD-7 ⩽ 10). We used linear regression including likelihood-ratio testing of interaction terms to assess how baseline anxiety altered the response of participants to mirtazapine as measured by 12-week GAD-7 and Beck Depression Inventory II (BDI-II) scores. Results: Baseline generalized anxiety moderated mirtazapine’s effect as measured by GAD-7 (p = 0.041) and BDI-II (p = 0.088) at 12 weeks. Participants with severe generalized anxiety receiving mirtazapine had lower 12-week GAD-7 score (adjusted difference between means (ADM) −2.82, 95% confidence interval (CI) −0.69 to −4.95) and larger decreases in BDI-II score (ADM −6.36, 95% CI −1.60 to −10.84) than placebo. Conversely, there was no anxiolytic benefit (ADM 0.28, 95% CI −1.05 to 1.60) or antidepressant benefit (ADM −0.17, 95% CI −3.02 to 2.68) compared with placebo in those with no/mild generalized anxiety. Conclusions: These findings extend the evidence for the effectiveness of mirtazapine to reduce generalized anxiety in TRD in primary care. These results may inform targeted prescribing in depression based on concurrent anxiety symptoms, although these conclusions are constrained by the post-hoc nature of this analysis.
Bilberry (Vaccinium myrtillus L.) Extracts Comparative Analysis Regarding Their Phytonutrient Profiles, Antioxidant Capacity along with the In Vivo Rescue Effects Tested on a Drosophila melanogaster High-Sugar Diet Model

Bilberries (Vaccinium myrtillus L.) have been reported to hold a plentitude of health-promoting properties beyond basic nutrition, mainly attributed to their anthocyanin content and antioxidant activity. In this article, we built the phytochemical profile of three wild bilberry fruit extract formulations (aqueous, methanolic, and hydro-methanolic) using UHPLC-ESI-MS/MS putative analysis, identifying 88 individual phytochemicals, mainly flavonoids (total content 8.41 ± 0.11 mg QE/g dw), free amino acids, polyphenols (total content 21.68 ± 0.19 mg GAE/g dw), carboxylic acids, and vitamins. Furthermore, the antioxidant activity of the extract was assessed, reaching 78.03 ± 0.16% DPPH free radical scavenging activity, comparable to literature values determined for bilberry extracts of other origin. Due to the increased prevalence of metabolic syndrome and based on the reviewed benefits of bilberries, we tested the most potent formulation of our bilberry extracts in this biological context. The in vivo rescue effect of a bilberry extract supplemented diet on Drosophila melanogaster was assessed by monitoring biochemical and genomic markers. Hemolymph trehalose levels were halved upon addition of 3% hydro-methanolic bilberry extract to a high-sugar (1.5 M sucrose) diet, as compared to the non-supplemented high-sugar diet. Noteworthy, the rescue seen for flies kept on the bilberry extract supplemented high-sugar diet appeared to parallel the trehalose levels observed in the case of the control diet (50 mM sucrose) flies. Moreover, next to the trehalose-lowering type of in vivo effects, other gene expression related rescues were also detected for genes such as InR, Akh, AstA, AstC, Irk, Npc2g, and CCHa2 upon supplementation of the high-sugar diet with our hydro-methanolic bilberry fruit extract. Our findings suggest that such a bilberry fruit extract could generate physiological and genomic type of compensatory mechanisms so that further translational approaches would advance the understanding of some human specific pathological conditions.
miR-98 Regulates TMPRSS2 Expression in Human Endothelial Cells: Key Implications for COVID-19

The two main co-factors needed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter human cells are angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Here, we focused on the study of microRNAs that specifically target TMPRSS2. Through a bioinformatic approach, we identified miR-98-5p as a suitable candidate. Since we and others have shown that endothelial cells play a pivotal role in the pathogenesis of the coronavirus disease 2019 (COVID-19), we mechanistically validated miR-98-5p as a regulator of TMPRSS2 transcription in two different human endothelial cell types, derived from the lung and from the umbilical vein. Taken together, our findings indicate that TMPRSS2 represents a valid target in COVID-19 treatment, which may be achieved by specific non-coding-RNA approaches.
Anticancer Potential of Compounds from the Brazilian Blue Amazon

Abstract “Blue Amazon” is used to designate the Brazilian Economic Exclusive Zone, which covers an area comparable in size to that of its green counterpart. Indeed, Brazil flaunts a coastline spanning 8000 km through tropical and temperate regions and hosting part of the organisms accredited for the countryʼs megadiversity status. Still, biodiversity may be expressed at different scales of organization; besides species inventory, genetic characteristics of living beings and metabolic expression of their genes meet some of these other layers. These metabolites produced by terrestrial creatures traditionally and lately added to by those from marine organisms are recognized for their pharmaceutical value, since over 50% of small molecule-based medicines are related to natural products. Nonetheless, Brazil gives a modest contribution to the field of pharmacology and even less when considering marine pharmacology, which still lacks comprehensive in-depth assessments toward the bioactivity of marine compounds so far. Therefore, this review examined the last 40 years of Brazilian natural products research, focusing on molecules that evidenced anticancer potential–which represents ~ 15% of marine natural products isolated from Brazilian species. This review discusses the most promising compounds isolated from sponges, cnidarians, ascidians, and microbes in terms of their molecular targets and mechanisms of action. Wrapping up, the review delivers an outlook on the challenges that stand against developing groundbreaking natural products research in Brazil and on a means of surpassing these matters.
Protective Role of St. John’s Wort and Its Components Hyperforin and Hypericin against Diabetes through Inhibition of Inflammatory Signaling: Evidence from In Vitro and In Vivo Studies

Diabetes mellitus is a very common chronic disease with progressively increasing prevalence. Besides the well-known autoimmune and inflammatory pathogenesis of type 1 diabetes, in many people, metabolic changes and inappropriate lifestyle favor a subtle chronic inflammatory state that contributes to development of insulin resistance and progressive loss of β-cell function and mass, eventually resulting in metabolic syndrome or overt type 2 diabetes. In this paper, we review the anti-inflammatory effects of the extract of Hypericum perforatum L. (St. John’s wort, SJW) and its main active ingredients firstly in representative pathological situations on inflammatory basis and then in pancreatic β cells and in obese or diabetic animal models. The simultaneous and long-lasting inhibition of signal transducer and activator of transcription (STAT)-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs)/c-jun N-terminal kinase (JNK) signaling pathways involved in pro-inflammatory cytokine-induced β-cell dysfunction/death and insulin resistance make SJW particularly suitable for both preventive and therapeutic use in metabolic diseases. Hindrance of inflammatory cytokine signaling is likely dependent on the hyperforin content of SJW extract, but recent data reveal that hypericin can also exert relevant protective effects, mediated by activation of the cyclic adenosine monophosphate (cAMP)/protein kinase cAMP-dependent (PKA)/adenosine monophosphate activated protein kinase (AMPK) pathway, against high-fat-diet-induced metabolic abnormalities. Actually, the mechanisms of action of the two main components of SJW appear complementary, strengthening the efficacy of the plant extract. Careful quantitative analysis of SJW components and suitable dosage, with monitoring of possible drug–drug interaction in a context of remarkable tolerability, are easily achievable pre-requisites for forthcoming clinical applications.
Oxygen transport kinetics underpin rapid and robust diaphragm recovery following chronic spinal cord injury

Spinal treatment can restore diaphragm function in all animals 1 month following C2 hemisection induced paralysis. Greater recovery occurs the longer after injury the treatment is applied. Through advanced assessment of muscle mechanics, innovative histology and oxygen tension modelling, we have comprehensively characterized in vivo diaphragm function and phenotype. Muscle work loops reveal a significant deficit in diaphragm functional properties following chronic injury and paralysis, which are normalized following restored muscle activity caused by plasticity‐induced spinal reconnection. Injury causes global and local alterations in diaphragm muscle vascular supply, limiting oxygen diffusion and disturbing function. Restoration of muscle activity reverses these alterations, restoring oxygen supply to the tissue and enabling recovery of muscle functional properties. There remain metabolic deficits following restoration of diaphragm activity, probably explaining only partial functional recovery. We hypothesize that these deficits need to be resolved to restore complete respiratory motor function.
A compact stereotactic system for image-guided surgical intervention

Objective. Stereotactic technology enables fine navigation to small structures in the human body. While current stereotactic systems facilitate accurate targeting, they are mechanically cumbersome and limited in scope. Here, we hypothesized that a stereotactic system could be developed with a reduced footprint while maintaining broad targeting capabilities in order to improve versatility in frame placement location and surgical workflow. Approach. We designed a stereotactic system around the center-of-arc principle, with mechanical properties that would enable a compact design and ample targeting and trajectory maneuverability. To examine the opportunity for a low-cost rapidly-deployable system we developed two fabrication variants, one using three dimensional (3D)-printing and the other using conventional machining. Mechanical and image-guided accuracies were tested in phantom studies using magnetic resonance imaging (MRI) and computed tomography. Using human cadaver head specimens, we assessed the system’s surgical workflow and its ability to reliably and accurately implant electrodes in deep brain stimulation (DBS) surgery. Main results. We developed a small 7.7 × 5.4 cm2 device platform that rigidly mounts to curvilinear bone and supports the attachment of surgical instrumentation. Attachment of two surgical instruments, an imaging localizer and a compact targeting device, demonstrated successful MRI-guided intervention in phantom studies with a vector error of 1.79 ± 0.41 mm. Evaluation of the 3D-printed system for DBS surgery confirmed ease of device platform attachment and instrument functionality, as well as demonstrated a surgical targeting accuracy of 1.83 ± 0.15 mm. In addition, we found the surgical time to be 78.3 ± 5.4 min for bilateral electrode implantation. Significance. We developed a light and compact stereotactic system whose accuracy is on par with those used clinically. This technology is suitable for clinical translation and its flexibility in positioning will seamlessly expand the capabilities for stereotaxy to treat a wide range of conditions, both within neurosurgery and beyond.