A Mathematical Model for Fibrous Dysplasia: The Role of the Flow of Mutant Cells.

Fibrous dysplasia (FD) is a mosaic non-inheritable genetic disorder of the skeleton in which normal bone is replaced by structurally unsound fibro-osseous tissue. There is no curative treatment for FD, partly because its pathophysiology is not yet fully known. We present a simple mathematical model of the disease incorporating its basic known biology, to gain insight on the dynamics of the involved bone-cell populations, and shed light on its pathophysiology. We develop an analytical study of the model and study its basic properties. The existence and stability of steady states are studied, an analysis of sensitivity on the model parameters is done, and different numerical simulations provide findings in agreement with the analytical results. We discuss the model dynamics match with known facts on the disease, and how some open questions could be addressed using the model.

Citizens from 13 countries share similar preferences for COVID-19 vaccine allocation priorities.

How does the public want a COVID-19 vaccine to be allocated? We conducted a conjoint experiment asking 15,536 adults in 13 countries to evaluate 248,576 profiles of potential vaccine recipients who varied randomly on five attributes. Our sample includes diverse countries from all continents. The results suggest that in addition to giving priority to health workers and to those at high risk, the public favors giving priority to a broad range of key workers and to those with lower income. These preferences are similar across respondents of different education levels, incomes, and political ideologies, as well as across most surveyed countries. The public favored COVID-19 vaccines being allocated solely via government programs but were highly polarized in some developed countries on whether taking a vaccine should be mandatory. There is a consensus among the public on many aspects of COVID-19 vaccination, which needs to be taken into account when developing and communicating rollout strategies.

Graph-Based Audio Classification Using Pre-Trained Models and Graph Neural Networks.

Sound classification plays a crucial role in enhancing the interpretation, analysis, and use of acoustic data, leading to a wide range of practical applications, of which environmental sound analysis is one of the most important. In this paper, we explore the representation of audio data as graphs in the context of sound classification. We propose a methodology that leverages pre-trained audio models to extract deep features from audio files, which are then employed as node information to build graphs. Subsequently, we train various graph neural networks (GNNs), specifically graph convolutional networks (GCNs), GraphSAGE, and graph attention networks (GATs), to solve multi-class audio classification problems. Our findings underscore the effectiveness of employing graphs to represent audio data. Moreover, they highlight the competitive performance of GNNs in sound classification endeavors, with the GAT model emerging as the top performer, achieving a mean accuracy of 83% in classifying environmental sounds and 91% in identifying the land cover of a site based on its audio recording. In conclusion, this study provides novel insights into the potential of graph representation learning techniques for analyzing audio data.

Soundscape Characterization Using Autoencoders and Unsupervised Learning.

Passive acoustic monitoring (PAM) through acoustic recorder units (ARUs) shows promise in detecting early landscape changes linked to functional and structural patterns, including species richness, acoustic diversity, community interactions, and human-induced threats. However, current approaches primarily rely on supervised methods, which require prior knowledge of collected datasets. This reliance poses challenges due to the large volumes of ARU data. In this work, we propose a non-supervised framework using autoencoders to extract soundscape features. We applied this framework to a dataset from Colombian landscapes captured by 31 audiomoth recorders. Our method generates clusters based on autoencoder features and represents cluster information with prototype spectrograms using centroid features and the decoder part of the neural network. Our analysis provides valuable insights into the distribution and temporal patterns of various sound compositions within the study area. By utilizing autoencoders, we identify significant soundscape patterns characterized by recurring and intense sound types across multiple frequency ranges. This comprehensive understanding of the study area's soundscape allows us to pinpoint crucial sound sources and gain deeper insights into its acoustic environment. Our results encourage further exploration of unsupervised algorithms in soundscape analysis as a promising alternative path for understanding and monitoring environmental changes.

Automatic Detection of Focal Cortical Dysplasia Using MRI: A Systematic Review.

Focal cortical dysplasia (FCD) is a congenital brain malformation that is closely associated with epilepsy. Early and accurate diagnosis is essential for effectively treating and managing FCD. Magnetic resonance imaging (MRI)-one of the most commonly used non-invasive neuroimaging methods for evaluating the structure of the brain-is often implemented along with automatic methods to diagnose FCD. In this review, we define three categories for FCD identification based on MRI: visual, semi-automatic, and fully automatic methods. By conducting a systematic review following the PRISMA statement, we identified 65 relevant papers that have contributed to our understanding of automatic FCD identification techniques. The results of this review present a comprehensive overview of the current state-of-the-art in the field of automatic FCD identification and highlight the progress made and challenges ahead in developing reliable, efficient methods for automatic FCD diagnosis using MRI images. Future developments in this area will most likely lead to the integration of these automatic identification tools into medical image-viewing software, providing neurologists and radiologists with enhanced diagnostic capabilities. Moreover, new MRI sequences and higher-field-strength scanners will offer improved resolution and anatomical detail for precise FCD characterization. This review summarizes the current state of automatic FCD identification, thereby contributing to a deeper understanding and the advancement of FCD diagnosis and management.

Phytochemical Profiling of Sambucus nigra L. Flower and Leaf Extracts and Their Antimicrobial Potential against Almond Tree Pathogens.

Despite extensive research on the chemical composition of elderberries and their numerous uses in pharmaceutical, beverage, and food production, there is still a lack of knowledge about Sambucus nigra leaves and flowers' antimicrobial activity against plant pathogens. In this study, the phytoconstituents of their aqueous ammonia extracts were first characterized by infrared spectroscopy and gas chromatography-mass spectrometry. The major phytocompounds identified in the flower extract were octyl 2-methylpropanoate; 3,5-dihydroxy-6-methyl-2,3-dihydropyran-4-one; propyl malonic acid; adenine; and 1-methyl-2-piperidinemethanol. Concerning the leaf extract, 1,6-anhydro-ß-D-glucopyranose; oleic acid; 2,1,3-benzothiadiazole; 2,3-dihydro-benzofuran; and 4-((1E)-3-hydroxy-1-propenyl)-2-methoxyphenol and other phenol derivatives were the main constituents. The potential of the extracts to act as bioprotectants was then investigated against three almond tree pathogens: Diaporthe amygdali, Phytophthora megasperma, and Verticillium dahliae. In vitro tests showed higher activity of the flower extract, with EC90 values in the 241-984 µg·mL-1 range (depending on the pathogen) vs. 354-1322 µg·mL-1 for the leaf extract. In addition, the flower extract led to full protection against P. megasperma at a dose of 1875 µg·mL-1 in ex situ tests on artificially-infected excised almond stems. These inhibitory concentrations were lower than those of commercial fungicides. These findings suggest that S. nigra aerial organs may be susceptible to valorization as an alternative to synthetic fungicides for the protection of this important crop.

Should asymptomatic bacteriuria be treated in lupus nephritis?

INTRODUCTION: The risk of infection in systemic lupus erythematosus (SLE) is associated with factors related to disease activity and immunosuppressive treatment. Recently, the persistence of asymptomatic bacteriuria (ASB) has been proposed as an environmental trigger for SLE and its flares, raising the question whether it should be treated systematically to reduce the risk of infection. To our knowledge, there is limited evidence on the screening and treatment of ASB in SLE. OBJECTIVE: The objective is to analyze the occurrence of infection and flare in patients with lupus nephritis with and without ASB. METHODS: A cross-sectional study of a cohort of patients with lupus nephritis during induction therapy with high-dose cyclophosphamide regimen was carried out between January 2018 and 2020, with a total of 37 patients investigated. Urine and blood samples from the two groups (with ASB and without ASB) where taken before the administration of cyclophosphamide. RESULTS: From the sampled 37 patients, 19 (51.4%) had ASB and 18 (48.6%) without ASB; both groups were well balanced in their demographics and clinical characteristics. No statistically significant association was found between the presence of ASB and the systemic lupus erythematosus disease activity index score (p = 0.604), and neither with the 24-h urine protein and leukocyte count (p > 0.177). Urinary tract infection occurred in 5.3% (1) of the patients with ASB, while 5.6% (1) of the patients in the group without ASB presented the infection, and the RR was 0.944 (0.06, 16.33) 95% CI; in addition, no statistically significant association was found between the presence of ASB and the occurrence of infection (p = 1,000). CONCLUSION: Our study did not find a statistically significant association of ASB with the occurrence of infection or disease activity. Further studies need it to clarify this, since treatment of ASB has been recognized as an important contributor to inappropriate antimicrobial use, which promotes emergence of antimicrobial resistance.

Genomic and Immunological Characterization of Hypermucoviscous Carbapenem-Resistant Klebsiella pneumoniae ST25 Isolates from Northwest Argentina.

In recent years, an increase in the prevalence hypermucoviscous carbapenem-resistant Klebsiella pneumoniae with sequence type 25 (ST25) was detected in hospitals of Tucuman (Northwest Argentina). In this work, the virulence and the innate immune response to two K. pneumoniae ST25 strains (LABACER 01 and LABACER 27) were evaluated in a murine model after a respiratory challenge. In addition, comparative genomics was performed with K. pneumoniae LABACER01 and LABACER27 to analyze genes associated with virulence. Both LABACER01 and LABACER27 were detected in the lungs of infected mice two days after the nasal challenge, with LABACER01 counts significantly higher than those of LABACER27. Only LABACER01 was detected in hemocultures. Lactate dehydrogenase (LDH) and albumin levels in bronchoalveolar lavage (BAL) samples were significantly higher in mice challenged with LABACER01 than in LABACER27-infected animals, indicating greater lung tissue damage. Both strains increased the levels of neutrophils, macrophages, TNF-α, IL-1ß, IL-6, KC, MCP-1, IFN-γ, and IL-17 in the respiratory tract and blood, with the effect of LABACER01 more marked than that of LABACER27. In contrast, LABACER27 induced higher levels of IL-10 in the respiratory tract than LABACER01. Genomic analysis revealed that K. pneumoniae LABACER01 and LABACER27 possess virulence factors found in other strains that have been shown to be hypervirulent, including genes required for enterobactin (entABCDEF) and salmochelin (iroDE) biosynthesis. In both strains, the genes of toxin-antitoxin systems, as well as regulators of the expression of virulence factors and adhesion genes were also detected. Studies on the genetic potential of multiresistant K. pneumoniae strains as well as their cellular and molecular interactions with the host are of fundamental importance to assess the association of certain virulence factors with the intensity of the inflammatory response. In this sense, this work explored the virulence profile based on genomic and in vivo studies of hypermucoviscous carbapenem-resistant K. pneumoniae ST25 strains, expanding the knowledge of the biology of the emerging ST25 clone in Argentina.

Holm Oak (Quercus ilex subsp. ballota (Desf.) Samp.) Bark Aqueous Ammonia Extract for the Control of Invasive Forest Pathogens.

Holm oak (Quercus ilex subsp. ballota (Desf.) Samp.) bark is a commonly used remedy to treat gastrointestinal disorders, throat and skin infections, hemorrhages, and dysentery. It has also been previously reported that its methanol extracts possess antibacterial activity, which can be related to the richness of Quercus spp. extracts in phenolic compounds, such as flavonoids and tannins. However, there is no information on the antifungal (including oomycete) properties of the bark from Q. ilex or its subspecies (ilex and ballota). In this work, we report the characterization of the aqueous ammonia extract of its bark by FTIR and GC-MS and the results of in vitro and ex situ inhibition tests against three phytopathogens. The main phytochemical components identified were inositols (19.5%), trans-squalene (13%), 4-butoxy-1-butanol (11.4%), gulopyranose (9.6%), lyxose (6.5%), 2,4-dimethyl-benzo[H]quinoline (5.1%), catechol (4.5%), and methoxyphenols (4.2%). The efficacy of the extract in controlling forest phytopathogens was tested in vitro against Fusarium circinatum (responsible for pitch canker of Pinus spp.), Cryphonectria parasitica (which causes chestnut blight), and Phytophthora cinnamomi (which causes 'root and crown rot' in a variety of hosts, including Castanea, conifers, Eucalyptus, Fagus, Juglans, Quercus, etc.), obtaining EC90 values of 322, 295, and 75 µg·mL-1, respectively, much lower than those attained for a commercial strobilurin fungicide (azoxystrobin). The extract was further tested ex situ against P. cinnamomi on artificially inoculated, excised stems of 'Garnem' almond rootstock, attaining complete protection at a dose of 782 µg·mL-1. The results suggest that holm oak bark extract may be a promising source of bioactive compounds against invasive forest pathogens, including the oomycete that is causing its decline, the so-called 'seca' in Spain.

Factors Associated With Diagnostic Delay of Axial Spondyloarthritis in Colombian Patients.

BACKGROUND/OBJECTIVE: The diagnostic delay of axial spondyloarthritis (axSpA) is globally reported to be between 3 and 11 years. Early diagnosis and treatment have long-term benefits for patients and the health care system. Several international studies have evaluated some factors associated with diagnostic delay, but there are no known studies in the Colombian population. This study assesses the factors associated with diagnostic delay of axSpA in a rheumatology center in Bogota, Colombia. METHODS: This monocentric analytical cross-sectional study was done in a specialized rheumatology center. Patients who fulfilled the 2009 Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axSpA were included. Information was obtained from medical records and a phone call. Bivariate and multivariate analyses were done to assess the associated factors with diagnostic delay. RESULTS: One hundred one patients were included, 54 were women (53.5%). The median diagnostic delay was 2 years (interquartile range, 1-7). The bivariate analysis showed that a younger age at diagnosis (p = 0.042) and previous diagnosis of lumbar degenerative disease (p = 0.029) were associated with a longer diagnostic delay. The logistical regression showed that previous lumbar degenerative disc disease (odds ratio, 2.8; 95% confidence interval, 1.09-7.53) and fibromyalgia (odds ratio, 4.0; 95% confidence interval, 1.2-13.1) diagnosis were both associated with a longer diagnostic delay. CONCLUSIONS: Factors associated with a longer diagnostic delay were previous diagnosis of lumbar degenerative disc disease and fibromyalgia. Additional studies are needed so that the reasons for diagnostic delay are understood and early diagnosis and management of axSpA are enabled.

[Impact of an active surveillance program and infection control measures on the incidence of carbapenem-resistant gram-negative bacilli in an intensive care unit]. / Impacto de un programa de vigilancia activa y medidas de control de infecciones sobre la incidencia de bacilos gram negativos resistentes a carbapenems en una unidad de cuidados intensivos.

Hospital-acquired infections caused by carbapenem-resistant Gram-negative bacteria (CRGNB) have been increasingly reported worldwide and are associated with high rates of mortality especially in intensive care units(ICUs). Early identification through rectal surveillance cultures and implementation of infection control measures(ICM) including contact precautions, staff education on cleaning and hand hygiene may reduce the spread of these microorganisms. The aim of this work was to assess the impact of enhanced ICM on CRGNB colonization and to describe the molecular epidemiology of these bacteria in a polyvalent ICU in a tertiary level hospital. A prospective study including audits and active surveillance culture program, with molecular characterization, was conducted before and after the implementation of prevention programs and infection control measures. Microbiological screening was performed in chromogenic media; PCR targeting ß-lactamases genes (blaKPC, blaNDM, blaVIM and blaOXA-48, blaSHV and blaCTX-M), molecular typing by PFGE; and MLST in K. pneumoniae were performed. CRGNB colonization was reduced from 16.92% to 9.67% upon implementing the infection control measures. In K. pneumoniae the most frequent carbapenemase type was KPC-2 associated with SHV-2 and CTX-M-15, and was disseminated in various STs (ST17, ST13, ST2256, ST353); there was no persistence of particular clones and virulence factors showed no association with hypervirulence. IMP-1 carbapenemase predominated in A. baumannii and the PFGE analysis individualized 3 clusters, assuming that the dissemination in the ICU was clonal. The early detection of patients colonized with CRBGN by using epidemiological surveillance cultures and the implementation of prophylactic measures are key to reducing the incidence of these microorganisms.

Downscaling of far-red solar-induced chlorophyll fluorescence of different crops from canopy to leaf level using a diurnal data set acquired by the airborne imaging spectrometer HyPlant.

Remote sensing-based measurements of solar-induced chlorophyll fluorescence (SIF) are useful for assessing plant functioning at different spatial and temporal scales. SIF is the most direct measure of photosynthesis and is therefore considered important to advance capacity for the monitoring of gross primary production (GPP) while it has also been suggested that its yield facilitates the early detection of vegetation stress. However, due to the influence of different confounding effects, the apparent SIF signal measured at canopy level differs from the fluorescence emitted at leaf level, which makes its physiological interpretation challenging. One of these effects is the scattering of SIF emitted from leaves on its way through the canopy. The escape fraction ( f esc ) describes the scattering of SIF within the canopy and corresponds to the ratio of apparent SIF at canopy level to SIF at leaf level. In the present study, the fluorescence correction vegetation index (FCVI) was used to determine f esc of far-red SIF for three structurally different crops (sugar beet, winter wheat, and fruit trees) from a diurnal data set recorded by the airborne imaging spectrometer HyPlant. This unique data set, for the first time, allowed a joint analysis of spatial and temporal dynamics of structural effects and thus the downscaling of far-red SIF from canopy ( SIF 760 canopy ) to leaf level ( SIF 760 leaf ). For a homogeneous crop such as winter wheat, it seems to be sufficient to determine f esc once a day to reliably scale SIF760 from canopy to leaf level. In contrast, for more complex canopies such as fruit trees, calculating f esc for each observation time throughout the day is strongly recommended. The compensation for structural effects, in combination with normalizing SIF760 to remove the effect of incoming radiation, further allowed the estimation of SIF emission efficiency ( ε SIF ) at leaf level, a parameter directly related to the diurnal variations of plant photosynthetic efficiency.

Superior Capsular Reconstruction With Autologous Fascia Lata Using a Single Lateral-Row Technique Is an Effective Option in Massive Irreparable Rotator Cuff Tears: Minimum 2-Year Follow-Up.

PURPOSE: The purpose of this study was to evaluate clinical and radiologic outcomes of arthroscopic superior capsular reconstruction (ASCR) with fascia lata autograft in patients with irreparable rotator cuff tears (IRCTs) performed using a single lateral-row fixation technique. METHODS: We studied a retrospective case series of patients with large or massive IRCTs for ASCR with fascia lata autograft. Clinical outcomes were evaluated using the Visual Analog Scale (VAS) and the Constant score. Healing of the graft was assessed by magntic resonance imaging or ultrasound. Acromiohumeral distance was evaluated by radiographs. RESULTS: Thirty-one patients with an average age of 61 years and an average follow-up of 35 months (24-51 months) underwent ASCR with fascia lata autograft. There was a significant improvement in VAS (7.7-0.7), Constant score (36.0-78.7), forward elevation (115°-171°), external rotation (33°-50°), strength (0.3 kg-2.3 kg), and acromiohumeral distance (6.1 mm-8.6 mm) (P < 0.001). Graft failure was present in 13.8% of patients, as shown by magnetic resonance imaging (26 patients) or ultrasound (3 patients). Patients with failed ASCR showed worse Constant scores (68.5.8 vs 80.2, P = 0.007), worse VAS (2.5 vs 0.4, P = 0.00002), worse external rotation (20° vs 54°, P = 0.004), lower acromiohumeral distance (5mm vs 9mm, P = 0.007), and a high association with the presence of os acromiale (χ2P = 0.003). No revision or subsequent surgical procedures were required. CONCLUSIONS: ASCR, with autologous fascia lata and single lateral row configuration, is an effective option in irreparable rotator cuff tears and results in clinical and radiologic improvement. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Detecting Attention Levels in ADHD Children with a Video Game and the Measurement of Brain Activity with a Single-Channel BCI Headset.

Attentional biomarkers in attention deficit hyperactivity disorder are difficult to detect using only behavioural testing. We explored whether attention measured by a low-cost EEG system might be helpful to detect a possible disorder at its earliest stages. The GokEvolution application was designed to train attention and to provide a measure to identify attentional problems in children early on. Attention changes registered with NeuroSky MindWave in combination with the CARAS-R psychological test were used to characterise the attentional profiles of 52 non-ADHD and 23 ADHD children aged 7 to 12 years old. The analyses revealed that the GokEvolution was valuable in measuring attention through its use of EEG-BCI technology. The ADHD group showed lower levels of attention and more variability in brain attentional responses when compared to the control group. The application was able to map the low attention profiles of the ADHD group when compared to the control group and could distinguish between participants who completed the task and those who did not. Therefore, this system could potentially be used in clinical settings as a screening tool for early detection of attentional traits in order to prevent their development.

Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study.

BACKGROUND: Upadacitinib, an oral Janus kinase (JAK)1-selective inhibitor, showed efficacy in combination with stable background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis who had an inadequate response to DMARDs. We aimed to evaluate the safety and efficacy of upadacitinib monotherapy after switching from methotrexate versus continuing methotrexate in patients with inadequate response to methotrexate. METHODS: SELECT-MONOTHERAPY was conducted at 138 sites in 24 countries. The study enrolled adults (≥18 years) who fulfilled the 2010 American College of Rheumatology (ACR)-European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis. Patients with active rheumatoid arthritis despite stable methotrexate were randomly assigned 2:2:1:1 to switch to once-daily monotherapy of of upadacitinib or to continue methotrexate at their existing dose as blinded study drug; starting from week 14, patients assigned to continue methotrexate were switched to 15 mg or 30 mg once-daily upadacitinib per prespecified random assignment at baseline. The primary endpoints in this report are proportion of patients achieving 20% improvement in the ACR criteria (ACR20) at week 14, and proportion achieving low disease activity defined as 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) of 3·2 or lower, both with non-responder imputation at week 14. Outcomes were assessed in patients who received at least one dose of study drug. This study is active but not recruiting and is registered with ClinicalTrials.gov, number NCT02706951. FINDINGS: Patients were screened between Feb 23, 2016, and May 19, 2017 and 648 were randomly assigned to treatment. 598 (92%) completed week 14. At week 14, an ACR20 response was achieved by 89 (41%) of 216 patients (95% CI 35-48) in the continued methotrexate group, 147 (68%) of 217 patients (62-74) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (65-77) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). DAS28(CRP) 3·2 or lower was met by 42 (19%) of 216 (95% CI 14-25) in the continued methotrexate group, 97 (45%) of 217 (38-51) receiving upadacitinib 15 mg, and 114 (53%) of 215 (46-60) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). Adverse events were reported in 102 patients (47%) on continued methotrexate, 103 (47%) on upadacitinib 15 mg, and 105 (49%) on upadacitinib 30 mg. Herpes zoster was reported by one (<1%) patient on continued methotrexate, three (1%) on upadacitinib 15 mg, and six (3%) on upadacitinib 30 mg. Three malignancies (one [<1%] on continued methotrexate, two [1%] on upadacitinib 15 mg), three adjudicated major adverse cardiovascular events (one [<1%] on upadacitinib 15 mg, two [<1%] on upadacitinib 30 mg), one adjudicated pulmonary embolism (<1%; upadacitinib 15 mg), and one death (<1%; upadacitinib 15 mg, haemorrhagic stroke [ruptured aneurysm]) were reported in the study. INTERPRETATION: Upadacitinib monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing methotrexate in this methotrexate inadequate-responder population. Safety observations were similar to those in previous upadacitinib rheumatoid arthritis studies. FUNDING: AbbVie Inc, USA.

Effects on goal directed behavior and habit in two animal models of Parkinson's disease.

Instrumental conditioning involves two different processes: Goal-directed behavior, characterized by its dependence on the causal relationship between action and outcome and the sensitivity of actions to changes in the value of the outcome; and habits, characterized for its persistence and insensitivity to changes after conditioning. It is known that the dopaminergic system is involved in both kind of learning. The present experiments analyzed two animal models of Parkinson's disease. The 6-OHDA model causes selective damage of the catecholaminergic neurons, specifically affecting the dopaminergic neurons in nigro-striatal system. This model simulates degenerative process symptomatology of Parkinson's disease. On the other hand, the LPS model generates an inflammation process in the infusion area. This model simulates the early symptoms of this disorder, including neuroinflammation and microglia activation. In order to validate both parkinsonian models, we studied if 6-OHDA and LPS models cause the same behavioral effects. The results showed that the 6-OHDA model interfered with the process involved in habit formation. In contrast, animals treated with LPS showed a goal-directed learning deficit. Differences between these models could be due to the different effects on Substantia Nigra neurons. 6-OHDA model might disrupt the nigrostriatal pathway, while LPS could interfere on efferences and afferences to Substantia Nigra.

An acylhydroquinone derivative produces OXPHOS uncoupling and sensitization to BH3 mimetic ABT-199 (Venetoclax) in human promyelocytic leukemia cells.

Since cancer cells have different mitochondrial bioenergetic requirements than non-cancerous cells, therapeutic inhibition of its mitochondrial functionality continues to be an important target for anticancer drug discovery. In this study, a series of acylhydroquinones with different acyl-chain length, and their chlorinated derivatives, in the aromatic ring, synthesized by Fries rearrangement under microwave irradiation, were evaluated for their anticancer activity in two leukemia cell lines. Findings from the primary and secondary screening of the 18 acylhydroquinones, tested at 5 µM on acute promyelocytic leukemia HL-60 and acute lymphoblastic leukemia CEM cells lines, identified an acylchlorohydroquinone (12) with a highly selective anti-proliferative effect toward HL-60 cells. This compound induced S-phase arrest in the cell cycle progression of HL-60 cells with insignificant toxicity on leukemic CEM cells and non-cancerous Hs27 cells. In HL-60 leukemic cells, 12 triggered increased mitochondrial NADH oxidation, increased respiration in presence of oligomycin (state 4o), mitochondrial depolarization, and ROS production, suggesting an uncoupling of OXPHOS. This provoked a metabolic adaptation dependent on AMPK/ACC/autophagy axis, having the mitochondrial ß-oxidation a pro-survival role since the combination of 12 and etomoxir, a carnitine palmitoyl-transferase (CPT) inhibitor promoted extensive HL-60 cell death. Finally, 12-induced metabolic stress sensitized to HL-60 cells to cell death by the FDA-approved anti-leukemic drug ABT-199, a BH3 mimetic. Therefore, our results suggest that acylchlorohydroquinone is a promising scaffold in anti-promyelocytic leukemia drug research.

Diabetes-related sex differences in the brain endothelin system following ischemia in vivo and in human brain endothelial cells in vitro.

The endothelin (ET) system has been implicated to contribute to the pathophysiology of cognitive impairment and stroke in experimental diabetes. Our goals were to test the hypotheses that (1) circulating and (or) periinfarct ET-1 levels are elevated after stroke in both sexes and this increase is greater in diabetes, (2) ET receptors are differentially regulated in the diabetic brain, (3) brain microvascular endothelial cells (BMVEC) of female and male origin express the ETA receptor subtype, and (4) diabetes- and stroke-mimicking conditions increase ET-1 levels in BMVECs of both sexes. Control and diabetic rats were randomized to sham or stroke surgery. BMVECs of male (hBEC5i) and female (hCMEC/D3) origin, cultured under normal and diabetes-mimicking conditions, were exposed to normoxia or hypoxia. Circulating ET-1 levels were higher in diabetic animals and this was more pronounced in the male cohort. Stroke did not further increase plasma ET-1. Tissue ET-1 levels were increased after stroke only in males, whereas periinfarct ET-1 increased in both control and diabetic females. Male BMVECs secreted more ET-1 than female cells and hypoxia increased ET-1 levels in both cell types. There was sexually dimorphic regulation of ET receptors in both tissue and cell culture samples. There are sex differences in the stroke- and diabetes-mediated changes in the brain ET system at the endothelial and tissue levels.

Inflammatory-Related Clinical and Metabolic Outcomes in COVID-19 Patients.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) infection elicits inflammatory manifestations that relate with a "cytokine storm." OBJECTIVE: The aim of this research was to assess the role of circulating interleukin 6 (IL-6) levels and other inflammatory markers in patients with coronavirus disease 2019 (COVID-19) on metabolic functions and accompanying clinical complications. Patients and Methods. A total of 165 patients diagnosed with COVID-19 pneumonia were examined for medical features and inflammatory markers such as blood IL-6, CRP, ferritin, LDH, neutrophil/lymphocyte index (NLI), D-Dimer, and Red Cell Distribution Width (RDW). Regression analyses concerning electronically collected medical data were adjusted by appropriate factors and confounding variables. Results. Plasma IL-6 determinations evidenced a consistent association with hospital stay days, Intensive Care Unit (ICU) admission, and mortality rates. Similar trends were found for other proinflammatory variables, where ferritin and NLI showed a remarkable value as surrogates. Hyperglycaemia and the Charlson Comorbidity Index Score were positively associated with the inflammatory response induced by the SARS-COV-2 infection. An unhealthy lifestyle such as smoking and alcoholic drinks consumption as well as excessive body adiposity influenced inflammatory-related outcomes in the screened patients. CONCLUSION: IL-6 together with other inflammatory biomarkers accompanied poor clinical and metabolic outcomes in COVID-19-infected patients. IL-6 may result in a suitable proxy to individually categorise patients in order to manage this infectious pandemic.

Anatomical variations in distal portion of the thoracic duct-A systematic review.

The objective of this study was to identify and analyze the anatomical variations in the termination of the thoracic duct (TD) in cadavers or patients by anatomical dissections and surgical or radiological procedures for better knowledge of the interindividual variations through a systematic review. The search strategy included PubMed and reference tracking. Studies were identified by searching the electronic Medline databases. The search terms included "TD," "Jugular Vein," "Subclavian Vein," or "Cervical," and the protocol used is reported herein. These search results yielded 20 qualitative review articles out of the 275 articles consulted. We collected all the important data from these 20 articles with 1,352 TD analyzed by varying sources in our search. Regarding the characteristics of the studies and the anatomy of the TD, the results were heterogeneous. The TD most commonly terminates in the internal jugular vein in 54.05% of cases (95% confidence interval [CI]: 54.03; 54.07), in the jugular-venous angle in 25.79% (95% CI: 25.77; 25.81), and in the subclavian vein in 8.16% of cases (95% CI: 8.14;8.18). Other terminations were found in 12% of cases. This systematic review provided an overview of the variations in the distal portion of the TD. This study can be helpful for surgeons in selecting the most appropriate methods to achieve successful surgical results and avoid complications, such as chylothorax; it also offers detailed information on the cervical termination of the TD in new diagnostic and therapeutic methods involving the TD. Clin. Anat. 32:99-107, 2019. © 2019 Wiley Periodicals, Inc.