Effect of intravenous pulses of methylprednisolone 250 mg versus dexamethasone 6 mg in hospitalised adults with severe COVID-19 pneumonia: An open-label randomised trial.

BACKGROUND: The efficacy and safety of high versus medium doses of glucocorticoids for the treatment of patients with COVID-19 has shown mixed outcomes in controlled trials and observational studies. We aimed to evaluate the effectiveness of methylprednisolone 250 mg bolus versus dexamethasone 6 mg in patients with severe COVID-19. METHODS: A randomised, open-label, controlled trial was conducted between February and August 2021 at four hospitals in Spain. The trial was suspended after the first interim analysis since the investigators considered that continuing the trial would be futile. Patients were randomly assigned in a 1:1 ratio to receive dexamethasone 6 mg once daily for up to 10 days or methylprednisolone 250 mg once daily for 3 days. RESULTS: Of the 128 randomised patients, 125 were analysed (mean age 60 ± 17 years; 82 males [66%]). Mortality at 28 days was 4.8% in the 250 mg methylprednisolone group versus 4.8% in the 6 mg dexamethasone group (absolute risk difference, 0.1% [95% CI, -8.8 to 9.1%]; p = 0.98). None of the secondary outcomes (admission to the intensive care unit, non-invasive respiratory or high-flow oxygen support, additional immunosuppressive drugs, or length of stay), or prespecified sensitivity analyses were statistically significant. Hyperglycaemia was more frequent in the methylprednisolone group at 27.0 versus 8.1% (absolute risk difference, -18.9% [95% CI, -31.8 to - 5.6%]; p = 0.007). CONCLUSIONS: Among severe but not critical patients with COVID-19, 250 mg/d for 3 days of methylprednisolone compared with 6 mg/d for 10 days of dexamethasone did not result in a decrease in mortality or intubation.

Beneficial effects of an algal oil rich in ω-3 polyunsaturated fatty acids on locomotor function and D2 dopamine receptor in haloperidol-induced parkinsonism.

INTRODUCTION: Parkinson's disease (PD) is a chronic neurological disorder whose pathogenesis involves the loss of dopaminergic neurons and dopamine terminals, formation of Lewy bodies, and microgliosis. Its treatment includes dopamine-based drugs with limited results and adverse effects. Additionally, some neuroleptic drugs used for mental disorders produce side effects referred to as parkinsonism. Dietary interventions with ω-3 polyunsaturated fatty acids (ω-3 PUFA) have attracted attention since they play a key role in most of the processes associated with PD etiology. OBJECTIVE: The purpose of our work was to investigate the effects of an ω-3 PUFA rich algal oil on locomotive alterations induced by haloperidol and D2 receptor protein and gene expression in Wistar rats. METHODOLOGY: Pre- and co-supplementation of algal oil (300 mg of ω-3 FA/kg/day for six weeks) and haloperidol (1.5 mg/kg/day for two weeks) were evaluated. RESULTS: Haloperidol provoked locomotive alterations in the Open Field Test and a 43% diminution in D2 receptor in brain membranes; in pre-supplemented rats a 93% increase in D2 receptor protein expression and a partial maintenance of locomotory performance were observed, while in co-supplemented rats D2 receptor protein expression was maintained as in control rats, although locomotive behavior was found diminished as in haloperidol rats. CONCLUSIONS: These results confirm the beneficial effects of ω-3 PUFA over locomotory alterations and as neuroprotective and neurorestorative compounds and demonstrates a stimulatory action on D2 receptor presence, as a mechanism by which these fatty acids participate in brain health.

Editorial Commentary: Isolated Patellofemoral Osteoarthritis May Be Treated Arthroscopically: Arthroscopic Partial Lateral Facetectomy Is a Good Alternative to More Aggressive Techniques.

Isolated patellofemoral osteoarthritis is not uncommon, and treatment remains controversial. Several surgical procedures have been performed to treat this condition. The success of surgery highly depends on the technique and the patient selection. The surgeon can choose between a relatively extreme total knee replacement, with predictable results, or operations demanding less surgical dissection and resection, but offering less certainty. Partial lateral facetectomy is a minimally invasive procedure that is simple and effective enough in selected patients with up to 10 years follow-up. An even less aggressive technique, the arthroscopic partial lateral facetectomy in combination with lateral retinacular release, has been shown to be safe, practical, reproducible, and with a low rate of complications and revision surgery at mid-term follow-up. Benefits of arthroscopic techniques include decreased bleeding, less postoperative pain, ability to treat concomitant pathology, and better cosmesis.

Ferulated Pectins and Ferulated Arabinoxylans Mixed Gel for Saccharomyces boulardii Entrapment in Electrosprayed Microbeads.

Ferulated polysaccharides such as pectin and arabinoxylan form covalent gels which are attractive for drug delivery or cell immobilization. Saccharomyces boulardii is a probiotic yeast known for providing humans with health benefits; however, its application is limited by viability loss under environmental stress. In this study, ferulated pectin from sugar beet solid waste (SBWP) and ferulated arabinoxylan from maize bioethanol waste (AX) were used to form a covalent mixed gel, which was in turn used to entrap S. boulardii (2.08 × 108 cells/mL) in microbeads using electrospray. SBWP presented a low degree of esterification (30%), which allowed gelation through Ca2+, making it possible to reduce microbead aggregation and coalescence by curing the particles in a 2% CaCl2 cross-linking solution. SBWP/AX and SBWP/AX+ S. boulardii microbeads presented a diameter of 214 and 344 µm, respectively, and a covalent cross-linking content (dimers di-FA and trimer tri-FA of ferulic acid) of 1.15 mg/g polysaccharide. The 8-5', 8-O-4'and 5-5'di-FA isomers proportions were 79%, 18%, and 3%, respectively. Confocal laser scanning microscopy images of propidium iodide-stained yeasts confirmed cell viability before and after microbeads preparation by electrospray. SBWP/AX capability to entrap S. boulardii would represent an alternative for probiotic immobilization in tailored biomaterials and an opportunity for sustainable waste upcycling to value-added products.

Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis.

The etiopathogenesis of autoimmune hepatitis (AIH) remains poorly understood. In this study, we sought to develop an animal model of human AIH to gain insight into the immunological mechanisms driving this condition. C57BL/6 mice were i.v. injected with adeno-associated viral vectors encoding murine IL-12 or luciferase under the control of a liver-specific promoter. Organ histology, response to immunosuppressive therapy, and biochemical and immunological parameters, including Ag-specific humoral and cellular response, were analyzed. Mechanistic studies were carried out using genetically modified mice and depletion of lymphocyte subpopulations. Adeno-associated virus IL-12-treated mice developed histological, biochemical, and immunological changes resembling type 1 AIH, including marked and persistent liver mononuclear cell infiltration, hepatic fibrosis, hypergammaglobulinemia, anti-nuclear and anti-smooth muscle actin Abs, and disease remission with immunosuppressive drugs. Interestingly, transgenic IL-12 was short-lived, but endogenous IL-12 expression was induced, and both IL-12 and IFN-γ remained elevated during the entire study period. IFN-γ was identified as an essential mediator of liver damage, and CD4 and CD8 T cells but not NK, NKT, or B cells were essential executors of hepatic injury. Furthermore, both MHC class I and MHC class II expression was upregulated at the hepatocellular membrane, and induction of autoreactive liver-specific T cells was detected. Remarkably, although immunoregulatory mechanisms were activated, they only partially mitigated liver damage. Thus, low and transient expression of transgenic IL-12 in hepatocytes causes loss of tolerance to hepatocellular Ags, leading to chronic hepatitis resembling human AIH type 1. This model provides a practical tool to explore AIH pathogenesis and novel therapies.

Emotional system in complex cognitive activities of working memory: A literature review of its role.

Cognitive processing is needed to elicit emotional responses. At the same time, emotional responses modulate and guide cognition to enable adaptive responses to the environment. However, most empirical studies and theoretical models of cognitive functions have been investigated without taking into account emotion, which is considered interference that is counterproductive to the correct functioning of the cognitive system. To understand how complex behaviors are carried out in the brain, an understanding of the interactions between emotion and cognition may be indispensable. Given the enormous scope of this topic for both cognition and emotion, these concepts will not be further defined here; instead, this review will be relatively narrow in scope and will emphasize several brain systems involved in the interactions between emotion and working memory because an important dimension of cognition involves working memory function. In attempting to understand the relationship between emotion and working memory, we will describe the projections of a set of brain structures that support our emotional life and the neuromodulator dopamine (which is also involved in emotion processing and incentive motivational behavior) in the prefrontal cortex. According to the literature, working memory engages the cortical regions. Thus, the prefrontal cortex, particularly the dorsolateral prefrontal cortex (DLPFC), although commonly viewed as a purely cognitive area, provides a test for the hypothesis that working memory and emotion are strongly integrated in the brain. In this review, we provide an overview of neuropsychological, neuroanatomical and molecular evidence, with the aim of establishing the extent to which working memory and emotion are related.

Pectin and Pectin-Based Composite Materials: Beyond Food Texture.

Pectins are plant cell wall natural heteropolysaccharides composed mainly of α-1-4 d-galacturonic acid units, which may or may not be methyl esterified, possesses neutral sugars branching that harbor functional moieties. Physicochemical features as pH, temperature, ions concentration, and cosolute presence, affect directly the extraction yield and gelling capacity of pectins. The chemical and structural features of this polysaccharide enables its interaction with a wide range of molecules, a property that scientists profit from to form new composite matrices for target/controlled delivery of therapeutic molecules, genes or cells. Considered a prebiotic dietary fiber, pectins meetmany regulations easily, regarding health applications within the pharmaceutical industry as a raw material and as an agent for the prevention of cancer. Thus, this review lists many emergent pectin-based composite materials which will probably palliate the impact of obesity, diabetes and heart disease, aid to forestall actual epidemics, expand the ken of food additives and food products design.

Rheology and microstructure of gels based on wheat arabinoxylans enzymatically modified in arabinose to xylose ratio.

BACKGROUND: Arabinoxylans (AX) are polysaccharides consisting of a backbone of xyloses with arabinose substituents ester-linked to ferulic acid (FA). The arabinose to xylose ratio (A/X) in AX may vary from 0.3 to 1.1. AX form covalent gels by cross-linking of FA but physical interactions between AX chains also contribute to the network formation. The present study aimed to investigate the rheological and microstructural characteristics of gels based on AX enzymatically modified in A/X. RESULTS: Tailored AX presented A/X ranging from 0.68 to 0.51 and formed covalent gels. Dimers of FA content and elasticity (G') increased from 0.31 to 0.39 g kg-1 AX and from 106 to 164 Pa when the A/X in the polysaccharide decreased from 0.68 to 0.51. Atomic force microscopy images of AX gels showed a sponge-like microstructure at A/X = 0.68, whereas, at lower values, gels presented a more compact microstructure. Scanning electron microscopy analysis of AX gels show an arrangement of different morphology, passing from an imperfect honeycomb (A/X = 0.68) to a flake-like microstructure (A/X = 0.51). CONCLUSION: Lower A/X values favor the aggregation of AX chains resulting in an increase in di-FA content, which improves the rheological and microstructural characteristics of the gel formed. © 2017 Society of Chemical Industry.

Evaluation of the safety and adjuvant effect of a detoxified listeriolysin O mutant on the humoral response to dengue virus antigens.

Listeriolysin O (LLO) has been proposed as a potential carrier or adjuvant molecule in the vaccination field. However, the cytotoxic and pro-apoptotic effects of LLO are the major limitations for this purpose. Here, we have performed a preclinical safety evaluation and characterized a new potential adjuvant application for a non-cytolytic LLO mutant (dtLLO) to enhance and modulate the immune response against the envelope (E) protein from dengue virus. In addition, we have studied the adjuvant effects of dtLLO on human immune cells and the role of membrane cholesterol for the binding and proinflammatory property of the toxoid. Our in-vivo results in the murine model confirmed that dtLLO is a safer molecule than wild-type LLO (wtLLO), with a significantly increased survival rate for mice challenged with dtLLO compared with mice challenged with wtLLO (P < 0·001). Histopathological analysis showed non-toxic effects in key target organs such as brain, heart, liver, spleen, kidney and lung after challenge with dtLLO. In vitro, dtLLO retained the capacity of binding to plasma membrane cholesterol on the surface of murine and human immune cells. Immunization of 6-8-week-old female BALB/c mice with a combination of dtLLO mixed with E protein elicited a robust specific humoral response with isotype diversification of immunoglobulin (Ig)G antibodies (IgG1 and IgG2a). Finally, we demonstrated that cholesterol and lipid raft integrity are required to induce a proinflammatory response by human cells. Taken together, these findings support a potential use of the dtLLO mutant as a safe and effective adjuvant molecule in vaccination.

Recombinant AAV Integration Is Not Associated With Hepatic Genotoxicity in Nonhuman Primates and Patients.

Recombinant adeno-associated viral vectors (rAAV) currently constitute a real therapeutic strategy for the sustained correction of diverse genetic conditions. Though a wealth of preclinical and clinical studies have been conducted with rAAV, the oncogenic potential of these vectors is still controversial, particularly when considering liver-directed gene therapy. Few preclinical studies and the recent discovery of incomplete wild-type AAV2 genomes integrated in human hepatocellular carcinoma biopsies have raised concerns on rAAV safety. In the present study, we have characterized the integration of both complete and partial rAAV2/5 genomes in nonhuman primate tissues and clinical liver biopsies from a trial aimed to treat acute intermittent porphyria. We applied a new multiplex linear amplification-mediated polymerase chain reaction (PCR) assay capable of detecting integration events that are originated throughout the rAAV genome. The integration rate was low both in nonhuman primates and patient's samples. Importantly, no integration clusters or events were found in genes previously reported to link rAAV integration with hepatocellular carcinoma development, thus showing the absence of genotoxicity of a systemically administered rAAV2/5 in a large animal model and in the clinical context.

Visual Servoing for an Autonomous Hexarotor Using a Neural Network Based PID Controller.

In recent years, unmanned aerial vehicles (UAVs) have gained significant attention. However, we face two major drawbacks when working with UAVs: high nonlinearities and unknown position in 3D space since it is not provided with on-board sensors that can measure its position with respect to a global coordinate system. In this paper, we present a real-time implementation of a servo control, integrating vision sensors, with a neural proportional integral derivative (PID), in order to develop an hexarotor image based visual servo control (IBVS) that knows the position of the robot by using a velocity vector as a reference to control the hexarotor position. This integration requires a tight coordination between control algorithms, models of the system to be controlled, sensors, hardware and software platforms and well-defined interfaces, to allow the real-time implementation, as well as the design of different processing stages with their respective communication architecture. All of these issues and others provoke the idea that real-time implementations can be considered as a difficult task. For the purpose of showing the effectiveness of the sensor integration and control algorithm to address these issues on a high nonlinear system with noisy sensors as cameras, experiments were performed on the Asctec Firefly on-board computer, including both simulation and experimenta results.

Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria.

BACKGROUND & AIMS: Acute intermittent porphyria (AIP) results from porphobilinogen deaminase (PBGD) haploinsufficiency, which leads to hepatic over-production of the neurotoxic heme precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) and the occurrence of neurovisceral attacks. Severe AIP is a devastating disease that can only be corrected by liver transplantation. Gene therapy represents a promising curative option. The objective of this study was to investigate the safety of a recombinant adeno-associated vector expressing PBGD (rAAV2/5-PBGD) administered for the first time in humans for the treatment of AIP. METHODS: In this phase I, open label, dose-escalation, multicenter clinical trial, four cohorts of 2 patients each received a single intravenous injection of the vector ranging from 5×10(11) to 1.8×10(13) genome copies/kg. Adverse events and changes in urinary PBG and ALA and in the clinical course of the disease were periodically evaluated prior and after treatment. Viral shedding, immune response against the vector and vector persistence in the liver were investigated. RESULTS: Treatment was safe in all cases. All patients developed anti-AAV5 neutralizing antibodies but no cellular responses against AAV5 or PBGD were observed. There was a trend towards a reduction of hospitalizations and heme treatments, although ALA and PBG levels remained unchanged. Vector genomes and transgene expression could be detected in the liver one year after therapy. CONCLUSIONS: rAAV2/5-PBGD administration is safe but AIP metabolic correction was not achieved at the doses tested in this trial. Notwithstanding, the treatment had a positive impact in clinical outcomes in most patients. LAY SUMMARY: Studies in an acute intermittent porphyria (AIP) animal model have shown that gene delivery of PBGD to hepatocytes using an adeno-associated virus vector (rAAV2/5-PBG) prevent mice from suffering porphyria acute attacks. In this phase I, open label, dose-escalation, multicenter clinical trial we show that the administration of rAAV2/5-PBGD to patients with severe AIP is safe but metabolic correction was not achieved at the doses tested; the treatment, however, had a positive but heterogeneous impact on clinical outcomes among treated patients and 2 out of 8 patients have stopped hematin treatment. CLINICAL TRIAL NUMBER: The observational phase was registered at Clinicaltrial.gov as NCT 02076763. The interventional phase study was registered at EudraCT as n° 2011-005590-23 and at Clinicaltrial.gov as NCT02082860.

Meniscal degeneration in human knee osteoarthritis: in situ hybridization and immunohistochemistry study.

OBJECTIVE: Meniscus injury is one of the causes of secondary osteoarthritis (OA). However, the role of meniscus is still unclear. Human meniscal distribution of cells and cartilage oligomeric matrix protein (COMP) and their changes in advanced OA were analyzed. PATIENTS AND METHODS: Thirty-one medial menisci from patients with knee OA that underwent a total knee arthroplasty were studied. Normal meniscal tissue was obtained from partial arthroscopic meniscectomy. Meniscal samples were processed for histology, immunohistochemistry and in situ hybridization, for cell assessment including density, active divisions, apoptosis, COMP distribution and proteoglycan content. RESULTS: Osteoarthritic menisci demonstrated areas of cell depletion and significant decrease in COMP immunostaining. Actively dividing cells were only found in the meniscectomy group, but not in the osteoarthritic group. Proteoglycan staining was less prominent in menisci from the osteoarthritis group. CONCLUSIONS: Our results show a decreased cell population, with low COMP and altered matrix organization in osteoarthritis menisci that suggest an altered meniscal scaffold and potential impairment of meniscal function. These meniscal changes may be associated with the development of knee osteoarthritis.

Gene delivery of suppressors of cytokine signaling (SOCS) inhibits inflammation and atherosclerosis development in mice.

Chronic activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway contributes to vascular inflammation and atherosclerosis by inducing expression of genes involved in cell proliferation, differentiation and migration. We aimed to investigate whether enforced expression of negative regulators, the suppressors of cytokine signaling (SOCS1 and SOCS3), inhibits harmful JAK/STAT-mediated responses and affects atherosclerosis in apolipoprotein E knockout mice. Adenovirus-mediated SOCS1 transgene expression impaired the onset and progression of atherosclerosis without impact on lipid profile, whereas SOCS3 was only effective on early atherosclerosis. Mechanistically, SOCS gene delivery, primarily SOCS1, attenuated STAT1 and STAT3 activation and reduced the expression of STAT-dependent genes (chemokine/chemokine receptors, adhesion molecules, pro-inflammatory cytokines and scavenger receptors) in aortic tissue. Furthermore, atherosclerotic plaques exhibit a more stable phenotype characterized by lower lipids, T cells and M1 macrophages and higher M2 macrophages and collagen. Atheroprotection was accompanied by a systemic alteration of T helper- and T regulatory-related genes and a reduced activation state of circulating monocytes. In vascular smooth muscle cells and macrophages, SOCS gene delivery inhibited cytokine-induced STAT activation, pro-inflammatory gene expression, cell migration and proliferation. In conclusion, targeting SOCS proteins, predominantly SOCS1, to suppress pathological mechanisms involved in atheroma plaque progression and destabilization could be an interesting anti-atherosclerotic strategy.

An analysis of the function and expression of D6 on lymphatic endothelial cells.

The mechanisms by which CC chemokine receptor (CCR)7 ligands are selectively presented on lymphatic endothelium in the presence of inflammatory chemokines are poorly understood. The chemokine-scavenging receptor D6 is expressed on lymphatic endothelial cells (LEC) and contributes to selective presentation of CCR7 ligands by suppressing inflammatory chemokine binding to LEC surfaces. As well as preventing inappropriate inflammatory cell attachment to LECs, D6 is specifically involved in regulating the ability of LEC to discriminate between mature and immature dendritic cells (DCs). D6 overexpression reduces immature DC (iDC) adhesion to LECs, whereas D6 knockdown increases adhesion of iDCs that displace mature DCs. LEC D6 expression is regulated by growth factors, cytokines, and tumor microenvironments. In particular, interleukin-6 and interferon-γ are potent inducers, indicating a preferential role for D6 in inflamed contexts. Expression of the viral interleukin-6 homolog from Kaposi sarcoma-associated herpesvirus is also sufficient to induce significant D6 upregulation both in vitro and in vivo, and Kaposi sarcoma and primary effusion lymphoma cells demonstrate high levels of D6 expression. We therefore propose that D6, which is upregulated in both inflammatory and tumor contexts, is an essential regulator of inflammatory leukocyte interactions with LECs and is required for immature/mature DC discrimination by LECs.

Peptide inhibitor of NF-κB translocation ameliorates experimental atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the arterial wall. NF-κB is a major regulator of inflammation that controls the expression of many genes involved in atherogenesis. Activated NF-κB was detected in human atherosclerotic plaques, and modulation of NF-κB inflammatory activity limits disease progression in mice. Herein, we investigate the anti-inflammatory and atheroprotective effects of a cell-permeable peptide containing the NF-κB nuclear localization sequence (NLS). In vascular smooth muscle cells and macrophages, NLS peptide specifically blocked the importin α-mediated nuclear import of NF-κB and prevented lipopolysaccharide-induced pro-inflammatory gene expression, cell migration, and oxidative stress. In experimental atherosclerosis (apolipoprotein E-knockout mice fed a high-fat diet), i.p., 0.13 µmol/day NLS peptide administration for 5 weeks attenuated NF-κB activation in atherosclerotic plaques. NLS peptide significantly inhibited lesion development at both early (age 10 weeks) and advanced (age 28 weeks) stages of atherosclerosis in mice, without affecting serum lipid levels. Plaques from NLS-treated mice contained fewer macrophages of pro-inflammatory M1 subtype than those from respective untreated controls. By contrast, the relative smooth muscle cell and collagen content was increased, indicating a more stable plaque phenotype. NLS peptide also attenuated pro-inflammatory gene expression and oxidative stress in aortic lesions. Our study demonstrates that targeting NF-κB nuclear translocation hampers inflammation and atherosclerosis development and identifies cell-permeable NLS peptide as a potential anti-atherosclerotic agent.

Entrapment of probiotics in water extractable arabinoxylan gels: rheological and microstructural characterization.

Due to their porous structure, aqueous environment and dietary fiber nature arabinoxylan (AX) gels could have potential applications for colon-specific therapeutic molecule delivery. In addition, prebiotic and health related effects of AX have been previously demonstrated. It has been also reported that cross-linked AX can be degraded by bacteria from the intestinal microbiota. However, AX gels have not been abundantly studied as carrier systems and there is no information available concerning their capability to entrap cells. In this regard, probiotic bacteria such as Bifidobacterium longum have been the focus of intense research activity lately. The objective of this research was to investigate the entrapment of probiotic B. longum in AX gels. AX solution at 2% (w/v) containing B. longum (1 × 107 CFU/cm) formed gels induced by laccase as cross-linking agent. The entrapment of B. longum decreased gel elasticity from 31 to 23 Pa, probably by affecting the physical interactions taking place between WEAX chains. Images of AX gels containing B. longum viewed under a scanning electron microscope show the gel network with the bacterial cells entrapped inside. The microstructure of these gels resembles that of an imperfect honeycomb. The results suggest that AX gels can be potential candidates for the entrapment of probiotics.

[Cornual ectopic pregnancy]. / Embarazo ectópico cornual. Reporte clinic.

This paper reports the case of a 16-year old patient, with menstrual delay of 9 weeks, with positive pregnancy test, who went to the hospital due to expulsion of organized material, as well as pain colic type in hypogastrium. It was carried out laparotomy, finding ectopic pregnancy in right horn, being carried out miometrial incision and trophoblast aspiration, with presence of multiple endometriosic focuses in later face of uterus. In later pregnancies, there are not studies about the solidity of the scar after the horn resection and uterine breaks have been described in the second and third trimester.