Can intravenous oxytocin infusion counteract hyperinflammation in COVID-19 infected patients?

Objectives Based on its well-documented anti-inflammatory and restorative properties we propose trials with the natural hormone oxytocin for treatment of hospitalised Covid-19 patients. Methods We searched for, retrieved, and commented on specific literature regarding multiple functions of oxytocin with a special focus on its modulation of inflammatory, immune, and restorative functions. Results Available data gathered in animals and humans support the anti-inflammatory properties of oxytocin. The multiple anti-inflammatory effects of oxytocin have been demonstrated in vitro and in vivo in various animal models and also in humans in response to intravenous infusion of oxytocin. Furthermore, oxytocin has been documented to activate several types of protective and restorative mechanisms and to exert positive effects on the immune system. Conclusions In addition, to being anti-inflammatory, it may be hypothesised, that oxytocin may be less suppressive on adaptive immune systems, as compared with glucocorticoids. Finally, by its restorative effects coupled with its anti-stress and healing properties, oxytocin may shorten the recovery period of the Covid-19 patients

Unsupervised, Efficient and Semantic Expertise Retrieval

We introduce an unsupervised discriminative model for the task of retrieving experts in online document collections. We exclusively employ textual evidence and avoid explicit feature engineering by learning distributed word representations in an unsupervised way. We compare our model to state-of-the-art unsupervised statistical vector space and probabilistic generative approaches. Our proposed log-linear model achieves the retrieval performance levels of state-of-the-art document-centric methods with the low inference cost of so-called profile-centric approaches. It yields a statistically significant improved ranking over vector space and generative models in most cases, matching the performance of supervised methods on various benchmarks. That is, by using solely text we can do as well as methods that work with external evidence and/or relevance feedback. A contrastive analysis of rankings produced by discriminative and generative approaches shows that they have complementary strengths due to the ability of the unsupervised discriminative model to perform semantic matching.Comment: WWW2016, Proceedings of the 25th International Conference on World Wide Web. 201

CD69 is a TGF-β/1α,25-dihydroxyvitamin D3 target gene in monocytes

CD69 is a transmembrane lectin that can be expressed on most hematopoietic cells. In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in which the leukotrienes, a class of highly potent inflammatory mediators, are produced. However, regarding CD69 gene expression and its regulatory mechanisms in monocytes, only scarce data are available. Here, we report that CD69 mRNA expression, analogous to that of 5-lipoxygenase, is induced by the physiologic stimuli transforming growth factor-β (TGF-β) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in monocytic cells. Comparison with T- and B-cell lines showed that the effect was specific for monocytes. CD69 expression levels were increased in a concentration-dependent manner, and kinetic analysis revealed a rapid onset of mRNA expression, indicating that CD69 is a primary TGF-β/1α,25(OH)2D3 target gene. PCR analysis of different regions of the CD69 mRNA revealed that de novo transcription was initiated and proximal and distal parts were induced concomitantly. In common with 5-lipoxygenase, no activation of 0.7 kb or ~2.3 kb promoter fragments by TGF-β and 1α,25(OH)2D3 could be observed in transient reporter assays for CD69. Analysis of mRNA stability using a transcription inhibitor and a 3′UTR reporter construct showed that TGF-β and 1α,25(OH)2D3 do not influence CD69 mRNA stability. Functional knockdown of Smad3 clearly demonstrated that upregulation of CD69 mRNA, in contrast to 5-LO, depends on Smad3. Comparative studies with different inhibitors for mitogen activated protein kinases (MAPKs) revealed that MAPK signalling is involved in CD69 gene regulation, whereas 5-lipoxygenase gene expression was only partly affected. Mechanistically, we found evidence that CD69 gene upregulation depends on TAK1-mediated p38 activation. In summary, our data indicate that CD69 gene expression, conforming with 5-lipoxygenase, is regulated monocyte-specifically by the physiologic stimuli TGF-β and 1α,25(OH)2D3 on mRNA level, although different mechanisms account for the upregulation of each gene

Arrhythmic risk profile and outcomes of patients undergoing cardiac sympathetic denervation for recurrent monomorphic ventricular tachycardia after ablation

Background Cardiac sympathetic denervation (CSD) has been used as a bailout strategy for refractory ventricular tachycardia (VT). Risk of VT recurrence in patients with scar-related monomorphic VT referred for CSD and the extent to which CSD can modify this risk is unknown. We aimed to quantify arrhythmia recurrence risk and impact of CSD in this population. Methods and Results Adjusted competing risk time to event models were developed to adjust for risk of VT recurrence and sustained VT/implantable cardioverter-defibrillator shocks after VT ablation based on patient comorbidities at the time of VT ablation. Adjusted VT and implantable cardioverter-defibrillator shock recurrence rates were estimated for the subgroup who subsequently required CSD after ablation. The expected adjusted recurrence rates were then compared with the observed rates after CSD. Data from 381 patients with scar-mediated monomorphic VT who underwent VT ablation were analyzed, excluding patients with polymorphic VT. Sixty eight patients underwent CSD for recurrent VT. CSD reduced the expected adjusted VT recurrence rate by 36% (expected rate of 5.61 versus observed rate of 3.58 per 100 person-months, P=0.01) and the sustained VT/implantable cardioverter-defibrillator shock rates by 34% (expected rate of 4.34 versus observed 2.85 per 100 person-months, P=0.03). The median number of sustained VT/implantable cardioverter-defibrillator shocks in the year before versus the year after CSD was reduced by 90% (10 versus 1, P<0.0001). Conclusions Patients referred for CSD for refractory scar-mediated monomorphic VT are at a higher risk of VT recurrence after ablation as compared with those not requiring CSD, mostly because of their cardiac comorbidities. CSD significantly reduced both the expected risk of recurrences and VT burden

In Vivo Dioxin Favors Interleukin-22 Production by Human CD4+ T Cells in an Aryl Hydrocarbon Receptor (AhR)-Dependent Manner

The transcription factor aryl hydrocarbon receptor (AhR) mediates the effects of a group of chemicals known as dioxins, ubiquitously present in our environment. However, it is poorly known how the in vivo exposure to these chemicals affects in humans the adaptive immune response. We therefore assessed the functional phenotype of T cells from an individual who developed a severe cutaneous and systemic syndrome after having been exposed to an extremely high dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).T cells of the TCDD-exposed individual were studied for their capacity to produce cytokines in response to polyclonal and superantigenic stimulation, and for the expression of chemokine receptors involved in skin homing. The supernatants from T cells of the exposed individual contained a substantially increased amount of interleukin (IL)-22 but not of IL-17A, interferon (IFN)-γ or IL-10 when compared to nine healthy controls. In vitro experiments confirmed a direct, AhR-dependent, enhancing effect of TCDD on IL-22 production by CD4+ T cells. The increased production of IL-22 was not dependent on AhR occupancy by residual TCDD molecules, as demonstrated in competition experiments with the specific AhR antagonist CH-223191. In contrast, it was due to an increased frequency of IL-22 single producing cells accompanied by an increased percentage of cells expressing the skin-homing chemokine receptors CCR6 and CCR4, identified through a multiparameter flow cytometry approach. Of interest, the frequency of CD4+CD25(hi)FoxP3+ T regulatory cells was similar in the TCDD-exposed and healthy individuals.This case strongly supports the contention that human exposure to persistent AhR ligands in vivo induce a long-lasting effect on the human adaptive immune system and specifically polarizes CD4+ T cells to produce IL-22 and not other T cell cytokines with no effect on T regulatory cells

Dopaminergic modulation of appetitive trace conditioning: the role of D1 receptors in medial prefrontal cortex

Rationale: Trace conditioning may provide a behavioural model suitable to examine the maintenance of ‘on line’ information and its underlying neural substrates. Objectives: Experiment la was run to establish trace conditioning in a shortened procedure which would be suitable to test the effects of dopamine (DA) D1 receptor agents administered by microinjection directly into the brain. Experiment lb examined the effects of the DA D1 agonist SKF81297 and the DA D1 antagonist SCH23390 following systemic administration in pre-trained animals. Experiment 2 went on to test the effects of systemically administered SKF81297 on the acquisition of trace conditioning. In experiment 3, SKF81297 was administered directly in prelimbic (PL) and infralimbic (IL) sub-regions of medial prefrontal cortex (mPFC) to compare the role of different mPFC sub-regions. Results: Whilst treatment with SCH23390 impaired motor responding and/or motivation, SKF81297 had relatively little effect in the pre-trained animals tested in experiment 1b. However, systemic SKF81297 depressed the acquisition function at the 2-s trace interval in experiment 2. Similarly, in experiment 3, SKF81297 (0.1 μg in 1.0 μl) microinjected into either PL or IL mPFC impaired appetitive conditioning at the 2-s trace interval. Conclusions: Impaired trace conditioning under SKF81297 is likely to be mediated in part (but not exclusively) within the IL and PL mPFC sub-regions. The finding that trace conditioning was impaired rather than enhanced under SKF81297 provides further evidence for the inverse U-function which has been suggested to be characteristic of mPFC DA function

In Vivo Evaluation of the Biocompatibility of Surface Modified Hemodialysis Polysulfone Hollow Fibers in Rat

Polysulfone (Psf) hollow fiber membranes (HFMs) have been widely used in blood purification but their biocompatibility remains a concern. To enhance their biocompatibility, Psf/TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate) composite HFMs and 2-methacryloyloxyethyl phosphorylcholine (MPC) coated Psf HFMs have been prepared. They have been evaluated for in vivo biocompatibility and graft acceptance and compared with sham and commercial membranes by intra-peritoneal implantation in rats at day 7 and 21. Normal body weights, tissue formation and angiogenesis indicate acceptance of implants by the animals. Hematological observations show presence of post-surgical stress which subsides over time. Serum biochemistry results reveal normal organ function and elevated liver ALP levels at day 21. Histological studies exhibit fibroblast recruitment cells, angiogenesis and collagen deposition at the implant surface indicating new tissue formation. Immuno-histochemistry studies show non-activation of MHC molecules signifying biocompatibilty. Additionally, Psf/TPGS exhibit most favorable tissue response as compared with other HFMs making them the material of choice for HFM preparation for hemodialysis applications

Hyperspectral Computed Tomographic Imaging Spectroscopy of Vascular Oxygen Gradients in the Rabbit Retina In Vivo

Diagnosis of retinal vascular diseases depends on ophthalmoscopic findings that most often occur after severe visual loss (as in vein occlusions) or chronic changes that are irreversible (as in diabetic retinopathy). Despite recent advances, diagnostic imaging currently reveals very little about the vascular function and local oxygen delivery. One potentially useful measure of vascular function is measurement of hemoglobin oxygen content. In this paper, we demonstrate a novel method of accurately, rapidly and easily measuring oxygen saturation within retinal vessels using in vivo imaging spectroscopy. This method uses a commercially available fundus camera coupled to two-dimensional diffracting optics that scatter the incident light onto a focal plane array in a calibrated pattern. Computed tomographic algorithms are used to reconstruct the diffracted spectral patterns into wavelength components of the original image. In this paper the spectral components of oxy- and deoxyhemoglobin are analyzed from the vessels within the image. Up to 76 spectral measurements can be made in only a few milliseconds and used to quantify the oxygen saturation within the retinal vessels over a 10–15 degree field. The method described here can acquire 10-fold more spectral data in much less time than conventional oximetry systems (while utilizing the commonly accepted fundus camera platform). Application of this method to animal models of retinal vascular disease and clinical subjects will provide useful and novel information about retinal vascular disease and physiology

Selection for antimicrobial resistance is reduced when embedded in a natural microbial community

This is the final version. Available from Springer Nature via the DOI in this record.Antibiotic resistance has emerged as one of the most pressing, global threats to public health. In single-species experiments selection for antibiotic resistance occurs at very low antibiotic concentrations. However, it is unclear how far these findings can be extrapolated to natural environments, where species are embedded within complex communities. We competed isogenic strains of Escherichia coli, differing exclusively in a single chromosomal resistance determinant, in the presence and absence of a pig faecal microbial community across a gradient of antibiotic concentration for two relevant antibiotics: gentamicin and kanamycin. We show that the minimal selective concentration was increased by more than one order of magnitude for both antibiotics when embedded in the community. We identified two general mechanisms were responsible for the increase in minimal selective concentration: an increase in the cost of resistance and a protective effect of the community for the susceptible phenotype. These findings have implications for our understanding of the evolution and selection of antibiotic resistance, and can inform future risk assessment efforts on antibiotic concentrations.Medical Research Council (MRC)European Commissio

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function