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Microbial communities in the gut can be highly individual. What engenders this specificity? The gut characteristically produces gram quantities of immunoglobulin A (IgA) antibody, which is presumed to protect the gut from pathogen attack. Donaldson et al. engineered strains of Bacteroides fragilis , a common human commensal, to modify its surface capsule, which affects its ability to colonize the germ-free mouse gut. Capsule changes altered the capacity of IgA to bind to the different mutants. It seems that this commensal species exploits IgA sticking power specifically to give it a competitive edge and to promote its establishment in the gut. Science , this issue p. 795 Bacteroides fragilis modifies its surface to induce an immunoglobulin A response that promotes stable mucosal association and colonization resistance. The immune system responds vigorously to microbial infection while permitting lifelong colonization by the microbiome. Mechanisms that facilitate the establishment and stability of the gut microbiota remain poorly described. We found that a regulatory system in the prominent human commensal Bacteroides fragilis modulates its surface architecture to invite binding of immunoglobulin A (IgA) in mice. Specific immune recognition facilitated bacterial adherence to cultured intestinal epithelial cells and intimate association with the gut mucosal surface in vivo. The IgA response was required for B. fragilis (and other commensal species) to occupy a defined mucosal niche that mediates stable colonization of the gut through exclusion of exogenous competitors. Therefore, in addition to its role in pathogen clearance, we propose that IgA responses can be co-opted by the microbiome to engender robust host-microbial symbiosis.

Key Points The past decade has seen a rapid emergence of epigenetics as a major contributor to carcinogenesis. Aberrations in the normal DNA methylation patterns and histone modifications have been recognized as targets for therapy which, unlike conventional chemotherapy, aim to revert the abnormal state of malignant cells to a more normal condition. Demethylating agents that belong to a group of nucleoside analogues all have cytosine-ring modifications that allow each compound to form a covalent complex with a DNA methyltransferase, thereby inhibiting further methylation. Other DNA-methylation inhibitors belong to a group of non-nucleoside analogues whose mechanism of inhibition is not well known. DNA methylation inhibitors have the disadvantages of lacking specificity and causing genome-wide hypomethylation which might activate appropriately silent genes and/or initiate genome instability, leading to undesirable consequences. These problems will be circumvented with more specific drugs directed to specific regions of the genome. It is anticipated that these drugs would be available in the form of chemically synthesized small molecules, which are more effective than cytidine analogues because they do not require incorporation into DNA and bind directly to the catalytic site of the DNA methyl transferases. Histone deacetylase (HDAC) inhibitors are divided into four groups but hybrid molecules combining functional groups with superior inhibitory effects have already been synthesized. Compounds that inhibit individual members of all HDAC classes will be synthesized in the future. Lysine methylation is another histone modification which could be essential in regulating gene expression but its use as a target for epigenetic therapy might not come to fruition until more complete classification of this type of epigenetic regulation is possible. Targeting the epigenetic changes that contribute to tumorigenesis has become an attractive therapeutic strategy. Yoo and Jones review the enzymes involved in epigenetic regulation that are emerging as targets and the numerous drug candidates that are currently being investigated. The initiation and progression of cancer is controlled by both genetic and epigenetic events. Unlike genetic alterations, which are almost impossible to reverse, epigenetic aberrations are potentially reversible, allowing the malignant cell population to revert to a more normal state. With the advent of numerous drugs that target specific enzymes involved in the epigenetic regulation of gene expression, the utilization of epigenetic targets is emerging as an effective and valuable approach to chemotherapy as well as chemoprevention of cancer.

A conformational difference in gum arabic (GA) in aqueous and emulsion systems can influence its interaction with guar gum (GG). Therefore, in this study, the rheological and tribological properties of GG mixed with an orange oil emulsion containing GA at varying concentrations were investigated and compared with those of GG-GA mixtures. As the GA concentration was increased, the apparent viscosity of GG mixtures with either GA or GA-based emulsion (GAE) tended to decrease. Specifically, with a higher GA concentration (> 1.5%), the GG-GA mixtures showed a lower relative apparent viscosity than the GG-GAE mixtures. In contrast, except for GG-GA mixture with 6.0% GA, all other mixtures showed lower tan δ values (0.66–0.69) than GG alone (0.72), indicating an enhancement of weak gel-like properties. At a lower GA concentration (< 3.0%), GG-GA interactions in the aqueous system produced a lower relative tan δ value than those in the emulsion system, whereas the opposite result was observed with a higher GA concentration (> 4.5%). In addition, each type of mixture exhibited different tribological properties. As the GA concentration was increased, the friction coefficient (μ) values of both tended to decrease. Especially, the GG-GAE mixtures attained lower μ values than the GG-GA mixtures, thereby indicating that the former have better lubricant properties. These results demonstrated that the conformational change in GA while emulsifying oil droplets influences its interactions with GG.

In this trial, obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, plus standard therapy provided significantly better renal responses than standard therapy alone in patients with lupus nephritis.

A high dose of glucocorticoid is suggested as initial management of Idiopathic inflammatory myopathies(IIMs), and immunosuppressive agents are added in severe cases [1]. However, since the diseases are rarely diagnosed, few studies have addressed the issue regarding the use of immunosuppressive agents with limited evidence [2]. The treatment of IIMs largely relies on empirical evidence and small studies [3]. As a results, The immunosuppressives have been indeed administered at the discretion of the physicians in practice. The initial glucocorticoid treatment usually leads to a stable phase for IIMs where clinical symptoms are improved, and glucocorticoids are tapered to low doses. A relapse is occasionally observed in clinical practice as the recurrence of muscle or cutaneous manifestations during and after glucocorticoids tapering, although there is no consensus on the definition regarding the relapse of IIMs [4]. Therefore, it is poorly understood which factors are essential to predicting the relapse of IIMs. Few studies have assessed risks for the relapse of idiopathic inflammatory myopathies (IIMs). We investigated relapse in patients with IIMs. Patients who were newly diagnosed with IIMs and underwent muscle biopsy between 2000 and 2017 were retrospectively reviewed. The relapse of IIMs was defined as the recurrence of muscle or cutaneous manifestations after reaching the stable phase, leading to ≥50 % increase in the glucocorticoid dosage. The factors associated with the relapse of IIMs were investigated by Cox proportional hazards analysis. Of the 105 patients with IIMs, relapse was observed in 65 patients (62%). The titer of an antinuclear antibody (ANA) was higher in the relapse group than in the non-relapse group (P = 0.033). In multivariable analysis, three factors were associated with the relapse of IIMs: histopathologic features consistent with IIMs (model 1; HR, 1.69; 95% CI, 1.01-2.83, P = 0.0453) and the use of immunosuppressants before relapse (model 2; HR, 0.50; 95% CI, 0.29-0.86, P = 0.0132). Doubling of ANA titer showed a trend toward an association with relapse albeit without statistical significance (model 1; HR, 1.13; 95% CI, 1.00-1.27, P = 0.0517). The use of immunosuppressants during a period of tapering glucocorticoid in the initial treatment would help reduce the risk of relapse of IIMs. [1]Meyer A, Scirè CA, Talarico R, Alexander T, Amoura Z, Avcin T, et al. Idiopathic inflammatory myopathies: state of the art on clinical practice guidelines. RMD open. 2019;4(Suppl 1):e000784. [2]Ruperto N, Pistorio A, Oliveira S, Zulian F, Cuttica R, Ravelli A, et al. Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial. The Lancet. 2016;387(10019):671-8. [3]Sunderkötter C, Nast A, Worm M, Dengler R, Dörner T, Ganter H, et al. Guidelines on dermatomyositis–excerpt from the interdisciplinary S2k guidelines on myositis syndromes by the German Society of Neurology. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2016;14(3):321-38. [4]Ponyi A, Constantin T, Balogh Z, Szalai Z, Borgulya G, Molnár K, et al. Disease course, frequency of relapses and survival of 73 patients with juvenile or adult dermatomyositis. Clinical and experimental rheumatology. 2005;23(1):50-6. NIL. None Declared. Table 1Factors associated with the relapse of Idiopathic inflammatory myopathies in univariate and multivariable analyses.Model 1Model 2Model 3FactorsHR95% CIPHR95% CIPHR95% CIPHistopathologic features consistent with IIMs1.691.01-2.830.04531.590.95-2.670.07911.590.95-2.670.0791ANA titera (reference: ANA negative)1.131.00-1.270.05171.100.98-1.250.11351.100.98-1.250.1135Immunosuppressant before relapse0.500.29-0.860.01320.500.29-0.860.0132Model 1: adjusted for factors at baselineModel 2: adjusted for factors at baseline and treatmentsModel 3: adjusted for factors at baseline, treatments, and follow-up laboratory findingsa doubling titer starting from 1:40

The overall objective of this study was to construct a 3D neuroanatomical map of the saphenous nerve based on cartesian coordinate data to define its course in 3D space relative to bony and soft tissue landmarks. Ten lower limb embalmed specimens were meticulously dissected, digitized, laser scanned, and modelled in 3D. The course of the main branches, number of collateral branches, and relationship of saphenous nerve to the great saphenous vein were defined and quantified using the high-fidelity 3D models. In 60% of specimens, the saphenous nerve was found to have three branches in the leg, infrapatellar, anterior, and posterior. In 40% of specimens, the posterior branch was absent. Three landmarks were found to consistently localize the anterior branch: the medial border of tibia at the level of the tibial tuberosity, the medial border of tibia at the level of the mid-point of leg, and the mid-point of the anterior border of the medial malleolus. The posterior branch, when present, had variable branching patterns but did not extend as far distally as the medial malleolus in any specimen. Anatomically, the anterior and posterior branches at the level of the tibial tuberosity could be most advantageous for nerve stimulation due to their close proximity to the bifurcation of the saphenous nerve where the branches are larger and more readily localizable than distally. Additionally, the tibial tuberosity is a prominent landmark that can be easily identified in most individuals and could be used to localize the anterior and posterior branch using ultrasound or other imaging modalities. These findings will enable implementation of highly realistic computational models that can be used to simulate saphenous nerve stimulation using percutaneous and implanted devices.

To better understand the effects of saphenous nerve (SN) stimulation on bladder function, we investigated the duration of electrical stimulation as a key variable in eliciting urodynamic changes. SN stimulation is a novel approach to electrically modulating bladder function. In previous animal studies, bladder‐inhibitory responses were evoked by low‐amplitude (25 μA) stimulus pulses applied in short‐duration (10 min) trials and at frequencies between 10 and 20 Hz. Experiments were performed in urethane‐anesthetized rats that were separated into three groups: intravesical saline infusion + SN stimulation (group A), intravesical 0.1% acetic acid infusion + SN stimulation (group B), and intravesical saline infusion + no SN stimulation (group C). Changes in bladder function— basal bladder pressure (P base), contraction amplitude (ΔP), and inter‐contraction interval (T ICI)—were measured in response to stimulation trials applied for different durations (10, 20, and 40 min). Trials were also repeated at frequencies of 10 and 20 Hz. In group A, longer‐duration (40 min) stimulation trials applied at 10 Hz evoked overflow incontinence (OI) episodes that were characterized by significant changes in P base (122.7 ± 9.1%, p = 0.026), ΔP (−60.8 ± 12.8%, p = 0.044), and T ICI (−43.2 ± 13.0%, p = 0.031). Stimulation‐evoked OI was observed in 5 of 8 animals and lasted for 56.5 ± 10.7 min. In contrast, no significant changes in bladder function were observed in either group B or group C. Our findings show that longer‐duration trials consisting of electrical pulses applied at 10 Hz are important stimulation parameters that elicit inhibitory bladder responses in anesthetized rodents. Electrical stimulation of the saphenous nerve is a novel approach to modulating bladder function in anesthetized rodents. Previous work showed that low‐amplitude, short duration trials can alter bladder contraction rate and bladder capacity.In this study, we found that increasing the dose of electrical stimulation (extending the duration of stimulation) can further inhibit reflex bladder activity.

Electrical signals from the peripheral nervous system have the potential to provide the necessary motor, sensory or autonomic information for implementing closed-loop control of neuroprosthetic or neuromodulatory systems. However, developing methods to recover information encoded in these signals is a significant challenge. Our goal was to test the feasibility of measuring physiologically generated nerve action potentials that can be classified as sensory or motor signals. A tetrapolar recording nerve cuff electrode was used to measure vagal nerve (VN) activity in a rodent model of upper airway obstruction. The effect of upper airway occlusions on VN activity related to respiration (RnP) was calculated and compared for 4 different cases: (1) intact VN, (2) VN transection only proximal to recording electrode, (3) VN transection only distal to the recording electrode, and (4) transection of VN proximal and distal to electrode. We employed a Support Vector Machine (SVM) model with Gaussian Kernel to learn a model capable of classifying efferent and afferent waveforms obtained from the tetrapolar electrode. In vivo results showed that the RnP values decreased significantly during obstruction by 91.7% ± 3.1%, and 78.2% ± 3.4% for cases of intact VN or proximal transection, respectively. In contrast, there were no significant changes for cases of VN transection at the distal end or both ends of the electrode. The SVM model yielded an 85.8% accuracy in distinguishing motor and sensory signals. The feasibility of measuring low-noise directionally-sensitive neural activity using a tetrapolar nerve cuff electrode along with the use of an SVM classifier was shown. Future experimental work in chronic implant studies is needed to support clinical translatability.

BackgroundGout is also closely associated with systemic disorders and cardiovascular (CV) risk profiles, such as hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, alcohol consumption, and obesity.[1] In addition, gout has been suggested as a cause of CV diseases via pathogenic mechanisms such as endothelial dysfunction, oxidative metabolism, platelet adhesiveness, and aggregation. [2-4] Accordingly, several epidemiological studies reported that patients with gout had an increased risk for CV events. [3, 4]In particular, differences in population characteristics between urban regions and other regions are getting more significant owing to recent rapid industrialization. Accordingly, a study on regional differences should be conducted; however, there are still few studies on it.ObjectivesWe aimed to investigate the risk of major cardiovascular events in gout patients in different regions.MethodsThis was a nationwide cohort study based on the claims database of the Korean National Health Insurance and the National Health Screening Program. Patients aged 20 to 90 years newly diagnosed with gout after January 2012 were included. After cardiovascular risk profiles before gout diagnosis were adjusted, the relative risks of incident cardiovascular events (myocardial infarction, cerebral infarction, and cerebral hemorrhage) in gout patients in different regions were assessed.ResultsIn total, 231,668 patients with gout were studied. Regional differences in cardiovascular risk profiles before the diagnosis were observed. Multivariable analysis showed that patients with gout in Jeolla/Gwangju had a significantly high risk of myocardial infarction (adjusted hazard ratio [aHR] 1.27 [95% confidence interval [CI], 1.02–1.56], P = 0.03). In addition, patients with gout in Gangwon (aHR 1.38 [95% CI, 1.09–1.74], P = 0.01), Jeolla/Gwangju (aHR 1.41 [95% CI, 1.19–1.67], P < 0.01), and Gyeongsang/Busan/Daegu/Ulsan (aHR 1.37 [95% CI, 1.19–1.59], P < 0.01) had a significantly high risk of cerebral infarction.ConclusionWe found there were regional differences in cardiovascular risk and associated risk factors in gout patients. Physicians should screen gout patients for cardiovascular risk profiles in order to facilitate prompt diagnosis and treatment.Figure 1.Forest plot of the risk of myocardial infarction (A), cerebral infarction (B), and cerebral hemorrhage (C).BP: blood pressure, DBP: diastolic blood pressure, HDL: High-density lipoprotein cholesterol, LDL: Low-density lipoprotein cholesterol, SBP: Systoric blood pressure, TG: TriglycerideReferences[1]Zhu Y, Pandya BJ, Choi HK. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008. Am J Med. 2012;125(7):679-87.e1.[2]Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol. 2002;13(12):2888-97.[3]Seminog OO, Goldacre MJ. Gout as a risk factor for myocardial infarction and stroke in England: evidence from record linkage studies. Rheumatology (Oxford). 2013;52(12):2251-9.[4]Abbott RD, Brand FN, Kannel WB, Castelli WP. Gout and coronary heart disease: the Framingham Study. Journal of clinical epidemiology. 1988;41(3):237-42.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

A study explores the relationships between selected marketing mix elements and the creation of brand equity. The authors proposed a conceptual framework in which marketing elements are related to the dimensions of brand equity, that is, perceived quality, brand loyalty, and brand associations combined with brand awareness. These dimensions are then related to brand equity. The empirical tests using a structural equation model support the research hypotheses. The results show that frequent price promotions, such as price deals, are related to low brand equity, whereas high advertising spending, high price, good store image, and high distribution intensity are related to high brand equity.