bluuebunny/crossref_metadata_2025 huggingface dataset:
Alarmin-activated B cells accelerate murine atherosclerosis after myocardial infarction via plasma cell-immunoglobulin-dependent mechanisms
Authors: Kyaw Tin , Loveland Paula , Kanellakis Peter , Cao Anh , Kallies Axel , Huang Alex L , Peter Karlheinz , Toh Ban-Hock , Bobik Alex
Published: November 2020

Aims 

Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI.

Methods and results 

We used an apolipoprotein-E-deficient (ApoE−/−) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE−/− mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis.

Conclusion 

Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke.
Tailored communication methods as key to implementation of evidence-based solutions in primary child health care
Authors: Zdunek Kinga , Schröder-Bäck Peter , Alexander Denise , Vlasblom Eline , Kocken Paul , Rigby Michael , Blair Mitch
Published: November 2020

Background

Evidence-based policies should underpin successful implementation of innovations within child health care. The EU-funded Models of Child Health Appraised project enabled research into effective methods to communicate research evidence. The objective of this study was to identify and categorize methods to communicate evidence-based research recommendations and means to tailor this to stakeholder audiences.

Methods

We conducted an online survey among national stakeholders in child health. Analysis of the most effective strategies to communicate research evidence and reach the target audience was carried out in order to ensure implementation of optimal child health care models at a national level.

Results

Representatives of stakeholders from 21 of the then 30 EU MS and EEA countries responded to the questionnaire. Three main approaches in defining the strategies for effective communication of research recommendations were observed, namely: dissemination of information, involvement of stakeholders and active attitude towards change expressed in actions. The target audience for communicating recommendations was divided into two layers: proximal, which includes those who are remaining in close contact with the child, and distal, which contains those who are institutionally responsible for high quality of child health services. They should be recipients of evidence-based results communicated by different formats, such as scientific, administrative, popular and personal.

Conclusions

Influential stakeholders impact the process of effective research dissemination and guide necessary actions to strengthen the process of effective communication of recommendations. Communication of evidence-based results should be targeted to each audience’s profile, both professional and non-professionals, by adjusting appropriate communication formats.
Salicylates Ameliorate Intestinal Inflammation by Activating Macrophage AMPK
Authors: Banskota Suhrid , Wang Huaqing , Kwon Yun Han , Gautam Jaya , Gurung Pallavi , Haq Sabah , Hassan F M Nazmul , Bowdish Dawn M , Kim Jung-Ae , Carling David , Fullerton Morgan D , Steinberg Gregory R , Khan Waliul I
Published: November 2020

Background

Inflammatory bowel diseases are the most common chronic intestinal inflammatory conditions, and their incidence has shown a dramatic increase in recent decades. Limited efficacy and questionable safety profiles with existing therapies suggest the need for better targeting of therapeutic strategies. Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of cellular metabolism and has been implicated in intestinal inflammation. Macrophages execute an important role in the generation of intestinal inflammation. Impaired AMPK in macrophages has been shown to be associated with higher production of proinflammatory cytokines; however, the role of macrophage AMPK in intestinal inflammation and the mechanism by which it regulates inflammation remain to be determined. In this study, we investigated the role of AMPK with a specific focus on macrophages in the pathogenesis of intestinal inflammation.

Methods

A dextran sodium sulfate-induced colitis model was used to assess the disease activity index, histological scores, macroscopic scores, and myeloperoxidase level. Proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β were measured by enzyme-linked immunosorbent assay. Transient transfection of AMPKβ1 and LC3-II siRNA in RAW 264.7 cells was performed to elucidate the regulation of autophagy by AMPK. The expression of p-AMPK, AMPK, and autophagy markers (eg, LC3-II, p62, Beclin-1, and Atg-12) was analyzed by Western blot.

Results

Genetic deletion of AMPKβ1 in macrophages upregulated the production of proinflammatory cytokines, aggravated the severity of dextran sodium sulfate-induced colitis in mice, which was associated with an increased nuclear translocation of nuclear factor-κB, and impaired autophagy both in vitro and in vivo. Notably, the commonly used anti-inflammatory 5-aminosalicylic acid (ie, mesalazine) and sodium salicylate ameliorated dextran sodium sulfate-induced colitis through the activation of macrophage AMPK targeting the β1 subunit.

Conclusions

Together, these data suggest that the development of therapeutic agents targeting AMPKβ1 may be effective in the treatment of intestinal inflammatory conditions including inflammatory bowel disease.
Reflection on modern methods: demystifying robust standard errors for epidemiologists
Authors: Mansournia Mohammad Ali , Nazemipour Maryam , Naimi Ashley I , Collins Gary S , Campbell Michael J
Published: November 2020

All statistical estimates from data have uncertainty due to sampling variability. A standard error is one measure of uncertainty of a sample estimate (such as the mean of a set of observations or a regression coefficient). Standard errors are usually calculated based on assumptions underpinning the statistical model used in the estimation. However, there are situations in which some assumptions of the statistical model including the variance or covariance of the outcome across observations are violated, which leads to biased standard errors. One simple remedy is to use robust standard errors, which are robust to violations of certain assumptions of the statistical model. Robust standard errors are frequently used in clinical papers (e.g. to account for clustering of observations), although the underlying concepts behind robust standard errors and when to use them are often not well understood. In this paper, we demystify robust standard errors using several worked examples in simple situations in which model assumptions involving the variance or covariance of the outcome are misspecified. These are: (i) when the observed variances are different, (ii) when the variance specified in the model is wrong and (iii) when the assumption of independence is wrong.
Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression
Authors: Rivas-Grajales Ana Maria , Salas Ramiro , Robinson Meghan E , Qi Karen , Murrough James W , Mathew Sanjay J
Published: November 2020

Background

Ketamine’s potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor–dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states.

Methods

Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined.

Results

A reduction in Montgomery–Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results.

Conclusions

These preliminary results suggest that the Hb might be involved in ketamine’s antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.
Translational Assessments of Reward Responsiveness in the Marmoset
Authors: Wooldridge Lisa M , Bergman Jack , Pizzagalli Diego A , Kangas Brian D
Published: November 2020

Background

Anhedonia, the loss of pleasure in previously rewarding activities, is a prominent feature of major depressive disorder and often resistant to first-line antidepressant treatment. A paucity of translatable cross-species tasks to assess subdomains of anhedonia, including reward learning, presents a major obstacle to the development of effective therapeutics. One assay of reward learning characterized by orderly behavioral and pharmacological findings in both humans and rats is the probabilistic reward task. In this computerized task, subjects make discriminations across numerous trials in which correct responses to one alternative are rewarded more often (rich) than correct responses to the other (lean). Healthy control subjects reliably develop a response bias to the rich alternative. However, participants with major depressive disorder as well as rats exposed to chronic stress typically exhibit a blunted response bias.

Methods

The present studies validated a touchscreen-based probabilistic reward task for the marmoset, a small nonhuman primate with considerable translational value. First, probabilistic reinforcement contingencies were parametrically examined. Next, the effects of ketamine (1.0–10.0 mg/kg), a US Food and Drug Administration-approved rapid-acting antidepressant, and phencyclidine (0.01–0.1 mg/kg), a pharmacologically similar N-methyl-D-aspartate receptor antagonist with no known antidepressant efficacy, were evaluated.

Results

Increases in the asymmetry of rich:lean probabilistic contingencies produced orderly increases in response bias. Consistent with their respective clinical profiles, ketamine but not phencyclidine produced dose-related increases in response bias at doses that did not reduce task discriminability.

Conclusions

Collectively, these findings confirm task and pharmacological sensitivity in the marmoset, which may be useful in developing medications to counter anhedonia across neuropsychiatric disorders.
251 Evaluation of Condensed Algal Residue Solubles as an Ingredient in Cattle Finishing Diets
Authors: Gibbons Calvin , Watson Andrea K , Erickson Galen E , Boyd Bradley M , McPhillips Levi J , Wilson Hannah C , Wilson Jonathan W
Published: November 2020

Algae oil production for Omega-3 fatty acid supplementation yields a byproduct called Condensed Algal Residue Solubles (CARS; 25.4% DM, 19.3% CP, 8.3% Fat, 9.96% Na on DM basis), de-oiled algae cells with residual fermentation substrates. This study evaluated the use of CARS in feedlot finishing diets. Crossbreed steers, (n=480) were blocked and stratified by initial body weight (BW) into 4 blocks, and assigned randomly to treatments. Treatments were designed as a 2 x 3 factorial with 3 inclusions of CARS (0, 2.5, 5% of diet DM) and 2 different base diets representing Northern and Southern Great Plains diets. The Southern diets contained steam flaked corn and dry distillers grains while the Northern diets had dry rolled and high moisture corn with wet distillers grains. CARS replaced corn in both diets. All blocks were harvested after 148 days on feed. Performance data were analyzed as a randomized block design with CARS inclusion, base diet, and interactions as fixed effects, BW block as a random effect and pen (n=48) as the experimental unit. Orthogonal contrasts were used to test linear and quadratic effects of CARS inclusion. There were no significant interactions between CARS inclusion and diet type (P ≥ 0.49). Main effects of CARS indicated positive quadratic responses for carcass adjusted ADG, G:F, 12th rib back fat, yield grade (P < 0.01; increasing to 2.5% inclusion, decreasing at 5%) and hot carcass weight was both linear and quadratic (P ≤ 0.01 and P ≥ 0.06 respectively; 969, 977, 935 as CARS increased). Linear decrease in DMI, final adjusted BW and ribeye area (P ≤ 0.01) as CARS increased. Cattle fed the Southern diets had greater ADG and G:F compared to Northern diets (P < 0.01). Including 2.5% CARS in the diet improved feed efficiency in both Northern and Southern based feedlot diets.
369 Amino acid nutrition in monogastrics: going beyond the ideal protein
Authors: Htoo John K
Published: November 2020

In addition to serving as building blocks for protein synthesis, AA are also involved in various important metabolic pathways in the body. Amino acids that regulates key metabolic pathways to improve health, growth, development and reproduction are considered as functional AA. The roles of AA for immune function have received more attention in recent years. Methionine serves as a methyl donor for important processes such as DNA methylation, polyamine synthesis and is a precursor to form Cys, which is needed for the synthesis of a major antioxidant glutathione. Tryptophan is involved in various metabolic pathways, including immune response and the formation of serotonin which involves in feed intake regulation. Threonine plays a key role in immune function through its incorporation into immunoglobulins and is preferentially utilized by the gut in pigs partly for synthesis of mucosal proteins including mucins which are high in Thr. The branched-chain amino acids (Leu, Val, Ile) are involved in maintaining intestinal barrier function, enterocyte proliferation and immune defenses in pigs. The other functional AA include Gln, Arg and Gly which are involved in immune system functioning and gut health. During sub-clinical level of diseases or inflammation, nutrients are prioritized to form tissues involved in immune response compromising growth, implying that the requirement of some key AA is increased to maintain immune function. Adjusting the ideal ratio of these functional AA to Lys in diets may maintain gut health and promote growth, because it can enhance immune status and gut integrity for weaned pigs, especially when sanitary and climatic conditions are challenging, and antibiotics are not or less used in the diets. Future research is warranted to quantitatively estimate the increased need of these functional AA in pigs raised under sub-optimal conditions as well as evaluate the interaction or synergistic effect of these AA on animals’ immunity.
425 Effects of pre-mortem stress on protein expression, steak color, and myofibrillar fragmentation index in the longissimus lumborum following harvest
Authors: Briggs Reganne K , Legako Jerrad F , Broadway Paul R , Carroll Jeff A , Burdick-Sanchez Nicole C , Smith Zachary K , Thornton Kara J , Ramanathan Ranjith
Published: November 2020

Undesirable variation in beef tenderness and stability of flavor and color may be associated with the abundance of heat shock proteins (HSP). This study aimed to determine whether pre-mortem stress impacts HSP expression in the skeletal muscle following harvest. Forty Holstein steers were administered an i.v. bolus dose of adrenocorticotropic hormone (ACTH; 0.1 IU/Kg BW) to mimic an acute pre-mortem stress. Longissimus lumborum (LD) biopsy samples were taken prior to the ACTH challenge. Serum cortisol was measured every 0.5 h from -2 to 6 h relative to the ACTH challenge. Skeletal muscle and blood samples from 10 steers were collected at each harvest timepoint at (2, 12, 24 and 48 h post-challenge). Samples were collected from the LD immediately after harvest and after 14 d of aging. Protein expression of HSPβ1, P-HSPβ1, HSPβ5, and DJ-1 was analyzed in muscle samples taken prior to the ACTH challenge, at harvest, and after 14 d of post-mortem wet aging. In addition, steak color and myofibrillar fragmentation index (MFI) was analyzed in 14 d aged samples. Harvest time point following the ACTH challenge affected (P < 0.05) protein expression of HSPβ1 and P-HSPβ1. Protein expression of DJ-1 prior to the ACTH challenge was different (P < 0.05) among steers harvested at different timepoints. In addition, time of harvest had no effect on HSPβ5 expression (P > 0.05). Regarding steak color, time of harvest had an effect (P < 0.01) on a*, b*, hue, chroma, and ratio, but no effect (P > 0.05) on L*. Lastly, time of harvest had an effect (P < 0.05) on MFI. These data indicate that HSP expression, steak color, and MFI in the LD after harvest may be related to time of harvest following a stressful event pre-mortem.
Port site hernia repair using the VersaOne™ Fascial Closure System: a case report
Authors: Hagui Emi , Kimura Masahiro , Katada Takeyasu , Nagasaki Takaya , Nakaya Seiichi , Eguchi Yuki , Sugita Saburo , Sawai Misato , Kuwabara Yoshiyuki , Mitsui Akira
Published: November 2020

The use of laparoscopic surgery has become widespread in recent years. One of its complications is port site hernia (PHS). It can be difficult to close the fascia at the time of laparoscopy, especially in obese patients, and there is a risk of herniation through a fascial defect with incomplete closure. It is important to ascertain closure of the defect when repairing PHS to prevent recurrence. We report a 47-year-old woman who developed a PHS at the superior aspect of the umbilicus. We repaired the defect using the VersaOneTM Fascial Closure System with laparoscopic guidance. This system allows the port site to be reliably closed while observing the suture from the abdominal cavity. The incision is the same size as a port site. If the abdominal wall is thick and the PHS has a diameter of ~10 mm, this method is considered to be indicated, regardless of the site.
Postoperative Vasodilatory Shock
Authors: Roberts Fiona , Gaffney Alan
Published: November 2020

This chapter discusses vasodilatory shock. The hallmark of vasodilatory shock is hypotension with normal or increased cardiac output. The hyperdynamic circulatory state of vasodilatory shock results in a tachycardia and an increased pulse pressure. Radiological and biochemical investigations can assist with determining the diagnosis of shock. The causes of vasodilatory shock are diverse; they include sepsis, surgical insult, anaphylaxis, and others such as trauma, burns, and pancreatitis. However, sepsis is by far the most common cause of vasodilatory shock. The pathophysiology of vasodilatory shock is also complex and multifactorial. Although still not fully understood, it is widely accepted that it includes activation of several intrinsic vasodilatory pathways and a vascular hyporesponsiveness to vasopressors. Early fluid resuscitation and appropriate antimicrobial therapy are the most crucial treatment interventions in septic shock. Meanwhile, noradrenaline is the first-line vasopressor of choice in septic shock.
The Central Benzodiazepine Receptor
Authors: Ossipov Michael H.
Published: November 2020

Benzodiazepines have been used clinically now for more than a half century for the management of anxiety and other conditions. Despite their widespread use, only now are their mechanisms of action and their pharmacologic implications, especially with long-term use, beginning to be appreciated. In the central nervous system, benzodiazepines act on an allosteric site of the GABAA receptor to enhance the activity of this inhibitory neurotransmitter. The GABA receptor consists of 5 subunits, which can vary among 19 different subtypes, resulting in a large number of possible configurations for the GABA receptor. Subunit structure can affect the binding of benzodiazepines to the receptor and can alter the nature of the interaction between the benzodiazepine binding site and the GABA binding site, resulting in different levels of receptor activation and allosteric enhancement. Moreover, the distribution of these different subtypes within the central nervous system, with their varying levels of benzodiazepine efficacy, can mean that benzodiazepines can have differential effects among the different sites of the brain. Consequently, in may be possible to design novel drugs that favor particular subunit configurations and thus produce different pharmacologic profiles. Drugs acting at the benzodiazepine site can be agonists, enhancing the activity of GABA; antagonists, blocking the effect of benzodiazepines at the binding site; or inverse agonists, producing an effect antipodal to that of benzodiazepine agonists.
Benzodiazepines Today and Tomorrow
Authors: Coleman John J.
Published: November 2020

Benzodiazepines (BZDs) and related drugs are widely used for treating a variety of conditions (with varying degrees of evidence-base), but their long-term use (more than 2–4 weeks) can be problematic. They were originally thought (or claimed) to be nonproblematic substitutes for barbiturates, but it is now clear that they have their own set of problems. In addition, they are commonly, albeit ill-advisedly, co-prescribed or used nonmedically in combination with other drug substances. The result of such combinations, particularly with the opioids, can be lethal. Administrative and statutory actions notwithstanding, it appears that reducing problems with BZDs will depend on a comprehensive approach that includes improved education for patients, prescribers, regulators, insurers, and the public. First and foremost, however, there is a pressing need for the government to improve its drug-abuse data collection, specifically how it monitors drug-related morbidity and mortality. This chapter reviews the information that demonstrates how an understanding of all of the dynamics is essential for designing effective public-health strategies to reduce BZD-associated problems.
Testing physical models for cosmic ray transport coefficients on galactic scales: self-confinement and extrinsic turbulence at ∼GeV energies
Authors: Hopkins Philip F , Squire Jonathan , Chan T K , Quataert Eliot , Ji Suoqing , Kereš Dušan , Faucher-Giguère Claude-André
Published: November 2020

The microphysics of ∼ GeV cosmic ray (CR) transport on galactic scales remain deeply uncertain, with almost all studies adopting simple prescriptions (e.g. constant diffusivity). We explore different physically motivated, anisotropic, dynamical CR transport scalings in high-resolution cosmological Feedback In Realistic Environment (FIRE) simulations of dwarf and ∼L* galaxies where scattering rates vary with local plasma properties motivated by extrinsic turbulence (ET) or self-confinement (SC) scenarios, with varying assumptions about e.g. turbulent power spectra on un-resolved scales, Alfvén-wave damping, etc. We self-consistently predict observables including γ-rays (Lγ), grammage, residence times, and CR energy densities to constrain the models. We demonstrate many non-linear dynamical effects (not captured in simpler models) tend to enhance confinement. For example, in multiphase media, even allowing arbitrary fast transport in neutral gas does not substantially reduce CR residence times (or Lγ), as transport is rate-limited by the ionized WIM and ‘inner CGM’ gaseous halo (104–106 K gas within $\lesssim 10\!-\!30\,$ kpc), and Lγ can be dominated by trapping in small ‘patches’. Most physical ET models contribute negligible scattering of ∼1–10 GeV CRs, but it is crucial to account for anisotropy and damping (especially of fast modes) or else scattering rates would violate observations. We show that the most widely assumed scalings for SC models produce excessive confinement by factors ≳100 in the warm ionized medium (WIM) and inner CGM, where turbulent and Landau damping dominate. This suggests either a breakdown of quasi-linear theory used to derive the CR transport parameters in SC, or that other novel damping mechanisms dominate in intermediate-density ionized gas.
Low-luminosity Type II supernovae – III. SN 2018hwm, a faint event with an unusually long plateau
Authors: Reguitti A , Pumo M L , Mazzali P A , Pastorello A , Pignata G , Elias-Rosa N , Prentice S J , Reynolds T , Benetti S , Rodrìguez O , Mattila S , Kuncarayakti H
Published: November 2020

In this work, we present photometric and spectroscopic data of the low-luminosity (LL) Type IIP supernova (SN) 2018hwm. The object shows a faint (Mr = −15 mag) and very long (∼130 d) plateau, followed by a 2.7 mag drop in the r band to the radioactive tail. The first spectrum shows a blue continuum with narrow Balmer lines, while during the plateau the spectra show numerous metal lines, all with strong and narrow P-Cygni profiles. The expansion velocities are low, in the 1000–1400 km s−1 range. The nebular spectrum, dominated by H α in emission, reveals weak emission from [O i] and [Ca ii] doublets. The absolute light curve and spectra at different phases are similar to those of LL SNe IIP. We estimate that 0.002 M⊙ of 56Ni mass were ejected, through hydrodynamical simulations. The best fit of the model to the observed data is found for an extremely low explosion energy of 0.055 foe, a progenitor radius of 215 R⊙, and a final progenitor mass of 9–10 M⊙. Finally, we performed a modelling of the nebular spectrum, to establish the amount of oxygen and calcium ejected. We found a low M(16O)$\approx 0.02\, \mathrm{ M}_{\odot }$, but a high M(40Ca) of 0.3 M⊙. The inferred low explosion energy, the low ejected 56Ni mass, and the progenitor parameters, along with peculiar features observed in the nebular spectrum, are consistent with both an electron-capture SN explosion of a superasymptotic giant branch star and with a low-energy, Ni-poor iron core-collapse SN from a 10–12 M⊙ red supergiant.
Effect of fructooligosaccharide on endothelial function in CKD patients: a randomized controlled trial
Authors: Armani Rachel G , Carvalho Aluizio B , Ramos Christiane I , Hong Valeria , Bortolotto Luiz A , Cassiolato Jose Luiz , Oliveira Natacha F , Cieslarova Zuzana , do Lago Claudimir L , Klassen Aline , Cuppari Lilian , Raj Dominic S , Canziani Maria Eugênia F
Published: November 2020

Background

Microbiota-derived uremic toxins have been associated with inflammation that could corroborate with endothelial dysfunction (ED) and increase cardiovascular risk in patients with chronic kidney disease (CKD). This trial aimed to evaluate the effect of the prebiotic fructooligosaccharide (FOS) on endothelial function and arterial stiffness in nondialysis CKD patients.

Methods

In a double-blind controlled trial, 46 nondiabetic CKD patients were randomized to receive 12 g/day of FOS or placebo (maltodextrin) for 3 months. Total p-cresyl sulfate (PCS) and indoxyl sulfate by high-performance liquid chromatography, urinary trimethylamine N-oxide by mass spectrometry, C-reactive protein, interleukin-6 (IL-6), serum nitric oxide and stroma-derived factor-1 alfa were measured at baseline and at the end of follow-up; endothelial function was assessed through flow-mediated dilatation (FMD) and arterial stiffness by pulse wave velocity (PWV).

Results

The mean (± standard deviation) age of the study participants was 57.6 ± 14.4 years, with an estimated glomerular filtration rate of 21.3 ± 7.3 mL/min/1.73 m2. During the follow-up, regarding the inflammatory markers and uremic toxins, there was a significant decrease in IL-6 levels (3.4 ± 2.1 pg/mL versus 2.6 ± 1.4 pg/mL; P = 0.04) and a trend toward PCS reduction (55.4 ± 38.1 mg/L versus 43.1 ± 32.4 mg/L, P = 0.07) only in the prebiotic group. Comparing both groups, there was no difference in FMD and PWV. In an exploratory analysis, including a less severe ED group of patients (FMD ≥2.2% at baseline), FMD remained stable in the prebiotic group, while it decreased in the placebo group (group effect P = 0.135; time effect P = 0.012; interaction P = 0.002).

Conclusions

The prebiotic FOS lowered circulating levels of IL-6 in CKD patients and preserved endothelial function only in those with less damaged endothelium. No effect of FOS in arterial stiffness was observed.
Clinical correlates for immune checkpoint therapy: significance for CNS malignancies
Authors: Ratnam Nivedita M , Frederico Stephen C , Gonzalez Javier A , Gilbert Mark R
Published: November 2020

Immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer immunotherapy. Most commonly, inhibitors of PD-1 and CTLA4 are used having received approval for the treatment of many cancers like melanoma, non-small-cell lung carcinoma, and leukemia. In contrast, to date, clinical studies conducted in patients with CNS malignancies have not demonstrated promising results. However, patients with CNS malignancies have several underlying factors such as treatment with supportive medications like corticosteroids and cancer therapies including radiation and chemotherapy that may negatively impact response to ICIs. Although many clinical trials have been conducted with ICIs, measures that reproducibly and reliably indicate that treatment has evoked an effective immune response have not been fully developed. In this article, we will review the history of ICI therapy and the correlative biology that has been performed in the clinical trials testing these therapies in different cancers. It is our aim to help provide an overview of the assays that may be used to gauge immunologic response. This may be particularly germane for CNS tumors, where there is currently a great need for predictive biomarkers that will allow for the selection of patients with the highest likelihood of responding.
Analysis of the quality of meningioma education resources available on the Internet
Authors: Lim Chloe Ah-Ryung , Ingledew Paris-Ann
Published: November 2020

Background

Meningiomas are the most common primary central nervous system tumors and patients face difficulty evaluating resources available online. The purpose of this study is to systematically evaluate the educational resources available for patients seeking meningioma information on the Internet.

Methods

A total of 127 meningioma websites were identified by inputting the term “meningioma” on Google and two meta-search engines. A structured rating tool developed by our research group was applied to top 100 websites to evaluate with respect to accountability, interactivity, readability, and content quality. Responses to general and personal patient questions were evaluated for promptness, accuracy, and completeness. The frequency of various social media account types was analyzed.

Results

Of 100 websites, only 38% disclosed authorship, and 32% cited sources. Sixty-two percent did not state date of creation or modification, and 32% provided last update less than 2 years ago. Websites most often discussed the definition (99%), symptoms (97%), and treatment (96%). Prevention (8%) and prognosis (47%) were most often not covered. Only 3% of websites demonstrated recommended reading level for general population. Of 84 websites contacted, 42 responded, 32 within 1 day.

Conclusions

Meningioma information is readily available online, but quality varies. Sites often lack markers for accountability, and content may be difficult to comprehend. Information on specific topics are often not available for patients. Physicians can direct meningioma patients to appropriate reliable online resources depicted in this study. Furthermore, future web developers can address the current gaps to design reliable online resources.
An association between chronic widespread pain and the gut microbiome
Authors: Freidin Maxim B , Stalteri Maria A , Wells Philippa M , Lachance Genevieve , Baleanu Andrei-Florin , Bowyer Ruth C E , Kurilshikov Alexander , Zhernakova Alexandra , Steves Claire J , Williams Frances M K
Published: November 2020

Objectives

Chronic widespread musculoskeletal pain (CWP) is a characteristic symptom of fibromyalgia, which has been shown to be associated with an altered gut microbiome. Microbiome studies to date have not examined the milder CWP phenotype specifically nor have they explored the role of raised BMI. The aim of this study was to investigate whether the microbiome is abnormal in CWP.

Methods

CWP was assessed using a standardized screening questionnaire in female volunteers from the TwinsUK cohort including 113 CWP cases and 1623 controls. The stool microbiome was characterized using 16S rRNA amplicon sequencing and amplicon sequence variants, and associations with CWP examined using linear mixed-effects models adjusting for BMI, age, diet, family relatedness and technical factors.

Results

Alpha diversity was significantly lower in CWP cases than controls (Mann–Whitney test, P-values 2.3e-04 and 1.2e-02, for Shannon and Simpson indices respectively). The species Coprococcus comes was significantly depleted in CWP cases (Padj = 3.04e-03). A genome-wide association study (GWAS) performed for C. comes in TwinsUK followed by meta-analysis with three Dutch cohorts (total n = 3521) resulted in nine suggestive regions, with the most convincing on chromosome 4 near the TRAM1L1 gene (rs76957229, P = 7.4e-8). A Mendelian randomization study based on the results of the GWAS did not support a causal role for C. comes on the development of CWP.

Conclusions

We have demonstrated reduced diversity in the microbiome in CWP, indicating an involvement of the gut microbiota in CWP; prospectively the microbiome may offer therapeutic opportunities for this condition.
Breaking Iron Triangles: Beliefs and Interests in Japanese Renewable Energy Policy
Authors: Watanabe Rie
Published: November 2020

This article analyses Japan’s renewable energy policy changes, with a focus on the interaction of multiple catalysts on changing positions, beliefs and interests of dominant-group members, and inducing non-incremental renewable policy changes (an innovative but less effective Renewable Portfolio Standard (RPS) in 2003 as well as a partial FIT for photovoltaics in 2009 and ultimately a more effective full-scale FIT to promote renewables in 2011). The examined multiple catalysts include the governing coalition change from the Liberal Democratic Party (LDP) to the Democratic Party of Japan (DPJ) in 2009 and four other catalysts (the oil crisis, climate change, electricity market liberalisation, and nuclear accidents) that relate to the values underlying Japan’s energy policymaking: energy security, environment, economic efficiency, and safety (3E+S). The article concludes that the latter four catalysts were critical in creating and expanding cleavages among dominant-group members over a long period sufficient to realise the introduction of RPS and a partial FIT, but not sufficient to introduce the full-scale FIT. The 3/11 disaster after the governing coalition change was indispensable to achieving a full-scale FIT as it affected dominant-group members’ interests in removing Kan Naoto from office, after Kan made the FIT law passage one of the conditions for his voluntary resignation. Based on the empirical study, this article also addresses one of the underexplored theoretical questions, the effects of and relationship between multiple catalysts in non-incremental policy change.
Apparent total tract and ileal amino acids digestibility values of vegetal protein meals with dietary protease to broiler diet
Authors: Bertechini Antonio G , Dalolio Felipe Santos , Carvalho Julio C C , Carvalho Andressa C , Sorbara Jose O B
Published: November 2020

This experiment was carried out to study the effect of dietary exogenous monocomponent protease on the coefficient apparent total tract (ATTD) and apparent ileal (AID) digestibility of amino acids of corn, soybean meal (SBM), and full fat soybean meal (FFSM) in broilers. A total of 400 males Cobb-500 (14 d of age) were equally allocated in 80 metabolic cages (50 cm × 50 cm × 45 cm) in a completely randomized design and a semi-controlled environment. Eight treatments (basal diet with or without a protease and three ingredients replacing the basal diets in 40% to corn and 30% to SBM and FFSM, with and without protease), with 10 replicates each were evaluated. The protease was added at 200 mg/kg resulting in 15,000 unit of PROT/kg. The total collection of excreta was held during 3 d, after 5 d for adaptation of broilers at the diets. The ileal content was collected on d 21, after slaughter of birds. The enzyme increased (P < 0.05) the ATTD and AID of most amino acids contained in SBM and FFSM. The digestibility of cysteine, glycine, proline, and threonine had higher (P < 0.05) ATTD and AID in all tested ingredients with the use of protease. On average, the dietary protease increased in 5.19% and 3.86% the total and ileal digestibility of amino acids, respectively. It was concluded that the dietary protease exerts major effects on toasted full-fat soybean, followed by soybean meal and corn to broilers.
Whole Genome Sequence Resource for Fusarium oxysporum f. sp. capsici 14003, the Causative Agent of Pepper Wilt
Authors: Shu Yongxin , Luo Mei , Dong Zhangyong
Published: November 2020

Pepper wilt, caused by the fungal pathogen Fusarium oxysporum f. sp. capsici, is one of the main diseases on pepper. In this study, we obtained the whole genome sequence of the highly virulent F. oxysporum f. sp. capsici strain 14003 sequenced using the Illumina HiSeq 2000 platform. In total, 3.87 million paired-end reads were obtained and assembled into 796 scaffolds with a genome-wide length of 47.6 Mb. In addition, we filtered genes that may be related to specific virulence factors and performed a comparative analysis between the genome of strain 14003 and the sequenced genomes of 36 isolates. The genome-sequencing results for strain 14003 will enhance the theoretical basis for pepper wilt prevention and control.
Extracellular Amylase Is Required for Full Virulence and Regulated by the Global Posttranscriptional Regulator RsmA inXanthomonas campestrisPathovarcampestris
Authors: Lin Yan , Liao Yong-Yan , Huang Ru-Xia , Li Ai-Zhou , An Shi-Qi , Tang Ji-Liang , Tang Dong-Jie
Published: November 2020

As with many phytopathogenic bacteria, the virulence of Xanthomonas campestris pv. campestris, the causal agent of black rot disease in cruciferous plants, relies on secretion of a suite of extracellular enzymes that includes cellulase (endoglucanase), pectinase, protease, and amylase. Although the role in virulence of a number of these enzymes has been assessed, the contribution of amylase to X. campestris pv. campestris virulence has yet to be established. In this work, we investigated both the role of extracellular amylase in X. campestris pv. campestris virulence and the control of its expression. Deletion of XC3487 (here renamed amyAXcc), a putative amylase-encoding gene from the genome of X. campestris pv. campestris strain 8004, resulted in a complete loss of extracellular amylase activity and significant reduction in virulence. The extracellular amylase activity and virulence of the amyAXccmutant could be restored to the wild-type level by expressing amyAXccin trans. These results demonstrated that amyAXccis responsible for the extracellular amylase activity of X. campestris pv. campestris and indicated that extracellular amylase plays an important role in X. campestris pv. campestris virulence. We also found that the expression of amyAXccis strongly induced by starch and requires activation by the global posttranscriptional regulator RsmA. RsmA binds specifically to the 5′-untranslated region of amyAXcctranscripts, suggesting that RsmA regulates amyAXccdirectly at the posttranscriptional level. Unexpectedly, in addition to posttranscriptional regulation, the use of a transcriptional reporter demonstrated that RsmA also regulates amyAXccexpression at the transcriptional level, possibly by an indirect mechanism.
Straw Competition and Wheat Root Endophytism of Trichoderma gamsii T6085 as Useful Traits in the Biological Control of Fusarium Head Blight
Authors: Sarrocco Sabrina , Esteban Pilar , Vicente Isabel , Bernardi Rodolfo , Plainchamp Tracy , Domenichini Séverine , Puntoni Grazia , Baroncelli Riccardo , Vannacci Giovanni , Dufresne Marie
Published: November 2020

Trichoderma gamsii T6085 has been investigated for many years as a beneficial isolate for use in the biocontrol of Fusarium head blight (FHB) of wheat caused primarily by Fusarium graminearum. Previous work focused on application of T6085 to wheat spikes at anthesis, whereas application to soil before or at sowing has received limited attention. In the present study, the competitive ability of T6085 on plant residues against F. graminearum was investigated. Results showed a significant reduction of wheat straw colonization by the pathogen and of the development of perithecia, not only when T6085 was applied alone but also in the presence of a F. oxysporum isolate (7121), well known as a natural competitor on wheat plant residues. T6085 was able to endophytically colonize wheat roots, resulting in internal colonization of the radical cortex area, without reaching the vascular system, as confirmed by confocal microscopy. This intimate interaction with the plant resulted in a significant increase of the expression of the plant defense-related genes PAL1 and PR1. Taken together, competitive ability, endophytic behavior, and host resistance induction represent three important traits that can be of great use in the application of T6085 against FHB not only on spikes at anthesis but potentially also in soil before or at sowing.
Cardiac and renal protective effects of 2,5-dimethylcelecoxib in angiotensin II and high-salt-induced hypertension model mice
Authors: Yamamoto Misaki , Takahashi-Yanaga Fumi , Arioka Masaki , Igawa Kazunobu , Tomooka Katsuhiko , Yamaura Ken , Sasaguri Toshiyuki
Published: November 2020

Background:

We reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative that is unable to inhibit cyclooxygenase-2, prevented cardiac remodeling induced by sarcomeric gene mutation, left ventricular pressure overload, or β-adrenergic receptor stimulation. This effect seemed to be mediated by the inhibition of the canonical Wnt/β-catenin signaling pathway, which has been suggested to play a key role in the development of chronic kidney disease and chronic heart failure.

Method:

We investigated the effect of DM-celecoxib on cardiac remodeling and kidney injury in hypertension model mice induced by angiotensin II infusion in the absence or presence of high-salt load.

Results:

DM-celecoxib prevented cardiac remodeling and markedly reduced urinary albumin excretion without altering blood pressure in those mice. Moreover, DM-celecoxib prevented podocyte injury, glomerulosclerosis, and interstitial fibrosis in the kidney of mice loaded with angiotensin II and high-salt load. DM-celecoxib reduced the phosphorylation level of Akt and activated glycogen synthase kinase-3, which led to the suppression of the Wnt/β-catenin signal in the heart and kidney. DM-celecoxib also reduced the expression level of snail, a key transcription factor for the epithelial–mesenchymal transition and of which gene is a target of the Wnt/β-catenin signal.

Conclusion:

Results of the current study suggested that DM-celecoxib could be beneficial for patients with hypertensive heart and kidney diseases.
Descemet Membrane Endothelial Keratoplasty in Vascularized Eyes: Outcome and Effect on Corneal Neovascularization
Authors: Hayashi Takahiko , Zhang Wei , Hos Deniz , Schrittenlocher Silvia , Nhat Hung Le Viet , Siebelmann Sebastian , Matthaei Mario , Bock Felix , Bachmann Björn , Cursiefen Claus
Published: November 2020

Purpose:

To report the outcomes after Descemet membrane endothelial keratoplasty (DMEK) in vascularized eyes.

Methods:

Consecutive cases of DMEK in vascularized eyes (involving ≥2 vascularized quadrants) were selected from a prospective database. Best corrected visual acuity, endothelial cell density (ECD), central corneal thickness, corneal transplant rejection episode, graft survival, and area of neovascularization (quantified using image analysis software) were evaluated.

Results:

In this study, 24 eyes of 24 patients were selected [mean age, 65.0 years; mean follow-up duration, 14.8 months (6–36 months)], which consists of 14 vascularized eyes after failed penetrating keratoplasty and 10 vascularized eyes with bullous keratopathy. Best corrected visual acuity improved from 1.60 ± 1.02 LogMAR preoperatively to 0.47 ± 0.37 LogMAR 12 months postoperatively (P < 0.001). Central corneal thickness decreased from 824 ± 193 μm preoperatively to 544 ± 48 μm 12 months postoperatively (P = 0.001). The donor ECD decreased from 2272 ± 723 cells/mm2 preoperatively to 1570 ± 279 cells/mm2 12 months postoperatively. The total loss of ECD at the last visit was 40.7% ± 13.0%. Eight of 24 eyes (33.3%) required rebubbling, which resulted in final attachment. The corneal neovascularization area significantly regressed from 4.68% ± 3.26% preoperatively to 2.28% ± 1.58% (n = 18, P = 0.021). Corneal transplant rejection episodes occurred in 1 eye of 24 patients (4.2%). There was no primary graft failure.

Conclusions:

DMEK is a feasible option to treat endothelial dysfunction in vascularized eyes.