Vitamin K effects in human health: new insights beyond bone and cardiovascular health

Vitamin K is a cofactor for the function of the enzyme \u3b3-glutamyl carboxylase, necessary for the activation of multiple vitamin K dependent-proteins. Vitamin K dependent-proteins (VKDPs) have important roles in bone health, vascular health, metabolism, reproduction as well as in cancer progression. Vitamin K deficiency is common in different conditions, including kidney disease, and it may influence the activity of VKDPs. This review discusses vitamin K status in human health and the physiologic and pathologic roles of VKDPs, beyond the established effects in skeletal and cardiovascular health

Chitosan-based hydrogel to support the paracrine activity of mesenchymal stem cells in spinal cord injury treatment

Abstract Advanced therapies which combine cells with biomaterial-based carriers are recognized as an emerging and powerful method to treat challenging diseases, such as spinal cord injury (SCI). By enhancing transplanted cell survival and grafting, biomimetic hydrogels can be properly engineered to encapsulate cells and locate them at the injured site in a minimally invasive way. In this work, chitosan (CS) based hydrogels were developed to host mesenchymal stem cells (MSCs), since their paracrine action can therapeutically enhance the SC regeneration, limiting the formation of a glial scar and reducing cell death at the injured site. An injectable and highly permeable CS-based hydrogel was fabricated having a rapid gelation upon temperature increase from 0 to 37 °C. CS was selected as former material both for its high biocompatibility that guarantees the proper environment for MSCs survival and for its ability to provide anti-inflammatory and anti-oxidant cues. MSCs were mixed with the hydrogel solution prior to gelation. MSC viability was not affected by the CS hydrogel and encapsulated MSCs were able to release MSC-vesicles as well as to maintain their anti-oxidant features. Finally, preliminary in vivo tests on SCI mice revealed good handling of the CS solution loading MSCs during implantation and high encapsulated MSCs survival after 7 days

Tribological properties of room temperature fluorinated graphite heat-treated under fluorine atmosphere

This work is concerned with the study of the tribologic properties of room temperature fluorinated graphite heat-treated under fluorine atmosphere. The fluorinated compounds all present good intrinsic friction properties (friction coefficient in the range 0.05–0.09). The tribologic performances are optimized if the materials present remaining graphitic domains (influenced by the presence of intercalated fluorinated species) whereas the perfluorinated compounds, where the fluorocarbon layers are corrugated (armchair configuration of the saturated carbon rings) present higher friction coefficients. Raman analyses reveal that the friction process induces severe changes in the materials structure especially the partial re-building of graphitic domains in the case of perfluorinated compounds which explains the improvement of μ during the friction tests for these last materials

POS0090 RISK OF QT INTERVAL PROLONGATION ASSOCIATED WITH CHRONIC USE OF HYDROXYCHLOROQUINE IN RHEUMATIC PATIENTS AND THE EFFECT OF COTREATMENTS

Background:Hydroxychloroquine (HCQ) has been used safely for over 60 years in rheumatic patients. However, following its recent use in covid-19 disease, its safety has been questioned, following controversial reports of cardiac toxicity1, possibly related to a prolongation of the QT interval2.Objectives:To explore the influence of chronic treatment with hydroxychloroquine on QT interval in rheumatic patients, and the possible effects of drug-to-drug interference3.Methods:12-lead electrocardiogram tracings were recorded with standard equipment in 229 ambulatory patients (SLE = 53, RA = 52, SSc = 56, UCTD = 38, Others = 30). The present analysis was performed on corrected QT intervals (QTc) calculated according to Framingham formula (QTc = QT+0.154 (1−RR)), with ULN = 449 ms in males, and 467 ms in females. Estimated glomerular filtrate rate (eGFR) was calculated from serum creatinine with the CKD-EPI equation. The influence on QTc values of demographic variables, chronic (≥3 months) HCQ treatment, and of the use of selected comedications -Statins, Angiotensin Converting Enzyme inhibitors (ACEi), Angiotensin Receptor Blockers (ARBs), Selective Serotonin Reuptake Inhibitors (SSRIs), Proton-Pump Inhibitors (PPI), Calcium Channel Blockers (CCBs) – were evaluated by parametric or non parametric statistical methods, as appropriate. All statistic al analyses were performed with the IBM SPSS statistical package version 25.Results:Table 1.Demographic and clinical variables in patients treated with HCQ (HCQ+) and in controls (HCQ-).NAgeYrs±SDFemaleN%eGFRmL/min/1.73m2StatinsN%ACEiN%ARBN%SSRIN%PPIN%CCBN%All22958.02±14.3620690.087.1418.962912.74821.8198.3146.113860.33013.1HCQ+13258.71±14.4912292.487.0020.041813.63224.2118.396.88060.61712.9HCQ-9757.51±14.308486.687.3217.471111.31616.588.255.25859.81313.4p0.5320.1830.8970.6900.1891.0000.7821.0001.000Demographic variables, and the use of evaluated comedications were not different in HCQ+ and HCQ- patients (Table 1). In the whole population, the QTc mean duration was 416.72 ± 20.70 ms, and was correlated with age (r = 0.215, p= 0.001), but not with gender (p = 0.548), eGFR (r = -0.93, p = 0.163), or disease (p = 0.092). In only 4 patients (HCQ+: 3 (2.3%) – HCQ-: 1 (1%), p = 0.639) QTc duration was above ULN.QTc duration was not associated with the use of Statins, ACEi, ARBs, or SSRIs (p = 0.454, 0.276, 0.475, and 0.131 respectively), but was significantly prolonged in patients treated with HCQ (421.26 ± 19.19 vs 410.55 ± 21.18 msec, p < 0.001), PPIs (420.57 ± 21.45 vs 410.89 ± 18.12 ms, p < 0.001), and CCBs (424.22 ± 25.97 vs 415.59 ± 19.62 ms, p < 0.033). Furthermore, as reported in Fig. 1, our data show a trend - albeit not statistically significant - towards an additive effect on QT prolongation of the association of PPIs and CCBs with HCQ, even more evident in the case of association of the 3 drug classes.Conclusion:In this study, the QTc interval was significantly prolonged in patients treated with hydroxychloroquine as compared to controls, although significant prolongation was extremely infrequent. Furthermore, our data revealed signs of drug-drug interference, suggesting that regular monitoring of the electrocardiogram is advisable in these patients, often undergoing cotreatment with multiple drugs.References:[1]Imad M. Tleyjeh, et al. The Cardiac Toxicity of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-regression Analysis. Mayo Clin Proc Innov Qual Outcomes. 2020 Nov 2 doi: 10.1016/j.mayocpiqo.2020.10.005 [Epub ahead of print].[2]Teodoro J. Oscanoa, et al. Frequency of Long QT in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine: A Meta-analysis. Int J Antimicrob Agents.[3]Byung Jin Choi, et al. Risk of QT prolongation through Drug-drug Interactions between Hydroxychloroquine and Concomitant Drugs Prescribed in Real-world Practice. Preprint from Research Square, 22 Sep 2020 DOI: 10.21203/rs.3.rs-79572/v1 PPR: PPR217328.Disclosure of Interests:None declare

Comparison of the therapeutic effect of treatment with antibiotics or nutraceuticals on clinical activity and the fecal microbiome of dogs with acute diarrhea

Dogs with acute diarrhea are often presented to clinical practice and, although this generally represents a self-limiting condition, antibiotics are still frequently used as treatment. The aim of this study was to evaluate the effects in dogs with acute non-hemorrhagic diarrhea of the administration of an antibiotic combination in comparison to a nutraceutical product. Thirty dogs were enrolled and randomly assigned to two groups: 15 dogs (group A) received a nutraceutical commercial product while 15 dogs (group B) received an antimicrobial combination of metronidazole and spiramycin. For each dog, the Canine Acute Diarrhea Severity Index, the fecal microbiota and the Dysbiosis Index were assessed. Both stool consistency and frequency decreased on day 2 in the dogs of group A compared to baseline, while in group B, these parameters significantly decreased at days 3 and 4. The global concern for rising antibiotic resistance associated with indiscriminate use of antimicrobials, in both humans and animals, suggests the necessity of avoiding empirical and injudicious use of these molecules in diarrheic dogs. These results suggest that the nutraceutical treatment had a similar clinical effect compared to the antibiotic formulation, representing a valid antibiotic-sparing therapeutic approach in canine acute diarrhea

Short communication: Characterization of molasses chemical composition

Beet and cane molasses are produced worldwide as a by-product of sugar extraction and are widely used in animal nutrition. Due to their composition, they are fed to ruminants as an energy source. However, molasses has not been properly characterized in the literature; its description has been limited to the type (sugarcane or beet) or to the amount of dry matter (DM), total or water-soluble sugars, crude protein, and ash. Our objective was to better characterize the composition of cane and beet molasses, examine possible differences, and obtain a proper definition of such feeds. For this purpose, 16 cane and 16 beet molasses samples were sourced worldwide and analyzed for chemical composition. The chemical analysis used in this trial characterized 97.4 and 98.3% of the compounds in the DM of cane and beet molasses, respectively. Cane molasses contained less DM compared with beet molasses (76.8 ± 1.02 vs. 78.3 ± 1.61%) as well as crude protein content (6.7 ± 1.8 vs. 13.5 ± 1.4% of DM), with a minimum value of 2.2% of DM in cane molasses and a maximum of 15.6% of DM in beet molasses. The amount of sucrose differed between beet and cane molasses (60.9 ± 4.4 vs. 48.8 ± 6.4% of DM), but variability was high even within cane molasses (39.2–67.3% of DM) and beet molasses. Glucose and fructose were detected in cane molasses (5.3 ± 2.7 and 8.1 ± 2.8% of DM, respectively), showing high variability. Organic acid composition differed as well. Lactic acid was more concentrated in cane molasses than in beet molasses (6.1 ± 2.8 vs. 4.5 ± 1.8% of DM), varying from 1.6 to 12.8% of DM in cane molasses. Dietary cation-anion difference showed numerical differences among cane and beet molasses (7 ± 53 vs. 66 ± 45 mEq/100 g of DM, on average). It varied from −76 to +155 mEq/100 g of DM in the cane group and from +0 to +162 mEq/100 g of DM in the beet group. Data obtained in this study detailed differences in composition between sources of molasses and suggested that a more complete characterization could improve the use of molasses in ration formulation

In vitro evaluation of sugar digestibility in molasses

Beet and cane molasses mainly contain mono- di-, and tri-saccharides, composed by hexoses, as well as pentoses in traces. However, rationing software consider sugars as only one entity, with a rate of digestion ∼20% h−1. The aim of this initial study was to investigate and evaluate the in&nbsp;vitro digestion dynamics and rates of the sugar fraction in molasses. Three beet and three cane molasses were randomly selected from a variety of samples collected world-wide and digested via in&nbsp;vitro rumen fermentation, at 1, 2, 3, 4, 6, 8, and 24 h. Samples were then analysed with a specific enzymatic kit to quantify residual sucrose, glucose, fructose, raffinose, galactose, and arabinose. Complete disappearance of sucrose happened within 3 hours of incubation. Glucose and fructose were completely digested within 4-6 h, showing variability among samples. Even if not so representative, galactose showed a similar trend of digestion (97% digestion within 3-4 h). Raffinose was quite slower in cane molasses, while it was completely digested within 1 h in beet molasses. Arabinose, a pentose, never reached a complete digestion, and its fermentation dynamic was different compared to other sugars. Calculated rates of digestion for sucrose, glucose and fructose, most representative sugars in molasses, were higher than 50% h−1 in both cane and beet. Obtained results showed that sugar fraction in molasses may vary, and different sugars are rapidly fermented by rumen microbes. Modern rationing models should consider a modification of sugar rates of digestion, since the actual one appears too slow than those observed in&nbsp;vitro.Highlights Molasses are unique blends of several sugars Major sugars are digested in few hours Rationing software should consider a faster rate of digestion for different sugars

In vitro evaluation of sugar digestibility in molasses

Beet and cane molasses mainly contain mono- di-, and tri-saccharides, composed by hexoses, as well as pentoses in traces. However, rationing software consider sugars as only one entity, with a rate of digestion similar to 20% h(-1). The aim of this initial study was to investigate and evaluate the in vitro digestion dynamics and rates of the sugar fraction in molasses. Three beet and three cane molasses were randomly selected from a variety of samples collected world-wide and digested via in vitro rumen fermentation, at 1, 2, 3, 4, 6, 8, and 24 h. Samples were then analysed with a specific enzymatic kit to quantify residual sucrose, glucose, fructose, raffinose, galactose, and arabinose. Complete disappearance of sucrose happened within 3 hours of incubation. Glucose and fructose were completely digested within 4-6 h, showing variability among samples. Even if not so representative, galactose showed a similar trend of digestion (97% digestion within 3-4 h). Raffinose was quite slower in cane molasses, while it was completely digested within 1 h in beet molasses. Arabinose, a pentose, never reached a complete digestion, and its fermentation dynamic was different compared to other sugars. Calculated rates of digestion for sucrose, glucose and fructose, most representative sugars in molasses, were higher than 50% h(-1) in both cane and beet. Obtained results showed that sugar fraction in molasses may vary, and different sugars are rapidly fermented by rumen microbes. Modern rationing models should consider a modification of sugar rates of digestion, since the actual one appears too slow than those observed in vitro

Hall Normalization Constants for the Bures Volumes of the n-State Quantum Systems

We report the results of certain integrations of quantum-theoretic interest, relying, in this regard, upon recently developed parameterizations of Boya et al of the n x n density matrices, in terms of squared components of the unit (n-1)-sphere and the n x n unitary matrices. Firstly, we express the normalized volume elements of the Bures (minimal monotone) metric for n = 2 and 3, obtaining thereby "Bures prior probability distributions" over the two- and three-state systems. Then, as an essential first step in extending these results to n > 3, we determine that the "Hall normalization constant" (C_{n}) for the marginal Bures prior probability distribution over the (n-1)-dimensional simplex of the n eigenvalues of the n x n density matrices is, for n = 4, equal to 71680/pi^2. Since we also find that C_{3} = 35/pi, it follows that C_{4} is simply equal to 2^{11} C_{3}/pi. (C_{2} itself is known to equal 2/pi.) The constant C_{5} is also found. It too is associated with a remarkably simple decompositon, involving the product of the eight consecutive prime numbers from 2 to 23. We also preliminarily investigate several cases, n > 5, with the use of quasi-Monte Carlo integration. We hope that the various analyses reported will prove useful in deriving a general formula (which evidence suggests will involve the Bernoulli numbers) for the Hall normalization constant for arbitrary n. This would have diverse applications, including quantum inference and universal quantum coding.Comment: 14 pages, LaTeX, 6 postscript figures. Revised version to appear in J. Phys. A. We make a few slight changes from the previous version, but also add a subsection (III G) in which several variations of the basic problem are newly studied. Rather strong evidence is adduced that the Hall constants are related to partial sums of denominators of the even-indexed Bernoulli numbers, although a general formula is still lackin

POS0230 INTESTINAL MICROBIOTA CHANGES TNF-INHIBITORS INDUCED IN IBD-RELATED SPONDYLOARTHRITIS

Background:the close relationship between joints and gut inflammation has long been known and several data suggest that the dysbiosis could represents the link between Spondyloarthritis (SpA) and Inflammatory Bowel Diseases (IBD). To date, the manipulation of the intestinal microbiota is considered the key to the cure or control of the natural history of several pathologies sustained or favored by dysbiosis. The introduction of biologic drugs, in particular Tumor Necrosis Factor inhibitors (TNFi), revolutionized the management of both these diseases, thanks to the strong inhibition of inflammation and partially indirectly with mechanisms not yet fully clarified. While the impact of conventional drugs on gut microbiota is well known poor data are available about TNFi.Objectives:to investigate the impact of TNFi on gut microbiota.Methods:we included CD or UC patients fulfilling criteria for axial or peripheral SpA (ASAS 2009) on a typical Mediterranean diet, naïve to biologics needing TNFi. Clinical history, physical examination, instrumental examinations, biochemical examination including C-reactive protein (CRP), erhytrocyte sedimentation rate (ESR), HLA-B27 and fecal calprotectin at the baseline and after 6 months were performed. TNFi included infliximab and adalimumab. Fecal samples were collected by patients themselves by 24 hours before the start of the therapy. The processing was performed through metagenomic NGS (next generation sequencing) including the amplification of the V3 and V4 regions of the 16S (V3 and V4) and sequencing on the Illumina MiSeq platform. All patients received the treatment at least until week 24. Clinical disease indices included Visual Analogue Scale (VAS)-pain and Visual Analgue Scale(VAS)-disease activity for all patients, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for axial involvement, clinical disease activity index (CDAI) and Health Assessment Questionnaire-Disability Index (HAQ-DI) for peripheral involvement, Harvey-Bradshaw Index for CD (HBI), or partial Mayo (pMAYO) score for UC, were assessed at baseline and at the end of the study. The study was approved by the ethics committee (approval code 0056924).Results:we evaluated 20 patients affected by enteropatic arthritis, naïve for biologic drugs, treated with TNFi. After six months of therapy we observed a significant increase in Lachnospiracae family (Δ +10.3, p 0.04) and in Coprococcus genus (Δ +2.8, p 0.003). We also observed a decrease trend in Proteobacteria (Δ -8.0 p 0.095) and Gammaproteobacteria (Δ -9, p 0.093) and an increase trend in Clostridia (Δ +8.2 p 0.083). We didn't find differences between TNFi responders (SpA improvement or IBD remission achieved) and not responders in terms of alpha and beta-diversity.Conclusion:the decrease of Proteobacteria and the increase of Lachnospiraceae and Coprococcus is consistent with the hypothesis that TNFi therapy, by decreasing inflammation, tends to restore the intestinal eubiosis. However further studies on larger cohort incuding the evaluation of gut virota and micobiota will be necessary to definitively clarify the effects of TNFi on the composition and function of the gut microbiota.References:[1]Bazin T et al. Sci Rep. 2018;8(1):5446.[2]Aden K et al. Gastroenterology. 2019;157(5):1279-1292.e11.Table 1.Comparison between clinical variables between baseline and T6 (six months)Clinical variablesT0T6P_valueFecal Calprotectin(μg/g)- median (IQR)207.5(125.5-446.2)81(50-197.2)0.004CRP(mg/L)- median(IQR)8.2(4.8-20.8)2.9(1-4)0.001ESR(mm/h)- median(IQR)21.5(10.8-34)11(7.8-21)0.003VAS_pain- median(IQR)50(38.8-60)35(10-42.5)0.001VAS_disease- median(IQR)50(38.8-50)37.5(25-42.5)0.006HAQ- mediana(IQR)0.6(0.1-0.8)0.2(0.1-0.6)0.004BASDAI_score- median(IQR)5.2(4.1-5.6)2.8(2.5-4.3)0.013CDAI_activity- median(IQR)13(10.5-16)7(5.2-11)0.004IBD activity n(%) - 011 (55%)20 (100%)0.174IBD activity n(%) - 16 (30%)0 (0%)IBD activity n(%) - 22 (10%)0 (0%)IBD activity n(%) - 31 (5%)0 (0%)Disclosure of Interests:None declared