Mortality in kittens is associated with a shift in ileum mucosa-associated enteroccoci from E. hirae to biofilm-forming E. faecalis and adherent E. coli

Approximately ~15% of foster kittens die before 8-wks of age with most of these kittens demonstrating clinical signs or post-mortem evidence of enteritis. While a specific cause of enteritis is not determined in most cases; these kittens are often empirically administered probiotics that contain enterococci. The enterococci are members of the commensal intestinal microbiota but can also function as opportunistic pathogens. Given the complicated role of enterococci in health and disease, it would be valuable to better understand what constitutes a “healthy” enterococcal community in these kittens and how this microbiota is impacted by severe illness. In this study, we characterize the ileum mucosa-associated enterococcal community of 50 apparently healthy and 50 terminally ill foster kittens. In healthy kittens, E. hirae was the most common species of ileum mucosa-associated enterococci and was often observed to adhere extensively to the small intestinal epithelium. These E. hirae isolates generally lacked virulence traits. In contrast, non-E. hirae enterococci, notably E. faecalis, were more commonly isolated from the ileum mucosa of kittens with terminal illness. Isolates of E. faecalis had numerous virulence traits and multiple antimicrobial resistance. Moreover, attachment of E. coli to the intestinal epithelium was significantly associated with terminal illness and was not observed in any kitten with adherent E. hirae. These findings identify a significant difference in species of enterococci cultured from the ileum mucosa of kittens with terminal illness compared to healthy kittens. In contrast to prior case studies that associate enteroadherent E. hirae with diarrhea in young animals, these controlled studies identified E. hirae as more often isolated from healthy kittens and adherence of E. hirae as more common and extensive in healthy compared to sick kittens

Phosphate and fibroblast growth factor 23 in diabetes

Diabetes is associated with a strongly elevated risk of cardiovascular disease, which is even more pronounced in patients with diabetic nephropathy. Currently available guideline-based efforts to correct traditional risk factors are only partly able to attenuate this risk, underlining the urge to identify novel treatment targets. Emerging data point towards a role for disturbances in phosphate metabolism in diabetes. In this review, we discuss the role of phosphate and the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) in diabetes. We address deregulations of phosphate metabolism in patients with diabetes, including diabetic ketoacidosis. Moreover, we discuss potential adverse consequences of these deregulations, including the role of deregulated phosphate and glucose as drivers of vascular calcification propensity. Finally, we highlight potential treatment options to correct abnormalities in phosphate and FGF23. While further studies are needed to more precisely assess their clinical impact, deregulations in phosphate and FGF23 are promising potential target in diabetes and diabetic nephropathy

Fibroblast Growth Factor 23, Glucose Homeostasis, and Incident Diabetes:Findings of 2 Cohort Studies

CONTEXT: The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood.OBJECTIVE: This study investigates potential crosstalk between FGF23 and glucose homeostasis.METHODS: First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (body mass index [BMI] 25-30) individuals using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI &gt; 30) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI.RESULTS: After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag = .04). In the population-based cohort (N = 5482; mean age 52 years, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (β = .13 [.03-.23]; P = .01), insulin (β = .10 [.03-.17]; P &lt; .001), and proinsulin (β = .06 [0.02-0.10]; P = .01) at baseline. On longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events [4%]; fully adjusted hazard ratio [HR] 1.66 [95% CI, 1.06-2.60]; P = .03) and development of obesity (241 events [6%]; fully adjusted HR 1.84 [95% CI, 1.34-2.50]; P &lt; .001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI.CONCLUSION: Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels, and obesity. These findings suggest crosstalk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.</p

Plasma phosphate and all-cause mortality in individuals with and without type 2 diabetes:the Dutch population-based lifelines cohort study

INTRODUCTION: Individuals with type 2 diabetes have a substantially elevated cardiovascular risk. A higher plasma phosphate level promotes vascular calcification, which may adversely affect outcomes in individuals with type 2 diabetes. We hypothesized that the association between plasma phosphate and all-cause mortality is stronger in individuals with type 2 diabetes, compared to those without diabetes. METHODS: We analysed the association between plasma phosphate and all-cause mortality in the Dutch population-based Lifelines cohort and in subgroups with and without type 2 diabetes, using multivariable Cox regression adjusted for potential confounders. Effect modification was tested using multiplicative interaction terms. RESULTS: We included 57,170 individuals with 9.4 [8.8-10.4] years follow-up. Individuals within the highest phosphate tertile (range 1.00-1.83 mmol/L) were at higher risk of all-cause mortality (fully adjusted HR 1.18 [95% CI 1.02-1.36], p = 0.02), compared with the intermediate tertile (range 0.85-0.99 mmol/L). We found significant effect modification by baseline type 2 diabetes status (p-interaction = 0.003). Within the type 2 diabetes subgroup (N = 1790), individuals within the highest plasma phosphate tertile had an increased mortality risk (HR 1.73 [95% CI 1.10-2.72], p = 0.02 vs intermediate tertile). In individuals without diabetes at baseline (N = 55,380), phosphate was not associated with mortality (HR 1.12 [95% CI 0.96-1.31], p = 0.14). Results were similar after excluding individuals with eGFR < 60 mL/min/1.73 m2. DISCUSSION: High-normal plasma phosphate levels were associated with all-cause mortality in individuals with type 2 diabetes. The association was weaker and non-significant in those without diabetes. Measurement of phosphate levels should be considered in type 2 diabetes; whether lowering phosphate levels can improve health outcomes in diabetes requires further study

Substituted anilides from chitin-based 3-acetamido-furfural

The synthesis of aromatic compounds from biomass-derived furans is a key strategy in the pursuit of a sustainable economy. Within this field, a Diels-Alder/aromatization cascade reaction with chitin-based furans is emerging as a powerful tool for the synthesis of nitrogen-containing aromatics. In this study we present the conversion of chitin-based 3-acetamido-furfural (3A5F) into an array of di- and tri-substituted anilides in good to high yields (62-90%) via a hydrazone mediated Diels-Alder/aromatization sequence. The addition of acetic anhydride expands the dienophile scope and improves yields. Moreover, replacing the typically used dimethyl hydrazone with its pyrrolidine analogue, shortens reaction times and further increases yields. The hydrazone auxiliary is readily converted into either an aldehyde or a nitrile group, thereby providing a plethora of functionalized anilides. The developed procedure was also applied to 3-acetamido-5-acetylfuran (3A5AF) to successfully prepare a phthalimide. </p

Interleukin 6 and Development of Heart Failure With Preserved Ejection Fraction in the General Population

Background The cause of heart failure with preserved ejection fraction (HFpEF) is poorly understood, and specific therapies are lacking. Previous studies suggested that inflammation plays a role in the development of HFpEF. Herein, we aimed to investigate in community-dwelling individuals whether a higher plasma interleukin 6 (IL-6) level is associated with an increased risk of developing new-onset heart failure (HF) over time, and specifically HFpEF. Methods and Results We performed a case-cohort study based on the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study, a prospective general population-based cohort study. We included 961 participants, comprising 200 participants who developed HF and a random group of 761 controls. HF with reduced ejection fraction or HFpEF was defined on the basis of the left ventricular ejection fraction of 40%, respectively. In Cox proportional hazard regression analyses, IL-6 levels were statistically significantly associated with the development of HF (hazard ratio [HR], 1.28; 95% CI, 1.02-1.61; P=0.03) after adjustment for key risk factors. Specifically, IL-6 levels were significantly associated with the development of HFpEF (HR, 1.59; 95% CI, 1.16-2.19; P=0.004), whereas the association with HF with reduced ejection fraction was nonsignificant (HR, 1.05; 95% CI, 0.75-1.47; P=0.77). In sensitivity analyses, defining HFpEF as left ventricular ejection fraction >= 50%, IL-6 levels were also significantly associated with the development of HFpEF (HR, 1.47; 95% CI, 1.04-2.06; P=0.03) after adjustment for key risk factors. Conclusions IL-6 is associated with new-onset HFpEF in community-dwelling individuals, independent of potential confounders. Our findings warrant further research to investigate whether IL-6 might be a novel treatment target to prevent HFpEF

Genetic Determinants of Serum Calcification Propensity and Cardiovascular Outcomes in the General Population

BACKGROUND: Serum calciprotein particle maturation time (T(50)), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T(50) and study their association with cardiovascular disease and mortality. METHODS: We performed a genome-wide association study of serum T(50) in 2,739 individuals of European descent participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, followed by a two-sample Mendelian randomization (MR) study to examine causal effects of T(50) on cardiovascular outcomes. Finally, we examined associations between T(50) loci and cardiovascular outcomes in 8,566 community-dwelling participants in the Rotterdam study. RESULTS: We identified three independent genome-wide significant single nucleotide polymorphism (SNPs) in the AHSG gene encoding fetuin-A: rs4917 (p = 1.72 × 10(−101)), rs2077119 (p = 3.34 × 10(−18)), and rs9870756 (p = 3.10 × 10(−8)), together explaining 18.3% of variation in serum T(50). MR did not demonstrate a causal effect of T(50) on cardiovascular outcomes in the general population. Patient-level analyses revealed that the minor allele of rs9870756, which explained 9.1% of variation in T(50), was associated with a primary composite endpoint of all-cause mortality or cardiovascular disease [odds ratio (95% CI) 1.14 (1.01–1.28)] and all-cause mortality alone [1.14 (1.00–1.31)]. The other variants were not associated with clinical outcomes. In patients with type 2 diabetes or chronic kidney disease, the association between rs9870756 and the primary composite endpoint was stronger [OR 1.40 (1.06–1.84), relative excess risk due to interaction 0.54 (0.01–1.08)]. CONCLUSIONS: We identified three SNPs in the AHSG gene that explained 18.3% of variability in serum T(50) levels. Only one SNP was associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease

Serum Calcification Propensity and the Risk of Cardiovascular and All-Cause Mortality in the General Population:The PREVEND Study

Objective: Vascular calcification contributes to the cause of cardiovascular disease. The calciprotein particle maturation time (T50) in serum, a measure of calcification propensity, has been linked with adverse outcomes in patients with chronic kidney disease, but its role in the general population is unclear. We investigated whether serum T50 is associated with cardiovascular mortality in a large general population-based cohort. Approach and Results: The relationship between serum T50 and cardiovascular mortality was studied in 6231 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort. All-cause mortality was the secondary outcome. Mean (±SD) age was 53±12 years, 50% were male, and mean serum T50 was 329±58 minutes. A shorter serum T50 is indicative of a higher calcification propensity. Serum T50 was inversely associated with circulating phosphate, age, estimated glomerular filtration rate, and alcohol consumption, whereas plasma magnesium was positively associated with serum T50 (P&lt;0.001, total multivariable model R2=0.281). During median (interquartile range) follow-up for 8.3 (7.8-8.9) years, 364 patients died (5.8%), of whom 95 (26.1%) died from a cardiovascular cause. In multivariable Cox proportional hazard models, each 60 minutes decrease in serum T50 was independently associated with a higher risk of cardiovascular mortality (fully adjusted hazard ratio [95% CI], 1.22 [1.04-1.36], P=0.021). This association was modified by diabetes mellitus; stratified analysis indicated a more pronounced association in individuals with diabetes mellitus. Conclusions: Serum T50 is independently associated with an increased risk of cardiovascular mortality in the general population and thus may be an early and potentially modifiable risk marker for cardiovascular mortality.</p

Mild Coronavirus Disease 2019 (COVID-19) Is Marked by Systemic Oxidative Stress:A Pilot Study

Oxidative stress has been implicated to play a critical role in the pathophysiology of coronavirus disease 2019 (COVID-19) and may therefore be considered as a relevant therapeutic target. Serum free thiols (R-SH, sulfhydryl groups) comprise a robust marker of systemic oxidative stress, since they are readily oxidized by reactive oxygen species (ROS). In this study, serum free thiol concentrations were measured in hospitalized and non-hospitalized patients with COVID-19 and healthy controls and their associations with relevant clinical parameters were examined. Serum free thiol concentrations were measured colorimetrically (Ellman’s method) in 29 non-hospitalized COVID-19 subjects and 30 age-, sex-, and body-mass index (BMI)-matched healthy controls and analyzed for associations with clinical and biochemical disease parameters. Additional free thiol measurements were performed on seven serum samples from COVID-19 subjects who required hospitalization to examine their correlation with disease severity. Non-hospitalized subjects with COVID-19 had significantly lower concentrations of serum free thiols compared to healthy controls (p = 0.014), indicating oxidative stress. Serum free thiols were positively associated with albumin (St. β = 0.710, p < 0.001) and inversely associated with CRP (St. β = −0.434, p = 0.027), and showed significant discriminative ability to differentiate subjects with COVID-19 from healthy controls (AUC = 0.69, p = 0.011), which was slightly higher than the discriminative performance of CRP concentrations regarding COVID-19 diagnosis (AUC = 0.66, p = 0.042). This study concludes that systemic oxidative stress is increased in patients with COVID-19 compared with healthy controls. This opens an avenue of treatment options since free thiols are amenable to therapeutic modulation

Fibroblast growth factor 23 is related to profiles indicating volume overload, poor therapy optimization and prognosis in patients with new-onset and worsening heart failure

Background: Fibroblast growth factor (FGF) 23 is a hormone that increases urinary phosphate excretion and regulates renal sodium reabsorption and plasma volume. We studied the role of plasma FGF23 in therapy optimization and outcomes in patients with new-onset and worsening heart failure (HF). Methods: We measured plasma C-terminal FGF23 levels at baseline in 2399 of the 2516 patients included in the BIOlogy Study to Tailored Treatment in Chronic HF (BIOSTAT-CHF) trial. The association between FGF23 and outcome was evaluated by Cox regression analysis adjusted for potential confounders. Results: Median FGF23 was 218.0 [IQR: 117.1–579.3] RU/ml; patients with higher FGF23 levels had a worse NYHA class, more signs of congestion, and were less likely to use an ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARBs) at baseline (all P &lt; 0.01). Higher FGF23 levels were independently associated with higher BNP, lower eGFR, the presence of oedema and atrial fibrillation (all P &lt; 0.001). In addition, higher FGF23 was independently associated with impaired uptitration of ACEi/ARBs after 3 months, but not of beta-blockers. In multivariable Cox regression analysis, FGF23 was independently associated with all-cause mortality (hazard ratio: 1.17 (1.09–1.26) per log increase, P &lt; 0.001), and the combined endpoint of all-cause mortality and HF hospitalization (1.15 (1.08–1.22) per log increase, P &lt; 0.001). Conclusions: In patients with new-onset and worsening HF, higher plasma FGF23 levels were independently associated with volume overload, less successful uptitration of ACEi/ARBs and an increased risk of all-cause mortality and HF hospitalization