Influence of dietary constituents on intestinal absorption of aluminum

Orally-ingested aluminum compounds have been implicated in the development of dialysis encephalopathy, osteomalacic dialysis osteodystrophy and other disorders in both hemodialyzed and nonhemodialyzed patients suffering from chronic renal failure [1–10]. Both dialysate aluminum content [7, 11, 12] and aluminum-containing phosphate binding agents [12–15] have been identified as contributing to hyperaluminemia in uremic patients. The health threat from dialysate fluids has been reduced by the recommendation that the dialysate contains less than 10 µg/liter of aluminum [16]. Alternative phosphate-binding agents which do not contain aluminum are available but these agents are not free of problems [17], and uremic patients continue to ingest significant doses of aluminum-containing phosphate binding agents.Aluminum is the most common metal in the biosphere of humans but, aside from uremic patients, causes no widespread toxicity. This may be as a result of the extremely limited solubility of aluminum at the pH range of the small intestine and blood [18]. Advances in analytical chemistry have made it possible to measure picogram quantities of aluminum in body fluids, thus enabling accurate determination of plasma aluminum levels in the part per billion (µg/liter) range. These analytical techniques have shown that orally ingested aluminum-containing antacids elevate plasma aluminum levels in man [13]. Balance studies monitoring aluminum absorption and elimination revealed an average positive balance from 23 to 313mg of aluminum per day when diets were supplemented with 1 to 3g of aluminum per day [15]. These studies show that a small fraction of the ingested aluminum is absorbed. This absorption presents potential toxic effects to uremic patients whose ability to eliminate aluminum is impaired.In addition, Slanina et al [19] have shown that addition of citric acid to aluminum-supplemented dietary regimens results in blood aluminum levels that are significantly higher than those found in subjects treated with aluminum-supplemented dietary regimens alone. This result suggests that dietary factors may contribute to aluminum absorption.This study was undertaken to determine if the form of aluminum present in the intestinal lumen significantly affects the absorption of aluminum following oral ingestion

UKRN Open Research Training Resources and Priorities Working Paper

UKRN Open Research Programme has released its first working paper about training priorities and resources aimed at accelerating the uptake of high quality open research practices

Iridoid Sex Pheromone Biosynthesis in Aphids Mimics Iridoid?Producing Plants

Biosynthesis of (1R,4aS,7S,7aR)?nepetalactol (1) and (4aS,7S,7aR)?nepetalactone (2) in plants involves iridoid synthase (ISY), an atypical reductive cyclase that catalyses the reduction of 8?oxogeranial into the reactive enol of (S)?8?oxocitronellal, and cyclization of this enol intermediate, either non?enzymatically or by a nepetalactol?related short chain dehydrogenase enzyme (NEPS) that yields the nepetalactols. In this study, we investigated the biosynthesis in?vivo of 1 and 2 in the pea aphid, Acyrthosiphon pisum, using a library of isotopically?labelled monoterpenoids as molecular probes. Topical application of deuterium?labelled probes synthesized from geraniol and nerol resulted in production of 2H4?lactol 1 and 2H4?lactone 2. However, deuterium incorporation was not evident using labelled probes synthesized from (S)?citronellol. These results suggest that iridoid biosynthesis in animals, specifically aphids, may follow a broadly similar route to that characterised for plants

The geography of wage inequality in British cities

There is widespread concern about the scale and implications of urban inequality in Great Britain, but little evidence on which cities are the most unequal and why. This paper investigates patterns of wage inequality in 60 British cities. It has two principal goals: (1) to describe which cities are most unequal and (2) to assess the important determinants of inequality. The results show a distinct geography of wage inequality, the most unequal cities tend to be affluent and located in parts of the Greater South East of England. A central determinant of these patterns is the geography of highly skilled workers. Because of this, the geography of urban wage inequality reflects the geography of affluence more generally

Emerging therapies for severe asthma

Many patients with asthma have poorly controlled symptoms, and particularly for those with severe disease, there is a clear need for improved treatments. Two recent therapies licensed for use in asthma are omalizumab, a humanized monoclonal antibody that binds circulating IgE antibody, and bronchial thermoplasty, which involves the delivery of radio frequency energy to the airways to reduce airway smooth muscle mass. In addition, there are new therapies under development for asthma that have good potential to reach the clinic in the next five years. These include biological agents targeting pro-inflammatory cytokines such as interleukin-5 and interleukin-13, inhaled ultra long-acting β2-agonists and once daily inhaled corticosteroids. In addition, drugs that block components of the arachidonic acid pathway that targets neutrophilic asthma and CRTH2 receptor antagonists that inhibit the proinflammatory actions of prostaglandin D2 may become available. We review the recent progress made in developing viable therapies for severe asthma and briefly discuss the idea that development of novel therapies for asthma is likely to increasingly involve the assessment of genotypic and/or phenotypic factors

Procalcitonin evaluation of antibiotic use in COVID-19 hospitalised patients (PEACH): protocol for a retrospective observational study

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although COVID-19 is a viral illness, many patients admitted to hospital are prescribed antibiotics, based on concerns that COVID-19 patients may experience secondary bacterial infections, and the assumption that they may respond well to antibiotic therapy. This has led to an increase in antibiotic use for some hospitalised patients at a time when accumulating antibiotic resistance is a major global threat to health. Procalcitonin (PCT) is an inflammatory marker measured in blood samples and widely recommended to help diagnose bacterial infections and guide antibiotic treatment. The PEACH study will compare patient outcomes from English and Welsh hospitals that used PCT testing during the first wave of the COVID-19 pandemic with those from hospitals not using PCT. It will help to determine whether, and how, PCT testing should be used in the NHS in future waves of COVID-19 to protect patients from antibiotic overuse. PEACH is a retrospective observational cohort study using patient-level clinical data from acute hospital Trusts and Health Boards in England and Wales. The primary objective is to measure the difference in antibiotic use between COVID-19 patients who did or did not have PCT testing at the time of diagnosis. Secondary objectives include measuring differences in length of stay, mortality, intensive care unit admission, and resistant bacterial infections between these groups

White and grey matter development in utero assessed using motion-corrected diffusion tensor imaging and its comparison to ex utero measures

Fetal brain diffusion tensor imaging (DTI) offers quantitative analysis of the developing brain. The objective was to 1) quantify DTI measures across gestation in a cohort of fetuses without brain abnormalities using full retrospective correction for fetal head motion 2) compare results obtained in utero to those in preterm infants. Motion-corrected DTI analysis was performed on data sets obtained at 1.5T from 32 fetuses scanned between 21.29 and 37.57 (median 31.86) weeks. Results were compared to 32 preterm infants scanned at 3T between 27.43 and 37.14 (median 33.07) weeks. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were quantified by region of interest measurements and tractography was performed. Fetal DTI was successful in 84% of fetuses for whom there was sufficient data for DTI estimation, and at least one tract could be obtained in 25 cases. Fetal FA values increased and ADC values decreased with age at scan (PLIC FA: p = 0.001; R  = 0.469; slope = 0.011; splenium FA: p < 0.001; R  = 0.597; slope = 0.019; thalamus ADC: p = 0.001; R  = 0.420; slope = - 0.023); similar trends were found in preterm infants. This study demonstrates that stable DTI is feasible on fetuses and provides evidence for normative values of diffusion properties that are consistent with aged matched preterm infants

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

CMB-S4: Forecasting Constraints on Primordial Gravitational Waves

CMB-S4---the next-generation ground-based cosmic microwave background (CMB) experiment---is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the Universe, from the highest energies at the dawn of time through the growth of structure to the present day. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semi-analytic projection tool, targeted explicitly towards optimizing constraints on the tensor-to-scalar ratio, $r$, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2--3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments given a desired scientific goal. To form a closed-loop process, we couple this semi-analytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for $r > 0.003$ at greater than $5\sigma$, or, in the absence of a detection, of reaching an upper limit of $r < 0.001$ at $95\%$ CL.Comment: 24 pages, 8 figures, 9 tables, submitted to ApJ. arXiv admin note: text overlap with arXiv:1907.0447

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data