On the calibration of a superconducting gravimeter using absolute gravity measurements

International audienceA 24 hr continuous parallel registration between an absolute free-fall gravimeter and a relative cryogenic gravimeter is analysed. Different adjustment procedures (L,, L2 norms) are applied to the sets of absolute and relative readings in order to estimate the value of the calibration factor of the superconducting meter, as well as its uncertainty. In addition, a sensitivity test is performed to investigate the influence of some parameters (like the laser frequency and its short-term drift) upon this factor. The precision in the calibration factor is found to be better than 1 per cent, but systematic effects related to the short time interval may add another one and half per cent uncertainty. From preliminary results, it appears that this calibration experiment leads to a close agreement between the values of the gravimetric factor for the reference tidal wave O1 observed with the superconducting meter and the theoretical value (Dehant-Wahr body tide + ocean loading)

Impact of the SGLT2 inhibitor empagliflozin on urinary supersaturations in kidney stone formers (SWEETSTONE trial): protocol for a randomised, double-blind, placebo-controlled cross-over trial.

INTRODUCTION Kidney stones are a global healthcare problem. Given high recurrence rates and the morbidity associated with symptomatic stone disease, effective medical prophylaxis is clearly an unmet need. Explanatory analyses of randomised controlled trials with sodium/glucose cotransporter isoform 2 inhibitors indicated a 30%-50% reduced rate of stone events in patients with diabetes. Underlying mechanisms remain unclear. We aim to determine the effect of empagliflozin on urinary supersaturations in non-diabetic kidney stone formers to evaluate their therapeutic potential for recurrence prevention. We will provide first clinical trial evidence on whether urinary supersaturations are affected by empagliflozin in kidney stone formers. METHODS AND ANALYSIS The SWEETSTONE trial is a randomised, double-blind, placebo-controlled, cross-over, exploratory study to assess the impact of empagliflozin on urinary supersaturations of calcium oxalate, calcium phosphate and uric acid in kidney stone formers. We plan to include 46 non-diabetic adults (18-74 years) with ≥1 past kidney stone event and stone composition with ≥80% of calcium or ≥80% of uric acid. Patients with secondary causes of kidney stones or chronic kidney disease will be excluded. Eligible individuals will be randomised in equal proportions to receive either a 14-day treatment with 25 mg empagliflozin followed after the 2-6 weeks wash out period by a 14-day treatment with a matching placebo or the reverse procedure. Secondary outcomes will include electrolyte concentrations, renal function, mineral metabolism and glycaemic parameters, urinary volume and safety.Results will be presented as effect measures (95% CIs) with p values and hypothesis testing for primary outcomes (significance level 0.02). ETHICS AND DISSEMINATION The SWEETSTONE trial was approved by the Swiss ethics committee and Swissmedic. First results are expected in the fourth quarter of 2022. TRIAL REGISTRATION NUMBER NCT04911660; Pre-results

Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial

Background: Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. However, evidence for benefits and harms of thiazides in the prevention of calcium containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known. Methods: The NOSTONE trial is an investigator-initiated 3-year prospective, multicenter, double-blind, placebo-controlled trial to assess the efficacy of standard and low dose hydrochlorothiazide treatment in the recurrence prevention of calcium containing kidney stones. We plan to include 416 adult (≥ 18 years) patients with recurrent (≥ 2 stone episodes in the last 10 years) calcium containing kidney stones (containing ≥50% of calcium oxalate, calcium phosphate or a mixture of both). Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo. The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome, safety and tolerability of hydrochlorothiazide treatment, changes in urinary biochemistry elicited by hydrochlorothiazide treatment and impact of baseline disease severity, biochemical abnormalities and stone composition on treatment response. Discussion: The NOSTONE study will provide long-sought information on the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones. Strengths of the study include the randomized, double-blind and placebo-controlled design, the large amount of patients studied, the employment of high sensitivity and high specificity imaging and the exclusive public funding support. Trial registration: ClinicalTrials.gov, NCT03057431. Registered on February 20 2017

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules

Twin and genealogy studies suggest a strong genetic component of nephrolithiasis. Likewise, urinary traits associated with renal stone formation were found to be highly heritable, even after adjustment for demographic, anthropometric and dietary covariates. Recent high-throughput sequencing projects of phenotypically well-defined cohorts of stone formers and large genome-wide association studies led to the discovery of many new genes associated with kidney stones. The spectrum ranges from infrequent but highly penetrant variants (mutations) causing mendelian forms of nephrolithiasis (monogenic traits) to common but phenotypically mild variants associated with nephrolithiasis (polygenic traits). About two-thirds of the genes currently known to be associated with nephrolithiasis code for membrane proteins or enzymes involved in renal tubular transport. The thick ascending limb of Henle and connecting tubules are of paramount importance for renal water and electrolyte handling, urinary concentration and maintenance of acid-base homeostasis. In most instances, pathogenic variants in genes involved in thick ascending limb of Henle and connecting tubule function result in phenotypically severe disease, frequently accompanied by nephrocalcinosis with progressive CKD and to a variable degree by nephrolithiasis. The aim of this article is to review the current knowledge on kidney stone disease associated with inherited defects in the thick ascending loop of Henle and the connecting tubules. We also highlight recent advances in the field of kidney stone genetics that have implications beyond rare disease, offering new insights into the most common type of kidney stone disease, i.e., idiopathic calcium stone disease

Structure of the catalytic domain of matriptase in complex with the 1^st Kunitz domain of HAI-1.

<p>The crystal structure of the complex was solved by Zhao et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094267#pone.0094267-Zhao1" target="_blank">[49]</a> and the atomic coordinates used for the figure were obtained from the Protein Data Bank (code 4ISO). The 1^st Kunitz domain of HAI-1 is shown in gray with the Tyr280 residue (magenta), and the cysteines (red) involved in disulfide bonds. The catalytic domain of the matriptase is represented in black with the cysteines (red) involved in disulfide bonds. <i>Insert</i>: substitution of the Tyr280 (magenta) in the KD1 of HAI-1with a cysteine pointing its side chain towards the Cys283.</p

Tissue distribution of mRNA expression of <i>Spint2</i> and membrane-bound serine proteases.

<p>Quantitative RT-PCRs were performed on selected organs from three wild-type adult mice. From stomach to distal colon, tissues were scraped to get fractions enriched in mucosal cells. Each gene was assessed in duplicates in two independent experiments. Results are expressed as arbitrary units (A.U.) based on standard dilution curves (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094267#s2" target="_blank">Material and Methods</a>).</p

Validation of the functional assay using ENaC as a reporter gene.

<p><b>A</b>, Representative recordings of amiloride-sensitive current (I_Na⁺) in the presence (filled bars) or absence of trypsin (5 μg/ml), in <i>Xenopus</i> oocytes injected with 0.11 ng/subunit ENaC alone (left panel), with ENaC and 0.25 ng tmprss13 (middle panel) and with ENaC, tmprss13 and 1.5 ng spint2 cRNA (right panel). 10 μM amiloride was used to block the ENaC-mediated current. <b>B</b>, Effects of increasing the amounts of injected tmprss13 and enteropeptidase cRNAs on I_Na⁺. I_Na⁺ was measured in oocytes injected with ENaC with/without of tmprss13 or enteropeptidase as indicated. I_Na⁺ was measured without (black bars) or with trypsin (5 μg/ml) perfused extracellularly (white bars) as a positive control for ENaC activation. <b>C</b>, Effects of increasing the amounts of injected spint2 cRNA to prevent the tmprss13- or enteropeptidase-mediated increase in I_Na⁺ (left and right panels, respectively). <b>D</b>, Effect of spint2 on I_Na⁺. I_Na⁺ was measured 12, 24 and 30 hours after injection (left, middle and right panels, respectively) in three independent experiments. n = 6-9 measured oocytes per condition from 2 different batches for each experiment. Data are means ± SEM; *, p<0.05/**, p<0.01 compared to ENaC alone or ENaC + protease (as indicated) after two-way repeated measure ANOVA followed by Dunnett's multiple comparisons test.</p