Novel Assay of Metformin Levels in Patients With Type 2 Diabetes and Varying Levels of Renal Function: Clinical recommendations

AbstractObjective: To study trough levels of metformin in serum and its intra individual variation in patients using a newly developed assay. Research Design and Methods: Trough serum levels of metformin was measured once using Liquid Chromatography Tandem Mass Spectrometry (LcMSMS) in 137 type 2 diabetes patients with varying renal function (99 men) and followed repeatedly during two months in 20 patients (16 men) with estimated GFR (eGFR) below 60 ml/min/1.73 m(2) body surface. Results: Patients with eGFR >60, 30-60, and <30 ml/min/1.73 m(2) had a median trough metformin concentration of 4.5 mumol/l (range 0.1-20.7, n=107), 7.71 mumol/l (0.12-15.15, n=21), and 8.88 mumol/l (5.99-18.60, n=9), respectively. The median intraindividual overall coefficient of variation (CV) was 29.4 % (range 9,8-74,2). Conclusions: Determination of serum metformin with the LCMSMS technique is useful in patients on metformin treatment. Few patients had values over 20 mumol/L. Metformin measurement is less suitable for dose titration

Direct competition results from strong competiton for limited resource

We study a model of competition for resource through a chemostat-type model where species consume the common resource that is constantly supplied. We assume that the species and resources are characterized by a continuous trait. As already proved, this model, although more complicated than the usual Lotka-Volterra direct competition model, describes competitive interactions leading to concentrated distributions of species in continuous trait space. Here we assume a very fast dynamics for the supply of the resource and a fast dynamics for death and uptake rates. In this regime we show that factors that are independent of the resource competition become as important as the competition efficiency and that the direct competition model is a good approximation of the chemostat. Assuming these two timescales allows us to establish a mathematically rigorous proof showing that our resource-competition model with continuous traits converges to a direct competition model. We also show that the two timescales assumption is required to mathematically justify the corresponding classic result on a model consisting of only finite number of species and resources (MacArthur, R. Theor. Popul. Biol. 1970:1, 1-11). This is performed through asymptotic analysis, introducing different scales for the resource renewal rate and the uptake rate. The mathematical difficulty relies in a possible initial layer for the resource dynamics. The chemostat model comes with a global convex Lyapunov functional. We show that the particular form of the competition kernel derived from the uptake kernel, satisfies a positivity property which is known to be necessary for the direct competition model to enjoy the related Lyapunov functional

A Novel Y152C KCNJ5 Mutation Responsible for Familial Hyperaldosteronism Type III

CONTEXT: Primary aldosteronism is a heterogeneous group of disorders comprising both sporadic and familial forms. Mutations in the KCNJ5 gene, which encodes the inward rectifier K(+) channel 4 (G protein-activated inward rectifier K(+) channel 4, Kir3.4), cause familial hyperaldosteronism type III (FH-III) and are involved in the pathogenesis of sporadic aldosterone-producing adenomas. OBJECTIVE: The objective of the study was to characterize the effects of a newly described KCNJ5 mutation in vitro. PATIENTS AND METHODS: The index case is a 62-year-old woman affected by primary aldosteronism, who underwent left adrenalectomy after workup for adrenal adenoma. Exon 1 of KCNJ5 was PCR amplified from adrenal tissue and peripheral blood and sequenced. Electrophysiological and gene expression studies were performed to establish the functional effects of the new mutation on the membrane potential and adrenal cell CYP11B2 expression. RESULTS: KCNJ5 sequencing in the index case revealed a new p.Y152C germline mutation; interestingly, the phenotype of the patient was milder than most of the previously described FH-III families. The tyrosine-to-cysteine substitution resulted in pathological Na(+) permeability, cell membrane depolarization, and disturbed intracellular Ca(2+) homeostasis, effects similar, albeit smaller, to the ones demonstrated for other KCNJ5 mutations. Gene expression studies revealed an increased expression of CYP11B2 and its transcriptional regulator NR4A2 in HAC15 adrenal cells overexpressing KCNJ5(Y152C) compared to the wild-type channel. The effect was clearly Ca(2+)-dependent, because it was abolished by the calcium channel blocker nifedipine. CONCLUSIONS: Herein we describe a new germline mutation in KCNJ5 responsible for FH-III

Mapping Dynamic Histone Acetylation Patterns to Gene Expression in Nanog-depleted Murine Embryonic Stem Cells

Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenetic mechanisms. In this study, we focus on quantifying the impact of histone 3 acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We analyze genome-wide histone acetylation patterns and gene expression profiles measured over the first five days of cell differentiation triggered by silencing Nanog, a key transcription factor in ESC regulation. We explore the temporal and spatial dynamics of histone acetylation data and its correlation with gene expression using supervised and unsupervised statistical models. On a genome-wide scale, changes in acetylation are significantly correlated to changes in mRNA expression and, surprisingly, this coherence increases over time. We quantify the predictive power of histone acetylation for gene expression changes in a balanced cross-validation procedure. In an in-depth study we focus on genes central to the regulatory network of Mouse ESC, including those identified in a recent genome-wide RNAi screen and in the PluriNet, a computationally derived stem cell signature. We find that compared to the rest of the genome, ESC-specific genes show significantly more acetylation signal and a much stronger decrease in acetylation over time, which is often not reflected in an concordant expression change. These results shed light on the complexity of the relationship between histone acetylation and gene expression and are a step forward to dissect the multilayer regulatory mechanisms that determine stem cell fate.Comment: accepted at PLoS Computational Biolog

Solar neutrino measurements in Super-Kamiokande-I

The details of Super--Kamiokande--I's solar neutrino analysis are given. Solar neutrino measurement in Super--Kamiokande is a high statistics collection of $^8$B solar neutrinos via neutrino-electron scattering. The analysis method and results of the 1496 day data sample are presented. The final oscillation results for the data are also presented.Comment: 32pages, 57figures, submitted to Physical Review

Three flavor neutrino oscillation analysis of atmospheric neutrinos in Super-Kamiokande

We report on the results of a three-flavor oscillation analysis using Super-Kamiokande~I atmospheric neutrino data, with the assumption of one mass scale dominance ($\Delta m_{12}^2$$=$0). No significant flux change due to matter effect, which occurs when neutrinos propagate inside the Earth for $\theta_{13}$$\neq$0, has been seen either in a multi-GeV $\nu_e$-rich sample or in a $\nu_\mu$-rich sample. Both normal and inverted mass hierarchy hypotheses are tested and both are consistent with observation. Using Super-Kamiokande data only, 2-dimensional 90 % confidence allowed regions are obtained: mixing angles are constrained to $\sin^2\theta_{13} < 0.14$ and $0.37 < \sin^2\theta_{23} < 0.65$ for the normal mass hierarchy. Weaker constraints, $\sin^2\theta_{13} < 0.27$ and $0.37 < \sin^2\theta_{23} < 0.69$, are obtained for the inverted mass hierarchy case.Comment: 7 figures, 3 table

Evidence for an oscillatory signature in atmospheric neutrino oscillation

Muon neutrino disappearance probability as a function of neutrino flight length L over neutrino energy E was studied. A dip in the L/E distribution was observed in the data, as predicted from the sinusoidal flavor transition probability of neutrino oscillation. The observed L/E distribution constrained nu_mu nu_tau neutrino oscillation parameters; 1.9x10^-3 < Delta m^2 < 3.0x10^-3 eV^2 and \sin^2(2theta) > 0.90 at 90% confidence level.Comment: 5 pages, 5 figures, submitted to PR

Search for nucleon decay via modes favored by supersymmetric grand unification models in Super-Kamiokande-I

We report the results for nucleon decay searches via modes favored by supersymmetric grand unified models in Super-Kamiokande. Using 1489 days of full Super-Kamiokande-I data, we searched for $p \to \bar{\nu} K^+$, $n \to \bar{\nu} K^0$, $p \to \mu^+ K^0$ and $p \to e^+ K^0$ modes. We found no evidence for nucleon decay in any of these modes. We set lower limits of partial nucleon lifetime 2.3$\times10^{33}$, 1.3$\times10^{32}$, 1.3$\times10^{33}$ and 1.0$\times10^{33}$ years at 90% confidence level for $p \to \bar{\nu} K^+$, $n \to \bar{\nu} K^0$, $p \to \mu^+ K^0$ and $p \to e^+ K^0$ modes, respectively. These results give a strong constraint on supersymmetric grand unification models.Comment: 14 pages, 13 figure

Contrast medium-induced nephropathy. Aspects on incidence, consequences, risk factors and prevention

Contrast media-induced nephropathy (CIN) is a well-known complication of radiological examinations employing iodine contrast media (I-CM). The rapid development and frequent use of coronary interventions and multi-channel detector computed tomography with concomitant administration of relatively large doses of I-CM has contributed to an increasing number of CIN cases during the last few years. Reduced renal function, especially when caused by diabetic nephropathy or renal arteriosclerosis, in combination with dehydration, congestive heart failure, hypotension, and administration of nephrotoxic drugs are risk factors for the development of CIN. When CM-based examinations cannot be replaced by other techniques in patients at risk of CIN, focus should be directed towards analysis of number and type of risk factors, adequate estimation of GFR, institution of proper preventive measures including hydration and post-procedural observation combined with surveillance of serum creatinine for 1-3 days. For the radiologist, there are several steps to consider in order to minimise the risk for CIN: use of “low-“ or “iso-osmolar” I-CM and dosing the I-CM in relation to GFR and body weight being the most important as well as utilizing radiographic techniques to keep the I-CM dose in gram iodine as low as possible below the numerical value of estimated GFR. There is as yet no pharmacological prevention that has been proven to be effective