Development of Zwitterionic Hydrophilic Liquid Chromatography (ZICⓇHILIC-MS) metabolomics method for Shotgun analysis of human urine

Urine is a product of the body’s metabolism and the majority of the metabolic products exiting via the renal system are rendered polar in order to be water soluble. Resolution of urinary metabolites for metabolomic studies requires the development of HPLC separation techniques that match this feature of biological chemistry. ZIC –HILIC is an ideal candidate to take forward resolution of such metabolites where reverse phase is unable to give adequate separation. Metabolomic data has to be processed by Shotgun multivariate analysis to sift through thousands of analytes and their variables such as ion intensity. In the development of ZIC-HILIC separation with mass spectrometric (IT-ToF) detection, methodological variability have to be minimized so that any Shotgun data analysis does not reveal potential biomarker analytes that are artifacts or are adversely affected of the separation and detection technique. Here, we report the development of a ZIC-HILIC mass spectrometry method that is suitable for SIMCA P+ data analysis of urine. Variables such as resolution, run reproducibility and sample storage temperature were evaluated in tandem with SIMCA P+ data analysis and quality control pre-processing. The developed method couples quality control runs that pre-process and exclude analytes that are insufficiently robust for further candidate biomarker studies. This meant labile analytes that could not be reproduced in 70% of QC runs (which are pools of all samples run that day) were excluded. However, urine samples stored at 4°C for more than 9 months will contain metabolites that will alter and produce small molecule marker artifacts when compared to samples stored at -20°C. In conclusion, the developed method is a robust method of ZIC-HILIC mass spectrometry shotgun analysis suitable for urinary metabolome discovery of robust biomarkers

Primordial Magnetic Field Limits from Cosmic Microwave Background Bispectrum of Magnetic Passive Scalar Modes

Primordial magnetic fields lead to non-Gaussian signals in the cosmic microwave background (CMB) even at the lowest order, as magnetic stresses and the temperature anisotropy they induce depend quadratically on the magnetic field. In contrast, CMB non-Gaussianity due to inflationary scalar perturbations arises only as a higher order effect. Apart from a compensated scalar mode, stochastic primordial magnetic fields also produce scalar anisotropic stress that remains uncompensated till neutrino decoupling. This gives rise to an adiabatic-like scalar perturbation mode that evolves passively thereafter (called the passive mode). We compute the CMB reduced bispectrum ($b_{l_{_1}l_{_2}l_{_3}}$) induced by this passive mode, sourced via the Sachs-Wolfe effect, on large angular scales. For any configuration of bispectrum, taking a partial sum over mode-coupling terms, we find a typical value of $l_1(l_1+1)l_3(l_3+1) b_{l_{_1}l_{_2}l_{_3}} \sim 6-9 \times 10^{-16}$, for a magnetic field of $B_0 \sim 3$ nG, assuming a nearly scale-invariant magnetic spectrum . We also evaluate, in full, the bispectrum for the squeezed collinear configuration over all angular mode-coupling terms and find $l_1(l_1+1)l_3(l_3+1) b_{l_{_1}l_{_2}l_{_3}} \approx -1.4 \times 10^{-16}$. These values are more than $\sim 10^6$ times larger than the previously calculated magnetic compensated scalar mode CMB bispectrum. Observational limits on the bispectrum from WMAP7 data allow us to set upper limits of $B_0 \sim 2$ nG on the present value of the cosmic magnetic field of primordial origin. This is over 10 times more stringent than earlier limits on $B_0$ based on the compensated mode bispectrum.Comment: 9 page

Green Function Monte Carlo with Stochastic Reconfiguration

A new method for the stabilization of the sign problem in the Green Function Monte Carlo technique is proposed. The method is devised for real lattice Hamiltonians and is based on an iterative ''stochastic reconfiguration'' scheme which introduces some bias but allows a stable simulation with constant sign. The systematic reduction of this bias is in principle possible. The method is applied to the frustrated J1-J2 Heisenberg model, and tested against exact diagonalization data. Evidence of a finite spin gap for J2/J1 >~ 0.4 is found in the thermodynamic limit.Comment: 13 pages, RevTeX + 3 encapsulated postscript figure

Simvastatin improves the sexual health-related quality of life in men aged 40 years and over with erectile dysfunction : Additional data from the Erectile Dysfunction and Statin trial

© 2014 Trivedi et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background: Erectile dysfunction is prevalent in men over 40 years, affecting their quality of life and that of their partners. The aims of this study were:a)To evaluate the internal reliability of the male erectile dysfunction specific quality of life (MED-QoL) scale and explore its factor structure.b)To evaluate the effect of simvastatin on subscales of the MED-QoL in men over forty years with erectile dysfunction. Methods: This is a double blind randomised controlled trial of 40 mg simvastatin or placebo given once daily for six months to men over forty years with untreated erectile dysfunction, who were not at high cardiovascular risk and were not on anti-hypertensive or lipid-lowering medication. 173 eligible men were recruited from 10 general practices in East of England. Data were collected at two points over 30 weeks. We report on the factor structure of MED-QoL, the internal reliability of the scale and the derived subscales, and the effect of simvastatin on MED-QoL subscales. Results: An initial analysis of the MED-QoL items suggested that a number of items should be removed (MED-QoL-R). Exploratory factor analysis identified three subscales within the MED-QoL-R which accounted for 96% of the variance, related to feelings of Control, initiating Intimacy, and Emotional response to erectile dysfunction. The alpha value for the revised scale (MED-Qol-R) was >0.95 and exceeded .82 for each subscale. Regression analysis showed that patients in the placebo group experienced a significantly reduced feeling of Control over erectile dysfunction than those in the statin group. Those in the placebo group had significantly lower Emotional response than those in the statin group at the close of trial, but there was no significant treatment effect on Intimacy. Conclusions: Our revised MED-QoL-R identified three subscales. Secondary analysis showed a significant improvement in sexual health related quality of life, specifically in relation to perception of control and emotional health in men with untreated erectile dysfunction given 40 mg simvastatin for six months. Trial registration: Current Controlled Trials ISRCTN66772971.Peer reviewe

Phase II Proof-of-Concept Trial of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Major Depressive Disorder.

BackgroundWe evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder.MethodsWe conducted a 6-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with major depressive disorder (partial responders to ongoing antidepressant therapy) were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo.ResultsDue to enrollment challenges, the study was terminated early, resulting in insufficient statistical power to detect a prespecified treatment difference; of 326 patients planned, 129 (40%) were randomized and 128 took treatment. There was no statistically significant difference in the primary endpoint of change from baseline to week 6 in Montgomery Asberg Depression Rating Scale total score; the estimated treatment difference for filorexant-placebo was -0.7 (with negative values favoring filorexant) (P=.679). The most common adverse events were somnolence and suicidal ideation.ConclusionsThe interpretation of the results is limited by the enrollment, which was less than originally planned, but the available data do not suggest efficacy of orexin receptor antagonism with filorexant for the treatment of depression. (Clinical Trial Registry: clinicaltrials.gov: NCT01554176)

Cotransplantation of Adipose Tissue-Derived Insulin-Secreting Mesenchymal Stem Cells and Hematopoietic Stem Cells: A Novel Therapy for Insulin-Dependent Diabetes Mellitus

Aims. Insulin dependent diabetes mellitus (IDDM) is believed to be an autoimmune disorder with disturbed glucose/insulin metabolism, requiring life-long insulin replacement therapy (IRT), 30% of patients develop end-organ failure. We present our experience of cotransplantation of adipose tissue derived insulin-secreting mesenchymal stem cells (IS-AD-MSC) and cultured bone marrow (CBM) as IRT for these patients. Methods. This was a prospective open-labeled clinical trial to test efficacy and safety of IS-AD-MSC+CBM co-transplantation to treat IDDM, approved by the institutional review board after informed consent in 11 (males : females: 7 : 4) patients with 1–24-year disease duration, in age group: 13–43 years, on mean values of exogenous insulin requirement of 1.14 units/kg BW/day, glycosylated hemoglobin (Hb1Ac): 8.47%, and c-peptide levels: 0.1 ng/mL. Intraportal infusion of xenogeneic-free IS-AD-MSC from living donors, subjected to defined culture conditions and phenotypically differentiated to insulin-secreting cells, with mean quantum: 1.5 mL, expressing Pax-6, Isl-1, and pdx-1, cell counts: 2.1 × 103/μL, CD45−/90+/73+:40/30.1%, C-Peptide level:1.8 ng/mL, and insulin level: 339.3  IU/mL with CBM mean quantum: 96.3 mL and cell counts: 28.1 × 103/μL, CD45−/34+:0.62%, was carried out. Results. All were successfully transplanted without any untoward effect. Over mean followup of 23 months, they had a decreased mean exogenous insulin requirement to 0.63 units/kgBW/day, Hb1Ac to 7.39%, raised serum c-peptide levels to 0.38 ng/mL, and became free of diabetic ketoacidosis events with mean 2.5 Kg weight gain on normal vegetarian diet and physical activities. Conclusion. This is the first report of treating IDDM with insulin-secreting-AD-MSC+CBM safely and effectively with relatively simple techniques

Review article: the diagnostic approach and current management of chylous ascites

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138889/1/apt14284.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138889/2/apt14284_am.pd

Particle-Hole Symmetry and the Effect of Disorder on the Mott-Hubbard Insulator

Recent experiments have emphasized that our understanding of the interplay of electron correlations and randomness in solids is still incomplete. We address this important issue and demonstrate that particle-hole (ph) symmetry plays a crucial role in determining the effects of disorder on the transport and thermodynamic properties of the half-filled Hubbard Hamiltonian. We show that the low-temperature conductivity decreases with increasing disorder when ph-symmetry is preserved, and shows the opposite behavior, i.e. conductivity increases with increasing disorder, when ph-symmetry is broken. The Mott insulating gap is insensitive to weak disorder when there is ph-symmetry, whereas in its absence the gap diminishes with increasing disorder.Comment: 4 pages, 4 figure