Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. Methods Genetic testing was performed for 1404 relatives. Mutation-positive individuals were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload–induced calcium release activity of the mutant channel in HEK293 cells. Results We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD cases. No SCD was observed among treated mutation-positive individuals over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive individuals) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive individuals, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload–induced calcium release activity under conditions that mimic catecholaminergic stress. Conclusion Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation

Hysteroscopic Management of an Interstitial Ectopic Pregnancy

We report a case of an interstitial ectopic pregnancy successfully managed by hysteroscopy. We highlight the benefits of using hysteroscopy, a non-invasive procedure, to preserve fertility

Fusarium Mycotoxins and Metabolites that Modulate Their Production

The genus Fusarium is a group of fungi producing several types of toxins with toxicological effect in both humans and animals. Such fungi are commonly found in soils so it can contaminate various types of crops, preferably cereals, leading to significant economic losses. Relative humidity, storage temperature and various handling in cereales increase the possibility of contamination by Fusarium toxins. Cereals naturally have secondary metabolites that may help attenuate contamination by these toxins, but it is necessary to know strategies and mechanisms that generate inactivation mycotoxins. This chapter reviews relevant information about cereal mycotoxin contamination, as well as the production of cereal secondary metabolites as a strategy to reduce the possibility of mycotoxin contamination

A Study of the Near-Ultraviolet Spectrum of Vega

UV, optical, and near-IR spectra of Vega have been combined to test our understanding of stellar atmospheric opacities, and to examine the possibility of constraining chemical abundances from low-resolution UV fluxes. We have carried out a detailed analysis assuming Local Thermodynamic Equilibrium (LTE) to identify the most important contributors to the UV continuous opacity: H, H$^{-}$, C I, and Si II. Our analysis also assumes that Vega is spherically symmetric and its atmosphere is well described with the plane parallel approximation. Comparing observations and computed fluxes we have been able to discriminate between two different flux scales that have been proposed, the IUE-INES and the HST scales, favoring the latter. The effective temperature and angular diameter derived from the analysis of observed optical and near-UV spectra are in very good agreement with previous determinations based on different techniques. The silicon abundance is poorly constrained by the UV observations of the continuum and strong lines, but the situation is more favorable for carbon and the abundances inferred from the UV continuum and optical absorption lines are in good agreement. Some spectral intervals in the UV spectrum of Vega that the calculations do not reproduce well are likely affected by deviations from LTE, but we conclude that our understanding of UV atmospheric opacities is fairly complete for early A-type stars.Comment: 13 pages, 9 figures, to be published in Ap

Phosphoproteomic Landscape of AML Cells Treated with the ATP-Competitive CK2 Inhibitor CX-4945

Casein kinase 2 (CK2) regulates a plethora of proteins with pivotal roles in solid and hematological neoplasia. Particularly, in acute myeloid leukemia (AML) CK2 has been pointed as an attractive therapeutic target and prognostic marker. Here, we explored the impact of CK2 inhibition over the phosphoproteome of two cell lines representing major AML subtypes. Quantitative phosphoproteomic analysis was conducted to evaluate changes in phosphorylation levels after incubation with the ATP-competitive CK2 inhibitor CX-4945. Functional enrichment, network analysis, and database mining were performed to identify biological processes, signaling pathways, and CK2 substrates that are responsive to CX-4945. A total of 273 and 1310 phosphopeptides were found differentially modulated in HL-60 and OCI-AML3 cells, respectively. Despite regulated phosphopeptides belong to proteins involved in multiple biological processes and signaling pathways, most of these perturbations can be explain by direct CK2 inhibition rather than off-target effects. Furthermore, CK2 substrates regulated by CX-4945 are mainly related to mRNA processing, translation, DNA repair, and cell cycle. Overall, we evidenced that CK2 inhibitor CX-4945 impinge on mediators of signaling pathways and biological processes essential for primary AML cells survival and chemosensitivity, reinforcing the rationale behind the pharmacologic blockade of protein kinase CK2 for AML targeted therapy

Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen

High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of ‘hit’ compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a ‘hit’ molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target

FIGO best practice guidance in surgical consent

Obtaining medical consent preoperatively is one of the key steps in preparing for surgery, and is an important step in informed decision making with the patient. According to good medical practice guidelines, doctors are required to have the knowledge and skills to treat patients as well as inform them, respect their wishes, and establish trust between themselves and their patients. Valid consent includes elements of competence, disclosure, understanding, and voluntariness. Documentation of these elements is also very important. The International Federation of Gynecology and Obstetrics (FIGO) Education Communication and Advocacy Consortium (ECAC) has realized that the quality of consent varies considerably across the world and has developed simple guidelines regarding consent and procedure-specific checklists for the most common obstetric and gynecological procedures

Optimized detection of homologous recombination deficiency improves the prediction of clinical outcomes in cancer

Peer reviewe

Rates of Tuberculosis Infection in Healthcare Workers Providing Services to HIV-Infected Populations

Objective: To assess the prevalence of tuberculosis (TB) or a positive skin test in healthcare workers (HCWs) providing services to human immunodeficiency virus (HIV)-infected individuals and to determine prospectively the incidence of new infections in this population. Design: This prospective cohort study enrolled 1,014 HCWs working with HIV-infected populations from 10 metropolitan areas. Purified protein derivative (PPD) tuberculin skin tests were placed at baseline and every 6 months afterwards on those without a history of TB or a positive PPD. Demographic, occupational, and TB exposure data also were collected. Setting: Outpatient clinics, hospitals, private practice offices, and drug treatment programs providing HIV-related healthcare and research programs. Participants: A voluntary sample of staff and volunteers from 16 Community Programs for Clinical Research on AIDS units. Results: Factors related to prior TB or a positive skin test at baseline included being foreign-born, increased length of time in health care, living in New York City, or previous bacille Calmette-Guerín vaccination. The rate of PPD conversion was 1.8 per 100 person years of follow-up. No independent relation was found between the amount or type of contact with HIV-infected populations and the risk of TB infection. Conclusion: These data provide some reassurance that caring for HIV-infected patients is not related to an increased rate ofTB infection among HCWs in these settings

Phase behaviour of Ag2CrO4 under compression: Structural, vibrational, and optical properties

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Physical Chemistry C, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jp401524sWe have performed an experimental study of the crystal structure, lattice dynamics, and optical properties of silver chromate (Ag2CrO4) at ambient temperature and high pressures. In particular, the crystal structure, Raman-active phonons, and electronic band gap have been accurately determined. When the initial orthorhombic Pnma Ag2CrO4 structure (phase I) is compressed up to 4.5 GPa, a previously undetected phase (phase II) has been observed with a 0.95% volume collapse. The structure of phase II can be indexed to a similar orthorhombic cell as phase I, and the transition can be considered to be an isostructural transition. This collapse is mainly due to the drastic contraction of the a axis (1.3%). A second phase transition to phase III occurs at 13 GPa to a structure not yet determined. First-principles calculations have been unable to reproduce the isostructural phase transition, but they propose the stabilization of a spinel-type structure at 11 GPa. This phase is not detected in experiments probably because of the presence of kinetic barriers. Experiments and calculations therefore seem to indicate that a new structural and electronic description is required to model the properties of silver chromate.This study was supported by the Spanish government MEC under grants MAT2010-21270-C04-01/03/04 and CTQ2009-14596-C02-01, by the Comunidad de Madrid and European Social Fund (S2009/PPQ1551 4161893), by the MALTA Consolider Ingenio 2010 project (CSD2007-00045), and by the Vicerrectorado de Investigacion y Desarrollo of the Universidad Politecnica de Valencia (UPV2011-0914 PAID-05-11 and UPV2011-0966 PAID-06-11). A.M. and P.R.-H. acknowledge computing time provided by Red Espanola de Supercomputacion (RES) and MALTA-Cluster. J.A.S. acknowledges Juan de la Cierva Fellowship Program for its financial support. Diamond and ALBA Synchrotron Light Sources are acknowledged for provisions of beam time. We also thank Drs. Peral, Popescu, and Fauth for technical support.Santamaría Pérez, D.; Bandiello, E.; Errandonea, D.; Ruiz-Fuertes, J.; Gomis Hilario, O.; Sans, JÁ.; Manjón Herrera, FJ.... (2013). Phase behaviour of Ag2CrO4 under compression: Structural, vibrational, and optical properties. Journal of Physical Chemistry C. 117(23):12239-12248. https://doi.org/10.1021/jp401524sS12239122481172