Genetic steps to organ laterality in zebrafish.

All internal organs are asymmetric along the left-right axis. Here we report a genetic screen to discover mutations which perturb organ laterality. Our particular focus is upon whether, and how, organs are linked to each other as they achieve their laterally asymmetric positions. We generated mutations by ENU mutagenesis and examined F3 progeny using a cocktail of probes that reveal early primordia of heart, gut, liver and pancreas. From the 750 genomes examined, we isolated seven recessive mutations which affect the earliest left-right positioning of one or all of the organs. None of these mutations caused discernable defects elsewhere in the embryo at the stages examined. This is in contrast to those mutations we reported previously (Chen et al., 1997) which, along with left-right abnormalities, cause marked perturbation in gastrulation, body form or midline structures. We find that the mutations can be classified on the basis of whether they perturb relationships among organ laterality. In Class 1 mutations, none of the organs manifest any left-right asymmetry. The heart does not jog to the left and normally leftpredominant BMP4 in the early heart tube remains symmetric. The gut tends to remain midline. There frequently is a remarkable bilateral duplication of liver and pancreas. Embryos with Class 2 mutations have organotypic asymmetry but, in any given embryo, organ positions can be normal, reversed or randomized. Class 3 reveals a hitherto unsuspected gene that selectively affects laterality of heart. We find that visceral organ positions are predicted by the direction of the preceding cardiac jog. We interpret this as suggesting that normally there is linkage between cardiac and visceral organ laterality. Class 1 mutations, we suggest, effectively remove the global laterality signals, with the consequence that organ positions are effectively symmetrical. Embryos with Class 2 mutations do manifest linkage among organs, but it may be reversed, suggesting that the global signals may be present but incorrectly orientated in some of the embryos. That laterality decisions of organs may be independently perturbed, as in the Class 3 mutation, indicates that there are distinctive pathways for reception and organotypic interpretation of the global signals

On the Legendre differential equation with uncertainties at the regular-singular point 1: Lp random power series solution and approximation of its statistical moments

"This is the peer reviewed version of the following article: Calatayud, J, Cortés, J-;C, Jornet, M. On the Legendre differential equation with uncertainties at the regular-singular point 1: Lp random power series solution and approximation of its statistical moments. Comp and Math Methods. 2019; 1:e1045. https://doi.org/10.1002/cmm4.1045 , which has been published in final form at https://doi.org/10.1002/cmm4.1045. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] In this paper, we construct two linearly independent response processes to the random Legendre differential equation on (-1,1)U(1,3), consisting of Lp(omega) convergent random power series around the regular¿singular point 1. A theorem on the existence and uniqueness of Lp(omega) solution to the random Legendre differential equation on the intervals (-1,1) and (1,3) is obtained. The hypotheses assumed are simple: initial conditions in Lp(omega) and random input A in L infinite(omega) (this is equivalent to A having absolute moments that grow at most exponentially). Thus, this paper extends the deterministic theory to a random framework. Uncertainty quantification for the solution stochastic process is performed by truncating the random series and taking limits in Lp(omega). In the numerical experiments, we approximate its expectation and variance for certain forms of the differential equation. The reliability of our approach is compared with Monte Carlo simulations and generalized polynomial chaos expansions.Spanish Ministerio de Economía y Competitividad, Grant/Award Number: MTM2017-89664-P; Programa de Ayudas de Investigación y Desarrollo; Universitat Politècnica de ValènciaCalatayud-Gregori, J.; Cortés, J.; Jornet-Sanz, M. (2019). On the Legendre differential equation with uncertainties at the regular-singular point 1: Lp random power series solution and approximation of its statistical moments. Computational and Mathematical Methods. 1(4):1-12. https://doi.org/10.1002/cmm4.1045S11214Calbo, G., Cortés, J.-C., Jódar, L., & Villafuerte, L. (2011). Solving the random Legendre differential equation: Mean square power series solution and its statistical functions. Computers & Mathematics with Applications, 61(9), 2782-2792. doi:10.1016/j.camwa.2011.03.045Villafuerte, L., Braumann, C. A., Cortés, J.-C., & Jódar, L. (2010). Random differential operational calculus: Theory and applications. Computers & Mathematics with Applications, 59(1), 115-125. doi:10.1016/j.camwa.2009.08.061Wong, E., & Hajek, B. (1985). Stochastic Processes in Engineering Systems. Springer Texts in Electrical Engineering. doi:10.1007/978-1-4612-5060-9Nouri, K., & Ranjbar, H. (2014). Mean Square Convergence of the Numerical Solution of Random Differential Equations. Mediterranean Journal of Mathematics, 12(3), 1123-1140. doi:10.1007/s00009-014-0452-8Lupulescu, V., O’Regan, D., & ur Rahman, G. (2014). Existence results for random fractional differential equations. Opuscula Mathematica, 34(4), 813. doi:10.7494/opmath.2014.34.4.813Villafuerte, L., & Chen-Charpentier, B. M. (2012). A random differential transform method: Theory and applications. Applied Mathematics Letters, 25(10), 1490-1494. doi:10.1016/j.aml.2011.12.033Licea, J. A., Villafuerte, L., & Chen-Charpentier, B. M. (2013). Analytic and numerical solutions of a Riccati differential equation with random coefficients. Journal of Computational and Applied Mathematics, 239, 208-219. doi:10.1016/j.cam.2012.09.040Lang, S. (1997). Undergraduate Analysis. Undergraduate Texts in Mathematics. doi:10.1007/978-1-4757-2698-5Cortés, J.-C., Romero, J.-V., Roselló, M.-D., Santonja, F.-J., & Villanueva, R.-J. (2013). Solving Continuous Models with Dependent Uncertainty: A Computational Approach. Abstract and Applied Analysis, 2013, 1-10. doi:10.1155/2013/983839Calatayud, J., Cortés, J. C., Jornet, M., & Villanueva, R. J. (2018). Computational uncertainty quantification for random time-discrete epidemiological models using adaptive gPC. Mathematical Methods in the Applied Sciences, 41(18), 9618-9627. doi:10.1002/mma.531

Local and global modes of drug action in biochemical networks

It becomes increasingly accepted that a shift is needed from the traditional target-based approach of drug development to an integrated perspective of drug action in biochemical systems. We here present an integrative analysis of the interactions between drugs and metabolism based on the concept of drug scope. The drug scope represents the set of metabolic compounds and reactions that are potentially affected by a drug. We constructed and analyzed the scopes of all US approved drugs having metabolic targets. Our analysis shows that the distribution of drug scopes is highly uneven, and that drugs can be classified into several categories based on their scopes. Some of them have small scopes corresponding to localized action, while others have large scopes corresponding to potential large-scale systemic action. These groups are well conserved throughout different topologies of the underlying metabolic network. They can furthermore be associated to specific drug therapeutic properties

Long-Term Opioid Contract Use for Chronic Pain Management in Primary Care Practice. A Five Year Experience

BACKGROUND: The use of opioid medications to manage chronic pain is complex and challenging, especially in primary care settings. Medication contracts are increasingly being used to monitor patient adherence, but little is known about the long-term outcomes of such contracts. OBJECTIVE: To describe the long-term outcomes of a medication contract agreement for patients receiving opioid medications in a primary care setting. DESIGN: Retrospective cohort study. SUBJECTS: All patients placed on a contract for opioid medication between 1998 and 2003 in an academic General Internal Medicine teaching clinic. MEASUREMENTS: Demographics, diagnoses, opiates prescribed, urine drug screens, and reasons for contract cancellation were recorded. The association of physician contract cancellation with patient factors and medication types were examined using the Chi-square test and multivariate logistic regression. RESULTS: A total of 330 patients constituting 4% of the clinic population were placed on contracts during the study period. Seventy percent were on indigent care programs. The majority had low back pain (38%) or fibromyalgia (23%). Contracts were discontinued in 37%. Only 17% were cancelled for substance abuse and noncompliance. Twenty percent discontinued contract voluntarily. Urine toxicology screens were obtained in 42% of patients of whom 38% were positive for illicit substances. CONCLUSIONS: Over 60% of patients adhered to the contract agreement for opioids with a median follow-up of 22.5 months. Our experience provides insight into establishing a systematic approach to opioid administration and monitoring in primary care practices. A more structured drug testing strategy is needed to identify nonadherent patients

The clinical features of the piriformis syndrome: a systematic review

Piriformis syndrome, sciatica caused by compression of the sciatic nerve by the piriformis muscle, has been described for over 70 years; yet, it remains controversial. The literature consists mainly of case series and narrative reviews. The objectives of the study were: first, to make the best use of existing evidence to estimate the frequencies of clinical features in patients reported to have PS; second, to identify future research questions. A systematic review was conducted of any study type that reported extractable data relevant to diagnosis. The search included all studies up to 1 March 2008 in four databases: AMED, CINAHL, Embase and Medline. Screening, data extraction and analysis were all performed independently by two reviewers. A total of 55 studies were included: 51 individual and 3 aggregated data studies, and 1 combined study. The most common features found were: buttock pain, external tenderness over the greater sciatic notch, aggravation of the pain through sitting and augmentation of the pain with manoeuvres that increase piriformis muscle tension. Future research could start with comparing the frequencies of these features in sciatica patients with and without disc herniation or spinal stenosis

Receptor Tyrosine Kinase (RTK) Mediated Tyrosine Phosphor-Proteome from Drosophila S2 (ErbB1) Cells Reveals Novel Signaling Networks

Protein phosphorylation mediates many critical cellular responses and is essential for many biological functions during development. About one-third of cellular proteins are phosphorylated, representing the phosphor-proteome, and phosphorylation can alter a protein's function, activity, localization and stability. Tyrosine phosphorylation events mediated by aberrant activation of Receptor Tyrosine Kinase (RTK) pathways have been proven to be involved in the development of several diseases including cancer. To understand the systems biology of RTK activation, we have developed a phosphor-proteome focused on tyrosine phosphorylation events under insulin and EGF signaling pathways using the PhosphoScan® technique coupled with high-throughput mass spectrometry analysis. Comparative proteomic analyses of all these tyrosine phosphorylation events revealed that around 70% of these pY events are conserved in human orthologs and paralogs. A careful analysis of published in vivo tyrosine phosphorylation events from literature and patents revealed that around 38% of pY events from Drosophila proteins conserved on 185 human proteins are confirmed in vivo tyrosine phosphorylation events. Hence the data are validated partially based on available reports, and the credibility of the remaining 62% of novel conserved sites that are unpublished so far is very high but requires further follow-up studies. The novel pY events found in this study that are conserved on human proteins could potentially lead to the discovery of drug targets and biomarkers for the detection of various cancers and neurodegenerative diseases

A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity

BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up