Recent work has described the software engineering and computational infrastructure that has been set up as part of the Cancer, Heart and Soft Tissue Environment (Chaste) project. Chaste is an open ...source software package that currently has heart and cancer modelling functionality. This software has been written using a programming paradigm imported from the commercial sector and has resulted in a code that has been subject to a far more rigorous testing procedure than that is usual in this field. In this paper, we explain how new functionality may be incorporated into Chaste. Whiteley has developed a numerical algorithm for solving the bidomain equations that uses the multi-scale (MS) nature of the physiology modelled to enhance computational efficiency. Using a simple geometry in two dimensions and a purpose-built code, this algorithm was reported to give an increase in computational efficiency of more than two orders of magnitude. In this paper, we begin by reviewing numerical methods currently in use for solving the bidomain equations, explaining how these methods may be developed to use the MS algorithm discussed above. We then demonstrate the use of this algorithm within the Chaste framework for solving the monodomain and bidomain equations in a three-dimensional realistic heart geometry. Finally, we discuss how Chaste may be developed to include new physiological functionality-such as modelling a beating heart and fluid flow in the heart-and how new algorithms aimed at increasing the efficiency of the code may be incorporated.
Cardiac metabolism is critical for the functioning of the heart, and disturbance in this homeostasis is likely to influence cardiac disorders or cardiomyopathy. Our laboratory has previously shown ...that SNRK (sucrose nonfermenting related kinase) enzyme, which belongs to the AMPK (adenosine monophosphate-activated kinase) family, was essential for cardiac metabolism in mammals. Snrk global homozygous knockout (KO) mice die at postnatal day 0, and conditional deletion of Snrk in cardiomyocytes (Snrk cmcKO) leads to cardiac failure and death by 8 to 10 months.
We performed additional cardiac functional studies using echocardiography and identified further cardiac functional deficits in Snrk cmcKO mice. Nuclear magnetic resonance-based metabolomics analysis identified key metabolic pathway deficits in SNRK knockdown cardiomyocytes in vitro. Specifically, metabolites involved in lipid metabolism and oxidative phosphorylation are altered, and perturbations in these pathways can result in cardiac function deficits and heart failure. A phosphopeptide-based proteomic screen identified ROCK (Rho-associated kinase) as a putative substrate for SNRK, and mass spec-based fragment analysis confirmed key amino acid residues on ROCK that are phosphorylated by SNRK. Western blot analysis on heart lysates from Snrk cmcKO adult mice and SNRK knockdown cardiomyocytes showed increased ROCK activity. In addition, in vivo inhibition of ROCK partially rescued the in vivo Snrk cmcKO cardiac function deficits.
Collectively, our data suggest that SNRK in cardiomyocytes is responsible for maintaining cardiac metabolic homeostasis, which is mediated in part by ROCK, and alteration of this homeostasis influences cardiac function in the adult heart.
Summary
Background
Limited data exist on transitioning patients with psoriasis from conventional systemic agents to biologics.
Objectives
The TRANSIT study aimed to assess the efficacy and safety of ...two methotrexate‐to‐ustekinumab transition strategies.
Methods
Patients with moderate‐to‐severe psoriasis and inadequate methotrexate response were randomized 1 : 1 to receive ustekinumab with immediate (arm 1) or 4‐week gradual (arm 2) methotrexate withdrawal. Patients weighing ≤ 100 kg or > 100 kg received ustekinumab 45 mg or 90 mg, respectively. The primary endpoint was the frequency of adverse events (AEs) at week 12. Secondary endpoints included additional safety, efficacy and patient‐reported outcomes. We report the 12‐week efficacy and safety results.
Results
Overall, 244 patients in arm 1 and 245 in arm 2 were randomized and received ustekinumab. Four patients per arm discontinued the trial by week 12. At week 12 in arms 1 and 2, respectively, 61% and 65% of patients experienced an AE, 2·9% and 2·4% had a serious AE, and 1·2% and 0·4% had an AE leading to ustekinumab discontinuation. In arms 1 and 2, respectively, median Psoriasis Area and Severity Index (PASI) score decreased from 15·2 and 15·4 at baseline to 2·9 and 2·8 at week 12; 58% and 62% of patients achieved a 75% reduction from baseline in PASI score (PASI 75) at week 12; median baseline Dermatology Life Quality Index fell from 8 and 9 at baseline to 1 (both arms) at week 16.
Conclusions
Ustekinumab was well tolerated and effective in patients who had an inadequate response to methotrexate. Both transition strategies resulted in similar week 12 safety and efficacy outcomes.
What's already known about this topic?
In patients with moderate‐to‐severe psoriasis, biologics are recommended for use after conventional systemic agents have failed, or in patients for whom they are not suitable.
There are limited data on how to transition patients from conventional systemic treatment to biologics.
What does this study add?
In patients with an inadequate response to methotrexate, similar efficacy and safety/tolerability outcomes were observed at week 12 after initiating ustekinumab, irrespective of whether methotrexate was immediately or gradually withdrawn. Therefore, immediate transitioning from methotrexate to ustekinumab can be recommended and a washout period is not needed.
No adverse safety or efficacy effects were noted after overlapping ustekinumab and methotrexate treatment for up to 1 month.
Resumen Metotrexato (MTX) es el fármaco sistémico convencional más empleado en el tratamiento de la psoriasis. A pesar de que la experiencia en su uso se remonta a más de 50 años, todavía existen ...aspectos en el manejo clínico poco estandarizados o conocidos. Bajo esta premisa, un grupo de 15 expertos participó en una conferencia de consenso en la que, a partir de una revisión sistemática y 2 rondas de validación previas, se validaron recomendaciones categorizadas por nivel de evidencia y grado de recomendación sobre el uso de MTX en la psoriasis. La elección de MTX en el tratamiento de la psoriasis moderada grave requiere la evaluación previa de la idoneidad del fármaco, incluyendo estado de vacunación, cribado de tuberculosis y gestación. La dosis recomendada de inicio es de 10-20 mg/semana si el paciente no presenta factores de riesgo, con una dosis terapéutica de 15 mg/semana para la mayoría de pacientes y máxima de 20 mg/semana. La mayor parte de pacientes que respondan al tratamiento mostrarán mejoría antes de las 8 semanas. Es preferible la administración parenteral de MTX cuando exista riesgo de error en la pauta de administración, incumplimiento, intolerancia gastrointestinal o respuesta insuficiente a dosis plenas por vía oral. Los métodos no invasivos son preferibles para la monitorización de la hepatotoxicidad. El tratamiento con MTX representa una buena opción en pacientes con antecedentes oncológicos, mientras que no se recomienda en pacientes portadores crónicos de virus de la hepatitis B o seropositivos para el virus de la inmunodeficiencia humana (VIH+).
Abstract Methotrexate (MTX) is the most frequently used conventional systemic drug in the treatment of psoriasis. Despite over 50 years of experience in this setting, certain aspects of the use of ...this drug in clinical practice are still little standardized and poorly understood. For this reason, a group of 15 experts took part in a consensus development conference to achieve consensus on a series of recommendations on the use of MTX in psoriasis. The guidelines, which were developed on the basis of a systematic review of the literature, were validated by 2 rounds of voting and categorized by level of evidence and grade of recommendation. Before MTX can be used to treat moderate to severe psoriasis, the patient must be evaluated to assess the suitability of the treatment, including consideration of vaccination status and screening for tuberculosis and pregnancy. The recommended starting dose for a patient with no risk factors is 10 to 20 mg/wk, the therapeutic dose for most patients is 15 mg/wk, and the maximum dose is 20 mg/wk. Most patients who respond to treatment will show improvement within 8 weeks. Parenteral administration of MTX is desirable when there is a risk of erroroneous dosing, nonadherence, gastrointestinal intolerance, or inadequate response to the therapeutic dose taken orally. Noninvasive methods are preferred for monitoring hepatotoxicity. MTX is a good treatment option for patients with a history of cancer, but is not recommended in patients with chronic hepatitis B infection or individuals who are seropositive for human immunodeficiency virus.
A series of 6-heteroaryl-pyrazolo3,4-
bpyridines has been optimised to afford potent inhibitors of Glycogen Synthase Kinase-3 (GSK-3). These analogues display excellent selectivity over the closely ...related Cyclin Dependant Kinase-2 (CDK-2).
Selectivity profiling of a series of 6-aryl-pyrazolo3,4-
bpyridines, revealed significant inhibition of CDK-2. Optimisation of this nucleus to exploit nonconserved interations led to the identification of a potent and selective series of 6-heteroaryl-pyrazolo3,4-
bpyridines.
The orientational behavior of microtubules assembled in strong magnetic fields has been studied. It is shown that when microtubules are assembled in a magnetic field, they align with their long axis ...parallel to the magnetic field. The effect of several parameters known to affect the microtubule assembly are investigated with respect to their effect on the final degree of alignment. Aligned samples of hydrated microtubules suitable for low-resolution x-ray fiber diffraction experiments have been produced, and the results obtained from the fiber diffraction experiments have been compared with the magnetic birefringence experiments. Comparisons with earlier fiber diffraction work and small-angle x-ray solution scattering experiments have been made.
Attosecond time delays in C 60 valence photoemissions at the giant plasmon Barillot, T; Magrakvelidze, M; Loriot, V ...
29th International Conference on Photonic, Electronic, and Atomic Collisions (ICPEAC),Toledo, Spain,2015-07-22 - 2015-07-28,
01/2015, Letnik:
635, Številka:
11
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
We perform time-dependent local density functional calculations of the time delay in C60 HOMO and HOMO-1 photoionization at giant plasmon energies. A semiclassical model is used to develop further ...insights.
Following hatching, pre-elongated conceptuses undergo elongation by intense proliferation, until implantation. We investigated
the changes in gene expression associated with these physiological ...events using human cDNA arrays containing 2370 known genes.
Comparison of pre-elongated, elongated, and implanting trophoblasts allowed the determination of 313 expressed genes, 63 of
which were differentially regulated. These were classified into four functional families. Pre-elongated trophoblasts were
characterized by preferential expression of genes involved in protein trafficking, whereas only latter developmental stages
expressed cell signaling genes and receptors. Among the 63 developmentally regulated genes, four exhibited the highest levels
of expression ( TMSB10, CTNNA1, NMP1, and CX3CL1 ). Each of these also represents a functional family and display a specific expression pattern. One of them, CX3CL1 (CX3C chemokine, also known as fractalkine), is a chemokine that seems to have potential importance in trophoblast development,
and which deserves further clarification of its role in implantation.
Abstract
The pre-elongated, elongated, and implanting ovine trophoblasts display a differential transcriptome
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