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Enhancer of zeste homolog 2 (EZH2), the core component of the polycomb group complex, plays a major role in normal hematopoiesis. The molecular function of EZH2 is to establish H3K27me3 mark on specific genes by which promotes transcriptional repression of target genes. The activity of EZH2 affects the balance between self-renewal and differentiation of hematopoietic stem cells. In addition, EZH2 contributes to the cell cycle regulation in mature lymphocytes. A large number of studies have been performed to identify the implication of EZH2 in tumor development of leukemia. Aberrant expression of EZH2 is increasingly recognized in leukemic malignancies. To clarify its therapeutic potential in hematopoietic malignancies it should be determined whether EZH2 is involved in the pathology of these neoplasms. This paper reviews the current knowledge of the role of EZH2 in the pathogenesis of myeloid and lymphoid leukemia. We will discuss the mechanisms in which microRNAs regulate the expression of EZH2 in different types of leukemias that may provide a means to alter cancer epigenetics associated to tumorogenesis to achieve therapeutic benefits., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Tsukamurella is an aerobic, Gram-positive and nonmotile bacterium. It was first isolated in 1941 from the mycetoma and ovaries of the bedbug. The primary strains were named Corynebacterium paurometabolum and Gordona aurantiaca and are different from the Collins et al. , 1988 classification of the new Tsukamurella genus. Human infections with Tsukamurella species are rare because the species is a kind of saprophyte bacterium; however, most information regarding this species comes from case reports. Molecular markers for the identification Tsukamurella include sequencing of 16S rRNA, groEL, rpoB, secA1 and ssrA genes. Given the lack of information on the treatment of Tsukamurella infections, a combination of various antibiotic agents is recommended.

This study aimed to determine the frequency and pattern of complementary and alternative medicine (CAM) use in thalassemia patients in south of Iran. The survey was done using a validated questionnaire which was distributed among 122 thalassemia patients. Only 108 questionnaires were completed and turned back (response rate 88.5%). Patients referred to an outpatient thalassemia clinic in Shiraz, southern Iran for blood transfusion. The mean age of the patients was 22.9 ± 7.9 years (range 4-45 years) with female/male ratio 1.84. Seventy four (68.5%) of the responders used CAM at least once during their life, and about half of them used it concurrently with their conventional treatments. The most reported CAM product was mint juice (50%). The most common reason of CAM use was increased general health. The most common information source about CAM was physicians who were the most trusted source as well. CAM is frequently being used in thalassemia patients to ensure their sense of well-being and help them overcome the complications of their illnesses.

Computational models of many aspects of the mammalian cardiovascular circulation have been developed. Indeed, along with orthopaedics, this area of physiology is one that has attracted much interest from engineers, presumably because the equations governing blood flow in the vascular system are well understood and can be solved with well-established numerical techniques. Unfortunately, there have been only a few attempts to create a comprehensive public domain resource for cardiovascular researchers. In this paper we propose a roadmap for developing an open source cardiovascular circulation model. The model should be registered to the musculo-skeletal system. The computational infrastructure for the cardiovascular model should provide for near real-time computation of blood flow and pressure in all parts of the body. The model should deal with vascular beds in all tissues, and the computational infrastructure for the model should provide links into CellML models of cell function and tissue function. In this work we review the literature associated with 1D blood flow modelling in the cardiovascular system, discuss model encoding standards, software and a model repository. We then describe the coordinate systems used to define the vascular geometry, derive the equations and discuss the implementation of these coupled equations in the open source computational software OpenCMISS. Finally, some preliminary results are presented and plans outlined for the next steps in the development of the model, the computational software and the graphical user interface for accessing the model., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Background: Thalassemia is a chronic, inherited blood disorder, which in its most severe form, causes life-threatening anemia. Thalassemia patients not only engage with difficulties of blood transfusion and iron chelating therapy but also have some social challenges and health threatening factors. There are some reports on quality of life in thalassemia patients around the world from southeast of Asia to Italy in Europe and United States. In this study, we tried to evaluate and compare Health Related Quality of life (HRQoL) and the health utility in beta thalassemia major patients receiving different types of iron chelators and living in different socio-economical situations. Subjects and Methods: EQ-5D-3L accompanied by a Visual Analogue Scale (VAS) questionnaire was used. The respondents were patients with beta thalassemia major that were at least 12 years old selected from 3 provinces of Sistan-Blouchestan, Fars and Mazandaran. Comorbidities including heart complication, Diabetes Mellitus and Hepatitis and also types of iron chelators (oral, injection, combination of both) were also asked. Cross tab and ANOVA analysis conducted to evaluate each dimension score and health utility differences between provinces, iron chelation methods, comorbidities, age group and gender. Results: 528 patients answered the questionnaires. The health utility of patients that received oral iron chelator were 0.87 ± .01 for oral iron chelators versus 0.81 ± .01 for injection dosage form (p<0.05). Increase in age was accompanied by decrease in health utility. Females faced more usual activity problems, anxiety and depression. Heart problems were more prevalent in males. Conclusion: This study suggests that the quality of life of beta thalassemia major patients is dependent on type of iron chelation treatment which they received, the gender they have, the comorbidities they suffer and socio-economical situations they live in.

Objectives: The survival rate of thalassemia patients has not been conclusively established, and the factors associated with survival remain unclear. This study aimed to determine the survival rate of thalassemia among patients in southern Iran and to identify the factors associated with mortality from thalassemia., Methods: This retrospective cohort study was conducted based on a retrospective review of the medical records of 911 beta-thalassemia patients in 2014. Data analysis was conducted using the Kaplan-Meier method and Cox regression analysis., Results: Overall, 212 patients (23.3%) died, and 26.8% had thalassemia intermedia. The 20-year, 40-year, and 60-year survival rates were 85%, 63%, and 54%, respectively. Both crude and adjusted analyses found that education, marital status, ferritin levels, and comorbidities were related to mortality., Conclusions: Sociodemographic and hematological factors were found to be significantly associated with the survival rate of thalassemia. Addressing these factors may help healthcare providers and physicians to provide the best possible care and to improve the survival rate.

Background: Hepcidin is a key regulator of iron absorption in humans. It is mainly affected by hypoxia and iron stores., Objectives: The current study aimed to determine the correlation between serum hepcidin and ferritin levels in patients with Thalassemia Major (TM) and Thalassemia Intermedia (TI)., Patients and Methods: The current cross-sectional study investigated 88 randomly selected patients with Thalassemia, 48 TM and 40 TI, registered at the Thalassemia Clinic of Shiraz University of Medical Sciences, a referral center for Thalassemia in Southern Iran in 2013. All patients with TI were receiving Hydroxyurea (HU) 10 - 15 mg/kg/day for at least 10 years. The serum hepcidin, ferritin levels, hemoglobin (Hb) and nucleated Red Blood Cell (RBC) of the two groups were measured., Results: No statistically significant correlation was observed between serum hepcidin and ferritin levels in any of the two groups of patients with TM (rs = 0.02, P = 0.892) or TI (rs = 0.055, P = 0.734). The median Interquartile Range (IQR) for serum hepcidin and ferritin levels were significantly higher in TM compared to TI group, (hepcidin: 87.6 (43.9) vs. 51.8 (23.4), P < 0.001; ferritin: 2208 (3761) vs. 465 (632), P < 0.001)., Conclusions: There was insignificant correlation between serum hepcidin and ferritin levels in the two groups of patients with TM and TI. It seems that regulation of hepcidin in patients with Thalassemia is more affected by erythropoeitic activity than iron stores. Also, hepcidin levels were significantly higher in patients with TM than TI, possibly due to higher erythropoeitic activity in TI. In TI, it seems that low dose HU increases Hb levels and leads to transfusion-independence, but it is not high enough to suppress bone marrow activity and ineffective erythropoiesis. Consequently, serum hepcidin level decreases.

A key challenge for the physiology modeling community is to enable the searching, objective comparison and, ultimately, re-use of models and associated data that are interoperable in terms of their physiological meaning. In this work, we outline the development of a workflow to modularize the simulation of tissue-level processes in physiology. In particular, we show how, via this approach, we can systematically extract, parcellate and annotate tissue histology data to represent component units of tissue function. These functional units are semantically interoperable, in terms of their physiological meaning. In particular, they are interoperable with respect to [i] each other and with respect to [ii] a circuitboard representation of long-range advective routes of fluid flow over which to model long-range molecular exchange between these units. We exemplify this approach through the combination of models for physiology-based pharmacokinetics and pharmacodynamics to quantitatively depict biological mechanisms across multiple scales. Links to the data, models and software components that constitute this workflow are found at http://open-physiology.org/.

OpenCMISS is an open-source modeling environment aimed, in particular, at the solution of bioengineering problems. OpenCMISS consists of two main parts: a computational library (OpenCMISS-Iron) and a field manipulation and visualization library (OpenCMISS-Zinc). OpenCMISS is designed for the solution of coupled multi-scale, multi-physics problems in a general-purpose parallel environment. CellML is an XML format designed to encode biophysically based systems of ordinary differential equations and both linear and non-linear algebraic equations. A primary design goal of CellML is to allow mathematical models to be encoded in a modular and reusable format to aid reproducibility and interoperability of modeling studies. In OpenCMISS, we make use of CellML models to enable users to configure various aspects of their multi-scale physiological models. This avoids the need for users to be familiar with the OpenCMISS internal code in order to perform customized computational experiments. Examples of this are: cellular electrophysiology models embedded in tissue electrical propagation models; material constitutive relationships for mechanical growth and deformation simulations; time-varying boundary conditions for various problem domains; and fluid constitutive relationships and lumped-parameter models. In this paper, we provide implementation details describing how CellML models are integrated into multi-scale physiological models in OpenCMISS. The external interface OpenCMISS presents to users is also described, including specific examples exemplifying the extensibility and usability these tools provide the physiological modeling and simulation community. We conclude with some thoughts on future extension of OpenCMISS to make use of other community developed information standards, such as FieldML, SED-ML, and BioSignalML. Plans for the integration of accelerator code (graphical processing unit and field programmable gate array) generated from CellML models is also discussed.

Because of insufficient erythropoiesis, peripheral hemolysis and increased gastrointestinal iron absorption, iron overload is still a matter of debate in β-thalassemia intermedia (β-TI) patients, which can be overcome using iron chelators. However, data on use of iron chelators in β-TI patients is highly restricted. The aim of this study was to evaluate the efficacy of oral administration of deferasirox (Exjade(®) or DFX) by assessment of serum ferritin levels in β-TI patients. In this quasi-experimental study, 50 β-TI patients with serum ferritin levels >1000 ng/mL were selected and received oral DFX for 12 consecutive months. Iron overload was measured by checking serum ferritin levels every 2 months and the results were compared with the baseline level. The mean serum ferritin was decreased during 1 year of chelation therapy without any toxic effect. Although the difference between baseline ferritin and ferritin levels at the end of second month was not remarkable (p = 0.88), a significant reduction in serum ferritin was observed after 4 (p = 0.01), 6 (p = 0.001), 8 (p < 0.001), 10 (p < 0.001) and 12 months (p < 0.001) of chelation therapy compared to its baseline levels. There was no correlation between baseline ferritin levels and age (p = 0.574). In addition, no statistically significant difference was observed about change in serum ferritin levels after 6 and also 12 months of therapy between patients who had undergone splenectomy and those who did not (p = 0.796 and 0.859, respectively). Iron chelation therapy with DFX is safe and effective in reducing serum ferritin levels in β-TI patients who suffer from side effects of iron overload.

Objectives: For the purpose of evaluation of exhaled NO as an index of airway inflammation, we assessed changes in fractional exhaled NO (FeNO) across a work shift and its relationship with respiratory complaints., Material and Methods: Chronic and work-aggravated respiratory complaints were assessed using a questionnaire in 89 male textile workers. FeNO and spirometry were performed before and after a work shift and all the changes were registered., Results: A significant increase in FeNO after a work shift was observed. Post-shift FeNO was significantly higher among the subjects with chronic respiratory complaints. There was an obvious decrease in FVC, and FEV1 after a work shift; however, we couldn't find a significant relationship between changes in respiratory parameters and concentration of inhalable dusts., Conclusions: FeNO increase after a work shift along with pulmonary function decrement and higher post-shift FeNO among subjects with respiratory complaints makes across-shift FeNO a non-invasive test for assessment of airway hyper-responsiveness in textile workers.

Background: Obstructive sleep apnea syndrome is associated with airway inflammation. Measurement of exhaled nitric oxide is a non-invasive method for evaluation of airway diseases. It seems that obesity is an exacerbating factor for airway inflammation. We aimed to evaluate the changes of exhaled nitric oxide after sleep in patients suffering from OSA regarding BMI., Method: In 54 patients referred for polysomnography, exhaled nitric oxide measurements were performed before and after sleep. Subjects were divided into three categories: normal, obese with sleep apnea and non-obese, based on polysomnographic recordings and BMI., Results: 47 subjects had abnormal apnea/hypopnea index (AHI mean = 39.7) and 7 were normal regarding AHI (AHI mean = 3.0). BMI was significantly correlated to AHI, number of desaturations and hypoxia. Among those with apnea, 31 subjects were obese and 16 were non-obese. Exhaled nitric oxide levels in normal and OSA subjects showed no significant change, but a significant increase was found in obese patients with apnea (14.7 pre-sleep mean, 20.0 post-sleep mean)., Conclusions: Obesity is an effective factor in the inflammation of airways in patients with obstructive apnea., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

An efficient one-pot synthesis of novel pyrano[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-ones via three-component condensation of kojic acid, 1-H-pyrazol-5-amines and aldehydes in the presence of a catalytic amount of Zn(OTf)(2) followed by H(2)O(2)-mediated oxidation is reported. Furthermore, the synthesis of 1'H-spiro[indoline-3,4'-pyrano[2,3-b]pyrazolo[3,4-e]pyridine]-2,8'(9'H)-diones were chosen for the library validation.

A variety of pyrazolo[3,4-d]pyrimidine-6(7H)-thione derivatives were easily synthesized with a novel, simple, efficient, and regioselective method via three-component condensation reaction of 5-methyl-1H-pyrazol-3-amine, arylisothiocyanates, and aldehydes in the presence of catalytic amount of p-toluenesulfonic acid (p-TSA) in 1-butyl-3-methylimidazolium bromide ionic liquid with excellent yields and short reaction times.

The VPH/Physiome Project is developing the model encoding standards CellML (cellml.org) and FieldML (fieldml.org) as well as web-accessible model repositories based on these standards (models.physiome.org). Freely available open source computational modelling software is also being developed to solve the partial differential equations described by the models and to visualise results. The OpenCMISS code (opencmiss.org), described here, has been developed by the authors over the last six years to replace the CMISS code that has supported a number of organ system Physiome projects. OpenCMISS is designed to encompass multiple sets of physical equations and to link subcellular and tissue-level biophysical processes into organ-level processes. In the Heart Physiome project, for example, the large deformation mechanics of the myocardial wall need to be coupled to both ventricular flow and embedded coronary flow, and the reaction-diffusion equations that govern the propagation of electrical waves through myocardial tissue need to be coupled with equations that describe the ion channel currents that flow through the cardiac cell membranes. In this paper we discuss the design principles and distributed memory architecture behind the OpenCMISS code. We also discuss the design of the interfaces that link the sets of physical equations across common boundaries (such as fluid-structure coupling), or between spatial fields over the same domain (such as coupled electromechanics), and the concepts behind CellML and FieldML that are embodied in the OpenCMISS data structures. We show how all of these provide a flexible infrastructure for combining models developed across the VPH/Physiome community., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The spinocerebellar ataxias (SCA) comprise a heterogeneous group of severe late-onset neurodegenerative diseases that are promoted by the expansion of a tandem-arrayed DNA sequence that modifies the primary structure of the protein., Methods: Genomic DNA of 20 patients affected with SCAs was extracted from peripheral blood and screened for deletions in mitochondrial DNA (mtDNA). Sequencing of tRNA(Leu), tRNA(Lys), cytochrome oxidase II, ATPase 6/8 and NADH dehydrogenase I (NDI) genes belonging to mtDNA from patients with SCAs was also carried out to detect the presence of variations., Results: We identified cytosine-adenine-guanine (CAG) trinucleotide repeat expansions in 20 patients. Seven of these patients had at least one nucleotide change in mtDNA. In such cases, 5 nucleotide variations resulted in amino acid changes with two novel variations T8256G and G9010A., Conclusion: SCA patients showed high levels of mtDNA variations in lymphocytes. It can be proposed that the SCA gene proteins (Ataxins) are involved in the complicated intracellular mechanisms that affect cellular organelles and their components, such as the mitochondrial genome. The instability of CAG repeats in polyglutamine diseases such as SCAs and Huntington's disease might be a causative factor in mtDNA variation or possible damage., (Copyright 2008 S. Karger AG, Basel.)