Неинвазивная диагностика заболеваний печени

Department of Pediatrics, Nicolae Testemitanu State Medical and Pharmaceutical University, Congresul III al Medicilor de Familie din Republica Moldova, 17–18 mai, 2012, Chişinău, Republica Moldova, Conferinţa Naţională „Maladii bronhoobstructive la copii”, consacrată profesorului universitar, doctor habilitat Victor Gheţeul, 27 aprilie, Chişinău, Republica MoldovaNoninvasive tests quickly and reliably differentiate patients with advanced fibrosis and those without fibrosis; they can be used as a rapid method of screening patients with infections and with hepatitisviruses B, C, D. Elastography is a method based on ultrasound, a non-invasive concept in assessing the nature of the tissue, which provides information about the elasticity of tissue examined and the degree of fibrosis. Noninvasive tests are an attractive alternative to liver puncture biopsy for staging and monitoring of chronic liver disease. Elastography examination for children is a priority because it is a noninvasive method with high information (data) and can be applied in medical practice in screening, diagnosis and monitoring of patients.Неинвазивные тесты позволяют оперативно и достоверно дифференцировать пациентов с F1-F4 стадиями фиброза печени и могут быть использованы в качестве как скрининга, так и мониторинга за пациентами с вирусными инфекциями B, C, D. Эластография является методом, основанным на ультразвуковой неинвазивной концепции в оценке морфологической структуры ткани, и предоставляет информацию об ее эластичности и степени фиброза. Неинвазивные тесты предстают привлекательной альтернативой пункционной биопсии печени для стадиализации и мониторинга хронических заболеваний печени. Метод эластографии печени у детей является приоритетным, поскольку является неинвазивным с высокой степенью информативности и достоверности и может применяться в медицинской практике в качестве скрининга, диагностики и мониторинга пациентов с патологией печени

Diagnostic possibilities of PID in the Republic of Moldova

Departament of Pediatrics, State Medical and Pharmaceutical University “Nicolae Testimiteanu”, Republic of MoldovaAwareness activities: PID are rather rare disorders but they are more common than it was estimated. The rate of recognition and diagnosis of PID is directly dependent on awareness of medical staff (JMF manuscript 2011). According to V.Modell (2011), founder of the JMF, the awareness of medical staff and patients concerning PID remains low all over the world and the majority of patients with recurrent infections are not diagnosed or underdiagnosed. In fact, PID prevalence levels exceed the official data. The handbook entitled “Primary Immunodeficiencies in children” was elaborated for family practitioners, pediatricians and medical residents, and published in 2012. It covers the following topics: general information about children immune system, 10 warning signs for children with PID, clinical presentation, immunological and genetic features of the most common PID syndromes, diagnostic algorithms, and tables with reference values of immunological tests. New diagnostic possibilities of PID in Moldova (2012). Determination of lymphocyte subpopulations using cytoflowmetric analysis, assessment of the IgG subclasses, IgD, evaluation of the C1-estherase activity, phagocytic burst-test using dihydrorhodamine, phagocyitosis killing activity (E.coli) using cytoflowmetric analysis. Algorithm diagnostic of PID in Moldova: Clinical screening – 10 warning signs of PID JMF(clinical features characteristic for well-defined syndromes of PID are also taken into consideration). At risk of PID patients primary are evaluated:: family history, clinical course of disease (especially infectious syndrome characteristic for different forms of PID), documented presence of other features of PID (autoimmunity, malignancy), documented presence of other conditions which can because of infectious susceptibility (structural abnormalities, cystic fi brosis, etc). Children with major risk of IDP are selected and laboratory screening: WBC manual count is made, total IgA, IgG, IgM, Ig E. Patients with major risk of PID are examined using different diagnostic protocols depending on clinical presentation. Different immunological tests are carried out according to the Practice Parameter for the diagnosis and management of PID (Bonilla F. et al., 2005). ESID criteria for PID are used to establish the possible, probable and definitive diagnosis of PID if appropriate. Current situation: 6 children are diagnosed with PID in Moldova currently: • 5 patients with IgA selective deficiency (6-8 years old) • 1 patient with Di George syndrome (4 years old) Currently more than 150 genetic defects determining severe disorders of the immune system have been described. According to the European Society for Primary Immunodefi ciencies database most of the reported immune deficiencies occur with a frequency of not less than 1:100000. The improvement of the diagnosis PID will help to achieve in 2013-2014 the Project “Complex diagnostic approach for patients with rare forms of primary immunodeficiency” which will be achieved with Belarus Republic. Objective of the Project: To elaborate effective diagnostic approach based on the analysis of retrospective and prospective clinical, immunological and genetic data of patients with rare primary immunodeficiency syndromes in the territory of the Republic of Moldova and the Republic of Belarus. It is aimed to perform an in-depth analysis of the disease history, clinical data and immunological disorders in patients with rare (1:100000 to 1:1000000) primary Immunodeficiencies in Moldova and the Republic of Belarus. At least 50 patients with 20 primary immunodefi ciency syndromes of rare incidence will be included. On the basis of the received data in Moldova and the Republic of Belarus a similar algorithm and check-list for clinical and immunological assessment will be developed for children with rare primary immunodefi ciencies. Therefore, a complex diagnostic approach must be elaborated for rare primary immunodefi ciency syndromes, which will include clinical, immunological and genetic features, and will contribute to the same effective as for common immunodefi - ciency syndromes early diagnosis and appropriate treatment. Activities which will help to improve PID diagnosis in Moldova: Implementation of lectures on childhood PID topics in the curricula of postgraduate training for family doctors and pediatricians. PhD research on PID problems. Organization of the J Project meeting in Moldova in the nearest future

TIN-X:target importance and novelty explorer

Abstract Motivation The increasing amount of peer-reviewed manuscripts requires the development of specific mining tools to facilitate the visual exploration of evidence linking diseases and proteins. Results We developed TIN-X, the Target Importance and Novelty eXplorer, to visualize the association between proteins and diseases, based on text mining data processed from scientific literature. In the current implementation, TIN-X supports exploration of data for G-protein coupled receptors, kinases, ion channels, and nuclear receptors. TIN-X supports browsing and navigating across proteins and diseases based on ontology classes, and displays a scatter plot with two proposed new bibliometric statistics: Importance and Novelty. Availability and Implementation http://www.newdrugtargets.org </jats:sec

Analysis of subcellular metabolite levels of potato tubers (Solanum tuberosum) displaying alterations in cellular or extracellular sucrose metabolism

The expression of a heterologous invertase in potato tubers (Solanum tuberosum) in either the cytosol or apoplast leads to a decrease in total sucrose content and to an increase in glucose. Depending on the targeting of the enzyme different changes in phenotype and metabolism of the tubers occur: the cytosolic invertase expressing tubers show an increase in the glycolytic flux, accumulation of amino acids and organic acids, and the appearance of novel disaccharides; however, these changes are not observed when the enzyme is expressed in the apoplast [Roessner et al. (2001). Plant Cell, 13, 11-29]. The analysis of these lines raised several questions concerning the regulation of compartmentation of metabolites in potato tubers. In the current study we addressed these questions by performing comparative subcellular metabolite profiling. We demonstrate that: (i) hexoses accumulate in the vacuole independently of their site of production, but that the cytosolic invertase expression led to a strong increase in the cytosolic glucose concentration and decrease in cytosolic sucrose, whereas these effects were more moderate in the apoplastic expressors; (ii) three out of four of the novel compounds found in the cytosolic overexpressors accumulate in the same compartment; (iii) despite changes in absolute cellular content the subcellular distribution of amino acids was invariant in the invertase overexpressing tubers. These results are discussed in the context of current models of the compartmentation of primary metabolism in heterotrophic plant tissues

Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor

Tamoxifen has been used for many years to target estrogen receptor signalling in breast cancer cells. Tamoxifen is also an agonist of the G protein-coupled estrogen receptor (GPER), a GPCR ubiquitously expressed in tissues that mediates the acute response to estrogens. Here we report that tamoxifen promotes mechanical quiescence in hepatic stellate cells (HSCs), stromal fibroblast-like cells whose activation triggers and perpetuates liver fibrosis in hepatocellular carcinomas. This mechanical deactivation is mediated by the GPER/RhoA/myosin axis and induces YAP deactivation. We report that tamoxifen decreases the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and the synthesis of extracellular matrix proteins through a mechanical mechanism that involves actomyosin-dependent contractility and mechanosensing of tissue stiffness. Our results implicate GPER-mediated estrogen signalling in the mechanosensory-driven activation of HSCs and put forward estrogenic signalling as an option for mechanical reprogramming of myofibroblast-like cells in the tumour microenvironment. Tamoxifen, with half a century of safe clinical use, might lead this strategy of drug repositioning.Peer reviewe

Complementarity Between a Docking and a High-Throughput Screen in Discovering New Cruzain Inhibitors†

Virtual and high-throughput screens (HTS) should have complementary strengths and weaknesses, but studies that prospectively and comprehensively compare them are rare. We undertook a parallel docking and HTS screen of 197861 compounds against cruzain, a thiol protease target for Chagas disease, looking for reversible, competitive inhibitors. On workup, 99 % of the hits were eliminated as false positives, yielding 146 well-behaved, competitive ligands. These fell into five chemotypes: two were prioritized by scoring among the top 0.1 % of the docking-ranked library, two were prioritized by behavior in the HTS and by clustering, and one chemotype was prioritized by both approaches. Determination of an inhibitor/cruzain crystal structure and comparison of the high-scoring docking hits to experiment illuminated the origins of docking false-negatives and false-positives. Prioritizing molecules that are both predicted by docking and are HTS-active yields well-behaved molecules, relatively unobscured by the false-positives to which both techniques are individually prone

Attenuation of Salt-Induced Cardiac Remodeling and Diastolic Dysfunction by the GPER Agonist G-1 in Female mRen2.Lewis Rats

The G protein-coupled estrogen receptor (GPER) is expressed in various tissues including the heart. Since the mRen2.Lewis strain exhibits salt-dependent hypertension and early diastolic dysfunction, we assessed the effects of the GPER agonist (G-1, 40 nmol/kg/hr for 14 days) or vehicle (VEH, DMSO/EtOH) on cardiac function and structure.Intact female mRen2.Lewis rats were fed a normal salt (0.5% sodium; NS) diet or a high salt (4% sodium; HS) diet for 10 weeks beginning at 5 weeks of age.Prolonged intake of HS in mRen2.Lewis females resulted in significantly increased blood pressure, mildly reduced systolic function, and left ventricular (LV) diastolic compliance (as signified by a reduced E deceleration time and E deceleration slope), increased relative wall thickness, myocyte size, and mid-myocardial interstitial and perivascular fibrosis. G-1 administration attenuated wall thickness and myocyte hypertrophy, with nominal effects on blood pressure, LV systolic function, LV compliance and cardiac fibrosis in the HS group. G-1 treatment significantly increased LV lusitropy [early mitral annular descent (e')] independent of prevailing salt, and improved the e'/a' ratio in HS versus NS rats (P<0.05) as determined by tissue Doppler.Activation of GPER improved myocardial relaxation in the hypertensive female mRen2.Lewis rat and reduced cardiac myocyte hypertrophy and wall thickness in those rats fed a high salt diet. Moreover, these advantageous effects of the GPER agonist on ventricular lusitropy and remodeling do not appear to be associated with overt changes in blood pressure

Natural products in modern life science

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science