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Item Open Access Scatter Factor/Hepatocyte Growth Factor and Its Receptor, the c-met Tyrosine Kinase, Can Mediate a Signal Exchange between Mesenchyme and Epithelia during Mouse Development(The Rockefeller University Press, 1993) Sonnenberg-Riethmacher, EvaScatter factor/hepatocyte growth factor (SF/HGF) has potent motogenic, mitogenic, and morphogenetic activities on epithelial cells in vitro. The cell surface receptor for this factor was recently identified: it is the product of the c - m e t protooncogene, a receptor-type tyrosine kinase. We report here the novel and distinct expression patterns of SF/HGF and its receptor during mouse development, which was determined by a combination of in situ hybridization and RNase protection experiments. Predominantly, we detect transcripts of c - m e t in epithelial cells of various developing organs, whereas the ligand is expressed in distinct mesenchymal cells in close vicinity. In addition, transient SF/HGF and c - m e t expression is found at certain sites of muscle formation; transient expression of the c - m e t gene is also detected in developing motoneurons. SF/HGF and the c-met receptor might thus play multiple developmental roles, most notably, mediate a signal given by mesenchyme and received by epithelial. Mesenchymal signals are known to govern differentiation and morphogenesis of many epithelia, but the molecular nature of the signals has remained poorly understood. Therefore, the known biological activities of SF/HGF in vitro and the embryonal expression pattern reported here indicate that this mesenchymal factor can transmit morphogenetic signals in epithelial development and suggest a molecular mechanism for mesenchymal epithelial interactions.Item Open Access The c-ros tvrosine kinase receptor I controls regionalization and differehiation of epithelial cells in the epididymis(Cold Spring Harbor Laboratory Press, 1996) Sonnenberg-Riethmacher, Eva; Walter, Barbara; Riethmacher, Dieter; Godecke, Stephanie; Birchmeie, CarmenThe c-ros gene was originally identified in mutant form as an oncogene. The proto-oncogene encodes a tyrosine kinase receptor that is expressed in a small number of epithelial cell types, including those of the epididymis. Targeted mutations of c-ros in the mouse reveal an essential role of the gene in male fertility. Male c-ros -1- animals do not reproduce, whereas the fertility of female animals is not affected. We demonstrate that c-ros is not required in a cell autonomous manner for male germ cell development or function. The gene, therefore, does not affect sperm generation or function in a direct manner. The primary defect in the mutant animals was located in the epididymis, showing that c-ros controls appropriate development of the epithelia, particularly regionalization and terminal differentiation. The epididymal defect does not interfere with production or storage of sperm but, rather, with sperm maturation and the ability of sperm to fertilize in vivo. Interestingly, sperm isolated from c-ros - / - animals can fertilize in vitro. Our results highlight the essential role of the epididymis in male fertility and demonstrate a highly specific function of the c-ros receptor tyrosine kinase during development of distinct epithelial cellsItem Open Access Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development(Cold Spring Harbor Laboratory Press, 1999) Woldeyesus, Masresha T.; Britsch, Stefan; Riethmacher, Dieter; Xu, Lan; Sonnenberg-Riethmacher, Eva; Abou-Rebyeh, Faikah; Harvey, Richard; Caroni, Pico; Birchmeier, CarmenThe ErbB2 tyrosine kinase functions as coreceptor for the neuregulin receptors ErbB3 and ErbB4 and can participate in signaling of EGF receptor (ErbB1), interleukin receptor gp130, and G-protein coupled receptors. ErbB2−/− mice die at midgestation because of heart malformation. Here, we report a genetic rescue of their heart development by myocardial expression of erbB2 cDNA that allows survival of the mutants to birth. In rescued erbB2 mutants, Schwann cells are lacking. Motoneurons form and can project to muscle, but nerves are poorly fasciculated and disorganized. Neuromuscular junctions form, as reflected in clustering of AChR and postsynaptic expression of the genes encoding the a-AChR, AChE, e-AChR, and the RI subunit of the cAMP protein kinase. However, a severe loss of motoneurons on cervical and lumbar, but not on thoracic levels occurs. Our results define the roles of Schwann cells during motoneuron and synapse development, and reveal different survival requirements for distinct motoneuron populationsItem Open Access Placental Failure in Mice Lacking the Mammalian Homolog of Glial Cells Missing, GCMa(American Society for Microbiology, 2000) Riethmacher-Sonnenberg, EvaThe GCM family of transcription factors consists of Drosophila melanogaster GCM, an important regulator of gliogenesis in the fly, and its two mammalian homologs, GCMa and GCMb. To clarify the function of these mammalian homologs, we deleted GCMa in mice. Genetic ablation of murine GCMa (mGCMa) is embryonic lethal, with mice dying between 9.5 and 10 days postcoitum. At the time of death, no abnormalities were apparent in the embryo proper. Nervous system development, in particular, was not impaired, as might have been expected in analogy to Drosophila GCM. Instead, placental failure was the cause of death. In agreement with the selective expression of mGCMa in labyrinthine trophoblasts, mutant placentas did not develop a functional labyrinth layer, which is necessary for nutrient and gas exchange between maternal and fetal blood. Only a few fetal blood vessels entered the placenta, and these failed to thrive and branch normally. Labyrinthine trophoblasts did not differentiate. All other layers of the placenta, including spongiotrophoblast and giant cell layer, formed normally. Our results indicate that mGCMa plays a critical role in trophoblast differentiation and the signal transduction processes required for normal vascularization of the placentaItem Open Access ANURIA SECONDARY TO HOT WEATHER-INDUCED HYPERURICAEMIA: DIAGNOSIS AND MANAGEMENT(Annals of Saudi Medicine, 2003-09) Al-Tawheed, Adel R.; Al-Awadi, Khaleel A.; Kehinde, Elijah O.; Abdul-Halim, Hamdy; Al-Hunayan, Adel; Ali, Yousef; Mohammed, Akram H.There is little information on the management of anuria secondary to severe volume depletion or as a rare manifestation of heat stroke in areas of the world with very hot summers. We present our experience with hot weather-induced hyperuricaemia in Kuwait.Item Open Access Rapid liquid chromatography–tandem mass spectrometry method for the determination of a broad mixture of pharmaceuticals in surface water(Journal of Chromatography A. www.sciencedirect.com, 2008) Conley, Justin; Symes, Steven; Kindelberger, Scott; Richards, SeanHerein, a new method for the detection of 13 different pharmaceuticals and one metabolite in surface water at low ng/L levels is described. The method utilizes ultra performance liquid chromatography–tandem mass spectrometry and a solid-phase extraction sample preparation. Mean method detection limits were low (4.10 ng/L) and overall solid-phase extraction recovery and reproducibility was adequate (mean recovery, 77.9%; mean RSD, 7.3%). The method allows for quick run times and minimal solvent use as compared with other previously reported high performance liquid chromatography-based methods. Application of this method for the detection of pharmaceuticals in Tennessee River surfacewater determined that caffeine, sulfamethoxazole, and carbamazepine were frequently detected (100% of samples). Trimethoprim was moderately detected (30% of samples); acetaminophen, atorvastatin, and lovastatin were infrequently detected (10% of samples); and ciprofloxacin, diltiazem, fluoxetine, levofloxacin, norfluoxetine, ranitidine, and sertraline were not detected. This study reports the first detection of lovastatin in surface water.Item Open Access The extracellular-matrix protein matrilin 2 participates in peripheral nerve regeneration(The Company of Biologists, 2009) Malin, Dmitry; Sonnenberg-Riethmacher, Eva; Guseva, Daria; Wagener, Raimund; Aszódi, Attila; Irintchev, Audrey; Riethmacher, DieterMatrilins are adaptor proteins of the extracellular matrix involved in the formation of both collagen-dependent and collagen-independent filamentous networks. Although their molecular structure and binding partners have been characterized, the functional roles of the four matrilin family members in vivo are still largely unknown. Here, we show that matrilin 2, expressed in pre-myelinating Schwann cells during normal development, profoundly influences the behaviour of glial cells and neurons in vitro. When offered as a uniform substrate, matrilin 2 increased neurite outgrowth of dorsal root ganglia (DRG) neurons and enhanced the migration of both cell line- and embryonic DRG-derived Schwann cells. Vice versa, axonal outgrowth and cell migration were decreased in DRG cultures prepared from matrilin-2-deficient mice compared with wild-type (wt) cultures. In stripe assays, matrilin 2 alone was sufficient to guide axonal growth and, interestingly, axons favoured the combination of matrilin 2 and laminin over laminin alone. In vivo, matrilin 2 was strongly upregulated in injured peripheral nerves of adult wild-type mice and failure of protein upregulation in knockout mice resulted in delayed regrowth of regenerating axons and delayed time-course of functional recovery. Strikingly, the functional recovery 2 months after nerve injury was inferior in matrilin-2-deficient mice compared with wild-type littermates, although motoneuron survival, quality of axonal regeneration, estimated by analyses of axonal diameters and degrees of myelination, and Schwann cell proliferation were not influenced by the mutation. These results show that matrilin 2 is a permissive substrate for axonal growth and cell migration, and that it is required for successful nerve regenerationItem Open Access Comparison of the sensitivity and specificity of urine cytology, urinary nuclear matrix protein-22 and multitarget fluorescence in situ hybridization assay in the detection of bladder cancer(Scandinavian Journal of Urology and Nephrology, 2010) Kehinde, Elijah; Al-Mulla, Fahd; Kapila, Kusum; Anim, Jehoram T.This study aimed to compare the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of urine cytology, BladderChek nuclear matrix protein-22 (NMP22) and UroVysion fluorescence in situ hybridization (FISH) tests in patients with newly diagnosed bladder cancer, those with recurrent bladder cancer, and those with bladder cancer but in remission during surveillance. Material and methods. Voided urine samples obtained from 178 patients with suspected or known bladder cancer about to undergo diagnostic or surveillance cystoscopy and 25 control subjects without the disease were divided into four and used for urine culture and cytology, NMP22 BladderChek and UroVysion FISH tests.Item Open Access Central Asia's Hidden Burden of Neglected Tropical Diseases(Public Library of Science, 2011-06-27) Hotez, Peter J.; Alibek, KenThe neglected tropical diseases (NTDs) are the most common infections of the world's poorest people living in developing countries [1]–[7]. They are mostly comprised of chronic parasitic and related infections, with the most common NTDs represented by the soil-transmitted helminthiases, schistosomiasis, lymphatic filariasis, onchocerciasis, and trachoma [1]. Among their common features, the NTDs result in prolonged periods of disability and actually help to promote poverty through their long-standing effects on child development and worker productivity [2]. It is not commonly appreciated that the NTDs are widespread throughout Central Asia where they are also a major determinant of poverty [8]. The five mostly landlocked Central Asian countries—Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan (Figure 1)—were established upon the breakup of the former Soviet Union in 1991. They are also linked in history as a vital crossroads (“the Silk Road”) between Asia and Europe and by a common geography comprised of a desert and piedmont region [9]. The five nations have a combined population of 60 million people, with three of them—Kyrgyzstan, Tajikstan, and Uzbekistan—exhibiting a Human Development Index (HDI) that is ranked below 100, whichis more or less equivalent to nations such as Guatemala, India, Indonesia, and South Africa [10].Item Open Access The Spread of HIV in Pakistan: Bridging of the Epidemic between Populations(Public Library of Science, 2011-07-25) Khanani, Muhammad R.; Somani, Mehreen; Rehmani, Sadiq S.; Veras, Nazle M. C.; Ali, Syed; Thorne, ClaireIn the last two decades, ‘concentrated epidemics’ of human immunodeficiency virus (HIV) have established in several high risk groups in Pakistan, including Injecting Drug Users (IDUs) and among men who have sex with men (MSM). To explore the transmission patterns of HIV infection in these major high-risk groups of Pakistan, 76 HIV samples were analyzed from MSM, their female spouses and children, along with 26 samples from a previously studied cohort of IDUs. Phylogenetic analysis of HIV gag gene sequences obtained from these samples indicated a substantial degree of intermixing between the IDU and MSM populations, suggesting a bridging of HIV infection from IDUs, via MSM, to the MSM spouses and children. HIV epidemic in Pakistan is now spreading to the female spouses and offspring of bisexual MSM. HIV control and awareness programs must be refocused to include IDUs, MSM, as well as bisexual MSM, and their spouses and children.Item Metadata only Chapter 21 Biomedical Applications of Carbon Adsorbents(Novel Carbon Adsorbents, 2012-01-01) Mikhalovsky, Sergey V.; Sandeman, Susan R.; Howell, Carol A.; Phillips, Gary J.; Nikolaev, Vladimir G.; Sergey V., MikhalovskyActivated carbon (AC) has a long history of use for medical applications due to its very high adsorption capacity and ability to adsorb a large range of substances. Recent advances in carbon materials science have produced a new generation of ACs with improved mechanical properties and porous structure, in a range of forms and with a breadth of applications in oral medicine, hemoperfusion devices, and wound care beyond that of traditional usage. The history and progressive development of AC for these applications are described including more recent developments in synthetic resin-based materials with optimized porosity to bind high molecular-weight and protein-bound biological toxins poorly removed by current systems. These highly optimized materials open up a range of treatment strategies with great potential to reduce healthcare cost burden and target improved acute and chronic disease treatment regimes.Item Open Access Значение автоматизированной антенатальной кардиотокографии для оценки функионального состояния плодов, имеющих задержку развития(Журнал акушерства и женских болезней, 2012-04) Курмангали, Ж. К.; Укыбасова, Т. М.; Бапаева, Г. Б.; Аймагамбетова, Г. Н.Применение в акушерской практике метода автоматизированной антенатальной кардиотокографии позволяет устранить субъективизм и повысить надежность оценки состояния плода в группе беременных высокого акушерского и перинатального риска. Установлено, что в группе беременных высокого риска нарушения состояния плода при кардиотокографическом динамическом наблюдении выявляются уже во II триместре. При этом наиболее ранними и достоверными показателями нарушения состояния плода являются: снижение вариабельности базального ритма частоты сердечных сокращений плода, отсутствие эпизодов высокой вариабельности или превалирование эпизодов низкой вариабельности над высокими, значение показателя STV — короткая вариабельность менее 4,0. Полученные данные позволяют рекомендовать применение метода автоматизированной антенатальной кардиотокографии в группе беременных высокого перинатального риска для ранней диагностики нарушения функционального состояния плода. Возможность оценить с высокой надежностью степень тяжести метаболического ацидоза плода позволит своевременно решить вопросы оптимальной акушерской тактики ведения беременности, срока и метода родоразрешения у данной категории беременных.Item Open Access Burden of Communicable Disease among the Native and Repatriating Afghans(Public Library of Science, 2012-10) Abidi, Syed H; Ali, Farwa; Shah, Farida; Abbas, Farhat; Ali, SyedOwing to the capricious political and economic conditions of Afghanistan during the past few decades, the burden of communicable disease, especially bloodborne and sexually transmitted infections, has been steadily mounting in this population. Afghan refugees who sought asylum and settled in foreign countries encountered many a barrier to standard health care, which led to the establishment of several epidemics in the refugee population as well. In recent years, repatriation of these refugees back to their homeland has raised new concerns about control and prevention of potential epidemics in the returning and indigenous Afghan populations. Mixing of existing infections, as well as of risk behaviors and practices, in the two populations, if left unattended, can lead to unforeseen, uncontrollable outcomes.Item Open Access Assessment of Risk Factors of Helicobacter Pylori Infection and Peptic Ulcer Disease(Journal of Global Infectious Diseases, 2013) Mhaskar, Rahul S.; Ricardo, Izurieta; Azizan, Azliyati; Laxminarayan, Rajaram; Amol, Bapaye; Santosh, Walujkar; Boo, KwaBackground: Helicobacter pylori (H. pylori) infection is a risk factor for peptic ulcer. There have been no studies addressing environmental and dietary risk factors in western India. We conducted a case control study enrolling peptic ulcer patients in Pune, India. Materials and Methods: Risk factors for peptic ulcer and H. pylori infection were assessed in a participant interview. H. pylori status was assessed from stool by monoclonal antigen detection. Results: We enrolled 190 peptic ulcer, 35 stomach cancer patients, and 125 controls. Fifty-one percent (180/350) of the participants were infected with H. pylori. Lower socioeconomic status (SES) [odds ratio (OR): 1.10, 95% confidence interval (CI): 1.02-1.39], meat consumption (OR: 2.35, 95% CI: 1.30-4.23), smoking (OR: 2.23, 95% CI: 1.24-4.02), eating restaurant food (OR: 3.77, 95% CI: 1.39-10.23), and drinking nonfiltered or nonboiled water (OR: 1.05, 95% CI: 1.01-1.23) were risk factors for H. pylori infection. H. pylori infection (OR: 1.70, 95% CI:I. 03-2.89), meat (OR: 1.10, 95% CI: 1.02-1.75), fish (OR: 1.05, 95% CI: 1.02-1.89) consumption, and a family history of ulcer (OR: 1.20, 95% CI: 1.08-1.60) were risk factors for peptic ulcer. Consumption of chili peppers (OR: 0.20, 95% CI: 0.10-0.37) and parasite infestation (OR: 0.44, 95% CI: 0.24-0.80) were protective against H. pylori infection. Conclusion: H. pylori infection is associated with peptic ulcer. Lower SES, consumption of restaurant food, meat, nonfiltered water, and smoking are risk factors for H. pylori. Consumption of meat, fish, and a family history of peptic ulcer are risk factors for peptic ulcer. Consumption of chili peppers and concurrent parasite infestation appear to be protective against H. pylori.Item Open Access The role of antioxidation and immunomodulation in postnatal multipotent stem cell-mediated cardiac repair(International Journal of Molecular Sciences, 2013) Saparov, Arman; Chen, Chien Wen; Beckman, Sarah A.; Wang, Yadong; Huard, JohnnyOxidative stress and inflammation play major roles in the pathogenesis of coronary heart disease including myocardial infarction (MI). The pathological progression following MI is very complex and involves a number of cell populations including cells localized within the heart, as well as cells recruited from the circulation and other tissues that participate in inflammatory and reparative processes. These cells, with their secretory factors, have pleiotropic effects that depend on the stage of inflammation and regeneration. Excessive inflammation leads to enlargement of the infarction site, pathological remodeling and eventually, heart dysfunction. Stem cell therapy represents a unique and innovative approach to ameliorate oxidative stress and inflammation caused by ischemic heart disease. Consequently, it is crucial to understand the crosstalk between stem cells and other cells involved in post-MI cardiac tissue repair, especially immune cells, in order to harness the beneficial effects of the immune response following MI and further improve stem cell-mediated cardiac regeneration. This paper reviews the recent findings on the role of antioxidation and immunomodulation in postnatal multipotent stem cell-mediated cardiac repair following ischemic heart disease, particularly acute MI and focuses specifically on mesenchymal, muscle and blood-vessel-derived stem cells due to their antioxidant and immunomodulatory properties.Item Open Access Macroporous Composite Cryogels with Embedded Polystyrene Divinylbenzene Microparticles for the Adsorption of Toxic Metabolites from Blood(Journal of Chemistry, 2013) Eichhorn, Tanja; Ivanov, Alexander E.; Dainiak, Maria B.; Leistner, André; Linsberger, Ingrid; Jungvid, Hans; Mikhalovsky, Sergey V.; Weber, ViktoriaComposite monolithic adsorbents were prepared by the incorporation of neutral polystyrene divinylbenzene (PS-DVB) microparticles into macroporous polymer structures produced by cryogelation of agarose or poly(vinyl alcohol). The composite materials exhibited excellent flow-through properties. Scanning electron microscopy of the composite cryogels revealed that the microparticles were covered by thin films of poly(vinyl alcohol) or agarose and thus were withheld in the monolith structure. Plain PS-DVB microparticles showed efficient adsorption of albumin-bound toxins related to liver failure (bilirubin and cholic acid) and of cytokines (tumor necrosis factor-alpha and interleukin-6). The rates of adsorption and the amount of adsorbed factors were lower for the embedded microparticles as compared to the parent PS-DVB microparticles, indicating the importance of the accessibility of the adsorbent pores. Still, the macroporous composite materials showed efficient adsorption of albuminbound toxins related to liver failure as well as efficient binding of cytokines, combined with good blood compatibility. Thus, the incorporation of microparticles into macroporous polymer structures may provide an option for the development of adsorption modules for extracorporeal blood purification.Item Open Access New recreational water testing alternatives(Park Science is a research and resource management journal, 2013-03-13) Kesteloot, Kurt; Azizan, Azliyati; Whitman, Richard; Nevers, MeredithEach year recreational water users descend on national parks by the millions. U.S. Environmental Protection Agency (EPA) regulations require monitoring waters for fecal indicator bacteria in order to safeguard human health, and obtaining results using the culturing method takes 18 hours or more of analytical time. Thus, under this surveillance regime swimmers can be exposed to waterborne disease organisms before health advisories can be issued. To address the need for timelier notification of recreational water quality, the EPA has evaluated and approved new and faster testing methods as of November 2012. This article discusses new recreational water testing methodologies such as qPCR, empirical predictive modeling, rainfall threshold levels, and advanced notification options for park managers to consider and tailor to their needs.Item Open Access Bacterial growth in media mimicking the high salt and alkalinity of extreme kazakhstan environments results in production of antimicrobial compounds in soil actinomycetes isolated from these extremophile locations(Journal of Pharmaceutical Technology & Drug Research, 2013-04-13) Roberts, Jill; Trenozhnikova, Lyudmila; Seaton, Lylah; Patel, Ami; Faza, Colton; Whitaker, Jacqueline; Mayer, Christen; Azizan, AzliyatiIncreasing antibiotic resistance among multidrug resistant pathogens necessitates the search for newer antimicrobials. Streptomyces historically produce the largest number of antibacterials and herein we describe isolation of antagonists from extremophiles using unusual culture media. Antagonists or antimicrobials produced under extremophile environmental conditions demonstrated activity against MRSA from Kazakhstan and the United States.Item Metadata only Tuberculosis diagnosis using immunodominant, secreted antigens of Mycobacterium tuberculosis(Tuberculosis, 2013-07-01) Bekmurzayeva, Aliya; Sypabekova, Marzhan; Kanayeva, Damira; Aliya, BekmurzayevaSummary Tuberculosis (TB) remains a major public health concern in most low-income countries. Hence, rapid and sensitive TB diagnostics play an important role in detecting and preventing the disease. In addition to established diagnostic methods, several new approaches have been reported. Some techniques are simple but time-consuming, while others require complex instrumentation. One prominent and readily available approach is to detect proteins that Mycobacterium tuberculosis secretes, such as Mpt64, the 6-kDa early secreted antigenic target (Esat6), the 10-kDa culture filtrate protein (Cfp10), and the antigen 85 (Ag85) complex. Although their functions are not fully understood, a growing body of molecular evidence implicates them in M. tuberculosis virulence. Currently these biomarkers are either being used or investigated for use in skin patch tests, biosensor analyses, and immunochromatographic, immunohistochemical, polymerase chain reaction-based, and enzyme-linked immunosorbent assays. This review provides a comprehensive discussion of the roles these immunodominant antigens play in M. tuberculosis pathogenesis and compares diagnostic methods based on the detection of these proteins with more established tests for TB.Item Metadata only CDP-choline (ceraxon) treatment with hypoxia in the newborn infant(Journal of the Neurological Sciences, 2013-10-15) Issayeva, R.; Pushkarev, K.; R., Issayeva