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MK
Selected AbstractsBlockade of the central generator of locomotor rhythm by noncompetitive NMDA receptor antagonists in Drosophila larvaeDEVELOPMENTAL NEUROBIOLOGY, Issue 1 2001Daniel Cattaert Abstract The noncompetitive antagonists of the vertebrate N -methyl- D -aspartate (NMDA) receptor dizocilpine (MK 801) and phencyclidine (PCP), delivered in food, were found to induce a marked and reversible inhibition of locomotor activity in Drosophilamelanogaster larvae. To determine the site of action of these antagonists, we used an in vitro preparation of the Drosophila third-instar larva, preserving the central nervous system and segmental nerves with their connections to muscle fibers of the body wall. Intracellular recordings were made from ventral muscle fibers 6 and 7 in the abdominal segments. In most larvae, long-lasting (>1 h) spontaneous rhythmic motor activities were recorded in the absence of pharmacological activation. After sectioning of the connections between the brain and abdominal ganglia, the rhythm disappeared, but it could be partially restored by perfusing the muscarinic agonist oxotremorine, indicating that the activity was generated in the ventral nerve cord. MK 801 and PCP rapidly and efficiently inhibited the locomotor rhythm in a dose-dependent manner, the rhythm being totally blocked in 2 min with doses over 0.1 mg/mL. In contrast, more hydrophilic competitive NMDA antagonists had no effect on the motor rhythm in this preparation. MK 801 did not affect neuromuscular glutamatergic transmission at similar doses, as demonstrated by monitoring the responses elicited by electrical stimulation of the motor nerve or pressure applied glutamate. The presence of oxotremorine did not prevent the blocking effect of MK 801. These results show that MK 801 and PCP specifically inhibit centrally generated rhythmic activity in Drosophila, and suggest a possible role for NMDA-like receptors in locomotor rhythm control in the insect CNS. © 2001 John Wiley & Sons, Inc. J Neurobiol 48: 58,73, 2001 [source] CD34+ cells derived from fetal liver contained a high proportion of immature megakaryocytic progenitor cellsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2000Dong-Chu Ma Abstract: Endoreplication and maturation of the megakaryocyte (MK) may be retarded or delayed during ontogenesis. In this study, CD34+ cells were isolated from both human fetal liver and adult bone marrow and incubated with thrombopoietin (TPO). The cell number, morphological characteristics, platelet-associated antigen phenotype, maturation stage and DNA ploidy of CD41+cells were examined from day 0 to day 12 in culture. 1) TPO stimulated the proliferation of fetal liver (FL)-derived CD34+ cells with a mean 73.14-fold increase of CD41+ cells after 12 d in culture. Adult BM-derived CD34+ cells increased only slightly, with a mean 8.18-fold increase of CD41+ cells. 2) Although the membrane phenotype of both FL CD34+ -derived MKs and BM CD34+ -derived MKs analyzed with CD41a, CD42a, CD61 and CD34 were similar, all FL CD34+ -derived MKs were in maturation stage I and II and in low ploidy (<4N) class. By comparison, BM CD34+ MKs possessed 15% MKs in maturation stage III and IV and with 23% MKs in high ploidy class (>4N). 3) Most of cultured FL-derived CD34+ cells did not have a well developed demarcation system (DM) and numerous ,-granules after 12 d incubation. von Willebrand factor (vWF) appeared earlier on the cultured BM-derived CD34+ cells than on FL-derived CD34+ cells. 4) The expression of both cyclin E and cyclin B1 progressively increased in FL CD34+cells induced by TPO during 12 d in culture. 5) The expression of cyclin D1 gradually decreased in FL CD34+cells induced by TPO over 12 d incubation. 6) Immunocytochemical analysis showed that cyclin D3 was detected only in cytoplasm of cultured FL-derived CD34+ cells, whereas in both cytoplasm and nuclei of cultured BM-derived CD34+ cells. These data suggest that FL-derived CD34+ cells contain a high proportion of immature megakaryocytic progenitor cells. It further suggests that TPO can push these progenitor cells into proliferation by upregulating the expression of cyclins B1 and E, and drive a high proportion of cells into megakaryocytic lineage. [source] MAP-kinase-activated protein kinase 2 expression and activity is induced after neuronal depolarizationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2008Tobias Thomas Abstract Mitogen-activated protein kinase-activated protein kinase (MK)2 is one of several downstream targets of p38 mitogen-activated protein kinase and has a well documented role in inflammation. Here, we describe a possible new function of MK2. We show that triggering depolarization by potassium chloride or increasing the cellular cAMP by forskolin treatment led to elevated levels of expression and activity of mouse MK2. In both treatments, the kinase inhibitor H89 completely prevented the up-regulation of MK2 at the transcript level. By the use of different cell lines we demonstrated that the induction of MK2 expression is characteristic of neuronal cells and is absent in fibroblasts, macrophages and kidney cells. In vivo, induction of a status epilepticus by systemic administration of the chemoconvulsant kainic acid resulted in markedly reduced neurodegeneration in the pyramidal layer of the hippocampus, dentate gyrus and hilus of MK2-deficient mice compared with wild-type mice. Together, our data suggest a possible role of MK2 in the cellular response after neuronal depolarization, in particular in excitotoxicity. [source] Expression of functional NR1/NR2B-type NMDA receptors in neuronally differentiated SK-N-SH human cell lineEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2002Marina Pizzi Abstract The present study demonstrates that human SK-N-SH neuroblastoma cells, differentiated by retinoic acid (RA), express functional NMDA receptors and become vulnerable to glutamate toxicity. During exposure to RA, SK-N-SH cells switched from non-neuronal to neuronal phenotype by showing antigenic changes typical of postmitotic neurons together with markers specific for cholinergic cells. Neuronally differentiated cells displayed positive immunoreactivity to the vesicular acetylcholine transporter and active acetylcholine release in response to depolarizing stimuli. The differentiation correlated with the expression of NMDA receptors. RT-PCR and immunoblotting analysis identified NMDA receptor subunits NR1 and NR2B, in RA-differentiated cultures. The NR1 protein immunolocalized to the neuronal cell population and assembled with the NR2B subunit to form functional N -methyl- d -aspartate (NMDA) receptors. Glutamate or NMDA application, concentration-dependently increased the intracellular Ca2+ levels and acetylcholine release in differentiated cultures, but not in undifferentiated SK-N-SH cells. Moreover, differentiated cultures became vulnerable to NMDA receptor-mediated excitotoxicity. The glutamate effects were enhanced by glycine application and were prevented by the NMDA receptor blocker MK 801, as well as by the NR2B selective antagonist ifenprodil. These data suggest that SK-N-SH cells differentiated by brief treatment with RA may represent an unlimited source of neuron-like cells suitable for studying molecular events associated with activation of human NR1/NR2B receptors. [source] Mutational spectrum and genotype,phenotype correlations in mevalonate kinase deficiency,HUMAN MUTATION, Issue 8 2006Saskia H.L. Mandey Abstract Mevalonate kinase deficiency (MKD) is an autosomal recessive autoinflammatory disorder caused by mutations in the MVK gene resulting in deficient activity of mevalonate kinase (MK). Depending on the clinical severity, MKD may present as hyper-IgD and periodic fever syndrome (HIDS) or the more severe mevalonic aciduria (MA). We analyzed the MVK gene in 57 patients with MKD and found 39 different mutations including 15 novel mutations, expanding the total mutational spectrum of MKD to 63 mutations. To get more insight into the genotype,phenotype correlation in MKD, we studied the effect of selected missense mutations on MK protein stability and activity in various patient fibroblast cell lines. All MKD cell lines showed markedly decreased MK activities that correlated well with the clinical severity and, for most of the cell lines, with the amount of MK protein. When fibroblasts of MKD patients were cultured under conditions known to promote a more controlled protein folding, all cell lines of patients with the HIDS phenotype and few cell lines of patients with the MA phenotype showed an increase in the residual MK activity. This increase in enzyme activity correlates well with an increase in the MK protein levels in these cell lines, indicating that most of the mutations in MKD affect stability and/or folding of the MK protein rather than affecting the catalytic properties of the enzyme. The finding that the residual activity in MKD can be manipulated by environmental conditions may offer therapeutic options to alleviate or prevent the clinical symptoms associated with MKD. Hum Mutat 27(8), 796,802, 2006. © 2006 Wiley-Liss, Inc. [source] Moving kriging interpolation and element-free Galerkin methodINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 1 2003Lei Gu Abstract A new formulation of the element-free Galerkin (EFG) method is presented in this paper. EFG has been extensively popularized in the literature in recent years due to its flexibility and high convergence rate in solving boundary value problems. However, accurate imposition of essential boundary conditions in the EFG method often presents difficulties because the Kronecker delta property, which is satisfied by finite element shape functions, does not necessarily hold for the EFG shape function. The proposed new formulation of EFG eliminates this shortcoming through the moving kriging (MK) interpolation. Two major properties of the MK interpolation: the Kronecker delta property (,I(sJ)=,IJ) and the consistency property (,In,I(x)=1 and ,In,I(x)xIi=xi) are proved. Some preliminary numerical results are given. Copyright © 2002 John Wiley & Sons, Ltd. [source] Ketonization of 1,5-Cyclooctadiene by Nitrous OxideADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 11-12 2009Dmitry Abstract The kinetics and mechanism of the liquid phase ketonization of 1,5-cyclooctadiene (COD) by nitrous oxide have been studied. The reaction proceeds without catalyst in the temperature range 473,553,K with the activation energy 113,kJ,mol,1 and is first order with respect to the initial reactants. The mechanism includes consecutive ketonization of two CC bonds in the COD molecule, with the intermediate formation of an unsaturated monoketone (MK). Further ketonization of MK leads to two isomeric diketones (DK): 1,4- and 1,5-cyclooctanedione. The 1,5-DK is a stable final product while the 1,4-DK undergoes further intramolecular aldol transformation leading to two bicyclic compounds, that retain the same number of carbon atoms. The distribution of mono- and diketones in the course of reaction is described by theoretical dependences pointing to identical reactivities of the CC double bonds residing in COD and MK molecules. The ketonization of COD by nitrous oxide exemplifies a prospective way for the preparation of valuable organic products in perfect harmony with the strategy of green chemistry. [source] Anaplastic lymphoma kinase proteins in growth control and cancerJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2004K. Pulford The normal functions of full-length anaplastic lymphoma kinase (ALK) remain to be completely elucidated. Although considered to be important in neural development, recent studies in Drosophila also highlight a role for ALK in gut muscle differentiation. Indeed, the Drosophila model offers a future arena for the study of ALK, its ligands and signalling cascades. The discovery of activated fusion forms of the ALK tyrosine kinase in anaplastic large cell lymphoma (ALCL) has dramatically improved our understanding of the pathogenesis of these lymphomas and enhanced the pathological diagnosis of this subtype of non-Hodgkin's lymphoma (NHL). Likewise, the realisation that a high percentage of inflammatory myofibroblastic tumours express activated-ALK fusion proteins has clarified the causation of these mesenchymal neoplasms and provided for their easier discrimination from other mesenchymal-derived inflammatory myofibroblastic tumour (IMT) mimics. Recent reports of ALK expression in a range of carcinoma-derived cell lines together with its apparent role as a receptor for PTN and MK, both of which have been implicated in tumourigenesis, raise the possibility that ALK-mediated signalling could play a role in the development and/or progression of a number of common solid tumours. The therapeutic targeting of ALK may prove to have efficacy in the treatment of many of these neoplasms. © 2004 Wiley-Liss, Inc. [source] CD41+ and CD42+ hematopoietic progenitor cells may predict platelet engraftment after allogeneic peripheral blood stem cell transplantationJOURNAL OF CLINICAL APHERESIS, Issue 2 2001T. Demirer Abstract The objective of this study was to quantify subpopulations of CD34+ cells such as CD41+ and CD42+ cells that might represent megakaryocyte (MK) precursors in peripheral blood stem cell (PBSC) collections of normal, recombinant human granulocyte-colony stimulating factor (rhG-CSF) primed donors and to determine whether there is a statistical association between the dose infused megakaryocytic precursors and the time course of the platelet recovery following an allogeneic PBSC transplantation. Twenty-six patients with various hematologic malignancies transplanted from their HLA identical siblings between July 1997 and December 1999 were used. All patients except one with severe aplastic anemia who had cyclophosphamide (CY) alone received busulfan-CY as preparative regimen and cyclosporine-methotrexate for GVHD prophylaxis. Normal healthy donors were given rhG-CSF 10 ,g/kg/day subcutaneously twice daily and PBSCs were collected on days 5 and 6. The median number of infused CD34+, CD41+ and CD42+ cells were 6.61 × 106/kg (range 1.47,21.41), 54.85 × 104/kg (5.38,204.19), and 49.86 × 104/kg (6.82,430.10), respectively. Median days of ANC 0.5 × 109/L and platelet 20 × 109/L were 11.5 (range 9,15) and 13 (8,33), respectively. In this study, the number of CD41+ and CD42+ cells infused much better correlated than the number of CD34+ cells infused with the time to platelet recovery of 20 × 109/L in 26 patients receiving an allogeneic match sibling PBSC transplantation (r = ,0.727 and P < 0.001 for CD41+ cells, r = ,0.806 and P < 0.001 for CD42+ cells, r = ,0.336 and P > 0.05 for CD34+ cells). There was an inverse correlation between the number of infused CD41+ and CD42+ cells and duration of platelet engraftment. Therefore, as the number of CD41+ and CD42+ cells increased, duration of platelet engraftment (time to reach platelet count of , 20 × 109/L) shortened significantly. Based on this data we may conclude that flow cytometric measurement of CD41+ and CD42+ progenitor cells may provide an accurate indication of platelet reconstitutive capacity of the allogeneic PBSC transplant. J. Clin. Apheresis. 16:67,73, 2001. © 2001 Wiley-Liss, Inc. [source] Identifying women with severe angiographic coronary diseaseJOURNAL OF INTERNAL MEDICINE, Issue 1 2010C. Kreatsoulas Abstract., Kreatsoulas C, Natarajan MK, Khatun R, Velianou JL, Anand SS (McMaster University; CARING Network, McMaster University; Population Health Research Institute, McMaster University and Hamilton Health Sciences; Interventional Cardiology, Hamilton Health Sciences; Eli Lilly Canada,May Cohen Chair in Women's Health, McMaster University; Michael G. DeGroote-Heart and Stroke Foundation of Ontario Chair in Population Health Research, McMaster University; Population Genomics Program, McMaster University; McMaster University, Hamilton, ON, Canada). Identifying women with severe angiographic coronary disease. J Intern Med 2010; 268:66,74. Objectives., To determine sex/gender differences in the distribution of risk factors according to age and identify factors associated with the presence of severe coronary artery disease (CAD). Design., We analysed 23 771 consecutive patients referred for coronary angiography from 2000 to 2006. Subjects., Patients did not have previously diagnosed CAD and were referred for first diagnostic angiography. Outcome measures., Patients were classified according to angiographic disease severity. Severe CAD was defined as left main stenosis ,50%, three-vessel disease with ,70% stenosis or two-vessel disease including proximal left anterior descending stenosis of ,70%. Univariate and multivariate logistic regression was used to assess the association between risk factors and angina symptoms with severe CAD. Results., Women were less likely to have severe CAD (22.3% vs. 36.5%) compared with men. Women were also significantly older (69.8 ± 10.6 vs. 66.3 ± 10.7 years), had higher rates of diabetes (35.0% vs. 26.6%), hypertension (74.8% vs. 63.3%) and Canadian Cardiovascular Society (CCS) class IV angina symptoms (56.7% vs. 47.8%). Men were more likely to be smokers (56.9% vs. 37.9%). Factors independently associated with severe CAD included age (OR = 1.05; 95% CI 1.05,1.05, P < 0.01), male sex (OR = 2.43; CI 2.26,2.62, P < 0.01), diabetes (OR = 2.00; CI 1.86,2.18, P < 0.01), hyperlipidaemia (OR = 1.50; CI 1.39,1.61, P < 0.01), smoking (OR = 1.10; CI 1.03,1.18, P = 0.06) and CCS class IV symptoms (OR = 1.43; CI 1.34,1.53, P < 0.01). CCS Class IV angina was a stronger predictor of severe CAD amongst women compared with men (women OR = 1.82; CI 1.61,2.04 vs. men OR = 1.28; CI 1.18,1.39, P < 0.01). Conclusions., Women referred for first diagnostic angiography have lower rates of severe CAD compared with men across all ages. Whilst conventional risk factors, age, sex, diabetes, smoking and hyperlipidaemia are primary determinants of CAD amongst women and men, CCS Class IV angina is more likely to be associated with severe CAD in women than men. [source] Chlamydia pneumoniae and luminal narrowing after coronary angioplastyJOURNAL OF INTERNAL MEDICINE, Issue 1 2001K. J. Mattila Mattila KJ, Juvonen JT, Kotamäki MK, Saikku PA (Helsinki University Hospital, Helsinki; Kainuu Central Hospital, Kajaani, and National Public Health Institute, Oulu, Finland). Chlamydia pneumoniae and luminal narrowing after coronary angioplasty. J Intern Med 2001; 250: 67,71. Objectives.,Numerous studies have linked Chlamydia pneumoniae with atherosclerotic vessel disease and a trend for an association of the bacteria with restenosis after percutaneous transluminae coronary angioplasty (PTCA) has also been observed. The aim of this study was to assess the role of Chlamydia pneumoniae in the luminal narrowing taking place after PTCA. Design.,A noninterventional 6-month follow-up study. Setting.,A university hospital. Subjects.,A total of 122 patients with angiographically proven coronary heart disease (CHD) referred for PTCA. Interventions.,None. Main outcome measures.,The degree of luminal narrowing in the coronary arteries following coronary angioplasty. Results.,The levels of C. pneumoniae antibodies (IgG, IgA and IgM classes) and immune complexes were not associated with luminal narrowing after PTCA in multivariate analyses whilst smoking, plasma endothelin levels and diabetes were. The serologic parameters did not change during the follow up either. Conclusions.,These results do not support a role for C. pneumoniae in luminal narrowing following PTCA. [source] 2-Deoxyglucose and NMDA inhibit protein synthesis in neurons and regulate phosphorylation of elongation factor-2 by distinct mechanismsJOURNAL OF NEUROCHEMISTRY, Issue 3 2006M. Maus Abstract Cerebral ischaemia is associated with brain damage and inhibition of neuronal protein synthesis. A deficit in neuronal metabolism and altered excitatory amino acid release may both contribute to those phenomena. In the present study, we demonstrate that both NMDA and metabolic impairment by 2-deoxyglucose or inhibitors of mitochondrial respiration inhibit protein synthesis in cortical neurons through the phosphorylation of eukaryotic elongation factor (eEF-2), without any change in phosphorylation of initiation factor eIF-2,. eEF-2 kinase may be activated both by Ca2+ -independent AMP kinase or by an increase in cytosolic Ca2+. Although NMDA decreases ATP levels in neurons, only the effects of 2-deoxyglucose on protein synthesis and phosphorylation of elongation factor eEF-2 were reversed by Na+ pyruvate. Protein synthesis inhibition by 2-deoxyglucose was not as a result of a secondary release of glutamate from cortical neurons as it was not prevented by the NMDA receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo-(a,d)-cyclohepten-5,10-imine hydrogen maleate (MK 801), nor to an increase in cytosolic-free Ca2+. Conversely, 2-deoxyglucose likely activates eEF-2 kinase through a process involving phosphorylation by AMP kinase. In conclusion, we provide evidence that protein synthesis can be inhibited by NMDA and metabolic deprivation by two distinct mechanisms involving, respectively, Ca2+ -dependent and Ca2+ -independent eEF-2 phosphorylation. [source] Use of micro-Raman spectroscopy to study reaction kinetics in blended white cement pastes containing metakaolinJOURNAL OF RAMAN SPECTROSCOPY, Issue 12 2009Moisés Frķas Abstract Curing temperature is known to play an important role in the formation, development, and stability of the hydrated phases appearing during pozzolanic reactions (chemical reaction between puzzolanic addition, metakaolin (MK), and calcium hydroxide from cement hydration). A typical example of this important reaction is to be found in metakaolin-bearing cement pastes, characterized by hexagonal phases whose thermodynamic stability declines with rising temperature. These phases cannot be exhaustively researched with traditional techniques (such as X-ray diffraction) due to their poor crystallinity. Consequently, micro-Raman spectroscopy was used in the present study to explore the behavior of white cement paste blends containing 0, 10, and 25% MK at two curing temperatures (20 and 60 °C). This led to the identification, for the first time using Raman spectroscopy, of phases C2ASH81 (stratlingite) and C3ASH6, which appear in the MK,white cement reaction. The CSH gel formed was characterized by Q1 dimers and a C/S ratio of 1.3,1.5. Raising the curing temperature favored the formation of C4AH13. Copyright © 2009 John Wiley & Sons, Ltd. [source] NMR spectra, GIAO and charge density calculations of five-membered aromatic heterocyclesMAGNETIC RESONANCE IN CHEMISTRY, Issue 7 2007Alan R. Katritzky Abstract The B3LYP/6-31 + G(d) molecular geometry optimized structures of 17 five-membered heterocycles were employed together with the gauge including atomic orbitals (GIAO) density functional theory (DFT) method at the B3LYP/6-31 + G(d,p), B3LYP/6-311 + + G(d,p) and B3LYP/6-311 + G(2d,p) levels of theory for the calculation of proton and carbon chemicals shifts and coupling constants. The method of geometry optimization for pyrrole (1), N -methylpyrrole (2) and thiophene (7) using the larger 6-311 + + G(d,p) basis sets at the B3LYP/6-31 + G(d,p), B3LYP/6-311 + + G(d,p), B3LYP/6-31 + G(2d,p) and B3LYP/cc-pVTZ levels of theory gave little difference between calculated and experimental values of coupling constants. In general, the 1H and 13C chemical shifts for all compounds are in good agreement with theoretical calculations using the smaller 6-31 basis set. The values of nJHH(n = 3, 4, 5) and rmnJCH(n = 1, 2, 3, 4) were predicted well using the larger 6-31 + G(d,p) and 6-311 + + G(d,p) basis sets and at the B3LYP/6-31 + G(d,p), B3LYP/6-311 + + G(d,p), B3LYP/6-31 + G(2d,2p) levels of theory. The computed atomic charges [Mülliken; Natural Bond Orbital Analysis (NBO); Merz-Kollman (MK); CHELP and CHELPG] for the B3LYP/6-311 + + G(d,p) geometry optimized structures of 1,17 were used to explore correlations with the experimental proton and carbon chemical shifts. Copyright © 2007 John Wiley & Sons, Ltd. [source] Risk of first-generation H1 -antihistamines: a GA2LEN position paperALLERGY, Issue 4 2010M. K. Church To cite this article: Church MK, Maurer M, Simons FER, Bindslev-Jensen C, van Cauwenberge P, Bousquet J, Holgate ST, Zuberbier T. Risk of first-generation H1 -antihistamines: a GA2LEN position paper. Allergy 2010; 65: 459,466. Abstract Background: First-generation H1 -antihistamines obtained without prescription are the most frequent form of self-medication for allergic diseases, coughs and colds and insomnia even though they have potentially dangerous unwanted effects which are not recognized by the general public. Aims:, To increase consumer protection by bringing to the attention of regulatory authorities, physicians and the general public the potential dangers of the indiscriminate use first-generation H1 -antihistamines purchased over-the counter in the absence of appropriate medical supervision. Methods:, A GA2LEN (Global Allergy and Asthma European Network) task force assessed the unwanted side-effects and potential dangers of first-generation H1-antihistamines by reviewing the literature (Medline and Embase) and performing a media audit of US coverage from 1996 to 2008 of accidents and fatal adverse events in which these drugs were implicated. Results:, First-generation H1 -antihistamines, all of which are sedating, are generally regarded as safe by laypersons and healthcare professionals because of their long-standing use. However, they reduce rapid eye movement (REM)-sleep, impair learning and reduce work efficiency. They are implicated in civil aviation, motor vehicle and boating accidents, deaths as a result of accidental or intentional overdosing in infants and young children and suicide in teenagers and adults. Some exhibit cardiotoxicity in overdose. Conclusions:, This review raises the issue of better consumer protection by recommending that older first-generation H1 -antihistamines should no longer be available over-the-counter as prescription- free drugs for self-medication of allergic and other diseases now that newer second- generation nonsedating H1 -antihistamines with superior risk/benefit ratios are widely available at competitive prices. [source] Adulthood asthma after wheezing in infancy: a questionnaire study at 27 years of ageALLERGY, Issue 4 2010M. Ruotsalainen To cite this article: Ruotsalainen M, Piippo-Savolainen E, Hyvärinen MK, Korppi M. Adulthood asthma after wheezing in infancy: a questionnaire study at 27 years of age. Allergy 2010; 65: 503,509. Abstract Background:, Wheezing in early childhood is a heterogeneous condition, the long-term prognosis varying from total recovery to chronic asthma. Though short-term outcome has been actively studied, there is lack of data on long-term outcome until adulthood. The aim of the study was to evaluate the prevalence and risk factors of asthma at 26,29 years of age after early-life wheezing. Methods:, At the median age of 27.3 years (range 26.3,28.6), a questionnaire was sent to 78 study subjects hospitalized for wheezing at <24 months of age, and 59 (76%) answered. Asthma, allergy and weight status were compared with selected controls followed up from birth and with non-selected population controls recruited for this adulthood study. Results:, Doctor-diagnosed asthma was present in 20% of the former bronchiolitis patients, compared with 5% in the two control groups (OR 2.1, 95% CI 0.3,17.9 vs selected controls; OR 5.2, 95% CI 1.7,15.8 vs nonselected controls). The respective figures for current self-reported asthma were 41% and 7,10% (OR 11.4, 95% CI 2.3,56.1 vs selected controls; OR 12.2, 95% CI 4.4,33.7 vs nonselected controls). Current allergic rhinitis and current smoking were significantly associated with asthma, but current overweight or obesity was not. In multivariate analyses, early-life wheezing was an independent risk factor of adulthood asthma. Conclusion:, An increased asthma risk in early-life wheezers continues, even after many symptom-free years at school age, at least until 27 years of age. [source] Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapyMEDICINAL RESEARCH REVIEWS, Issue 3 2008Rongshi Li Abstract Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) involved in the genesis of several human cancers; indeed, ALK was initially identified in constitutively activated and oncogenic fusion forms,the most common being nucleophosmin (NPM)-ALK,in a non-Hodgkin's lymphoma (NHL) known as anaplastic large-cell lymphoma (ALCL) and subsequent studies identified ALK fusions in the human sarcomas called inflammatory myofibroblastic tumors (IMTs). In addition, two recent reports have suggested that the ALK fusion, TPM4-ALK, may be involved in the genesis of a subset of esophageal squamous cell carcinomas. While the cause-effect relationship between ALK fusions and malignancies such as ALCL and IMT is very well established, more circumstantial links implicate the involvement of the full-length, normal ALK receptor in the genesis of additional malignancies including glioblastoma, neuroblastoma, breast cancer, and others; in these instances, ALK is believed to foster tumorigenesis following activation by autocrine and/or paracrine growth loops involving the reported ALK ligands, pleiotrophin (PTN) and midkine (MK). There are no currently available ALK small-molecule inhibitors approved for clinical cancer therapy; however, recognition of the variety of malignancies in which ALK may play a causative role has recently begun to prompt developmental efforts in this area. This review provides a succinct summary of normal ALK biology, the confirmed and putative roles of ALK fusions and the full-length ALK receptor in the development of human cancers, and efforts to target ALK using small-molecule kinase inhibitors. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 3, 372,412, 2008 [source] Lactococcus lactis produces short-chain quinones that cross-feed Group B Streptococcus to activate respiration growthMOLECULAR MICROBIOLOGY, Issue 5 2008Lahcen Rezaļki Summary Quinones are essential components of the respiration chain that shuttle electrons between oxidoreductases. We characterized the quinones synthesized by Lactococcus lactis, a fermenting bacterium that activates aerobic respiration when a haem source is provided. Two distinct subgroups were characterized: Menaquinones (MK) MK-8 to MK-10, considered as hallmarks of L. lactis, are produced throughout growth. MK-3 and demethylMK-3 [(D)MK-3] are newly identified and are present only late in growth. Production of (D)MK-3 was conditional on the carbon sugar and on the presence of carbon catabolite regulator gene ccpA. Electron flux driven by both (D)MK fractions was shared between the quinol oxidase and extracellular acceptors O2, iron and, with remarkable efficiency, copper. Purified (D)MK-3, but not MK-8,10, complemented a menB defect in L. lactis. We previously showed that a respiratory metabolism is activated in Group B Streptococcus (GBS) by exogenous haem and MK, and that this activity is implicated in virulence. Here we show that growing lactococci donate (D)MK to GBS to activate respiration and stimulate growth of this opportunist pathogen. We propose that conditions favouring (D)MK production in dense microbial ecosystems, as present in the intestinal tract, could favour implantation of (D)MK-scavengers like GBS within the complex. [source] Surface tension of poly(ester urethane)s and poly(ether urethane)sPOLYMER INTERNATIONAL, Issue 3 2007Mihaela Lupu Abstract The correlation between the surface tension parameters and the chemical composition of poly(ester urethane) and poly(ether urethane) thin films with different soft and hard segments, both before and after plasma treatment, was investigated. Calculations are based on the geometric mean approach of Owens and Wendt (Owens DK and Wendt RC, J Appl Polym Sci13:1741 (1969)), Rabel (Rabel W, Physikalische Blätter33:151 (1977)) and Kälble (Kälble DH, J Adhesion1:102 (1969)), on the Lifshitz,van der Waals acid/base approach of van Oss and co-workers (van Oss CJ, Good RJ and Chaudhury MK, Langmuir4:884 (1988); van Oss CJ, Ju L, Chaudhury MK and Good RJ, Chem Rev88:927 (1988); van Oss CJ, Interfacial Forces in Aqueous Media. Marcel Dekker, New York (1994)) and on the theoretical methods involving quantitative structure,property relationships (Bicerano J, JMS Rev Macromol Chem PhysC36:161 (1996)). For all investigated films, the polar terms contribute significantly to the total surface tensions, as due to the large electron donor, , interactions. Plasma treatment alters the surface energy of samples by changing their surface polarity and hydrophilicity. The hydrophilicity trends for polyurethanes were also studied by means of the free energy of hydration between compounds and water. Preliminary blood contact tests of the selected polyurethane sample with higher hydrophilicity were developed for biomedical applications. Copyright © 2006 Society of Chemical Industry [source] Patients' Knowledge about Risk Factors for Erectile Dysfunction is PoorTHE JOURNAL OF SEXUAL MEDICINE, Issue 10 2008Martin K. Baumgartner MD ABSTRACT Introduction., Well informed and educated patients ideally manage to prevent or delay the onset of severe chronic diseases. With respect to erectile dysfunction (ED) this is of importance because ED is considered to herald debilitating cardiovascular diseases like coronary artery disease. Aim., This survey aimed to assess patient's knowledge about risk factors (RF) for ED and to identify their preferred source of information. Main Outcome Measures., Knowledge of RF for ED and sources used to gather information about ED as reported by patients with ED. Methods., Between July 2004 and June 2006, 126 patients who presented at our outpatient clinic for an assessment of their ED were prospectively evaluated. The patients received a questionnaire about their demographic and socioeconomic circumstances, their strategies to gather information about ED, and their knowledge of specific RF for this disease. The questionnaire was completed by 81 patients (64%). Results., Forty-one patients (51%) could not name one single RF for ED. Three men knew more than three RF. The two most popular sources of information were the Internet and general practitioners. Well-educated patients were significantly better informed than others. Patients using the Internet as source for health information were significantly younger and had a better knowledge about RF for ED compared to those not using the Internet. Conclusions., Patients' knowledge about RF for ED is poor. The Internet seems to be the most useful information source for patients with ED and is predominantly used by younger and better educated patients. Given that ED is considered to be a precursor lesion of severe cardiovascular diseases, patient information and education deserves more attention. Baumgartner MK, Hermanns T, Cohen A, Schmid DM, Seifert B, Sulser T, and Strebel RT. Patients' knowledge about risk factors for erectile dysfunction is poor. J Sex Med 2008;5:2399,2404. [source] The Effect of Korean Red Ginseng Extract on the Relaxation Response in Isolated Rabbit Vaginal Tissue and Its MechanismTHE JOURNAL OF SEXUAL MEDICINE, Issue 9 2008Sun-Ouck Kim MD ABSTRACT Introduction., Ginseng is an herbal medicine with a variety of biological activities. Aim., The purpose of this study was to investigate the effect of Korean red ginseng (KRG) extract on the relaxation response in isolated rabbit vaginal tissue and its mechanism as a potential therapeutic agent for female sexual dysfunction. Method., Strips of rabbit vagina were mounted in organ chambers to measure isometric tension. After the strips were precontracted with phenylephrine, the contractile responses to KRG extract (1,20 mg/mL), nitric oxide inhibitor (N[omega]-nitro-L-arginine methyl ester [L-NAME]), an inhibitor of soluble guanylate cyclase (methylene blue), an inhibitor of Ca2+ -activated K+ channels (tetraethylammonium [TEA]), and an adenosine triphosphate (ATP)-sensitive K+ channel blocker (glybenclamide) were examined. Main Outcome Measures., The relaxation of the vaginal tissue strip was assessed after treating KRG extract or other chemicals. Results., KRG (1,20 mg/mL) extract relaxed the vaginal tissue strip in a dose-dependent manner up to 85%. The relaxation effect was significantly inhibited by L-NAME (30 µM) and methylene blue (30 µM) (P < 0.05). In addition, KRG inhibited the contraction induced by depolarization with 10, 20, and 40 mM KCl. The KRG-induced relaxation effect was significantly inhibited by TEA (300 µM) (P < 0.05), and not by glybenclamide (30 µM). Conclusions., These data show that KRG extract has a relaxing effect on rabbit vaginal smooth muscle tissue. These effects might be mediated partly through the NO pathway and hyperpolarization via Ca2+ -activated K+ channels. Kim S-O, Kim MK, Lee H-S, Park JK, and Park K. The effect of Korean red ginseng extract on the relaxation response in isolated rabbit vaginal tissue and its mechanism. J Sex Med 2008;5:2079,2084. [source] ORIGINAL RESEARCH,WOMEN'S SEXUAL HEALTH: Genital Sensation and Sexual Function in Women Bicyclists and Runners: Are Your Feet Safer than Your Seat?THE JOURNAL OF SEXUAL MEDICINE, Issue 6 2006Marsha K. Guess MD ABSTRACT Introduction., Bicycling is associated with neurological impairment and impotence in men. Similar deficits have not been confirmed in women. Aim., To evaluate the effects of bicycling on genital sensation and sexual function in women. Methods., Healthy, premenopausal, competitive women bicyclists and runners (controls) were compared. Main Outcome Measures., (1) Genital vibratory thresholds (VTs) were determined using the Medoc Vibratory Sensation Analyzer 3000. (2) Sexual function and sexually related distress were assessed by the Dennerstein Personal Experience Questionnaire (SPEQ) and the Female Sexual Distress Scale (FSDS). Results., Forty-eight bicyclists and 22 controls were enrolled. The median age was 33 years. The bicyclists were older, had higher body mass indices (BMIs), were more diverse in their sexual orientation, and were more likely to have a current partner. Bicyclists rode an average of 28.3 ± 19.7 miles/day (range 4,100), 3.8 ± 1.5 days/week, for an average of 2.1 ± 1.8 hours/ride. The mean number of years riding was 7.9 ± 7.1 years (range 0.5,30). Controls ran an average of 4.65 ± 2.1 miles/day (range 1.5,8) and 5.0 ± 1.2 days/week. On bivariate analysis, bicyclists had significantly higher VTs than runners, indicating worse neurological function at all sites (P < 0.05). Multivariate analysis found significant correlations between higher VTs and bicycling at the left and right perineum, posterior vagina, left and right labia. Increasing VTs at the clitoris, anterior vagina, and urethra were associated with age. In bicyclists, there were no correlations between VTs and miles biked per week, duration of riding, or BMI. Composite SPEQ scores indicated normal sexual function in all sexually active subjects. Neither group suffered from sexually related distress. Conclusion., There is an association between bicycling and decreased genital sensation in competitive women bicyclists. Negative effects on sexual function and quality of life were not apparent in our young, healthy premenopausal cohort. Guess MK, Connell K, Schrader S, Reutman S, Wang A, LaCombe J, Toennis C, Lowe B, Melman A, and Mikhail MK. Genital sensation and sexual function in women bicyclists and runners: Are your feet safer than your seat? J Sex Med 2006;3:1018,1027. [source] Neutron and electron diffraction studies of La(Zn1/2Ti1/2)O3 perovskiteACTA CRYSTALLOGRAPHICA SECTION B, Issue 4 2006Yi Hu The crystallography and microwave dielectric properties of La(Zn1/2Ti1/2)O3 (LZT) ceramics prepared via the mixed-oxide route were investigated in this study. While samples were largely single phase, small amounts of ZnO impurity were detected in sintered pellets. Observed reflections in electron and neutron diffraction patterns indicate that the symmetry of LZT is P21/n. The B site is ordered on {110} or pseudocubic {111}, but the presence of the pseudocubic (111) reflection is in itself insufficient to indicate the existence of such order. Rietveld refinements of the neutron diffraction data yield an excellent fit for such a model. The structure is highly twinned, with variants related through common {211} composition planes and 90° rotations about ,011,. The microwave dielectric properties measured were ,r = 34, Qf = 36,090 and ,f = ,70,MK,1. [source] EMK: A Novel Program for Family-Based Allelic and Genotypic Association Tests on Quantitative TraitsANNALS OF HUMAN GENETICS, Issue 3 2008Y. W. Li Summary The QTDT program is a widely-used program for analyzing quantitative trait data, but the methods mainly test allelic association. Since the genotype of a marker is a direct observation for an individual, it is of interest to assess association at the genotypic level. In this study, we extended the allele-based association method developed by Monks and Kaplan (MK method) to genotype-based association tests for quantitative traits. We implemented a novel extended MK (EMK) program that can perform both allele- and genotype- based association tests in any pedigree structure. To evaluate the performance of EMK, we utilized simulated pedigree data and real data from our previous report of GSTO1 and GSTO2 genes in Alzheimer disease (AD). Both allele- and genotype-based EMK methods (allele-EMK and geno-EMK) showed correct type I error for various pedigree structures and admixture populations. The geno-EMK method showed comparable power to the allele-EMK test. By treating age-at-onset (AAO) as a quantitative trait, the EMK program was able to detect significant associations for rs4925 in GSTO1 (P= 0.006 for allele-EMK and P= 0.009 for geno-EMK), and rs2297235 in GSTO2 (P= 0.005 for allele-EMK and P= 0.009 for geno-EMK), which are consistent with our previous findings. [source] Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in IcelandAPMIS, Issue 9 2010GEIR TRYGGVASON Tryggvason G, Hilmarsdottir B, Gunnarsson GH, Jónsson JJ, Jónasson JG, Magnśsson MK. Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in Iceland. APMIS 2010; 118: 648,56. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. It is characterized by activating mutations in the tyrosine kinase genes c-kit or PDGFRA. This study examined the mutation rate and type in a population-based material. All gastrointestinal mesenchymal tumors over the years 1990,2004 were evaluated and GIST tumors identified using immunohistochemistry (c-kit) and conventional pathologic parameters. Paraffin sections from all tumors were subjected to mutation analysis on exons 9, 11, 13 and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene. To screen for mutations, we used a highly sensitive conformation-sensitive gel electrophoresis (CSGE) and to define the mutated alleles, we employed direct automated DNA sequencing. All c-kit-positive gastrointestinal mesenchymal tumors were entered into the study. Fifty-six tumors from 55 patients were analyzed. Mutations were found in 52 tumors representing a 92.9% mutational rate. Most of the mutations were found in c-kit exon 11 (76.8%), followed by c-kit exon 9 (10.7%). PDGFRA mutations were only found in three tumors. No correlation of mutation type with biologic behavior was found. This population-based study, using a sensitive CSGE method, identifies mutations in the great majority of patients with GIST. [source] Persistence of borrelial DNA in the joints of Borrelia burgdorferi -infected mice after ceftriaxone treatmentAPMIS, Issue 9 2010HETA YRJÄNÄINEN Yrjänäinen H, Hytönen J, Hartiala P, Oksi J, Viljanen MK. Persistence of borrelial DNA in the joints of Borrelia burgdorferi -infected mice after ceftriaxone treatment. APMIS 2010; 118: 665,73. We have earlier shown that Borrelia burgdorferi -infected and ceftriaxone-treated mice have viable spirochetes in their body, since immunosuppressive treatment allows B. burgdorferi to be detected by culture. However, the niche of the persisting spirochetes remained unknown. In the present study, we analyzed the tissues of B. burgdorferi -infected and ceftriaxone-treated mice by culture and PCR to reveal the foci of persisting spirochetes. C3H/HeN mice were infected via intradermal needle injection with B. burgdorferi s.s. N40. The mice were treated as follows: (i) short (5 days) and (ii) long (18 days) course of ceftriaxone at 2 weeks of infection and killed after either 10 or 30 weeks, or (iii) the mice received ceftriaxone for 5 days at 18 weeks of infection and were killed 21 weeks after the treatment. All samples of ceftriaxone-treated mice were culture negative, whereas all untreated controls were culture positive. Importantly, B. burgdorferi DNA was detected in the joints of 30,100% of the treated mice. In conclusion, these results combined with earlier results suggest that the joint or a tissue adjacent to the joint is the niche of persisting B. burgdorferi in ceftriaxone-treated mice. [source] Vancomycin-resistant Enterococcus spp.: validation of susceptibility testing and in vitro activity of vancomycin, linezolid, tigecycline and daptomycinAPMIS, Issue 1 2010MATHIAS RATHE Rathe M, Kristensen L, Ellermann-Eriksen S, Thomsen MK, Schumacher H. Vancomycin-resistant Enterococcus spp.: validation of susceptibility testing and in vitro activity of vancomycin, linezolid, tigecycline and daptomycin. APMIS 2010; 118: 66,73. Vancomycin-resistant enterococci (VRE) have emerged to become a significant nosocomial pathogen. However, detection may be challenging and treatment possibilities are limited. Reports of resistance to linezolide, daptomycin and tigecycline underline the need for reliable susceptibility testing with respect to these compounds. We evaluated the in vitro activity of vancomycin, linezolid, daptomycin and tigecycline against a panel of VRE and vancomycin-susceptible enterococci by broth microdilution (BMD). Etest for determination of minimum inhibitory concentration of these four antibiotics and two disc diffusion assays for detecting VRE and for susceptibility testing against tigecycline and linezolid were evaluated. Before susceptibility testing, all isolates were classified by polymerase chain reaction as vanA or vanB gene positive or vanA/B gene negative. Linezolid, daptomycin and tigecycline had excellent in vitro activity towards all isolates. For daptomycin and tigecycline, the overall agreement between BMD and Etest was suboptimal. For both disc diffusion assays, use of current break points was inadequate to detect vancomycin resistance for isolates carrying the vanB gene. Inspection of the inhibition zone for a diffuse edge, as recommended, accurately predicted presence of the vanB gene. [source] A composite K -band luminosity function for cluster galaxiesASTRONOMISCHE NACHRICHTEN, Issue 9-10 2009R. De Propris Abstract We present a composite K -band luminosity function for 10 clusters at low redshift, where member galaxies are identified from an existing spectroscopic survey (the 2dF galaxy redshift survey). Our kinematically selected K -band luminosity function is well fitted by a Schechter function with MK * = ,24.50 + 5 log h and , = ,0.98 over ,27 , MK ,5 log h < ,22. This is very similar to the 2dF field value and suggests that the integrated mass accretion history of galaxies does not vary strongly with environment (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Trends and abrupt changes of precipitation maxima in the Pearl River basin, ChinaATMOSPHERIC SCIENCE LETTERS, Issue 2 2009Q. Zhang Abstract We applied the Mann-Kendall (MK) test and Bayesian model to systematically explore trends and abrupt changes of the precipitation series in the Pearl River basin. The results showed that no significant trends were detected for annual precipitation and summer or winter precipitation totals. Significant negative trends were identified for the number of rainy days across the Pearl River basin; significant positive trends were observed regarding precipitation intensity (PI). In particular, the precipitation totals and frequencies of extremely high precipitation events are subject to significant positive trends. In addition, the number of extremely low precipitation events was also increasing significantly. Factors affecting the changes in precipitation patterns are the weakening Asian monsoon and consequently increasing moisture transport to Southern China and the Pearl River basin. In summary, the main findings of this study are: (1) increased precipitation variability and high-intensity rainfall was observed though rainy days and low-intensity rainfall have decreased, and (2) the amount of rainfall has changed little but its variability has increased over the time interval divided by change points. These finds indicate potentially increased risk for both agriculture and in locations subject to flooding, both urban and rural, across the Pearl River basin. Copyright © 2009 Royal Meteorological Society [source] Effects of the Non-Competitive NMDA Receptor Antagonist Memantine on the Volitional Consumption of Ethanol by Alcohol-Preferring RatsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2010Gloria E. Malpass This study examined the effects of memantine, a low-affinity, open channel NMDA antagonist, on volitional consumption of ethanol by alcohol-preferring rats and potential locomotor, sedative and hypothermic effects. Volitional consumption of ethanol in a 24-hr two-choice paradigm was determined for male Myers' high-ethanol-preferring (mHEP) rats. Effects of memantine (0.3, 1.0, 3.0 and 10.0 mg/kg, i.p., b.i.d. [twice daily] for 3 days) or vehicle on volitional consumption of ethanol, proportion of ethanol to total fluids consumed, total fluid intake and consumption of food were observed. Potential sedating and locomotor effects of memantine (10.0 mg/kg, i.p., b.i.d.) were determined using an elevated plus maze and an Auto-Track Opto-Varimex activity monitoring system. Rectal temperature was measured to determine if memantine (10.0 mg/kg, i.p.) produces a hypothermic effect. The results indicate that memantine dose-dependently decreased the amount of ethanol and proportion of ethanol to total fluids consumed daily, reaching 48% and 24%, respectively, at the highest dose. These effects did not appear to be anti-caloric. Memantine (10.0 mg/kg) partially reversed both the sedation and the reductions in locomotor activity induced by ethanol. This dose did, however, produce a small, partially reversible hypothermic effect. In conclusion, memantine may decrease ethanol consumption with fewer side effects than other NMDA receptor antagonists, such as phencyclidine (PCP), MK 801 and ketamine. [source] | ||||||||||||||||||||||||||||||||||||||||