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Sample records for atypical kinase implicated

  1. Complement Mutations in Diacylglycerol Kinase-ε–Associated Atypical Hemolytic Uremic Syndrome

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    Sánchez Chinchilla, Daniel; Pinto, Sheila; Hoppe, Bernd; Adragna, Marta; Lopez, Laura; Justa Roldan, Maria Luisa; Peña, Antonia; Lopez Trascasa, Margarita; Sánchez-Corral, Pilar; Rodríguez de Córdoba, Santiago

    2014-01-01

    Background and objectives Atypical hemolytic uremic syndrome is characterized by vascular endothelial damage caused by complement dysregulation. Consistently, complement inhibition therapies are highly effective in most patients with atypical hemolytic uremic syndrome. Recently, it was shown that a significant percentage of patients with early-onset atypical hemolytic uremic syndrome carry mutations in diacylglycerol kinase-ε, an intracellular protein with no obvious role in complement. These data support an alternative, complement-independent mechanism leading to thrombotic microangiopathy that has implications for treatment of early-onset atypical hemolytic uremic syndrome. To get additional insights into this new form of atypical hemolytic uremic syndrome, the diacylglycerol kinase-ε gene in a cohort with atypical hemolytic uremic syndrome was analyzed. Design, setting, participants, & measurements Eighty-three patients with early-onset atypical hemolytic uremic syndrome (<2 years) enrolled in the Spanish atypical hemolytic uremic syndrome registry between 1999 and 2013 were screened for mutations in diacylglycerol kinase-ε. These patients were also fully characterized for mutations in the genes encoding factor H, membrane cofactor protein, factor I, C3, factor B, and thrombomodulin CFHRs copy number variations and rearrangements, and antifactor H antibodies. Results Four patients carried mutations in diacylglycerol kinase-ε, one p.H536Qfs*16 homozygote and three compound heterozygotes (p.W322*/p.P498R, two patients; p.Q248H/p.G484Gfs*10, one patient). Three patients also carried heterozygous mutations in thrombomodulin or C3. Extensive plasma infusions controlled atypical hemolytic uremic syndrome recurrences and prevented renal failure in the two patients with diacylglycerol kinase-ε and thrombomodulin mutations. A positive response to plasma infusions and complement inhibition treatment was also observed in the patient with concurrent diacylglycerol

  2. Complement mutations in diacylglycerol kinase-ε-associated atypical hemolytic uremic syndrome.

    Science.gov (United States)

    Sánchez Chinchilla, Daniel; Pinto, Sheila; Hoppe, Bernd; Adragna, Marta; Lopez, Laura; Justa Roldan, Maria Luisa; Peña, Antonia; Lopez Trascasa, Margarita; Sánchez-Corral, Pilar; Rodríguez de Córdoba, Santiago

    2014-09-05

    Atypical hemolytic uremic syndrome is characterized by vascular endothelial damage caused by complement dysregulation. Consistently, complement inhibition therapies are highly effective in most patients with atypical hemolytic uremic syndrome. Recently, it was shown that a significant percentage of patients with early-onset atypical hemolytic uremic syndrome carry mutations in diacylglycerol kinase-ε, an intracellular protein with no obvious role in complement. These data support an alternative, complement-independent mechanism leading to thrombotic microangiopathy that has implications for treatment of early-onset atypical hemolytic uremic syndrome. To get additional insights into this new form of atypical hemolytic uremic syndrome, the diacylglycerol kinase-ε gene in a cohort with atypical hemolytic uremic syndrome was analyzed. Eighty-three patients with early-onset atypical hemolytic uremic syndrome (<2 years) enrolled in the Spanish atypical hemolytic uremic syndrome registry between 1999 and 2013 were screened for mutations in diacylglycerol kinase-ε. These patients were also fully characterized for mutations in the genes encoding factor H, membrane cofactor protein, factor I, C3, factor B, and thrombomodulin CFHRs copy number variations and rearrangements, and antifactor H antibodies. Four patients carried mutations in diacylglycerol kinase-ε, one p.H536Qfs*16 homozygote and three compound heterozygotes (p.W322*/p.P498R, two patients; p.Q248H/p.G484Gfs*10, one patient). Three patients also carried heterozygous mutations in thrombomodulin or C3. Extensive plasma infusions controlled atypical hemolytic uremic syndrome recurrences and prevented renal failure in the two patients with diacylglycerol kinase-ε and thrombomodulin mutations. A positive response to plasma infusions and complement inhibition treatment was also observed in the patient with concurrent diacylglycerol kinase-ε and C3 mutations. Data suggest that complement dysregulation influences

  3. Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics.

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    Li, Xiaohua; Rosborough, Kelley M; Friedman, Ari B; Zhu, Wawa; Roth, Kevin A

    2007-02-01

    Glycogen synthase kinase-3 (GSK3) has been recognized as an important enzyme that modulates many aspects of neuronal function. Accumulating evidence implicates abnormal activity of GSK3 in mood disorders and schizophrenia, and GSK3 is a potential protein kinase target for psychotropics used in these disorders. We previously reported that serotonin, a major neurotransmitter involved in mood disorders, regulates GSK3 by acutely increasing its N-terminal serine phosphorylation. The present study was undertaken to further determine if atypical antipsychotics, which have therapeutic effects in both mood disorders and schizophrenia, can regulate phospho-Ser-GSK3 and inhibit its activity. The results showed that acute treatment of mice with risperidone rapidly increased the level of brain phospho-Ser-GSK3 in the cortex, hippocampus, striatum, and cerebellum in a dose-dependent manner. Regulation of phospho-Ser-GSK3 was a shared effect among several atypical antipsychotics, including olanzapine, clozapine, quetiapine, and ziprasidone. In addition, combination treatment of mice with risperidone and a monoamine reuptake inhibitor antidepressant imipramine or fluoxetine elicited larger increases in brain phospho-Ser-GSK3 than each agent alone. Taken together, these results provide new information suggesting that atypical antipsychotics, in addition to mood stabilizers and antidepressants, can inhibit the activity of GSK3. These findings may support the pharmacological mechanisms of atypical antipsychotics in the treatment of mood disorders.

  4. The Link between Protein Kinase CK2 and Atypical Kinase Rio1

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    Konrad Kubiński

    2017-02-01

    Full Text Available The atypical kinase Rio1 is widespread in many organisms, ranging from Archaebacteria to humans, and is an essential factor in ribosome biogenesis. Little is known about the protein substrates of the enzyme and small-molecule inhibitors of the kinase. Protein kinase CK2 was the first interaction partner of Rio1, identified in yeast cells. The enzyme from various sources undergoes CK2-mediated phosphorylation at several sites and this modification regulates the activity of Rio1. The aim of this review is to present studies of the relationship between the two different kinases, with respect to CK2-mediated phosphorylation of Rio1, regulation of Rio1 activity, and similar susceptibility of the kinases to benzimidazole inhibitors.

  5. Structure of the human protein kinase MPSK1 reveals an atypical activation loop architecture.

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    Eswaran, Jeyanthy; Bernad, Antonio; Ligos, Jose M; Guinea, Barbara; Debreczeni, Judit E; Sobott, Frank; Parker, Sirlester A; Najmanovich, Rafael; Turk, Benjamin E; Knapp, Stefan

    2008-01-01

    The activation segment of protein kinases is structurally highly conserved and central to regulation of kinase activation. Here we report an atypical activation segment architecture in human MPSK1 comprising a beta sheet and a large alpha-helical insertion. Sequence comparisons suggested that similar activation segments exist in all members of the MPSK1 family and in MAST kinases. The consequence of this nonclassical activation segment on substrate recognition was studied using peptide library screens that revealed a preferred substrate sequence of X-X-P/V/I-phi-H/Y-T*-N/G-X-X-X (phi is an aliphatic residue). In addition, we identified the GTPase DRG1 as an MPSK1 interaction partner and specific substrate. The interaction domain in DRG1 was mapped to the N terminus, leading to recruitment and phosphorylation at Thr100 within the GTPase domain. The presented data reveal an atypical kinase structural motif and suggest a role of MPSK1 regulating DRG1, a GTPase involved in regulation of cellular growth.

  6. Clinical Heterogeneity of Atypical Pantothenate Kinase-Associated Neurodegeneration in Koreans

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    Jae-Hyeok Lee

    2016-01-01

    Full Text Available Objective Neurodegeneration with brain iron accumulation (NBIA represents a group of inherited movement disorders characterized by iron accumulation in the basal ganglia. Recent advances have included the identification of new causative genes and highlighted the wide phenotypic variation between and within the specific NBIA subtypes. This study aimed to investigate the current status of NBIA in Korea. Methods We collected genetically confirmed NBIA patients from twelve nationwide referral hospitals and from a review of the literature. We conducted a study to describe the phenotypic and genotypic characteristics of Korean adults with atypical pantothenate kinase-associated neurodegeneration (PKAN. Results Four subtypes of NBIA including PKAN (n = 30, PLA2G6-related neurodegeneration (n = 2, beta-propeller protein-associated neurodegeneration (n = 1, and aceruloplasminemia (n = 1 have been identified in the Korean population. The clinical features of fifteen adults with atypical PKAN included early focal limb dystonia, parkinsonism-predominant feature, oromandibular dystonia, and isolated freezing of gait (FOG. Patients with a higher age of onset tended to present with parkinsonism and FOG. The p.R440P and p.D378G mutations are two major mutations that represent approximately 50% of the mutated alleles. Although there were no specific genotype-phenotype correlations, most patients carrying the p.D378G mutation had a late-onset, atypical form of PKAN. Conclusions We found considerable phenotypic heterogeneity in Korean adults with atypical PKAN. The age of onset may influence the presentation of extrapyramidal symptoms.

  7. The atypical mitogen-activated protein kinase ERK3 is essential for establishment of epithelial architecture.

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    Takahashi, Chika; Miyatake, Koichi; Kusakabe, Morioh; Nishida, Eisuke

    2018-06-01

    Epithelia contribute to physical barriers that protect internal tissues from the external environment and also support organ structure. Accordingly, establishment and maintenance of epithelial architecture are essential for both embryonic development and adult physiology. Here, using gene knockout and knockdown techniques along with gene profiling, we show that extracellular signal-regulated kinase 3 (ERK3), a poorly characterized atypical mitogen-activated protein kinase (MAPK), regulates the epithelial architecture in vertebrates. We found that in Xenopus embryonic epidermal epithelia, ERK3 knockdown impairs adherens and tight-junction protein distribution, as well as tight-junction barrier function, resulting in epidermal breakdown. Moreover, in human epithelial breast cancer cells, inhibition of ERK3 expression induced thickened epithelia with aberrant adherens and tight junctions. Results from microarray analyses suggested that transcription factor AP-2α (TFAP2A), a transcriptional regulator important for epithelial gene expression, is involved in ERK3-dependent changes in gene expression. Of note, TFAP2A knockdown phenocopied ERK3 knockdown in both Xenopus embryos and human cells, and ERK3 was required for full activation of TFAP2A-dependent transcription. Our findings reveal that ERK3 regulates epithelial architecture, possibly together with TFAP2A. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. The Atypical Kinase RIOK1 Promotes Tumor Growth and Invasive Behavior

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    Florian Weinberg

    2017-06-01

    Full Text Available Despite being overexpressed in different tumor entities, RIO kinases are hardly characterized in mammalian cells. We investigated the role of these atypical kinases in different cancer cells. Using isogenic colon-, breast- and lung cancer cell lines, we demonstrate that knockdown of RIOK1, but not of RIOK2 or RIOK3, strongly impairs proliferation and invasiveness in conventional and 3D culture systems. Interestingly, these effects were mainly observed in RAS mutant cancer cells. In contrast, growth of RAS wildtype Caco-2 and Bcr-Abl-driven K562 cells is not affected by RIOK1 knockdown, suggesting a specific requirement for RIOK1 in the context of oncogenic RAS signaling. Furthermore, we show that RIOK1 activates NF-κB signaling and promotes cell cycle progression. Using proteomics, we identified the pro-invasive proteins Metadherin and Stathmin1 to be regulated by RIOK1. Additionally, we demonstrate that RIOK1 promotes lung colonization in vivo and that RIOK1 is overexpressed in different subtypes of human lung- and breast cancer. Altogether, our data suggest RIOK1 as a potential therapeutic target, especially in RAS-driven cancers.

  9. The atypical structure and function of newborn arterial endothelium is mediated by Rho/Rho kinase signaling.

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    Flavahan, Sheila; Flavahan, Nicholas A

    2014-08-15

    Endothelium of fetal or newborn arteries is atypical, displaying actin stress fibers and reduced nitric oxide (NO)-mediated dilatation. This study tested the hypothesis that Rho/Rho kinase signaling, which promotes endothelial stress fibers and inhibits endothelial dilatation, contributed to this phenotype. Carotid arteries were isolated from newborn [postnatal day 1 (P1)], P7, and P21 mice. Endothelial dilatation to acetylcholine (pressure myograph) was minimal at P1, increased at P7, and further increased at P21. Inhibition of Rho (C3 transferase) or Rho kinase (Y27632, fasudil) significantly increased dilatation to acetylcholine in P1 arteries but had no effect in P7 or P21 arteries. After inhibition of NO synthase (N(G)-nitro-l-arginine methyl ester), Rho kinase inhibition no longer increased acetylcholine responses in P1 arteries. Rho kinase inhibition did not affect dilatation to the NO donor DEA-NONOate. The endothelial actin cytoskeleton was labeled with phalloidin and visualized by laser-scanning microscopy. In P1 arteries, the endothelium had prominent transcytoplasmic stress fibers, whereas in P7 and P21 arteries, the actin fibers had a significantly reduced intensity and were restricted to cell borders. Phosphorylation of myosin light chains, a Rho kinase substrate, was highest in P1 endothelium and significantly reduced in P7 and P21 endothelium (laser-scanning microscopy). In P1 arteries, inhibition of Rho (C3 transferase) or Rho kinase (Y27632) significantly reduced the intensity of actin fibers, which were restricted to cell borders. Similarly, in P1 arteries, Rho inhibition significantly reduced endothelial levels of phosphorylated myosin light chains. These results indicate that the atypical function and morphology of newborn endothelium is mediated by Rho/Rho kinase signaling. Copyright © 2014 the American Physiological Society.

  10. The diacylglycerol kinase α/atypical PKC/β1 integrin pathway in SDF-1α mammary carcinoma invasiveness.

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    Elena Rainero

    Full Text Available Diacylglycerol kinase α (DGKα, by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5β1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of β1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and β1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - β1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells.

  11. Association of atypical protein kinase C isotypes with the docker protein FRS2 in fibroblast growth factor signaling.

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    Lim, Y P; Low, B C; Lim, J; Wong, E S; Guy, G R

    1999-07-02

    FRS2 is a docker protein that recruits signaling proteins to the plasma membrane in fibroblast growth factor signal transduction. We report here that FRS2 was associated with PKC lambda when Swiss 3T3 cells were stimulated with basic fibroblast growth factor. PKC zeta, the other member of the atypical PKC subfamily, could also bind FRS2. The association between FRS2 and PKC lambda is likely to be direct as shown by yeast two-hybrid analysis. The C-terminal fragments of FRS2 (amino acid residues 300-508) and SNT2 (amino acids 281-492), an isoform bearing 50% identity to FRS2, interacted with PKC lambda at a region (amino acids 240-562) that encompasses the catalytic domain. In vitro kinase assays revealed neither FRS2 nor SNT2 was a substrate of PKC lambda or zeta. Mutation of the alanine residue (Ala-120) to glutamate in the pseudo-substrate region of PKC lambda results in a constitutively active kinase that exhibited more than 2-fold greater binding to FRS2 in vitro than its "closed" wild-type counterpart. Tyrosine phosphorylation of FRS2 did not affect its binding to the constitutively active PKC lambda mutant, suggesting that the activation of PKC lambda is necessary and sufficient for its association with FRS2. It is likely that FRS2 serves as an anchoring protein for targeting activated atypical PKCs to the cell plasma membrane in signaling pathways.

  12. Cellular localization of the atypical isoforms of protein kinase C (aPKCζ/PKMζ and aPKCλ/ι) on the neuromuscular synapse.

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    Besalduch, Núria; Lanuza, Maria A; Garcia, Neus; Obis, Teresa; Santafe, Manel M; Tomàs, Marta; Priego, Mercedes; Tomàs, Josep

    2013-11-27

    Several classic and novel protein kinase C (PKC) isoforms are selectively distributed in specific cell types of the adult neuromuscular junction (NMJ), in the neuron, glia and muscle components, and are involved in many functions, including neurotransmission. Here, we investigate the presence in this paradigmatic synapse of atypical PKCs, full-length atypical PKC zeta (aPKCζ), its separated catalytic part (PKMζ) and atypical lambda-iota PKC (aPKCλ/ι). High resolution immunohistochemistry was performed using a pan-atypical PKC antibody. Our results show moderate immunolabeling on the three cells (presynaptic motor nerve terminal, teloglial Schwann cell and postsynaptic muscle cell) suggesting the complex involvement of atypical PKCs in synaptic function. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. Association of Factor V Secretion with Protein Kinase B Signaling in Platelets from Horses with Atypical Equine Thrombasthenia.

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    Norris, J W; Pombo, M; Shirley, E; Blevins, G; Tablin, F

    2015-01-01

    Two congenital bleeding diatheses have been identified in Thoroughbred horses: Glanzmann thrombasthenia (GT) and a second, novel diathesis associated with abnormal platelet function in response to collagen and thrombin stimulation. Platelet dysfunction in horses with this second thrombasthenia results from a secretory defect. Two affected and 6 clinically normal horses. Ex vivo study. Washed platelets were examined for (1) expression of the αIIb-β3 integrin; (2) fibrinogen binding capacity in response to ADP and thrombin; (3) secretion of dense and α-granules; (4) activation of the mammalian target of rapamycin (mTOR)-protein kinase B (AKT) signaling pathway; and (5) cellular distribution of phosphatidylinositol-4-phosphate-3-kinase, class 2B (PIK3C2B) and SH2 containing inositol-5'-phosphatase 1 (SHIP1). Platelets from affected horses expressed normal amounts of αIIb-β3 integrin and bound fibrinogen normally in response to ADP, but bound 80% less fibrinogen in response to thrombin. α-granules only released 50% as much Factor V as control platelets, but dense granules released their contents normally. Protein kinase B (AKT) phosphorylation was reduced after thrombin activation, but mTOR Complex 2 (mTORC2) and phosphoinositide-dependent kinase 1 (PDK1) signaling were normal. SH2-containing inositol-5'-phosphatase 1 (SHIP1) did not localize to the cytoskeleton of affected platelets and was decreased overall consistent with reduced AKT phosphorylation. Defects in fibrinogen binding, granule secretion, and signal transduction are unique to this thrombasthenia, which we designate as atypical equine thrombasthenia. Copyright © The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.

  14. The role of the atypical kinases ABC1K7 and ABC1K8 in abscisic acid responses

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    Anna eManara

    2016-03-01

    Full Text Available The ABC1K family of atypical kinases (activity of bc1 complex kinase is represented in bacteria, archaea and eukaryotes. In plants they regulate diverse physiological processes in the chloroplasts and mitochondria, but their precise functions are poorly defined. ABC1K7 and ABC1K8 are probably involved in oxidative stress responses, isoprenyl lipid synthesis and distribution of iron within chloroplasts. Because reactive oxygen species take part in abscisic acid (ABA-mediated processes, we investigated the functions of ABC1K7 and ABC1K8 during germination, stomatal movement and leaf senescence. Both genes were upregulated by ABA treatment and some ABA-responsive physiological processes were affected in abc1k7 and abc1k8 mutants. Germination was more severely affected by ABA, osmotic stress and salt stress in the single and double mutants; the stomatal aperture was smaller in the mutants under standard growth conditions and was not further reduced by exogenous ABA application; ABA-induced senescence symptoms were more severe in the leaves of the single and double mutants compared to wild type leaves. Taken together, our results suggest that ABC1K7 and ABC1K8 might be involved in the cross-talk between ABA and ROS signaling.

  15. Spinal atypical protein kinase C activity is necessary to stabilize inactivity-induced phrenic motor facilitation

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    Strey, K.A.; Nichols, N.L.; Baertsch, N.A.; Broytman, O.; Baker-Herman, T.L.

    2012-01-01

    The neural network controlling breathing must establish rhythmic motor output at a level adequate to sustain life. Reduced respiratory neural activity elicits a novel form of plasticity in circuits driving the diaphragm known as inactivity-induced phrenic motor facilitation (iPMF), a rebound increase in phrenic inspiratory output observed once respiratory neural drive is restored. The mechanisms underlying iPMF are unknown. Here, we demonstrate in anesthetized rats that spinal mechanisms give rise to iPMF, and that iPMF consists of at least two mechanistically distinct phases: 1) an early, labile phase that requires atypical PKC (PKCζ and/or PKCΙ/λ) activity to transition to a 2) late, stable phase. Early (but not late) iPMF is associated with increased interactions between PKCζ/Ι and the scaffolding protein ZIP/p62 in spinal regions associated with the phrenic motor pool. Although PKCζ/Ι activity is necessary for iPMF, spinal aPKC activity is not necessary for phrenic long-term facilitation (pLTF) following acute intermittent hypoxia, an activity-independent form of spinal respiratory plasticity. Thus, while iPMF and pLTF both manifest as prolonged increases in phrenic burst amplitude, they arise from distinct spinal cellular pathways. Our data are consistent with the hypotheses that: 1) local mechanisms sense and respond to reduced respiratory-related activity in the phrenic motor pool, and 2) inactivity-induced increases in phrenic inspiratory output require local PKCζ/Ι activity to stabilize into a long-lasting iPMF. Although the physiological role of iPMF is unknown, we suspect that iPMF represents a compensatory mechanism, assuring adequate motor output in a physiological system where prolonged inactivity ends life. PMID:23152633

  16. Atypicality of Atypical Antipsychotics

    OpenAIRE

    Farah, Andrew

    2005-01-01

    Objective: To review the current definition of atypicality, discuss the unique features of each atypical antipsychotic, and determine whether the available drugs in this class really meet the classical definition of atypicality.

  17. High expression of atypical protein kinase C lambda/iota in gastric cancer as a prognostic factor for recurrence.

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    Takagawa, Ryo; Akimoto, Kazunori; Ichikawa, Yasushi; Akiyama, Hirotoshi; Kojima, Yasuyuki; Ishiguro, Hitoshi; Inayama, Yoshiaki; Aoki, Ichiro; Kunisaki, Chikara; Endo, Itaru; Nagashima, Yoji; Ohno, Shigeo

    2010-01-01

    The atypical protein kinase C lambda/iota (aPKClambda/iota) is involved in several signal transduction pathways that influence cell growth, apoptosis, and the establishment and maintenance of epithelial cell polarity. Overexpression of aPKClambda/iota has been reported in several cancers and been shown to be associated with oncogenesis. However, the expression and role of aPKClambda/iota in gastric cancer, one of the commonest cancers in Asia, have not so far been investigated. This study aimed to clarify the relationship between aPKClambda/iota expression and the clinicopathological features of gastric cancer. Gastric adenocarcinoma samples were obtained from 177 patients who underwent gastrectomy at the Yokohama City University Hospital between 1999 and 2004. Expression of aPKClambda/iota and E: -cadherin was examined immunohistochemically and compared with clinicopathological features of the tumors. Univariate and multivariate analyses were performed for both disease-specific and relapse-free survival. Overexpression of aPKClambda/iota protein was detected in 126 of the 177 (71.2%) gastric cancers. Immunohistological staining for aPKClambda/iota was stronger in gastric adenocarcinoma of intestinal type than diffuse type (p = 0.036), but was not correlated with E: -cadherin expression. A multivariate analysis suggested that nodal metastasis and aPKClambda/iota overexpression were prognostic factors for disease recurrence. Our results suggested that aPKClambda/iota overexpression was a strong prognostic factor for gastric adenocarcinoma recurrence. As well as being a new prognostic indicator, aPKClambda/iota is also likely to be a novel therapeutic target for gastric cancer.

  18. Atypical protein kinase C activity is required for extracellular matrix degradation and invasion by Src-transformed cells.

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    Rodriguez, Elena M; Dunham, Elizabeth E; Martin, G Steven

    2009-10-01

    Atypical protein kinase C (aPKC) isoforms have been shown to mediate Src-dependent signaling in response to growth factor stimulation. To determine if aPKC activity contributes to the transformed phenotype of cells expressing oncogenic Src, we have examined the activity and function of aPKCs in 3T3 cells expressing viral Src (v-Src). aPKC activity and tyrosine phosphorylation were found to be elevated in some but not all clones of mouse fibroblasts expressing v-Src. aPKC activity was inhibited either by addition of a membrane-permeable pseudosubstrate, by expression of a dominant-negative aPKC, or by RNAi-mediated knockdown of specific aPKC isoforms. aPKC activity contributes to morphological transformation and stress fiber disruption, and is required for migration of Src-transformed cells and for their ability to polarize at the edge of a monolayer. The lambda isoform of aPKC is specifically required for invasion through extracellular matrix in Boyden chamber assays and for degradation of the extracellular matrix in in situ zymography assays. Tyrosine phosphorylation of aPKClambda is required for its ability to promote cell invasion. The defect in invasion upon aPKC inhibition appears to result from a defect in the assembly and/or function of podosomes, invasive adhesions on the ventral surface of the cell that are sites of protease secretion. aPKC was also found to localize to podosomes of v-Src transformed cells, suggesting a direct role for aPKC in podosome assembly and/or function. We conclude that basal or elevated aPKC activity is required for the ability of Src-transformed cells to degrade and invade the extracellular matrix. Copyright 2009 Wiley-Liss, Inc.

  19. Kinases and Cancer

    OpenAIRE

    Jonas Cicenas; Egle Zalyte; Amos Bairoch; Pascale Gaudet

    2018-01-01

    Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases [...

  20. ω-3 and ω-6 Fatty Acids Modulate Conventional and Atypical Protein Kinase C Activities in a Brain Fatty Acid Binding Protein Dependent Manner in Glioblastoma Multiforme

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    Marwa E. Elsherbiny

    2018-04-01

    Full Text Available Glioblastoma multiforme (GBM is a highly infiltrative brain cancer with a dismal prognosis. High levels of brain fatty acid binding protein (B-FABP are associated with increased migration/infiltration in GBM cells, with a high ratio of arachidonic acid (AA to docosahexaenoic acid (DHA driving B-FABP-mediated migration. Since several protein kinase Cs (PKCs are overexpressed in GBM and linked to migration, we explored a possible relationship between B-FABP and levels/activity of different PKCs, as a function of AA and DHA supplementation. We report that ectopic expression of B-FABP in U87 cells alters the levels of several PKCs, particularly PKCζ. Upon analysis of PKCζ RNA levels in a panel of GBM cell lines and patient-derived GBM neurospheres, we observed a trend towards moderate positive correlation (r = 0.624, p = 0.054 between B-FABP and PKCζ RNA levels. Analysis of PKC activity in U87 GBM cells revealed decreased typical PKC activity (23.4% in B-FABP-expressing cells compared with nonexpressing cells, with no difference in novel and atypical PKC activities. AA and DHA modulated both conventional and atypical PKC activities in a B-FABP-dependent manner, but had no effect on novel PKC activity. These results suggest that conventional and atypical PKCs are potential downstream effectors of B-FABP/fatty acid-mediated alterations in GBM growth properties.

  1. Involvement of atypical protein kinase C in the regulation of cardiac glucose and long-chain fatty acid uptake

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    Habets, Daphna D J; Luiken, Joost J F P; Ouwens, Margriet

    2012-01-01

    Aim: The signaling pathways involved in the regulation of cardiac GLUT4 translocation/glucose uptake and CD36 translocation/long-chain fatty acid uptake are not fully understood. We compared in heart/muscle-specific PKC-¿ knockout mice the roles of atypical PKCs (PKC-¿ and PKC-¿) in regulating...

  2. Involvement of atypical protein kinase C in the regulation of cardiac glucose and long-chain fatty acid uptake

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    Daphna D.J. Habets

    2012-09-01

    Full Text Available Aim: The signaling pathways involved in the regulation of cardiac GLUT4 translocation/glucose uptake and CD36 translocation/ long-chain fatty acid uptake are not fully understood. We compared in heart/muscle-specific PKC-λ knockout mice the roles of atypical PKCs (PKC-ζ and PKC-λ in regulating cardiac glucose and fatty acid uptake. Results: Neither insulin-stimulated nor AMPK-mediated glucose and fatty acid uptake were inhibited upon genetic PKC-λ ablation in cardiomyocytes. In contrast, myristoylated PKC-ζ pseudosubstrate inhibited both insulin-stimulated and AMPK-mediated glucose and fatty acid uptake by >80% in both wild-type and PKC-λ-knockout cardiomyocytes. In PKC-λ knockout cardiomyocytes, PKC-ζ is the sole remaining atypical PKC isoform, and its expression level is not different from wild-type cardiomyocytes, in which it contributes to 29% and 17% of total atypical PKC expression and phosphorylation, respectively. Conclusion: Taken together, atypical PKCs are necessary for insulin-stimulated and AMPK-mediated glucose uptake into the heart, as well as for insulin-stimulated and AMPK-mediated fatty acid uptake. However, the residual PKC-ζ activity in PKC-λ-knockout cardiomyocytes is sufficient to allow optimal stimulation of glucose and fatty acid uptake, indicating that atypical PKCs are necessary but not rate-limiting in the regulation of cardiac substrate uptake and that PKC-λ and PKC-ζ have interchangeable functions in these processes.

  3. Typical Versus Atypical Anorexia Nervosa Among Adolescents: Clinical Characteristics and Implications for ICD-11.

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    Silén, Yasmina; Raevuori, Anu; Jüriloo, Elisabeth; Tainio, Veli-Matti; Marttunen, Mauri; Keski-Rahkonen, Anna

    2015-09-01

    There is scant research on the clinical utility of differentiating International Classification of Diseases (ICD) 10 diagnoses F50.0 anorexia nervosa (typical AN) and F50.1 atypical anorexia. We reviewed systematically records of 47 adolescents who fulfilled criteria for ICD-10 F50.0 (n = 34) or F50.1 (n = 13), assessing the impact of diagnostic subtype, comorbidity, background factors and treatment choices on recovery. Atypical AN patients were significantly older (p = 0.03), heavier (minimum body mass index 16.7 vs 15.1 kg/m(2) , p = 0.003) and less prone to comorbidities (38% vs 71%, p = 0.04) and had shorter, less intensive and less costly treatments than typical AN patients. The diagnosis of typical versus atypical AN was the sole significant predictor of treatment success: recovery from atypical AN was 4.3 times (95% confidence interval [1.1, 17.5]) as likely as recovery from typical AN. Overall, our findings indicate that a broader definition of AN may dilute the prognostic value of the diagnosis, and therefore, ICD-11 should retain its distinction between typical and atypical AN. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.

  4. Structure-function analysis of STRUBBELIG, an Arabidopsis atypical receptor-like kinase involved in tissue morphogenesis.

    Directory of Open Access Journals (Sweden)

    Prasad Vaddepalli

    Full Text Available Tissue morphogenesis in plants requires the coordination of cellular behavior across clonally distinct histogenic layers. The underlying signaling mechanisms are presently being unraveled and are known to include the cell surface leucine-rich repeat receptor-like kinase STRUBBELIG in Arabidopsis. To understand better its mode of action an extensive structure-function analysis of STRUBBELIG was performed. The phenotypes of 20 EMS and T-DNA-induced strubbelig alleles were assessed and homology modeling was applied to rationalize their possible effects on STRUBBELIG protein structure. The analysis was complemented by phenotypic, cell biological, and pharmacological investigations of a strubbelig null allele carrying genomic rescue constructs encoding fusions between various mutated STRUBBELIG proteins and GFP. The results indicate that STRUBBELIG accepts quite some sequence variation, reveal the biological importance for the STRUBBELIG N-capping domain, and reinforce the notion that kinase activity is not essential for its function in vivo. Furthermore, individual protein domains of STRUBBELIG cannot be related to specific STRUBBELIG-dependent biological processes suggesting that process specificity is mediated by factors acting together with or downstream of STRUBBELIG. In addition, the evidence indicates that biogenesis of a functional STRUBBELIG receptor is subject to endoplasmic reticulum-mediated quality control, and that an MG132-sensitive process regulates its stability. Finally, STRUBBELIG and the receptor-like kinase gene ERECTA interact synergistically in the control of internode length. The data provide genetic and molecular insight into how STRUBBELIG regulates intercellular communication in tissue morphogenesis.

  5. Adenomyoepithelioma of the breast with associated atypical lobular hyperplasia: a previously unrecognized association with management implications.

    Science.gov (United States)

    Zhang, Shuang; Huo, Lei; Arribas, Elsa; Middleton, Lavinia P

    2015-02-01

    Adenomyoepitheliomas of breast are rare tumors. We report for the first time a case of an adenomyoepithelioma of the breast with associated lobular neoplasia. A 53-year-old woman had an annual screening mammogram, which identified areas of asymmetry in her left breast at 4-5-o'clock position. Resection of the masses revealed a well-circumscribed, gray-white, firm discrete nodule (0.8 × 0.4 × 0.3 cm). The tumor was composed of both adenomyoepithelial cell hyperplasia and focal atypical lobular hyperplasia. The 2 cell populations had some overlapping histologic features. Immunohistochemical analysis demonstrated a biphasic proliferation with approximately equal parts of luminal epithelial cells with clear and rounded appearance and myoepithelial cells. The myoepithelial component of the proliferation expressed myosin, p63, CK5/6, S-100, and dimly expressed E-cadherin. The epithelial component of the proliferation strongly expressed E-cadherin. In the areas of atypical lobular hyperplasia, there was distinct loss E-cadherin expression. Awareness of this association is highly important to provide these patients adequate follow-up and treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Tyrosine Kinase Receptor Landscape in Lung Cancer: Therapeutical Implications

    Directory of Open Access Journals (Sweden)

    A. Quintanal-Villalonga

    2016-01-01

    Full Text Available Lung cancer is a heterogeneous disease responsible for the most cases of cancer-related deaths. The majority of patients are clinically diagnosed at advanced stages, with a poor survival rate. For this reason, the identification of oncodrivers and novel biomarkers is decisive for the future clinical management of this pathology. The rise of high throughput technologies popularly referred to as “omics” has accelerated the discovery of new biomarkers and drivers for this pathology. Within them, tyrosine kinase receptors (TKRs have proven to be of importance as diagnostic, prognostic, and predictive tools and, due to their molecular nature, as therapeutic targets. Along this review, the role of TKRs in the different lung cancer histologies, research on improvement of anti-TKR therapy, and the current approaches to manage anti-TKR resistance will be discussed.

  7. Natural infection of cattle with an atypical 'HoBi'-like pestivirus--implications for BVD control and for the safety of biological products.

    Science.gov (United States)

    Ståhl, Karl; Kampa, Jaruwan; Alenius, Stefan; Persson Wadman, Annie; Baule, Claudia; Aiumlamai, Suneerat; Belák, Sándor

    2007-01-01

    During a study on Bovine Viral Diarrhoea (BVD) epidemiology in Thailand, a pestivirus was detected in serum from a calf. Comparative nucleotide sequence analysis showed that this virus was closely related to a recently described atypical pestivirus (D32/00_'HoBi') that was first isolated from a batch of foetal calf serum collected in Brazil. The results from virus neutralisation tests performed on sera collected from cattle in the herd of the infected calf, showed that these cattle had markedly higher antibody titres against the atypical pestivirus 'HoBi' than against Bovine Viral Diarrhoea Virus types 1 and 2, or Border Disease Virus. The results also supported, consequently, the results from the molecular analysis, and demonstrated that a 'HoBi'-like pestivirus had been introduced to, and was now circulating in the herd. This study is the first to report a natural infection in cattle with a virus related to this atypical pestivirus, and it suggests that this group of pestiviruses may already be spread in cattle populations. The findings have implications for BVD control and for the biosafety of vaccines and other biological products produced with foetal calf serum. Consequently, these atypical pestiviruses should be included in serological assays, and any diagnostic assay aimed at detection of pestiviruses in biological products or animals should be tested for its ability to detect them.

  8. Perspectives on the rhythm–grammar link and its implications for typical and atypical language development

    Science.gov (United States)

    Gordon, Reyna L.; Jacobs, Magdalene S.; Schuele, C. Melanie; McAuley, J. Devin

    2014-01-01

    This paper reviews the mounting evidence for shared cognitive mechanisms and neural resources for rhythm and grammar. Evidence for a role of rhythm skills in language development and language comprehension is reviewed here in three lines of research: (a) behavioral and brain data from adults and children, showing that prosody and other aspects of timing of sentences influence online morpho-syntactic processing; (b) co-morbidity of impaired rhythm with grammatical deficits in children with language impairment; and (c) our recent work showing a strong positive association between rhythm perception skills and expressive grammatical skills in young school-age children with typical development. Our preliminary follow-up study presented here revealed that musical rhythm perception predicted variance in six-year-old children’s production of complex syntax, as well as online reorganization of grammatical information (transformation); these data provide an additional perspective on the hierarchical relations potentially shared by rhythm and grammar. A theoretical framework for shared cognitive resources for the role of rhythm in perceiving and learning grammatical structure is elaborated on in light of potential implications for using rhythm-emphasized musical training to improve language skills in children. PMID:25773612

  9. Atypical Antidepressants

    Science.gov (United States)

    ... health-medications/index.shtml. Accessed May 16, 2016. Hirsch M, et al. Atypical antidepressants: Pharmacology, admininstration, and ... www.uptodate.com/home. Accessed May 23, 2016. Hirsch M, et al. Discontinuing antidepressant medications in adults. ...

  10. Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors.

    Science.gov (United States)

    Kwiatkowski, Jacek; Liu, Boping; Tee, Doris Hui Ying; Chen, Guoying; Ahmad, Nur Huda Binte; Wong, Yun Xuan; Poh, Zhi Ying; Ang, Shi Hua; Tan, Eldwin Sum Wai; Ong, Esther Hq; Nurul Dinie; Poulsen, Anders; Pendharkar, Vishal; Sangthongpitag, Kanda; Lee, May Ann; Sepramaniam, Sugunavathi; Ho, Soo Yei; Cherian, Joseph; Hill, Jeffrey; Keller, Thomas H; Hung, Alvin W

    2018-05-24

    Protein kinase C iota (PKC-ι) is an atypical kinase implicated in the promotion of different cancer types. A biochemical screen of a fragment library has identified several hits from which an azaindole-based scaffold was chosen for optimization. Driven by a structure-activity relationship and supported by molecular modeling, a weakly bound fragment was systematically grown into a potent and selective inhibitor against PKC-ι.

  11. Analysis of Kinase Gene Expression in the Frontal Cortex of Suicide Victims: Implications of Fear and Stress

    Directory of Open Access Journals (Sweden)

    Kwang eChoi

    2011-07-01

    Full Text Available Suicide is a serious public health issue that results from an interaction between multiple risk factors including individual vulnerabilities to complex feelings of hopelessness, fear and stress. Although kinase genes have been implicated in fear and stress, including the consolidation and extinction of fearful memories, expression profiles of those genes in the brain of suicide victims are less clear. Using gene expression microarray data from the Online Stanley Genomics Database (www.stanleygenomics.org and a quantitative PCR, we investigated the expression profiles of multiple kinase genes including the calcium calmodulin-dependent kinase (CAMK, the cyclin-dependent kinase (CDK, the mitogen-activated protein kinase (MAPK, and the protein kinase C (PKC in the prefrontal cortex (PFC of mood disorder patients died with suicide (n=45 and without suicide (N=38. We also investigated the expression pattern of the same genes in the PFC of developing humans ranging in age from birth to 49 year (n=46. The expression levels of CAMK2B, CDK5, MAPK9, and PRKCI were increased in the PFC of suicide victims as compared to non-suicide controls (FDR-adjusted p < 0.05, fold change > 1.1. Those genes also showed changes in expression pattern during the postnatal development (FDR-adjusted p < 0.05. These results suggest that multiple kinase genes undergo age-dependent changes in normal brains as well as pathological changes in suicide brains. These findings may provide an important link to protein kinases known to be important for the development of fear memory, stress-associated neural plasticity and up-regulation in the PFC of suicide victims. More research is needed to better understand the functional role of these kinase genes that may be associated with the pathophysiology of suicide.

  12. Elimination of A-type inclusion formation enhances cowpox virus replication in mice: implications for orthopoxvirus evolution.

    Science.gov (United States)

    Kastenmayer, Robin J; Maruri-Avidal, Liliana; Americo, Jeffrey L; Earl, Patricia L; Weisberg, Andrea S; Moss, Bernard

    2014-03-01

    Some orthopoxviruses including cowpox virus embed virus particles in dense bodies, comprised of the A-type inclusion (ATI) protein, which may provide long-term environmental protection. This strategy could be beneficial if the host population is sparse or spread is inefficient or indirect. However, the formation of ATI may be neutral or disadvantageous for orthopoxviruses that rely on direct respiratory spread. Disrupted ATI open reading frames in orthopoxviruses such as variola virus, the agent of smallpox, and monkeypox virus suggests that loss of this feature provided positive selection. To test this hypothesis, we constructed cowpox virus mutants with deletion of the ATI gene or another gene required for embedding virions. The ATI deletion mutant caused greater weight loss and higher replication in the respiratory tract than control viruses, supporting our hypothesis. Deletion of the gene for embedding virions had a lesser effect, possibly due to known additional functions of the encoded protein. Published by Elsevier Inc.

  13. The frequencies and clinical implications of mutations in 33 kinase-related genes in locally advanced rectal cancer: a pilot study.

    LENUS (Irish Health Repository)

    Abdul-Jalil, Khairun I

    2014-08-01

    Locally advanced rectal cancer (LARC: T3\\/4 and\\/or node-positive) is treated with preoperative\\/neoadjuvant chemoradiotherapy (CRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and related pathways are implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic mutations in these pathways and LARC clinical outcomes.

  14. Expression pattern of cdkl5 during zebrafish early development: implications for use as model for atypical Rett syndrome.

    Science.gov (United States)

    Vitorino, Marta; Cunha, Nídia; Conceição, Natércia; Cancela, M Leonor

    2018-05-11

    Atypical Rett syndrome is a child neurodevelopmental disorder induced by mutations in CDKL5 gene and characterized by a progressive regression in development with loss of purposeful use of the hands, slowed brain and head growth, problems with walking, seizures, and intellectual disability. At the moment, there is no cure for this pathology and little information is available concerning animal models capable of mimicking its phenotypes, thus the development of additional animal models should be of interest to gain more knowledge about the disease. Zebrafish has been used successfully as model organism for many human genetic diseases; however, no information is available concerning the spatial and temporal expression of cdkl5 orthologous in this organism. In the present study, we identified the developmental expression patterns of cdkl5 in zebrafish by quantitative PCR and whole-mount in situ hybridization. cdkl5 is expressed maternally at low levels during the first 24 h of development. After that the expression of the gene increases significantly and it starts to be expressed mainly in the nervous system and in several brain structures, such as telencephalon, mesencephalon and diencephalon. The expression patterns of cdkl5 in zebrafish is in accordance with the tissues known to be affected in humans and associated to symptoms and deficits observed in Rett syndrome patients thus providing the first evidence that zebrafish could be an alternative model to study the molecular pathways of this disease as well as to test possible therapeutic approaches capable of rescuing the phenotype.

  15. Substrate-specific reorganization of the conformational ensemble of CSK implicates novel modes of kinase function.

    Directory of Open Access Journals (Sweden)

    Michael A Jamros

    Full Text Available Protein kinases use ATP as a phosphoryl donor for the posttranslational modification of signaling targets. It is generally thought that the binding of this nucleotide induces conformational changes leading to closed, more compact forms of the kinase domain that ideally orient active-site residues for efficient catalysis. The kinase domain is oftentimes flanked by additional ligand binding domains that up- or down-regulate catalytic function. C-terminal Src kinase (Csk is a multidomain tyrosine kinase that is up-regulated by N-terminal SH2 and SH3 domains. Although the X-ray structure of Csk suggests the enzyme is compact, X-ray scattering studies indicate that the enzyme possesses both compact and open conformational forms in solution. Here, we investigated whether interactions with the ATP analog AMP-PNP and ADP can shift the conformational ensemble of Csk in solution using a combination of small angle x-ray scattering and molecular dynamics simulations. We find that binding of AMP-PNP shifts the ensemble towards more extended rather than more compact conformations. Binding of ADP further shifts the ensemble towards extended conformations, including highly extended conformations not adopted by the apo protein, nor by the AMP-PNP bound protein. These ensembles indicate that any compaction of the kinase domain induced by nucleotide binding does not extend to the overall multi-domain architecture. Instead, assembly of an ATP-bound kinase domain generates further extended forms of Csk that may have relevance for kinase scaffolding and Src regulation in the cell.

  16. DAF-16/FoxO directly regulates an atypical AMP-activated protein kinase gamma isoform to mediate the effects of insulin/IGF-1 signaling on aging in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Jennifer M A Tullet

    2014-02-01

    Full Text Available The DAF-16/FoxO transcription factor controls growth, metabolism and aging in Caenorhabditis elegans. The large number of genes that it regulates has been an obstacle to understanding its function. However, recent analysis of transcript and chromatin profiling implies that DAF-16 regulates relatively few genes directly, and that many of these encode other regulatory proteins. We have investigated the regulation by DAF-16 of genes encoding the AMP-activated protein kinase (AMPK, which has α, β and γ subunits. C. elegans has 5 genes encoding putative AMP-binding regulatory γ subunits, aakg-1-5. aakg-4 and aakg-5 are closely related, atypical isoforms, with orthologs throughout the Chromadorea class of nematodes. We report that ∼75% of total γ subunit mRNA encodes these 2 divergent isoforms, which lack consensus AMP-binding residues, suggesting AMP-independent kinase activity. DAF-16 directly activates expression of aakg-4, reduction of which suppresses longevity in daf-2 insulin/IGF-1 receptor mutants. This implies that an increase in the activity of AMPK containing the AAKG-4 γ subunit caused by direct activation by DAF-16 slows aging in daf-2 mutants. Knock down of aakg-4 expression caused a transient decrease in activation of expression in multiple DAF-16 target genes. This, taken together with previous evidence that AMPK promotes DAF-16 activity, implies the action of these two metabolic regulators in a positive feedback loop that accelerates the induction of DAF-16 target gene expression. The AMPK β subunit, aakb-1, also proved to be up-regulated by DAF-16, but had no effect on lifespan. These findings reveal key features of the architecture of the gene-regulatory network centered on DAF-16, and raise the possibility that activation of AMP-independent AMPK in nutritionally replete daf-2 mutant adults slows aging in C. elegans. Evidence of activation of AMPK subunits in mammals suggests that such FoxO-AMPK interactions may be

  17. DAF-16/FoxO directly regulates an atypical AMP-activated protein kinase gamma isoform to mediate the effects of insulin/IGF-1 signaling on aging in Caenorhabditis elegans.

    Science.gov (United States)

    Tullet, Jennifer M A; Araiz, Caroline; Sanders, Matthew J; Au, Catherine; Benedetto, Alexandre; Papatheodorou, Irene; Clark, Emily; Schmeisser, Kathrin; Jones, Daniel; Schuster, Eugene F; Thornton, Janet M; Gems, David

    2014-02-01

    The DAF-16/FoxO transcription factor controls growth, metabolism and aging in Caenorhabditis elegans. The large number of genes that it regulates has been an obstacle to understanding its function. However, recent analysis of transcript and chromatin profiling implies that DAF-16 regulates relatively few genes directly, and that many of these encode other regulatory proteins. We have investigated the regulation by DAF-16 of genes encoding the AMP-activated protein kinase (AMPK), which has α, β and γ subunits. C. elegans has 5 genes encoding putative AMP-binding regulatory γ subunits, aakg-1-5. aakg-4 and aakg-5 are closely related, atypical isoforms, with orthologs throughout the Chromadorea class of nematodes. We report that ∼75% of total γ subunit mRNA encodes these 2 divergent isoforms, which lack consensus AMP-binding residues, suggesting AMP-independent kinase activity. DAF-16 directly activates expression of aakg-4, reduction of which suppresses longevity in daf-2 insulin/IGF-1 receptor mutants. This implies that an increase in the activity of AMPK containing the AAKG-4 γ subunit caused by direct activation by DAF-16 slows aging in daf-2 mutants. Knock down of aakg-4 expression caused a transient decrease in activation of expression in multiple DAF-16 target genes. This, taken together with previous evidence that AMPK promotes DAF-16 activity, implies the action of these two metabolic regulators in a positive feedback loop that accelerates the induction of DAF-16 target gene expression. The AMPK β subunit, aakb-1, also proved to be up-regulated by DAF-16, but had no effect on lifespan. These findings reveal key features of the architecture of the gene-regulatory network centered on DAF-16, and raise the possibility that activation of AMP-independent AMPK in nutritionally replete daf-2 mutant adults slows aging in C. elegans. Evidence of activation of AMPK subunits in mammals suggests that such FoxO-AMPK interactions may be evolutionarily conserved.

  18. Investigation of the Flexibility of Protein Kinases Implicated in the Pathology of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Michael P. Mazanetz

    2014-06-01

    Full Text Available The pathological characteristics of Alzheimer’s Disease (AD have been linked to the activity of three particular kinases—Glycogen Synthase Kinase 3β (GSK3β, Cyclin-Dependent Kinase 5 (CDK5 and Extracellular-signal Regulated Kinase 2 (ERK2. As a consequence, the design of selective, potent and drug-like inhibitors of these kinases is of particular interest. Structure-based design methods are well-established in the development of kinase inhibitors. However, progress in this field is limited by the difficulty in obtaining X-ray crystal structures suitable for drug design and by the inability of this method to resolve highly flexible regions of the protein that are crucial for ligand binding. To address this issue, we have undertaken a study of human protein kinases CDK5/p25, CDK5, ERK2 and GSK3β using both conventional molecular dynamics (MD and the new Active Site Pressurisation (ASP methodology, to look for kinase-specific patterns of flexibility that could be leveraged for the design of selective inhibitors. ASP was used to examine the intrinsic flexibility of the ATP-binding pocket for CDK5/p25, CDK5 and GSK3β where it is shown to be capable of inducing significant conformational changes when compared with X-ray crystal structures. The results from these experiments were used to quantify the dynamics of each protein, which supported the observations made from the conventional MD simulations. Additional information was also derived from the ASP simulations, including the shape of the ATP-binding site and the rigidity of the ATP-binding pocket. These observations may be exploited in the design of selective inhibitors of GSK3β, CDK5 and ERK2.

  19. Protein implicated in nonsyndromic mental retardation regulates protein kinase A (PKA) activity

    KAUST Repository

    Altawashi, Azza; Jung, Sung Yun; Liu, Dou; Su, Bing; Qin, Jun

    2012-01-01

    capacitytoformdendritesandsynapsesinculture. Atthebiochemical level,CC2D1Atransduces signals to the cyclic adenosine 3?,5?-monophosphate (cAMP)-protein kinase A (PKA) pathway during neuronal cell differentiation. PKA activity is compromised, and the translocation of its catalytic subunit

  20. Specific RSK kinase inhibition by dibenzyl trisulfide and implication for therapeutic treatment of cancer.

    Science.gov (United States)

    Lowe, Henry I C; Facey, Caroline O B; Toyang, Ngeh J; Bryant, Joseph L

    2014-04-01

    The Jamaican "Guinea Hen Weed" (Petiveria alliacea L.) plant has been traditionally used in folklore medicine to treat a variety of diseases including cancer. In the present study we investigated on the therapeutic feasibility of dibenzyl trisulfide (DTS) (isolated from the Jamaican Guinea Hen Weed) as a potent small-molecule kinase inhibitor to treat cancer. We investigated the inhibitory effects of DTS against a large panel of kinases using a well-established competitive binding assay. Cell proliferation data were obtained using the WST-1 colorimetric assay. DTS inhibited the activity of the C-terminal kinase domain of RSK1 (80% compared to control) with a Kd of 1.3 μM. Anti-proliferative effects of DTS were observed in small lung, pancreatic, breast, and prostate cancer cells with IC50 values ranging from 0.34-0.84 μM. We have identified DTS as a highly selective and isoform-specific RSK1 kinase inhibitor with broad cancer therapeutic potential.

  1. p56Lck and p59Fyn Regulate CD28 Binding to Phosphatidylinositol 3-Kinase, Growth Factor Receptor-Bound Protein GRB-2, and T Cell-Specific Protein-Tyrosine Kinase ITK: Implications for T-Cell Costimulation

    Science.gov (United States)

    Raab, Monika; Cai, Yun-Cai; Bunnell, Stephen C.; Heyeck, Stephanie D.; Berg, Leslie J.; Rudd, Christopher E.

    1995-09-01

    T-cell activation requires cooperative signals generated by the T-cell antigen receptor ξ-chain complex (TCRξ-CD3) and the costimulatory antigen CD28. CD28 interacts with three intracellular proteins-phosphatidylinositol 3-kinase (PI 3-kinase), T cell-specific protein-tyrosine kinase ITK (formerly TSK or EMT), and the complex between growth factor receptor-bound protein 2 and son of sevenless guanine nucleotide exchange protein (GRB-2-SOS). PI 3-kinase and GRB-2 bind to the CD28 phosphotyrosine-based Tyr-Met-Asn-Met motif by means of intrinsic Src-homology 2 (SH2) domains. The requirement for tyrosine phosphorylation of the Tyr-Met-Asn-Met motif for SH2 domain binding implicates an intervening protein-tyrosine kinase in the recruitment of PI 3-kinase and GRB-2 by CD28. Candidate kinases include p56Lck, p59Fyn, ξ-chain-associated 70-kDa protein (ZAP-70), and ITK. In this study, we demonstrate in coexpression studies that p56Lck and p59Fyn phosphorylate CD28 primarily at Tyr-191 of the Tyr-Met-Asn-Met motif, inducing a 3- to 8-fold increase in p85 (subunit of PI 3-kinase) and GRB-2 SH2 binding to CD28. Phosphatase digestion of CD28 eliminated binding. In contrast to Src kinases, ZAP-70 and ITK failed to induce these events. Further, ITK binding to CD28 was dependent on the presence of p56Lck and is thus likely to act downstream of p56Lck/p59Fyn in a signaling cascade. p56Lck is therefore likely to be a central switch in T-cell activation, with the dual function of regulating CD28-mediated costimulation as well as TCR-CD3-CD4 signaling.

  2. AKT (protein kinase B) is implicated in meiotic maturation of porcine oocytes

    Czech Academy of Sciences Publication Activity Database

    Kalous, Jaroslav; Kubelka, Michal; Šolc, Petr; Šušor, Andrej; Motlík, Jan

    2009-01-01

    Roč. 138, - (2009), s. 645-654 ISSN 1470-1626 R&D Projects: GA ČR GA204/06/1297; GA ČR GA523/03/0857; GA ČR GA524/07/1087 Institutional research plan: CEZ:AV0Z50450515 Keywords : protein kinase * porcine oocyte * oocyte maturation Subject RIV: CE - Biochemistry Impact factor: 2.579, year: 2009

  3. Molecular evolution of a-kinase anchoring protein (AKAP-7: implications in comparative PKA compartmentalization

    Directory of Open Access Journals (Sweden)

    Johnson Keven R

    2012-07-01

    Full Text Available Abstract Background A-Kinase Anchoring Proteins (AKAPs are molecular scaffolding proteins mediating the assembly of multi-protein complexes containing cAMP-dependent protein kinase A (PKA, directing the kinase in discrete subcellular locations. Splice variants from the AKAP7 gene (AKAP15/18 are vital components of neuronal and cardiac phosphatase complexes, ion channels, cardiac Ca2+ handling and renal water transport. Results Shown in evolutionary analyses, the formation of the AKAP7-RI/RII binding domain (required for AKAP/PKA-R interaction corresponds to vertebrate-specific gene duplication events in the PKA-RI/RII subunits. Species analyses of AKAP7 splice variants shows the ancestral AKAP7 splice variant is AKAP7α, while the ancestral long form AKAP7 splice variant is AKAP7γ. Multi-species AKAP7 gene alignments, show the recent formation of AKAP7δ occurs with the loss of native AKAP7γ in rats and basal primates. AKAP7 gene alignments and two dimensional Western analyses indicate that AKAP7γ is produced from an internal translation-start site that is present in the AKAP7δ cDNA of mice and humans but absent in rats. Immunofluorescence analysis of AKAP7 protein localization in both rat and mouse heart suggests AKAP7γ replaces AKAP7δ at the cardiac sarcoplasmic reticulum in species other than rat. DNA sequencing identified Human AKAP7δ insertion-deletions (indels that promote the production of AKAP7γ instead of AKAP7δ. Conclusions This AKAP7 molecular evolution study shows that these vital scaffolding proteins developed in ancestral vertebrates and that independent mutations in the AKAP7 genes of rodents and early primates has resulted in the recent formation of AKAP7δ, a splice variant of likely lesser importance in humans than currently described.

  4. Implication of cyclin-dependent kinase 5 in the development of psychological dependence on and behavioral sensitization to morphine.

    Science.gov (United States)

    Narita, Minoru; Shibasaki, Masahiro; Nagumo, Yasuyuki; Narita, Michiko; Yajima, Yoshinori; Suzuki, Tsutomu

    2005-06-01

    In the present study, we investigated the role of cyclin-dependent kinase 5 (cdk5) in the brain dynamics changed by repeated in vivo treatment with morphine. The level of phosphorylated-cdk5 was significantly increased in the cingulate cortex of mice showing the morphine-induced rewarding effect. Under these conditions, roscovitine, a cdk5 inhibitor, given intracerebroventricularly (i.c.v.) caused a dose-dependent and significant inhibition of the morphine-induced rewarding effect. In addition, the dose-response effect of the morphine-induced rewarding effect was dramatically attenuated in cdk5 heterozygous (+/-) knockout mice. Furthermore, the development of behavioral sensitization by intermittent administration of morphine was virtually abolished in cdk5 (+/-) mice. These findings suggest that the induction and/or activation of cdk5 are implicated in the development of psychological dependence on morphine.

  5. Differential action of small molecule HER kinase inhibitors on receptor heterodimerization: therapeutic implications.

    Science.gov (United States)

    Sánchez-Martín, M; Pandiella, A

    2012-07-01

    Deregulation of ErbB/HER receptor tyrosine kinases has been linked to several types of cancer. The mechanism of activation of these receptors includes establishment of receptor dimers. Here, we have analyzed the action of different small molecule HER tyrosine kinase inhibitors (TKIs) on HER receptor dimerization. Breast cancer cell lines were treated with distinct TKIs and the formation of HER2-HER3 dimers was analyzed by coimmunoprecipitation and western blot or by Förster resonance energy transfer assays. Antibody-dependent cellular cytotoxicity was analyzed by measuring the release of lactate dehydrogenase and cell viability. Lapatinib and neratinib interfered with ligand-induced dimerization of HER receptors; while pelitinib, gefitinib, canertinib or erlotinib did not. Moreover, lapatinib and neratinib were able to disrupt previously formed receptor dimers. Structural analyses allowed the elucidation of the mechanism by which some TKIs prevent the formation of HER receptor dimers, while others do not. Experiments aimed at defining the functional importance of dimerization indicated that TKIs that impeded dimerization prevented down-regulation of HER2 receptors, and favored the action of trastuzumab. We postulate that TKIs that prevent dimerization and down-regulation of HER2 may augment the antitumoral action of trastuzumab, and this mechanism of action should be considered in the treatment of HER2 positive tumors which combine TKIs with antireceptor antibodies. Copyright © 2011 UICC.

  6. Mitochondrial DNA depletion by ethidium bromide decreases neuronal mitochondrial creatine kinase: Implications for striatal energy metabolism.

    Science.gov (United States)

    Warren, Emily Booth; Aicher, Aidan Edward; Fessel, Joshua Patrick; Konradi, Christine

    2017-01-01

    Mitochondrial DNA (mtDNA), the discrete genome which encodes subunits of the mitochondrial respiratory chain, is present at highly variable copy numbers across cell types. Though severe mtDNA depletion dramatically reduces mitochondrial function, the impact of tissue-specific mtDNA reduction remains debated. Previously, our lab identified reduced mtDNA quantity in the putamen of Parkinson's Disease (PD) patients who had developed L-DOPA Induced Dyskinesia (LID), compared to PD patients who had not developed LID and healthy subjects. Here, we present the consequences of mtDNA depletion by ethidium bromide (EtBr) treatment on the bioenergetic function of primary cultured neurons, astrocytes and neuron-enriched cocultures from rat striatum. We report that EtBr inhibition of mtDNA replication and transcription consistently reduces mitochondrial oxygen consumption, and that neurons are significantly more sensitive to EtBr than astrocytes. EtBr also increases glycolytic activity in astrocytes, whereas in neurons it reduces the expression of mitochondrial creatine kinase mRNA and levels of phosphocreatine. Further, we show that mitochondrial creatine kinase mRNA is similarly downregulated in dyskinetic PD patients, compared to both non-dyskinetic PD patients and healthy subjects. Our data support a hypothesis that reduced striatal mtDNA contributes to energetic dysregulation in the dyskinetic striatum by destabilizing the energy buffering system of the phosphocreatine/creatine shuttle.

  7. Mitochondrial DNA depletion by ethidium bromide decreases neuronal mitochondrial creatine kinase: Implications for striatal energy metabolism.

    Directory of Open Access Journals (Sweden)

    Emily Booth Warren

    Full Text Available Mitochondrial DNA (mtDNA, the discrete genome which encodes subunits of the mitochondrial respiratory chain, is present at highly variable copy numbers across cell types. Though severe mtDNA depletion dramatically reduces mitochondrial function, the impact of tissue-specific mtDNA reduction remains debated. Previously, our lab identified reduced mtDNA quantity in the putamen of Parkinson's Disease (PD patients who had developed L-DOPA Induced Dyskinesia (LID, compared to PD patients who had not developed LID and healthy subjects. Here, we present the consequences of mtDNA depletion by ethidium bromide (EtBr treatment on the bioenergetic function of primary cultured neurons, astrocytes and neuron-enriched cocultures from rat striatum. We report that EtBr inhibition of mtDNA replication and transcription consistently reduces mitochondrial oxygen consumption, and that neurons are significantly more sensitive to EtBr than astrocytes. EtBr also increases glycolytic activity in astrocytes, whereas in neurons it reduces the expression of mitochondrial creatine kinase mRNA and levels of phosphocreatine. Further, we show that mitochondrial creatine kinase mRNA is similarly downregulated in dyskinetic PD patients, compared to both non-dyskinetic PD patients and healthy subjects. Our data support a hypothesis that reduced striatal mtDNA contributes to energetic dysregulation in the dyskinetic striatum by destabilizing the energy buffering system of the phosphocreatine/creatine shuttle.

  8. The use of 14C-FIAU to predict bacterial thymidine kinase presence: Implications for radiolabeled FIAU bacterial imaging

    International Nuclear Information System (INIS)

    Peterson, Kristin L.; Reid, William C.; Freeman, Alexandra F.; Holland, Steven M.; Pettigrew, Roderic I.; Gharib, Ahmed M.; Hammoud, Dima A.

    2013-01-01

    Currently available infectious disease imaging techniques cannot differentiate between infection and sterile inflammation or between different types of infections. Recently, radiolabeled FIAU was found to be a substrate for the thymidine kinase (TK) enzyme of multiple pathogenic bacteria, leading to its translational use in the imaging of bacterial infections. Patients with immunodeficiencies, however, are susceptible to a different group of pathogenic bacteria when compared to immunocompetent subjects. In this study, we wanted to predict the usefulness of radiolabeled FIAU in the detection of bacterial infections commonly occurring in patients with immunodeficiencies, in vitro, prior to attempting in vivo imaging with 124 I-FIAU-PET. Methods: We obtained representative strains of bacterial pathogens isolated from actual patients with genetic immunodeficiencies. We evaluated the bacterial susceptibility of different strains to the effect of incubation with FIAU, which would implicate the presence of the thymidine kinase (TK) enzyme. We also incubated the bacteria with 14 C-FIAU and consequently measured its rate of incorporation in the bacterial DNA using a liquid scintillation counter. Results: Unlike the other bacterial strains, the growth of Pseudomonas aeruginosa was not halted by FIAU at any concentration. All the tested clinical isolates demonstrated different levels of 14 C-FIAU uptake, except for P. aeruginosa. Conclusion: Radiolabeled FIAU has been successful in delineating bacterial infections, both in preclinical and pilot translational studies. In patients with immunodeficiencies, Pseudomonas infections are commonly encountered and are usually difficult to differentiate from fungal infections. The use of radiolabeled FIAU for in vivo imaging of those patients, however, would not be useful, considering the apparent lack of TK enzyme in Pseudomonas. One has to keep in mind that not all pathogenic bacteria possess the TK enzyme and as such will not all

  9. AMP-activated protein kinase: Role in metabolism and therapeutic implications.

    Science.gov (United States)

    Schimmack, Greg; Defronzo, Ralph A; Musi, Nicolas

    2006-11-01

    AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge which becomes activated in situations of energy consumption. AMPK functions to restore cellular ATP levels by modifying diverse metabolic and cellular pathways. In the skeletal muscle, AMPK is activated during exercise and is involved in contraction-stimulated glucose transport and fatty acid oxidation. In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. In the liver, AMPK inhibits the production of glucose, cholesterol and triglycerides and stimulates fatty acid oxidation. Recent studies have shown that AMPK is involved in the mechanism of action of metformin and thiazolidinediones, and the adipocytokines leptin and adiponectin. These data, along with evidence that pharmacological activation of AMPK in vivo improves blood glucose homeostasis, cholesterol concentrations and blood pressure in insulin-resistant rodents, make this enzyme an attractive pharmacological target for the treatment of type 2 diabetes, ischaemic heart disease and other metabolic diseases.

  10. Atypical pathogens and challenges in community-acquired pneumonia

    African Journals Online (AJOL)

    Atypical organisms such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila are implicated in up to 40 percent of cases of community-acquired pneumonia. Antibiotic treatment is empiric and includes coverage for both typical and atypical organisms. Doxycycline, a fluoroquinolone with ...

  11. Protein implicated in nonsyndromic mental retardation regulates protein kinase A (PKA) activity

    KAUST Repository

    Altawashi, Azza

    2012-02-28

    Mutation of the coiled-coil and C2 domain-containing 1A (CC2D1A) gene, which encodes a C2 domain and DM14 domain-containing protein, has been linked to severe autosomal recessive nonsyndromic mental retardation. Using a mouse model that produces a truncated form of CC2D1A that lacks the C2 domain and three of the four DM14 domains, we show that CC2D1A is important for neuronal differentiation and brain development. CC2D1A mutant neurons are hypersensitive to stress and have a reduced capacitytoformdendritesandsynapsesinculture. Atthebiochemical level,CC2D1Atransduces signals to the cyclic adenosine 3?,5?-monophosphate (cAMP)-protein kinase A (PKA) pathway during neuronal cell differentiation. PKA activity is compromised, and the translocation of its catalytic subunit to the nucleus is also defective in CC2D1A mutant cells. Consistently, phosphorylation of the PKA target cAMP-responsive element-binding protein, at serine 133, is nearly abolished in CC2D1A mutant cells. The defects in cAMP/PKA signaling were observed in fibroblast, macrophage, and neuronal primary cells derived from the CC2D1A KO mice. CC2D1A associates with the cAMP-PKA complex following forskolin treatment and accumulates in vesicles or on the plasma membrane in wild-type cells, suggesting that CC2D1A may recruit the PKA complex to the membrane to facilitate signal transduction. Together, our data show that CC2D1A is an important regulator of the cAMP/PKA signaling pathway, which may be the underlying cause for impaired mental function in nonsyndromic mental retardation patients with CC2D1A mutation. 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. LIM kinase1 modulates function of membrane type matrix metalloproteinase 1: implication in invasion of prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Chakrabarti Ratna

    2011-01-01

    Full Text Available Abstract Background LIM kinase 1 (LIMK1 is an actin and microtubule cytoskeleton modulatory protein that is overexpressed in a number of cancerous tissues and cells and also promotes invasion and metastasis of prostate and breast cancer cells. Membrane type matrix metalloproteinase 1 (MT1-MMP is a critical modulator of extracellular matrix (ECM turnover through pericellular proteolysis and thus plays crucial roles in neoplastic cell invasion and metastasis. MT1-MMP and its substrates pro-MMP-2 and pro-MMP-9 are often overexpressed in a variety of cancers including prostate cancer and the expression levels correlate with the grade of malignancy in prostate cancer cells. The purpose of this study is to determine any functional relation between LIMK1 and MT1-MMP and its implication in cell invasion. Results Our results showed that treatment with the hydroxamate inhibitor of MT1-MMP, MMP-2 and MMP-9 ilomastat inhibited LIMK1-induced invasion of benign prostate epithelial cells. Over expression of LIMK1 resulted in increased collagenolytic activity of MMP-2, and secretion of pro-MMP2 and pro-MMP-9. Cells over expressing LIMK1 also exhibited increased expression of MT1-MMP, transcriptional activation and its localization to the plasma membrane. LIMK1 physically associates with MT1-MMP and is colocalized with it to the Golgi vesicles. We also noted increased expression of both MT1-MMP and LIMK1 in prostate tumor tissues. Conclusion Our results provide new information on regulation of MT1-MMP function by LIMK1 and showed for the first time, involvement of MMPs in LIMK1 induced cell invasion.

  13. Evolutionary relationships of Aurora kinases: Implications for model organism studies and the development of anti-cancer drugs

    Directory of Open Access Journals (Sweden)

    Patrick Denis R

    2004-10-01

    Full Text Available Abstract Background As key regulators of mitotic chromosome segregation, the Aurora family of serine/threonine kinases play an important role in cell division. Abnormalities in Aurora kinases have been strongly linked with cancer, which has lead to the recent development of new classes of anti-cancer drugs that specifically target the ATP-binding domain of these kinases. From an evolutionary perspective, the species distribution of the Aurora kinase family is complex. Mammals uniquely have three Aurora kinases, Aurora-A, Aurora-B, and Aurora-C, while for other metazoans, including the frog, fruitfly and nematode, only Aurora-A and Aurora-B kinases are known. The fungi have a single Aurora-like homolog. Based on the tacit assumption of orthology to human counterparts, model organism studies have been central to the functional characterization of Aurora kinases. However, the ortholog and paralog relationships of these kinases across various species have not been rigorously examined. Here, we present comprehensive evolutionary analyses of the Aurora kinase family. Results Phylogenetic trees suggest that all three vertebrate Auroras evolved from a single urochordate ancestor. Specifically, Aurora-A is an orthologous lineage in cold-blooded vertebrates and mammals, while structurally similar Aurora-B and Aurora-C evolved more recently in mammals from a duplication of an ancestral Aurora-B/C gene found in cold-blooded vertebrates. All so-called Aurora-A and Aurora-B kinases of non-chordates are ancestral to the clade of chordate Auroras and, therefore, are not strictly orthologous to vertebrate counterparts. Comparisons of human Aurora-B and Aurora-C sequences to the resolved 3D structure of human Aurora-A lends further support to the evolutionary scenario that vertebrate Aurora-B and Aurora-C are closely related paralogs. Of the 26 residues lining the ATP-binding active site, only three were variant and all were specific to Aurora-A. Conclusions In

  14. Regulation of protein kinase C-related kinase (PRK) signalling by the TPα and TPβ isoforms of the human thromboxane A2 receptor: Implications for thromboxane- and androgen- dependent neoplastic and epigenetic responses in prostate cancer.

    Science.gov (United States)

    O'Sullivan, Aine G; Mulvaney, Eamon P; Kinsella, B Therese

    2017-04-01

    The prostanoid thromboxane (TX) A 2 and its T Prostanoid receptor (the TP) are increasingly implicated in prostate cancer (PCa). Mechanistically, we recently discovered that both TPα and TPβ form functional signalling complexes with members of the protein kinase C-related kinase (PRK) family, AGC- kinases essential for the epigenetic regulation of androgen receptor (AR)-dependent transcription and promising therapeutic targets for treatment of castrate-resistant prostate cancer (CRPC). Critically, similar to androgens, activation of the PRKs through the TXA 2 /TP signalling axis induces phosphorylation of histone H3 at Thr11 (H3Thr11), a marker of androgen-induced chromatin remodelling and transcriptional activation, raising the possibility that TXA 2 -TP signalling can mimic and/or enhance AR-induced cellular changes even in the absence of circulating androgens such as in CRPC. Hence the aim of the current study was to investigate whether TXA 2 /TP-induced PRK activation can mimic and/or enhance AR-mediated cellular responses in the model androgen-responsive prostate adenocarcinoma LNCaP cell line. We reveal that TXA 2 /TP signalling can act as a neoplastic- and epigenetic-regulator, promoting and enhancing both AR-associated chromatin remodelling (H3Thr11 phosphorylation, WDR5 recruitment and acetylation of histone H4 at lysine 16) and AR-mediated transcriptional activation (e.g of the KLK3/prostate-specific antigen and TMPRSS2 genes) through mechanisms involving TPα/TPβ mediated-PRK1 and PRK2, but not PRK3, signalling complexes. Overall, these data demonstrate that TPα/TPβ can act as neoplastic and epigenetic regulators by mimicking and/or enhancing the actions of androgens within the prostate and provides further mechanistic insights into the role of the TXA 2 /TP signalling axis in PCa, including potentially in CRPC. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation

    DEFF Research Database (Denmark)

    Klein, H H; Müller, R; Vestergaard, H

    1999-01-01

    We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. In the father who has a heterozygote Arg1174-->Gln mutation, in sit...

  16. The low risk of precancer after a screening result of human papillomavirus-negative/atypical squamous cells of undetermined significance papanicolaou and implications for clinical management.

    Science.gov (United States)

    Gage, Julia C; Katki, Hormuzd A; Schiffman, Mark; Castle, Philip E; Fetterman, Barbara; Poitras, Nancy E; Lorey, Thomas; Cheung, Li C; Behrens, Catherine; Sharma, Abha; Zhao, Fang-Hui; Cuzick, Jack; Yang, Zi Hua; Kinney, Walter K

    2014-11-01

    Different US practice guidelines have conflicting recommendations for when women should return after a screening result of human papillomavirus (HPV)-negative with an equivocal Papanicolaou (Pap) result of atypical squamous cells of undetermined significance (ASC-US) (ie, return in either 3 or 5 years). One way to determine management is to compare the risk of precancer/cancer after an HPV-negative/ASC-US result with the risks after other negative screening results. For example, if the risk after an HPV-negative/ASC-US result was similar to the risk after a negative Pap test, a 3-year return would be preferred because guidelines agree that women with negative Pap test results should return in 3 years. Alternatively, if the risk after an HPV-negative/ASC-US result is similar to that after a cotest-negative result (HPV negative/Pap test negative), a 5-year return would be preferred because guidelines agree that women testing cotest negative should return in 5 years. The authors compared risks of cervical intraepithelial neoplasia of grade 3 or higher (CIN3+) and cervical cancer among women aged 30 years to 64 years at Kaiser Permanente Northern California with the following test results from 2003 through 2012: 17,191 women testing HPV negative/ASC-US; 980,268 women testing Pap test negative (regardless of HPV result); and 892,882 women testing cotest negative. The 5-year CIN3+ and cancer risks after an HPV-negative/ASC-US result were closer to the risks after a negative Pap test result (CIN3+: 0.48% vs 0.31% [P =.0019]; and cancer: 0.043% vs 0.031% [P =.4]) than after a negative cotest (CIN3+: 0.48% vs 0.11% [P<.0001]; and cancer: 0.043% vs 0.014% [P =.016]). Women testing HPV negative/ASC-US were found to have precancer/cancer risks that were more closely aligned with women with negative Pap test results, suggesting that women testing HPV negative/ASC-US should be managed similarly to women testing negative on Pap tests with a 3-year return for screening. © 2014

  17. Atypical Presentations of Tularemia.

    Science.gov (United States)

    Odegaard, Karah; Boersma, Beth; Keegan, James

    2017-05-01

    Francisella tularensis is a gram-negative coccobacillus that causes a condition commonly referred to as tularemia. There has been a dramatic increase in tularemia cases reported in South Dakota, many of which were challenging to diagnose due to atypical clinical manifestations. We describe an interesting case of pneumonic tularemia and summarize six similar cases, several of which presented with lung nodules suggestive of malignancy. According to the literature, this is only the third outbreak of pneumonic tularemia reported in the U.S. We believe it is important for clinicians to be aware of the increased incidence of tularemia in the area and to be vigilant in the diagnosis and management of these atypically presenting cases. Copyright© South Dakota State Medical Association.

  18. Conns' syndrome - atypical presentations

    International Nuclear Information System (INIS)

    Kumar, K V S Hari; Modi, K D; Jha, Sangeeta; Jha, Ratan

    2009-01-01

    Primary hyperaldosteronism (Conns' syndrome) commonly presents with a combination of clinical features of hypokalemia and hypertension. Atypical presentations like normotension, normokalemia and neurological ailments are described in few cases. We encountered two such cases, the first presenting with acute neurological complaint and second case having insignificant hypertension. Both the patients had a characteristic biochemical and imaging profile consistent with primary hyperaldosteronism and responded to surgical resection of adrenal adenoma. (author)

  19. Protein Kinases and Transcription Factors Activation in Response to UV-Radiation of Skin: Implications for Carcinogenesis

    OpenAIRE

    Laurence A. Marchat; Elena Aréchaga Ocampo; Mavil López Casamichana; Carlos Pérez-Plasencia; César López-Camarillo; Elizbeth Álvarez-Sánchez

    2011-01-01

    Solar ultraviolet (UV) radiation is an important environmental factor that leads to immune suppression, inflammation, photoaging, and skin carcinogenesis. Here, we reviewed the specific signal transduction pathways and transcription factors involved in the cellular response to UV-irradiation. Increasing experimental data supporting a role for p38, MAPK, JNK, ERK1/2, and ATM kinases in the response network to UV exposure is discussed. We also reviewed the participation of NF-?B, AP-1, and NRF2...

  20. Structures of Staphylococcus aureus D-tagatose-6-phosphate kinase implicate domain motions in specificity and mechanism.

    Science.gov (United States)

    Miallau, Linda; Hunter, William N; McSweeney, Sean M; Leonard, Gordon A

    2007-07-06

    High resolution structures of Staphylococcus aureus d-tagatose-6-phosphate kinase (LacC) in two crystal forms are herein reported. The structures define LacC in apoform, in binary complexes with ADP or the co-factor analogue AMP-PNP, and in a ternary complex with AMP-PNP and D-tagatose-6-phosphate. The tertiary structure of the LacC monomer, which is closely related to other members of the pfkB subfamily of carbohydrate kinases, is composed of a large alpha/beta core domain and a smaller, largely beta "lid." Four extended polypeptide segments connect these two domains. Dimerization of LacC occurs via interactions between lid domains, which come together to form a beta-clasp structure. Residues from both subunits contribute to substrate binding. LacC adopts a closed structure required for phosphoryl transfer only when both substrate and co-factor are bound. A reaction mechanism similar to that used by other phosphoryl transferases is proposed, although unusually, when both substrate and co-factor are bound to the enzyme two Mg(2+) ions are observed in the active site. A new motif of amino acid sequence conservation common to the pfkB subfamily of carbohydrate kinases is identified.

  1. The RON receptor tyrosine kinase in pancreatic cancer pathogenesis and its potential implications for future targeted therapies.

    Science.gov (United States)

    Kang, Chang Moo; Babicky, Michele L; Lowy, Andrew M

    2014-03-01

    Pancreatic cancer remains a devastating disease with a mortality rate that has not changed substantially in decades. Novel therapies are therefore desperately needed. The RON receptor tyrosine kinase has been identified as an important mediator of KRAS oncogene addiction and is overexpressed in the majority of pancreatic cancers. Preclinical studies show that inhibition of RON function decreases pancreatic cancer cell migration, invasion, and survival and can sensitize pancreatic cancer cells to chemotherapy. This article reviews the current state of knowledge regarding RON biology and pancreatic cancer and discusses its potential as a therapeutic target.

  2. Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation.

    Directory of Open Access Journals (Sweden)

    Sabine Kuettel

    2011-05-01

    Full Text Available BACKGROUND: The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP utilizing adenosine triphosphate (ATP as the preferred phosphoryl donor. METHODS AND FINDINGS: Here, we present the first structures of Trypanosoma brucei rhodesiense adenosine kinase (TbrAK: the structure of TbrAK in complex with the bisubstrate inhibitor P(1,P(5-di(adenosine-5'-pentaphosphate (AP5A at 1.55 Å, and TbrAK complexed with the recently discovered activator 4-[5-(4-phenoxyphenyl-2H-pyrazol-3-yl]morpholine (compound 1 at 2.8 Å resolution. CONCLUSIONS: The structural details and their comparison give new insights into substrate and activator binding to TbrAK at the molecular level. Further structure-activity relationship analyses of a series of derivatives of compound 1 support the observed binding mode of the activator and provide a possible mechanism of action with respect to their activating effect towards TbrAK.

  3. Atypical Manifestations of Hyperthyroidism

    Science.gov (United States)

    Boxall, E. A.; Lauener, R. W.; McIntosh, H. W.

    1964-01-01

    Patients with hyperthyroidism usually present with symptoms of hypermetabolism with or without goitre and/or eye signs. Occasionally, however, the chief complaints are not immediately suggestive of hyperthyroidism. Patients with hyperthyroidism are described who presented with such atypical manifestations as periodic muscular paralysis, myasthenia, myopathy, encephalopathy, psychosis, angina pectoris, atrial fibrillation, heart failure without underlying heart disease, skeletal demineralization, pretibial myxedema, unilateral eye signs, and pitting edema of the ankles. ImagesFig. 2Fig. 3Fig. 5Fig. 7Fig. 8Fig. 9Fig. 10 PMID:14178405

  4. Prostaglandin E2 stimulates normal bronchial epithelial cell growth through induction of c-Jun and PDK1, a kinase implicated in oncogenesis.

    Science.gov (United States)

    Fan, Yu; Wang, Ye; Wang, Ke

    2015-12-18

    Cyclooxygenase-2-derived prostaglandin E2 (PGE2), a bioactive eicosanoid, has been implicated in many biological processes including reproduction, inflammation and tumor growth. We previously showed that PGE2 stimulated lung cancer cell growth and progression through PGE2 receptor EP2/EP4-mediated kinase signaling pathways. However, the role of PGE2 in controlling lung airway epithelial cell phenotype remains unknown. We evaluated the effects of c-Jun and 3-phosphoinositede dependent protein kinase-1 (PDK1) in mediating epithelial cell hyperplasia induced by PGE2. The bronchial epithelial cell lines BEAS-2B and HBEc14-KT were cultured and then treated with PGE2. PDK1 small interfering RNA (siRNA) and a PDK1 inhibitor, an antagonist of the PGE2 receptor subtype EP4 and EP4 siRNA, c-Jun siRNA, and overexpressions of c-Jun and PDK1 have been used to evaluate the effects on cell proliferation. We demonstrated that PGE2 increased normal bronchial epithelial cell proliferation through induction of PDK1, an ankyrin repeat-containing Ser/Thr kinase implicated in the induction of apoptosis and the suppression of tumor growth. PDK1 siRNA and a PDK1 inhibitor blocked the effects of PGE2 on normal cell growth. The PGE2-induced PDK1 expression was blocked by an antagonist of the PGE2 receptor subtype EP4 and by EP4 siRNA. In addition, we showed that induction of PDK1 by PGE2 was associated with induction of the transcription factor, c-Jun protein. Silencing of c-Jun using siRNA and point mutations of c-Jun sites in the PDK1 gene promoter resulted in blockade of PDK1 expression and promoter activity induced by PGE2. In contrast, overexpression of c-Jun induced PDK1 gene promoter activity and expression followed increased cell proliferation. PGE2 increases normal bronchial epithelial cell proliferation through increased PDK1 gene expression that is dependent on EP4 and induction of c-Jun. Therewith, our data suggest a new role of c-Jun and PDK1 in mediating epithelial cell

  5. Drug information update. Atypical antipsychotics and neuroleptic malignant syndrome: nuances and pragmatics of the association.

    Science.gov (United States)

    Sarkar, Siddharth; Gupta, Nitin

    2017-08-01

    Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal adverse event associated with the use of antipsychotics. Although atypical antipsychotics were initially considered to carry no risk of NMS, reports have accumulated over time implicating them in NMS causation. Almost all atypical antipsychotics have been reported to be associated with NMS. The clinical profile of NMS caused by certain atypical antipsychotics such as clozapine has been reported to be considerably different from the NMS produced by typical antipsychotics, with diaphoresis encountered more commonly, and rigidity and tremor encountered less frequently. This article briefly discusses the evidence relating to the occurrence, presentation and management of NMS induced by atypical antipsychotics.

  6. Phosphorylation of Cytochrome c Threonine 28 Regulates Electron Transport Chain Activity in Kidney: IMPLICATIONS FOR AMP KINASE.

    Science.gov (United States)

    Mahapatra, Gargi; Varughese, Ashwathy; Ji, Qinqin; Lee, Icksoo; Liu, Jenney; Vaishnav, Asmita; Sinkler, Christopher; Kapralov, Alexandr A; Moraes, Carlos T; Sanderson, Thomas H; Stemmler, Timothy L; Grossman, Lawrence I; Kagan, Valerian E; Brunzelle, Joseph S; Salomon, Arthur R; Edwards, Brian F P; Hüttemann, Maik

    2017-01-06

    Mammalian cytochrome c (Cytc) plays a key role in cellular life and death decisions, functioning as an electron carrier in the electron transport chain and as a trigger of apoptosis when released from the mitochondria. However, its regulation is not well understood. We show that the major fraction of Cytc isolated from kidneys is phosphorylated on Thr 28 , leading to a partial inhibition of respiration in the reaction with cytochrome c oxidase. To further study the effect of Cytc phosphorylation in vitro, we generated T28E phosphomimetic Cytc, revealing superior behavior regarding protein stability and its ability to degrade reactive oxygen species compared with wild-type unphosphorylated Cytc Introduction of T28E phosphomimetic Cytc into Cytc knock-out cells shows that intact cell respiration, mitochondrial membrane potential (ΔΨ m ), and ROS levels are reduced compared with wild type. As we show by high resolution crystallography of wild-type and T28E Cytc in combination with molecular dynamics simulations, Thr 28 is located at a central position near the heme crevice, the most flexible epitope of the protein apart from the N and C termini. Finally, in silico prediction and our experimental data suggest that AMP kinase, which phosphorylates Cytc on Thr 28 in vitro and colocalizes with Cytc to the mitochondrial intermembrane space in the kidney, is the most likely candidate to phosphorylate Thr 28 in vivo We conclude that Cytc phosphorylation is mediated in a tissue-specific manner and leads to regulation of electron transport chain flux via "controlled respiration," preventing ΔΨ m hyperpolarization, a known cause of ROS and trigger of apoptosis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Phosphorylation of Cytochrome c Threonine 28 Regulates Electron Transport Chain Activity in Kidney: IMPLICATIONS FOR AMP KINASE

    Energy Technology Data Exchange (ETDEWEB)

    Mahapatra, Gargi; Varughese, Ashwathy; Ji, Qinqin; Lee, Icksoo; Liu, Jenney; Vaishnav, Asmita; Sinkler, Christopher; Kapralov, Alexandr A.; Moraes, Carlos T.; Sanderson, Thomas H.; Stemmler, Timothy L.; Grossman, Lawrence I.; Kagan, Valerian E.; Brunzelle, Joseph S.; Salomon, Arthur R.; Edwards, Brian F. P.; Hüttemann, Maik

    2016-10-07

    Mammalian cytochrome c (Cytc) plays a key role in cellular life and death decisions, functioning as an electron carrier in the electron transport chain and as a trigger of apoptosis when released from the mitochondria. However, its regulation is not well understood. We show that the major fraction of Cytc isolated from kidneys is phosphorylated on Thr28, leading to a partial inhibition of respiration in the reaction with cytochrome c oxidase. To further study the effect of Cytc phosphorylation in vitro, we generated T28E phosphomimetic Cytc, revealing superior behavior regarding protein stability and its ability to degrade reactive oxygen species compared with wild-type unphosphorylated Cytc. Introduction of T28E phosphomimetic Cytc into Cytc knock-out cells shows that intact cell respiration, mitochondrial membrane potential (ΔΨm), and ROS levels are reduced compared with wild type. As we show by high resolution crystallography of wild-type and T28E Cytc in combination with molecular dynamics simulations, Thr28 is located at a central position near the heme crevice, the most flexible epitope of the protein apart from the N and C termini. Finally, in silico prediction and our experimental data suggest that AMP kinase, which phosphorylates Cytc on Thr28 in vitro and colocalizes with Cytc to the mitochondrial intermembrane space in the kidney, is the most likely candidate to phosphorylate Thr28 in vivo. We conclude that Cytc phosphorylation is mediated in a tissue-specific manner and leads to regulation of electron transport chain flux via “controlled respiration,” preventing ΔΨm hyperpolarization, a known cause of ROS and trigger of apoptosis.

  8. Microenvironmental influence on pre-clinical activity of polo-like kinase inhibition in multiple myeloma: implications for clinical translation.

    Directory of Open Access Journals (Sweden)

    Douglas W McMillin

    Full Text Available Polo-like kinases (PLKs play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM. We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM and rapid (commitment to cell death <24 hrs in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM

  9. Atypical idiopathic inflammatory demyelinating lesions

    DEFF Research Database (Denmark)

    Wallner-Blazek, Mirja; Rovira, Alex; Fillipp, Massimo

    2013-01-01

    Atypical lesions of a presumably idiopathic inflammatory demyelinating origin present quite variably and may pose diagnostic problems. The subsequent clinical course is also uncertain. We, therefore, wanted to clarify if atypical idiopathic inflammatory demyelinating lesions (AIIDLs) can be class......Atypical lesions of a presumably idiopathic inflammatory demyelinating origin present quite variably and may pose diagnostic problems. The subsequent clinical course is also uncertain. We, therefore, wanted to clarify if atypical idiopathic inflammatory demyelinating lesions (AIIDLs) can...... be classified according to previously suggested radiologic characteristics and how this classification relates to prognosis. Searching the databases of eight tertiary referral centres we identified 90 adult patients (61 women, 29 men; mean age 34 years) with ≥1 AIIDL. We collected their demographic, clinical...

  10. Atypical Odontalgia (Phantom Tooth Pain)

    Science.gov (United States)

    ... atypical facial pain, phantom tooth pain, or neuropathic orofacial pain, is characterized by chronic pain in a tooth ... such as a specialist in oral medicine or orofacial pain. The information contained in this monograph is for ...

  11. Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling.

    Science.gov (United States)

    Araki, Tsuyoshi; Kawata, Takefumi; Williams, Jeffrey G

    2012-07-10

    SH2 domains are integral to many animal signaling pathways. By interacting with specific phosphotyrosine residues, they provide regulatable protein-protein interaction domains. Dictyostelium is the only nonmetazoan with functionally characterized SH2 domains, but the cognate tyrosine kinases are unknown. There are no orthologs of the animal tyrosine kinases, but there are very many tyrosine kinase-like kinases (TKLs), a group of kinases which, despite their family name, are classified mainly as serine-threonine kinases. STATs are transcription factors that dimerize via phosphotyrosine-SH2 domain interactions. STATc is activated by phosphorylation on Tyr922 when cells are exposed to the prestalk inducer differentiation inducing factor (DIF-1), a chlorinated hexaphenone. We show that in a null mutant for Pyk2, a tyrosine-specific TKL, exposure to DIF-1 does not activate STATc. Conversely, overexpression of Pyk2 causes constitutive STATc activation. Pyk2 phosphorylates STATc on Tyr922 in vitro and complexes with STATc both in vitro and in vivo. This demonstration that a TKL directly activates a STAT has significant implications for understanding the evolutionary origins of SH2 domain-phosphotyrosine signaling. It also has mechanistic implications. Our previous work suggested that a predicted constitutive STATc tyrosine kinase activity is counterbalanced in vivo by the DIF-1-regulated activity of PTP3, a Tyr922 phosphatase. Here we show that the STATc-Pyk2 complex is formed constitutively by an interaction between the STATc SH2 domain and phosphotyrosine residues on Pyk2 that are generated by autophosphorylation. Also, as predicted, Pyk2 is constitutively active as a STATc kinase. This observation provides further evidence for this highly atypical, possibly ancestral, STAT regulation mechanism.

  12. Atypical Cutaneous Manifestations in Syphilis.

    Science.gov (United States)

    Ivars Lleó, M; Clavo Escribano, P; Menéndez Prieto, B

    2016-05-01

    Although the diversity of the clinical manifestations of syphilis is well-known, atypical presentations can also occur. Such atypical presentations are associated with a high risk of transmission as a result of diagnostic confusion and treatment delays owing to the disease's ability to mimic other common skin diseases, deviate from classic clinical presentations, and adopt unique forms. Cases of atypical syphilis have been described most frequently in patients with concomitant human immunodeficiency virus (HIV) infection. Because the incidence of syphilis has been growing over recent years -particularly in patients with HIV co-infection- dermatologists need to be familiar with the less well-known clinical presentations of this venereal disease. Copyright © 2015 AEDV. Published by Elsevier España, S.L.U. All rights reserved.

  13. Novel CDKL5 Mutations in Czech Patients with Phenotypes of Atypical Rett Syndrome and Early-Onset Epileptic Encephalopathy.

    Science.gov (United States)

    Záhoráková, D; Langová, M; Brožová, K; Laštůvková, J; Kalina, Z; Rennerová, L; Martásek, P

    2016-01-01

    The X-linked CDKL5 gene, which encodes cyclin-dependent kinase-like 5 protein, has been implicated in early-onset encephalopathy and atypical Rett syndrome with early-onset seizures. The CDKL5 protein is a kinase required for neuronal development and morphogenesis, but its precise functions are still largely unexplored. Individuals with CDKL5 mutations present with severe global developmental delay, intractable epilepsy, and Rett-like features. A clear genotype-phenotype correlation has not been established due to an insufficient number of reported cases. The aim of this study was to analyse the CDKL5 gene in Czech patients with early-onset seizures and Rett-like features. We performed mutation screening in a cohort of 83 individuals using high-resolution melting analysis, DNA sequencing and multiplex ligation- dependent probe amplification. Molecular analyses revealed heterozygous pathogenic mutations in three girls with severe intellectual disability and intractable epilepsy starting at the age of two months. All three identified mutations, c.637G>A, c.902_977+29del105, and c.1757_1758delCT, are novel, thus significantly extending the growing spectrum of known pathogenic CDKL5 sequence variants. Our results support the importance of genetic testing of the CDKL5 gene in patients with early-onset epileptic encephalopathy and Rett-like features with early-onset seizures. This is the first study referring to molecular defects of CDKL5 in Czech cases.

  14. Atypical sexual behavior during sleep.

    Science.gov (United States)

    Guilleminault, Christian; Moscovitch, Adam; Yuen, Kin; Poyares, Dalva

    2002-01-01

    This article reports a case series of atypical sexual behavior during sleep, which is often harmful to patients or bed partners. Eleven subjects underwent clinical evaluation of complaints of sleep-related atypical sexual behavior. Complaints included violent masturbation, sexual assaults, and continuous (and loud) sexual vocalizations during sleep. One case was a medical-legal case. Sleep logs, clinical evaluations, sleep questionnaires, structured psychiatric interviews, polysomnography, actigraphy, home electroencephalographic monitoring during sleep, and clinical electroencephalographic monitoring while awake and asleep were used to determine clinical diagnoses. Atypical sexual behaviors during sleep were associated with feelings of guilt, shame, and depression. Because of these feelings, patients and bed partners often tolerated the abnormal behavior for long periods of time without seeking medical attention. The following pathologic sleep disorders were demonstrated on polysomnography: partial complex seizures, sleep-disordered breathing, stage 3 to 4 non-rapid eye movement (REM) sleep parasomnias, and REM sleep behavior disorder. These findings were concurrent with morning amnesia. The atypical behaviors were related to different syndromes despite the similarity of complaints from bed partners. In most cases the disturbing and often harmful symptoms were controlled when counseling was instituted and sleep disorders were treated. In some cases treatment of seizures or psychiatric disorders was also needed. Clonazepam with simultaneous psychotherapy was the most common successful treatment combination. The addition of antidepressant or antiepileptic medications was required in specific cases.

  15. MANIFESTATIONS OF AGGRESSIVE ATYPICAL KAPOSI'S ...

    African Journals Online (AJOL)

    ... weight loss (86.8%), skin nodules (86.4%) and diarrhoea (55.3%). Virtually, all occupational groups were affected, with students, civil servants and businessmen topping the list. Key Words: Atypical Aggressive Kaposi's sarcoma, HIV infection. African Journal Of Clinical And Experimental Microbiology Jan 2004 Vol.5 No.1 ...

  16. Constitutive Activation of NF-kappaB in Prostate Carcinoma Cells Through a Positive Feedback Loop: Implication of Inducible IKK-Related Kinase (IKKi)

    National Research Council Canada - National Science Library

    Budunova, Irina V

    2004-01-01

    The overall goal of this project is to understand the role of inducible IKK-related kinase IKKi in constitutive activation of anti-apoptotic transcription factor NF-kB prostate carcinoma (PC) cells...

  17. Constitutive Activation of NF-KB in Prostate Carcinoma Cells Through a Positive Feedback Loop: Implication of Inducible IKK-Related Kinase (IKKi)

    National Research Council Canada - National Science Library

    Budunova, Irina V

    2005-01-01

    The overall goal of this project is to understand the role of inducible IKK-related kinase IKKi in constitutive activation of anti-apoptotic transcription factor NF-KB prostate carcinoma (PC) cells...

  18. Harmane: an atypical neurotransmitter?

    Science.gov (United States)

    Abu Ghazaleh, Haya; Lalies, Maggie D; Nutt, David J; Hudson, Alan L

    2015-03-17

    Harmane is an active component of clonidine displacing substance and a candidate endogenous ligand for imidazoline binding sites. The neurochemistry of tritiated harmane was investigated in the present study examining its uptake and release properties in the rat brain central nervous system (CNS) in vitro. At physiological temperature, [(3)H]harmane was shown to be taken up in rat brain cortex. Further investigations demonstrated that treatment with monoamine uptake blockers (citalopram, nomifensine and nisoxetine) did not alter [(3)H]harmane uptake implicating that the route of [(3)H]harmane transport was distinct from the monoamine uptake systems. Furthermore, imidazoline ligands (rilmenidine, efaroxan, 2-BFI and idazoxan) showed no prominent effect on [(3)H]harmane uptake suggesting the lack of involvement of imidazoline binding sites. Subsequent analyses showed that disruption of the Na(+) gradient using ouabain or choline chloride did not block [(3)H]harmane uptake suggesting a Na(+)-independent transport mechanism. Moreover, higher temperatures (50°C) failed to impede [(3)H]harmane uptake implying a non-physiological transporter. The failure of potassium to evoke the release of preloaded [(3)H]harmane from rat brain cortex indicates that the properties of this putative endogenous ligand for imidazoline binding sites do not resemble that of a conventional neurotransmitter. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Casein kinases

    DEFF Research Database (Denmark)

    Issinger, O G

    1993-01-01

    The present review on casein kinases focuses mainly on the possible metabolic role of CK-2, with special emphasis on its behavior in pathological tissues. From these data at least three ways to regulate CK-2 activity emerge: (i) CK-2 activity changes during embryogenesis, being high at certain...

  20. 1.88 Ga São Gabriel AMCG association in the southernmost Uatumã-Anauá Domain: Petrological implications for post-collisional A-type magmatism in the Amazonian Craton

    Science.gov (United States)

    Valério, Cristóvão da Silva; Macambira, Moacir José Buenano; Souza, Valmir da Silva; Dantas, Elton Luiz; Nardi, Lauro Valentim Stoll

    2018-02-01

    In the southernmost Uatumã-Anauá Domain, central Amazonian craton (Brazil), crop out 1.98 Ga basement inliers represented by (meta)leucosyenogranites and amphibolites (Igarapé Canoas Suite), 1.90-1.89 Ga high-K calc-alkaline granitoids (Água Branca Suite), a 1.88-1.87 Ga alkali-calcic A-type volcano-plutonic system (Iricoumé-Mapuera), Tonian SiO2-satured alkaline granitoids, 1.45-1.25 Ga orthoderived metamorphic rocks (Jauaperi Complex) and Orosirian-Upper Triassic mafic intrusions. New data on petrography, multielementar geochemistry, in situ zircon U-Pb ages and Nd and Hf isotopes of alkali-calcic A-type granites (São Gabriel Granite, Mapuera Suite) and related rocks are indicative of a 1.89-1.87 Ga volcano-plutonic system integrated to the São Gabriel AMCG association. Its magmatic evolution was controlled by the fractional crystallization combined with magma mixing and cumulation processes. Nd isotope values (εNdt values = - 3.71 to + 0.51 and Nd TDM model age = 2.44 to 2.12 Ga) and U-Pb inherited zircon crystals (2115 ± 22 Ma; 2206 ± 21 Ma; 2377 ± 17 Ma, 2385 ± 17 Ma) of the São Gabriel system indicate a large participation of Siderian-Rhyacian crust (granite-greenstones and granulites) and small contribution of Rhyacian mantelic magma. εHft values (+ 5.2 to - 5.8) and Hf TDM ages (3.27-2.14 Ga) also point to contribution of Paleoarchean-Rhyacian crustal melts and small participation of Siderian-Rhyacian mantle melts. Residual melts from the lower crust have been mixed with basaltic melts generated by partial melting of the subcontinental lithospheric mantle (peridotite) in a post-collisional setting at 1.89-1.87 Ga. The mafic melts of such a mixture could have been originated through partial melting of residual ocean plate fragments (eclogites) which ascended onto a residual mantle wedge (hornblende peridotite) and melted it, resulting in modified basaltic magma which, by underplating, led heat to the anatexis of the lower continental crust

  1. Atypical antipsychotics and glucose homeostasis.

    Science.gov (United States)

    Bergman, Richard N; Ader, Marilyn

    2005-04-01

    Persistent reports have linked atypical antipsychotics with diabetes, yet causative mechanisms responsible for this linkage are unclear. Goals of this review are to outline the pathogenesis of nonimmune diabetes and to survey the available literature related to why antipsychotics may lead to this disease. We accessed the literature regarding atypical antipsychotics and glucose homeostasis using PubMed. The search included English-language publications from 1990 through October 2004. Keywords used included atypical antipsychotics plus one of the following: glucose, insulin, glucose tolerance, obesity, or diabetes. In addition, we culled information from published abstracts from several national and international scientific meetings for the years 2001 through 2004, including the American Diabetes Association, the International Congress on Schizophrenia Research, and the American College of Neuropsychopharmacology. The latter search was necessary because of the paucity of well-controlled prospective studies. We examined publications with significant new data or publications that contributed to the overall comprehension of the impact of atypical antipsychotics on glucose metabolism. We favored original peer-reviewed articles and were less likely to cite single case studies and/or anecdotal information. Approximately 75% of the fewer than 150 identified articles were examined and included in this review. Validity of data was evaluated using the existence of peer-review status as well as our own experience with methodology described in the specific articles. The metabolic profile caused by atypical antipsychotic treatment resembles type 2 diabetes. These agents cause weight gain in treated subjects and may induce obesity in both visceral and subcutaneous depots, as occurs in diabetes. Insulin resistance, usually associated with obesity, occurs to varying degrees with different antipsychotics, although more comparative studies with direct assessment of resistance are

  2. Atypical manifestations of early syphilis

    Directory of Open Access Journals (Sweden)

    R V Koranne

    1990-01-01

    Full Text Available A study of 36 untreated patients with early syphilis revealed atypical variations namely; long incubation period of 101 days in I patient, more than 3 chancres in 1, undermined margin of the chancre along with tenderness in 1 and moderate to severe tenderness of the ulcers in 2 cases. In 3 patients there was no indurations of the ulcers. Three patients with primary syphilis had unilateral lymphadenitis, and in I case the lymph nodes were not only tender but showed tendency towardsmatingawell. Insecondarysyphilis, 11 out of 16 patients having condylomata lata had no other muco-cutaneous lesions. Concomitant presence of other venereal disease to account for the atypical manifestations was discounted- by appropriate laboratory tests, response to therapeutic agents and follow up.

  3. Fluctuation theorems and atypical trajectories

    International Nuclear Information System (INIS)

    Sahoo, M; Lahiri, S; Jayannavar, A M

    2011-01-01

    In this work, we have studied simple models that can be solved analytically to illustrate various fluctuation theorems. These fluctuation theorems provide symmetries individually to the distributions of physical quantities such as the classical work (W c ), thermodynamic work (W), total entropy (Δs tot ) and dissipated heat (Q), when the system is driven arbitrarily out of equilibrium. All these quantities can be defined for individual trajectories. We have studied the number of trajectories which exhibit behaviour unexpected at the macroscopic level. As the time of observation increases, the fraction of such atypical trajectories decreases, as expected at the macroscale. The distributions for the thermodynamic work and entropy production in nonlinear models may exhibit a peak (most probable value) in the atypical regime without violating the expected average behaviour. However, dissipated heat and classical work exhibit a peak in the regime of typical behaviour only.

  4. An Atypical Presentation on Insulinoma

    Science.gov (United States)

    2017-06-16

    PUBLICATIONS/ PRESENTATIONS 1. TO: CLINICAL RESEARCH 2. FROM: (Author’s Name, Rank, Grade, Office Symbol) 3. GME/GHSE STUDENT: 4. PROTOCOL NUMBER: Kluesner...PROCESSING OF PROFESSIONAL MEDICAL RESEARCH/TECHNICAL PUBLICATIONS/ PRESENTATIONS 1st ENDORSEMENT (59 MDW/SGVU Use Only) TO: Clinical Research Division 24...CAPT JOSEPH KLUESNER FROM: 59 MDW/SGYU SUBJECT: Professional Presentation Approval 1. Your paper, entitled An Atypical Presentation of Insulinoma

  5. Atypical work and employment continuity

    OpenAIRE

    Addison, John T.; Surfield, Christopher J.

    2009-01-01

    Atypical employment arrangements such as agency temporary work and contracting have long been criticized as offering more precarious and unstable work than regular employment. Using data from two datasets – the CAEAS and the NLSY79 – we determine whether workers who take such jobs rather than regular employment, or the alternative of continued job search, subsequently experience greater or lesser employment continuity. Observed differences between the various working arrangements are starkest...

  6. Atypical centrioles during sexual reproduction.

    Science.gov (United States)

    Avidor-Reiss, Tomer; Khire, Atul; Fishman, Emily L; Jo, Kyoung H

    2015-01-01

    Centrioles are conserved, self-replicating, microtubule-based, 9-fold symmetric subcellular organelles that are essential for proper cell division and function. Most cells have two centrioles and maintaining this number of centrioles is important for animal development and physiology. However, how animals gain their first two centrioles during reproduction is only partially understood. It is well established that in most animals, the centrioles are contributed to the zygote by the sperm. However, in humans and many animals, the sperm centrioles are modified in their structure and protein composition, or they appear to be missing altogether. In these animals, the origin of the first centrioles is not clear. Here, we review various hypotheses on how centrioles are gained during reproduction and describe specialized functions of the zygotic centrioles. In particular, we discuss a new and atypical centriole found in sperm and zygote, called the proximal centriole-like structure (PCL). We also discuss another type of atypical centriole, the "zombie" centriole, which is degenerated but functional. Together, the presence of centrioles, PCL, and zombie centrioles suggests a universal mechanism of centriole inheritance among animals and new causes of infertility. Since the atypical centrioles of sperm and zygote share similar functions with typical centrioles in somatic cells, they can provide unmatched insight into centriole biology.

  7. Atypical Centrioles During Sexual Reproduction

    Directory of Open Access Journals (Sweden)

    Tomer eAvidor-Reiss

    2015-04-01

    Full Text Available Centrioles are conserved, self-replicating, microtubule-based 9-fold symmetric subcellular organelles that are essential for proper cell division and function. Most cells have two centrioles and maintaining this number of centrioles is important for animal development and physiology. However, how animals gain their first two centrioles during reproduction is only partially understood. It is well established that in most animals, the centrioles are contributed to the zygote by the sperm. However, in humans and many animals, the sperm centrioles are modified in their structure and protein composition, or they appear to be missing altogether. In these animals, the origin of the first centrioles is not clear. Here, we review various hypotheses on how centrioles are gained during reproduction and describe specialized functions of the zygotic centrioles. In particular, we discuss a new and atypical centriole found in sperm and zygote, the proximal centriole-like structure (PCL. We also discuss another type of atypical centriole, the zombie centriole, which is degenerated but functional. Together, the presence of centrioles, PCL, and zombie centrioles suggests a universal mechanism of centriole inheritance among animals and new causes of infertility. Since the atypical centrioles of sperm and zygote share similar functions with typical centrioles in somatic cells, they can provide unmatched insight into centriole biology.

  8. Prevalence and correlates of atypical patterns of drug use progression: findings from the South African Stress and Health Study

    Science.gov (United States)

    Myers, B; van Heerden, MS; Grimsrud, A; Myer, L; Williams, DR; Stein, DJ

    2012-01-01

    Objective Atypical sequences of drug use progression are thought to have important implications for the development of substance dependence. The extent to which this assumption holds for South African populations is unknown. This paper attempts to address this gap by examining the prevalence and correlates of atypical patterns of drug progression among South Africans. Method Data on substance use and other mental health disorders from a nationally representative sample of 4351 South Africans were analysed. Weighted cross tabulations were used to estimate prevalence and correlates of atypical patterns of drug use progression. Results Overall, 12.2% of the sample reported atypical patterns of drug use progression. The most common violation was the use of extra-medical drugs prior to alcohol and tobacco. Gender was significantly associated with atypical patterns of drug use with the risk pattern varying by the type of drug. None of the anxiety or mood disorders were associated with atypical patterns of use. Atypical patterns of drug use were not associated with increased risk for a lifetime substance use disorder. Conclusion Atypical patterns of drug use initiation seem more prevalent in South Africa compared to other countries. The early use of extra-medical drugs is common, especially among young women. Drug availability and social environmental factors may influence patterns of drug use. The findings have important implications for prevention initiatives and future research. PMID:21509404

  9. Kinase fusions are frequent in Spitz tumors and spitzoid melanomas

    Science.gov (United States)

    Esteve-Puig, Rosaura; Botton, Thomas; Yeh, Iwei; Lipson, Doron; Otto, Geoff; Brennan, Kristina; Murali, Rajmohan; Garrido, Maria; Miller, Vincent A.; Ross, Jeffrey S; Berger, Michael F.; Sparatta, Alyssa; Palmedo, Gabriele; Cerroni, Lorenzo; Busam, Klaus J.; Kutzner, Heinz; Cronin, Maureen T; Stephens, Philip J; Bastian, Boris C.

    2014-01-01

    Spitzoid neoplasms are a group of melanocytic tumors with distinctive histopathologic features. They include benign tumors (Spitz nevi), malignant tumors (spitzoid melanomas), and tumors with borderline histopathologic features and uncertain clinical outcome (atypical Spitz tumors). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbor kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%), and RET (3%) in a mutually exclusive pattern. The chimeric proteins are constitutively active, stimulate oncogenic signaling pathways, are tumorigenic, and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz nevi, 56% of atypical Spitz tumors, and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signaling of the fusion proteins in vitro. In summary, kinase fusions account for the majority of oncogenic aberrations in spitzoid neoplasms, and may serve as therapeutic targets for metastatic spitzoid melanomas. PMID:24445538

  10. RhoA, Rho kinase, JAK2, and STAT3 may be the intracellular determinants of longevity implicated in the progeric influence of obesity: Insulin, IGF-1, and leptin may all conspire to promote stem cell exhaustion.

    Science.gov (United States)

    Tapia, Patrick C

    2006-01-01

    The aging process in higher mammals is increasingly being shown to feature a potentially substantial contribution from the longitudinal deterioration of normative stem cell dynamics seen with the passage of time. The precise mechanistic sequence producing this phenomenon is not entirely understood, but recent evidence has strongly implicated intracellular downstream effectors of endocrinologic pathways thought to be engaged by the obese state, specifically the insulin, IGF-1, and leptin signaling pathways. Among the intracellular effectors of these signals, a uniquely potent influence on stem cell dynamics may be attributable to Rho/ROCK, JAK kinase activity and STAT3 activity. In particular, it has already been shown that specific tyrosine kinase activities, such as that seen with Rho kinase, are presently thought to be associated with adverse health outcomes in numerous clinical contexts. Furthermore, the Rho GTPase is thought to be contributing to end-stage renal disease. However, in addition to its contribution to organ system dysfunction, the Rho/ROCK pathway has recently been shown to be activated by insulin and IGF-1, providing a tantalizing connection to nutrition and aging science. The JAK-STAT pathway, in contrast, has long been associated with pro-inflammatory cytokines, but has recently been implicated in leptin signaling as well. Importantly, JAK-STAT signaling has, similarly to Rho/ROCK signaling, been implicated as capable of accelerating stem cell proliferation. The implications of these recent determinations, in light of the recent finding of telomere attrition in humans associated with obesity, are that the intracellular determinants of aging may already be known, and the known common influence of these signaling elements on longitudinal stem cell dynamics is a pronounced induction of proliferation, an elevation that has been linked to the pathologic evolution of longitudinal organ-level dysfunction and the organismal-level physiologic decline

  11. Mineral chemistry and geochemistry of the Late Neoproterozoic Gabal Abu Diab granitoids, Central Eastern Dessert, Egypt: Implications for the origin of rare metal post-orogenic A-type granites

    Science.gov (United States)

    Sami, Mabrouk; Ntaflos, Theodoros; Farahat, Esam S.; Ahmed, Awaad F.; Mohamed, Haroun A.

    2015-04-01

    within A-type granite worldwide. According to Zhang et al., 2012, the garnet crystallized at the expense of biotite from the MnO-rich evolved melt after fractionation of biotite, plagioclase, K-feldspar, zircon, apatite, and ilmenite. The granitoids are alkali feldspar granites showing distinct geochemical features and most likely, belong to the post-orogenic younger Egyptian granitoids. They are peraluminous A-type alkaline rocks but they have lower Fe2O3, MgO, MnO, CaO, TiO2, P2O5, Sr, Ba, V, and higher SiO2, Na2O, K2O, Nb, Ta, U, Zr, Th, Ga/Al and Rb than the typical rocks of this type. The positive correlation between Ba and Sr, and the negative correlation between Rb and K/Rb reveal fractional crystallization of alkali feldspar. The similarity in most geochemical characteristics suggests that Abu Diab granitoids are genetically related to each other and extremely enrichment in incompatible elements such as Nb and Ta, indicating that they crystallized from extremely differentiated magmas. References: Zhang, J., Ma, C. and She, Z., 2012. An Early Cretaceous garnet-bearing metaluminous A-type granite intrusion in the East Qinling Orogen, central China: Petrological, mineralogical and geochemical constraints. Geoscience Frontiers 3 (5), 635-646.

  12. Atypical disease phenotypes in pediatric ulcerative colitis

    DEFF Research Database (Denmark)

    Levine, Arie; de Bie, Charlotte I; Turner, Dan

    2013-01-01

    Definitive diagnosis of pediatric ulcerative colitis (UC) may be particularly challenging since isolated colitis with overlapping features is common in pediatric Crohn's disease (CD), while atypical phenotypes of UC are not uncommon. The Paris classification allows more accurate phenotyping...... of atypical inflammatory bowel disease (IBD) patients. Our aim was to identify the prevalence of atypical disease patterns in new-onset pediatric UC using the Paris classification....

  13. Implication de la protéine kinase C dans les troubles bipolaires : vers de nouvelles cibles thérapeutiques

    OpenAIRE

    Abrial , Erika

    2013-01-01

    Bipolar disorder is a devastating long-term disease characterized by alternate episodes of mania and depression. Despite extensive research, the molecular and cellular underpinnings of bipolar disorder remain to be fully elucidated. Protein kinase C (PKC) has emerged as a potential molecular target for the treatment of bipolar disorder. The present study investigated the role of PKC in manic- and depressive-like behaviors. Our results showed that PKC inhibition produced an antimanic-like effe...

  14. Atypical Manifestation of Vestibular Schwannoma

    Directory of Open Access Journals (Sweden)

    Webster, Guilherme

    2013-09-01

    Full Text Available Introduction: Vestibular schwannoma (also known as acoustic neuroma is a benign tumor whose cells are derived from Schwann sheaths, which commonly occurs from the vestibular portion of the eighth cranial nerve. Furthermore, vestibular schwannomas account for ∼8% of intracranial tumors in adults and 80 to 90% of tumors of the cerebellopontine angle. Its symptoms are varied, but what stands out most is a unilateral sensorineural hearing loss, with a low index of speech recognition. Objective: Describe an atypical manifestation of vestibular schwannoma. Case Report: The 46-year-old woman had vertigo and binaural hearing loss and fullness, with ear, nose, and throat examination suggestive of cochlear injury. After 6 months, the patient developed worsening of symptoms and onset of right unilateral tinnitus. In further exams the signs of cochlear damage remained, except for the vestibular test (hyporeflexia. Magnetic resonance imaging showed an expansive lesion in the right cerebellopontine angle. Discussion: This report warns about the atypical manifestations of vestibular schwannoma, which must always be remembered in investigating and diagnosing hearing loss.

  15. The small GTPase RhoH is an atypical regulator of haematopoietic cells

    Directory of Open Access Journals (Sweden)

    Kubatzky Katharina F

    2008-09-01

    Full Text Available Abstract Rho GTPases are a distinct subfamily of the superfamily of Ras GTPases. The best-characterised members are RhoA, Rac and Cdc42 that regulate many diverse actions such as actin cytoskeleton reorganisation, adhesion, motility as well as cell proliferation, differentiation and gene transcription. Among the 20 members of that family, only Rac2 and RhoH show an expression restricted to the haematopoietic lineage. RhoH was first discovered in 1995 as a fusion transcript with the transcriptional repressor LAZ3/BCL6. It was therefore initially named translation three four (TTF but later on renamed RhoH due to its close relationship to the Ras/Rho family of GTPases. Since then, RhoH has been implicated in human cancer as the gene is subject to somatic hypermutation and by the detection of RHOH as a translocation partner for LAZ3/BCL6 or other genes in human lymphomas. Underexpression of RhoH is found in hairy cell leukaemia and acute myeloid leukaemia. Some of the amino acids that are crucial for GTPase activity are mutated in RhoH so that the protein is a GTPase-deficient, so-called atypical Rho GTPase. Therefore other mechanisms of regulating RhoH activity have been described. These include regulation at the mRNA level and tyrosine phosphorylation of the protein's unique ITAM-like motif. The C-terminal CaaX box of RhoH is mainly a target for farnesyl-transferase but can also be modified by geranylgeranyl-transferase. Isoprenylation of RhoH and changes in subcellular localisation may be an additional factor to fine-tune signalling. Little is currently known about its signalling, regulation or interaction partners. Recent studies have shown that RhoH negatively influences the proliferation and homing of murine haematopoietic progenitor cells, presumably by acting as an antagonist for Rac1. In leukocytes, RhoH is needed to keep the cells in a resting, non-adhesive state, but the exact mechanism has yet to be elucidated. RhoH has also been

  16. Genome-Wide Identification and Evolutionary Analysis of Sarcocystis neurona Protein Kinases.

    Science.gov (United States)

    Murungi, Edwin K; Kariithi, Henry M

    2017-03-21

    The apicomplexan parasite Sarcocystis neurona causes equine protozoal myeloencephalitis (EPM), a degenerative neurological disease of horses. Due to its host range expansion, S. neurona is an emerging threat that requires close monitoring. In apicomplexans, protein kinases (PKs) have been implicated in a myriad of critical functions, such as host cell invasion, cell cycle progression and host immune response evasion. Here, we used various bioinformatics methods to define the kinome of S. neurona and phylogenetic relatedness of its PKs to other apicomplexans. We identified 97 putative PKs clustering within the various eukaryotic kinase groups. Although containing the universally-conserved PKA (AGC group), S. neurona kinome was devoid of PKB and PKC. Moreover, the kinome contains the six-conserved apicomplexan CDPKs (CAMK group). Several OPK atypical kinases, including ROPKs 19A, 27, 30, 33, 35 and 37 were identified. Notably, S. neurona is devoid of the virulence-associated ROPKs 5, 6, 18 and 38, as well as the Alpha and RIO kinases. Two out of the three S. neurona CK1 enzymes had high sequence similarities to Toxoplasma gondii TgCK1-α and TgCK1-β and the Plasmodium PfCK1. Further experimental studies on the S. neurona putative PKs identified in this study are required to validate the functional roles of the PKs and to understand their involvement in mechanisms that regulate various cellular processes and host-parasite interactions. Given the essentiality of apicomplexan PKs in the survival of apicomplexans, the current study offers a platform for future development of novel therapeutics for EPM, for instance via application of PK inhibitors to block parasite invasion and development in their host.

  17. Genome-Wide Identification and Evolutionary Analysis of Sarcocystis neurona Protein Kinases

    Directory of Open Access Journals (Sweden)

    Edwin K. Murungi

    2017-03-01

    Full Text Available The apicomplexan parasite Sarcocystis neurona causes equine protozoal myeloencephalitis (EPM, a degenerative neurological disease of horses. Due to its host range expansion, S. neurona is an emerging threat that requires close monitoring. In apicomplexans, protein kinases (PKs have been implicated in a myriad of critical functions, such as host cell invasion, cell cycle progression and host immune response evasion. Here, we used various bioinformatics methods to define the kinome of S. neurona and phylogenetic relatedness of its PKs to other apicomplexans. We identified 97 putative PKs clustering within the various eukaryotic kinase groups. Although containing the universally-conserved PKA (AGC group, S. neurona kinome was devoid of PKB and PKC. Moreover, the kinome contains the six-conserved apicomplexan CDPKs (CAMK group. Several OPK atypical kinases, including ROPKs 19A, 27, 30, 33, 35 and 37 were identified. Notably, S. neurona is devoid of the virulence-associated ROPKs 5, 6, 18 and 38, as well as the Alpha and RIO kinases. Two out of the three S. neurona CK1 enzymes had high sequence similarities to Toxoplasma gondii TgCK1-α and TgCK1-β and the Plasmodium PfCK1. Further experimental studies on the S. neurona putative PKs identified in this study are required to validate the functional roles of the PKs and to understand their involvement in mechanisms that regulate various cellular processes and host-parasite interactions. Given the essentiality of apicomplexan PKs in the survival of apicomplexans, the current study offers a platform for future development of novel therapeutics for EPM, for instance via application of PK inhibitors to block parasite invasion and development in their host.

  18. Petrogenesis and geodynamic implications of Ediacaran highly fractionated A-type granitoids in the north Arabian-Nubian Shield (Egypt): Constraints from whole-rock geochemistry and Sr-Nd isotopes

    Science.gov (United States)

    Sami, Mabrouk; Ntaflos, Theodoros; Farahat, Esam S.; Mohamed, Haroun A.; Hauzenberger, Christoph; Ahmed, Awaad F.

    2018-04-01

    Mineral chemistry, whole-rock geochemical and Sr-Nd isotopic data are reported for the Abu-Diab granitoids in the northern Arabian-Nubian Shield (ANS) of Egypt, to investigate their petrogenesis and geodynamic significance. Gabal Abu-Diab constitute a multiphase pluton, consisting largely of two-mica granites (TMGs) enclosing microgranular enclaves and intruded by garnet bearing muscovite granites (GMGs) and muscovite granites (MGs). The granitoids are weakly peraluminous (A/CNK = 1.01-1.12) and show high SiO2 (>72.9 wt%) and alkali (K2O + Na2O = 8.60-9.13) contents. The geochemical features show that they are post-collisional and highly fractionated A-type granitoids. Compared to their host TMGs, the microgranular enclaves are strongly peraluminous (A/CNK = 1.18-1.24) with lower SiO2 and higher abundances of trace elements. The TMGs are depleted in Ba, Nb, P and Ti and are enriched in LREEs relative to HREEs with weakly negative Eu anomalies (Eu/Eu* = 0.45-0.64). In contrast, the GMGs and MGs are extremely depleted in Ba, Sr and Ti and have tetrad-type REE patterns (TE1-3 = 1.1-1.3) with strongly pronounced negative Eu anomalies (Eu/Eu* = 0.03-0.26), similar to rare metals bearing granites. The Ediacaran (585 ± 24 Ma) TMGs, are characterized by restricted and relatively low initial 87Sr/86Sr ratios (0.70337-0.70382) that suggests their derivation from a depleted mantle source, with little contamination from the older continental crust. In contrast, the GMGs and MGs have extremely high 87Rb/86Sr and 87Sr/86Sr ratios that reflect the disturbance of the Rb-Sr isotopic system and may give an indication for magmatic-fluid interaction. However, all the granitoids display positive εNd(t) (4.41-6.57) and depleted mantle model ages TDM2 between 777 and 956 Ma, which indicate their derivation from a Neoproterozoic juvenile magma sources and preclude the occurrence of pre-Neoproterozoic crustal rocks in the ANS. The microgranular enclaves represent globules of hot mafic

  19. Gender-Atypical Mental Illness as Male Gender Threat.

    Science.gov (United States)

    Michniewicz, Kenneth S; Bosson, Jennifer K; Lenes, Joshua G; Chen, Jason I

    2016-07-01

    The present study examined whether men view gender-atypical (i.e., feminine) psychological disorders as threats to their gender status. Men and women (N = 355) rated their expectations of gender status loss, feelings of distress, and help-seeking intentions in response to 10 different stereotypically masculine and feminine psychological disorders. Men as compared to women expected greater gender status loss for, and reported more distress to, gender-atypical versus gender-typical disorders. Expectations of gender status loss partially mediated the link between participant gender and distress at the thought of gender-atypical disorders. These findings suggest that feminine disorders pose more powerful gender status threats for men than masculine disorders do and that men's expectations of gender status loss for feminine disorders drive their negative reactions to these mental illnesses. The discussion emphasizes the importance of considering the gender-typicality of disorders, and the implications of these findings for clinical interventions. © The Author(s) 2015.

  20. [Development of an Atypical Response Scale.

    Science.gov (United States)

    Mendelsohn, Mark; Linden, James

    The development of an objective diagnostic scale to measure atypical behavior is discussed. The Atypical Response Scale (ARS) is a structured projective test consisting of 17 items, each weighted 1, 2, or 3, that were tested for convergence and reliability. ARS may be individually or group administered in 10-15 minutes; hand scoring requires 90…

  1. The PH domain of phosphoinositide-dependent kinase-1 exhibits a novel, phospho-regulated monomer-dimer equilibrium with important implications for kinase domain activation: single-molecule and ensemble studies.

    Science.gov (United States)

    Ziemba, Brian P; Pilling, Carissa; Calleja, Véronique; Larijani, Banafshé; Falke, Joseph J

    2013-07-16

    Phosphoinositide-dependent kinase-1 (PDK1) is an essential master kinase recruited to the plasma membrane by the binding of its C-terminal PH domain to the signaling lipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). Membrane binding leads to PDK1 phospho-activation, but despite the central role of PDK1 in signaling and cancer biology, this activation mechanism remains poorly understood. PDK1 has been shown to exist as a dimer in cells, and one crystal structure of its isolated PH domain exhibits a putative dimer interface. It has been proposed that phosphorylation of PH domain residue T513 (or the phospho-mimetic T513E mutation) may regulate a novel PH domain dimer-monomer equilibrium, thereby converting an inactive PDK1 dimer to an active monomer. However, the oligomeric states of the PH domain on the membrane have not yet been determined, nor whether a negative charge at position 513 is sufficient to regulate its oligomeric state. This study investigates the binding of purified wild-type (WT) and T513E PDK1 PH domains to lipid bilayers containing the PIP3 target lipid, using both single-molecule and ensemble measurements. Single-molecule analysis of the brightness of the fluorescent PH domain shows that the PIP3-bound WT PH domain on membranes is predominantly dimeric while the PIP3-bound T513E PH domain is monomeric, demonstrating that negative charge at the T513 position is sufficient to dissociate the PH domain dimer and is thus likely to play a central role in PDK1 monomerization and activation. Single-molecule analysis of two-dimensional (2D) diffusion of PH domain-PIP3 complexes reveals that the dimeric WT PH domain diffuses at the same rate as a single lipid molecule, indicating that only one of its two PIP3 binding sites is occupied and there is little penetration of the protein into the bilayer as observed for other PH domains. The 2D diffusion of T513E PH domain is slower, suggesting the negative charge disrupts local structure in a way that allows

  2. Nonmotor Features in Atypical Parkinsonism.

    Science.gov (United States)

    Bhatia, Kailash P; Stamelou, Maria

    2017-01-01

    Atypical parkinsonism (AP) comprises mainly multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which are distinct pathological entities, presenting with a wide phenotypic spectrum. The classic syndromes are now called MSA-parkinsonism (MSA-P), MSA-cerebellar type (MSA-C), Richardson's syndrome, and corticobasal syndrome. Nonmotor features in AP have been recognized almost since the initial description of these disorders; however, research has been limited. Autonomic dysfunction is the most prominent nonmotor feature of MSA, but also gastrointestinal symptoms, sleep dysfunction, and pain, can be a feature. In PSP and CBD, the most prominent nonmotor symptoms comprise those deriving from the cognitive/neuropsychiatric domain. Apart from assisting the clinician in the differential diagnosis with Parkinson's disease, nonmotor features in AP have a big impact on quality of life and prognosis of AP and their treatment poses a major challenge for clinicians. © 2017 Elsevier Inc. All rights reserved.

  3. Atypical gorlin′s syndrome

    Directory of Open Access Journals (Sweden)

    Yesudian Devakar

    1995-01-01

    Full Text Available A 21-year-old woman presented with complaints of skin lesions on her face, palms and soles. On examination, 8 to 10 well-defined, pigmented nodules with raised and pearly borders were seen on the face. Multiple pits were present on the palms and soles. Biopsy of both lesions revealed the presence of basal cell epitheliomas. The patient also gave history of removal of a keratocyst of mandible 10 years back. The case was diagnosed as Gorlin′s syndrome. It is atypical due to the low number of basal cell epitheliomas, the occurrence of only a single odontogenic cyst and the absence of other features usually associated with this condition

  4. Are Atypical Things More Popular?

    Science.gov (United States)

    Berger, Jonah; Packard, Grant

    2018-04-01

    Why do some cultural items become popular? Although some researchers have argued that success is random, we suggest that how similar items are to each other plays an important role. Using natural language processing of thousands of songs, we examined the relationship between lyrical differentiation (i.e., atypicality) and song popularity. Results indicated that the more different a song's lyrics are from its genre, the more popular it becomes. This relationship is weaker in genres where lyrics matter less (e.g., dance) or where differentiation matters less (e.g., pop) and occurs for lyrical topics but not style. The results shed light on cultural dynamics, why things become popular, and the psychological foundations of culture more broadly.

  5. Atypical combinations and scientific impact.

    Science.gov (United States)

    Uzzi, Brian; Mukherjee, Satyam; Stringer, Michael; Jones, Ben

    2013-10-25

    Novelty is an essential feature of creative ideas, yet the building blocks of new ideas are often embodied in existing knowledge. From this perspective, balancing atypical knowledge with conventional knowledge may be critical to the link between innovativeness and impact. Our analysis of 17.9 million papers spanning all scientific fields suggests that science follows a nearly universal pattern: The highest-impact science is primarily grounded in exceptionally conventional combinations of prior work yet simultaneously features an intrusion of unusual combinations. Papers of this type were twice as likely to be highly cited works. Novel combinations of prior work are rare, yet teams are 37.7% more likely than solo authors to insert novel combinations into familiar knowledge domains.

  6. Atypical presentations of celiac disease

    Directory of Open Access Journals (Sweden)

    Balasa Adriana Luminita

    2016-08-01

    Full Text Available In this study we evaluated the association of celiac disease in 81 children with autoimmune disease and genetic syndromes over a two years periods (January 2014 to July 2016 in Pediatric Clinic in Constanta. Because the extraintestinal symptoms are an atypical presentation of celiac disease we determined in these children the presence of celiac disease antibodies: Anti-tissue Transglutaminase Antibody IgA and IgA total serum level as a screening method followeds in selective cases by Anti-tissue Transglutaminase Antibody IgG, anti-endomysial antibodies, deamidated gliadin antibodies IgA and IgG and intestinal biopsia. In our study 8 patients had been diagnosed with celiac disease with extraintestinal symptoms, of which 4 with type 1 diabetes, 1 patient with ataxia, 2 patients with dermatitis herpetiformis and 1 patient with Down syndrome that associate also autoimmune thyroiditis, alopecia areata, enamel hypoplasia.

  7. Geochronology and petrogenesis of the Early Cretaceous A-type granite from the Feie'shan W-Sn deposit in the eastern Guangdong Province, SE China: Implications for W-Sn mineralization and geodynamic setting

    Science.gov (United States)

    Liu, Peng; Mao, Jingwen; Santosh, M.; Bao, Zhian; Zeng, Xiaojian; Jia, Lihui

    2018-02-01

    juvenile mantle-derived melts resulting in the formation of mafic dikes, and I- or A-type granitic intrusions related to the W-Sn ore mineral systems.

  8. Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT.

    Science.gov (United States)

    Beker, Mustafa Caglar; Caglayan, Berrak; Yalcin, Esra; Caglayan, Ahmet Burak; Turkseven, Seyma; Gurel, Busra; Kelestemur, Taha; Sertel, Elif; Sahin, Zafer; Kutlu, Selim; Kilic, Ulkan; Baykal, Ahmet Tarik; Kilic, Ertugrul

    2018-03-01

    Occurrence of stroke cases displays a time-of-day variation in human. However, the mechanism linking circadian rhythm to the internal response mechanisms against pathophysiological events after ischemic stroke remained largely unknown. To this end, temporal changes in the susceptibility to ischemia/reperfusion (I/R) injury were investigated in mice in which the ischemic stroke induced at four different Zeitgeber time points with 6-h intervals (ZT0, ZT6, ZT12, and ZT18). Besides infarct volume and brain swelling, neuronal survival, apoptosis, ischemia, and circadian rhythm related proteins were examined using immunohistochemistry, Western blot, planar surface immune assay, and liquid chromatography-mass spectrometry tools. Here, we present evidence that midnight (ZT18; 24:00) I/R injury in mice resulted in significantly improved infarct volume, brain swelling, neurological deficit score, neuronal survival, and decreased apoptotic cell death compared with ischemia induced at other time points, which were associated with increased expressions of circadian proteins Bmal1, PerI, and Clock proteins and survival kinases AKT and Erk-1/2. Moreover, ribosomal protein S6, mTOR, and Bad were also significantly increased, while the levels of PRAS40, negative regulator of AKT and mTOR, and phosphorylated p53 were decreased at this time point compared to ZT0 (06:00). Furthermore, detailed proteomic analysis revealed significantly decreased CSKP, HBB-1/2, and HBA levels, while increased GNAZ, NEGR1, IMPCT, and PDE1B at midnight as compared with early morning. Our results indicate that nighttime I/R injury results in less severe neuronal damage, with increased neuronal survival, increased levels of survival kinases and circadian clock proteins, and also alters the circadian-related proteins.

  9. Role of protein kinase C β and vascular endothelial growth factor receptor in malignant pleural mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism

    Directory of Open Access Journals (Sweden)

    Sivakumar Loganathan

    2011-01-01

    Full Text Available Purpose: To examine the role of both protein kinase C (PKC-β and vascular endothelial growth factor receptor (VEGFR-2 in malignant pleural mesothelioma (MPM using respective inhibitors, enzastaurin and KRN633. Materials and Methods: MPM cell lines, control cells, and a variety of archived MPM tumor samples were used to determine the protein expression levels of PKC-β, VEGFR-2, VEGF, and p-AKT. Effects of enzastaurin and KRN633 on phosphorylation status of key signaling molecules and viability of the mesothelioma cells were determined. The common soil nematode, Caenorhabditis elegans, was treated with enzastaurin to determine its suitability to screen for highly potent kinase inhibitors. Results: PKC-β1, PKC-β2 and VEGFR-2/KDR were overexpressed in MPM cell lines and MPM tumor tissues. Enzastaurin treatment resulted in significant loss in viability of VEGF induced cell proliferation; however, the effect of KRN633 was much less. Enzastaurin also dramatically decreased the phosphorylation of PKC-β, its downstream target p-AKT, and surprisingly, the upstream VEGFR-2. The combination of the two drugs at best was additive and similar results were obtained with respect to cell viability. Treatment of C. elegans with enzastaurin resulted in clear phenotypic changes and the worms were hypermotile with abnormal pattern and shape of eggs, suggesting altered fecundity. Conclusions: PKC-β1 and VEGFR-2 are both excellent therapeutic targets in MPM. Enzastaurin was better at killing MPM cells than KRN633 and the combination lacked synergy. In addition, we show here that C. elegans can be used to screen for the next generation inhibitors as treatment with enzastaurin resulted in clear phenotypic changes that could be assayed.

  10. cGMP-dependent protein kinase type I is implicated in the regulation of the timing and quality of sleep and wakefulness.

    Directory of Open Access Journals (Sweden)

    Sonja Langmesser

    Full Text Available Many effects of nitric oxide (NO are mediated by the activation of guanylyl cyclases and subsequent production of the second messenger cyclic guanosine-3',5'-monophosphate (cGMP. cGMP activates cGMP-dependent protein kinases (PRKGs, which can therefore be considered downstream effectors of NO signaling. Since NO is thought to be involved in the regulation of both sleep and circadian rhythms, we analyzed these two processes in mice deficient for cGMP-dependent protein kinase type I (PRKG1 in the brain. Prkg1 mutant mice showed a strikingly altered distribution of sleep and wakefulness over the 24 hours of a day as well as reductions in rapid-eye-movement sleep (REMS duration and in non-REM sleep (NREMS consolidation, and their ability to sustain waking episodes was compromised. Furthermore, they displayed a drastic decrease in electroencephalogram (EEG power in the delta frequency range (1-4 Hz under baseline conditions, which could be normalized after sleep deprivation. In line with the re-distribution of sleep and wakefulness, the analysis of wheel-running and drinking activity revealed more rest bouts during the activity phase and a higher percentage of daytime activity in mutant animals. No changes were observed in internal period length and phase-shifting properties of the circadian clock while chi-squared periodogram amplitude was significantly reduced, hinting at a less robust oscillator. These results indicate that PRKG1 might be involved in the stabilization and output strength of the circadian oscillator in mice. Moreover, PRKG1 deficiency results in an aberrant pattern, and consequently a reduced quality, of sleep and wakefulness, possibly due to a decreased wake-promoting output of the circadian system impinging upon sleep.

  11. Fatal case of bacteremia caused by an atypical strain of Corynebacterium mucifaciens

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    Vlademir Vicente Cantarelli

    Full Text Available Corynebacterium species have often been considered normal skin flora or contaminants; however, in recent years they have been increasingly implicated in serious infections. Moreover, many new species have been discovered and old species renamed, especially after molecular biology techniques were introduced. Corynebacterium mucifaciens is mainly isolated from blood and from other normally-sterile body fluids; it forms slightly yellow, mucoid colonies on blood agar. We report a fatal case of bacteremia due to an atypical strain of C. mucifaciens. This strain had atypical colony morphology; analysis of the 16S rRNA gene was used to define the species.

  12. Computerized tomography in atypical Pott's disease

    International Nuclear Information System (INIS)

    Cabrera, M.N.B.; Wang, E.H.M.

    1993-01-01

    Classical Pott's disease is described as a two-vertebrae disease with the destruction of the intervening invertebral disc. Computerized tomography has been used in the differential diagnosis of spine infections and neoplasms. We reviewed CT scans of patients seen at the Philippine General Hospital over a two-year period with atypical presentations of atypical tuberculous spondylitis. We used the computerized tomography findings described as characteristic of classical Pott's disease as criteria in evaluating the CT scans of patients diagnosed to have Atypical Pott's Disease. Although the number of patients prevented sensitivity and specificity studies to be done, our results strongly suggest that the same CT criteria used to diagnose Classical Pott's Disease may also be used to diagnose Pott's disease in its atypical form. (Author.). 13 refs

  13. Atypical imaging appearances of intracranial meningiomas

    Energy Technology Data Exchange (ETDEWEB)

    O' Leary, S. [Radiology Department, Derriford Hospital, Plymouth (United Kingdom); Adams, W.M. [Radiology Department, Derriford Hospital, Plymouth (United Kingdom); Parrish, R.W. [Radiology Department, Derriford Hospital, Plymouth (United Kingdom); Mukonoweshuro, W. [Radiology Department, Derriford Hospital, Plymouth (United Kingdom)]. E-mail: William.mukonoweshuro@phnt.swest.nhs.uk

    2007-01-15

    Meningiomas are the commonest primary, non-glial intracranial tumours. The diagnosis is often correctly predicted from characteristic imaging appearances. This paper presents some examples of atypical imaging appearances that may cause diagnostic confusion.

  14. Atypical presentations of Wolframs syndrome

    Directory of Open Access Journals (Sweden)

    S Saran

    2012-01-01

    Full Text Available Background: Wolfram syndrome is a rare hereditary or sporadic neurodegenerative disorder also known as DIDMOAD. The classically described presentation is of insulin-dependent diabetes, followed by optic atrophy, central diabetes insipidus, and sensory neural deafness. Also included are less well-described presentations of Wolframs syndrome. We here present three cases of atypical presentation of this syndrome. Case 1: A 15-year-old boy with insulin-dependent diabetes was presented for evaluation of depressive symptoms associated with suicidal tendency. Neuropsychiatric manifestations are described with Wolframs syndrome, and wolframin gene, in recessive inheritance, is associated with psychiatric illnesses without other manifestations of Wolframs syndrome. Case 2: A 17-year-old diabetic boy on insulin with good control of blood sugar presented for evaluation of delayed puberty. Central hypogonadism and other anterior pituitary hormone dysfunctions are the less publicized hormone dysfunctions in Wolframs syndrome. Case 3: A 23-year-old female who was on insulin for diabetes for the past 14 years, got admitted for evaluation of sudden loss of vision. This patient had developed a vitreous hemorrhage and, on evaluation, was found to have optic atrophy, sensory neural hearing loss, and diabetes insipidus, and presented differently from the gradual loss of vision described in Wolframs syndrome. Conclusion: Wolframs syndrome being a multisystem degenerative disorder can have myriad other manifestations than the classically described features. Neuropsychiatric manifestations, depression with suicidal risk, central hypogonadism, and secondary adrenal insufficiency are among the less well-described manifestations of this syndrome.

  15. Chronic exposure to high glucose impairs bradykinin-stimulated nitric oxide production by interfering with the phospholipase-C-implicated signalling pathway in endothelial cells: evidence for the involvement of protein kinase C.

    Science.gov (United States)

    Tang, Y; Li, G D

    2004-12-01

    Overwhelming evidence indicates that endothelial cell dysfunction in diabetes is characterised by diminished endothelium-dependent relaxation, but the matter of the underlying molecular mechanism remains unclear. As nitric oxide (NO) production from the endothelium is the major player in endothelium-mediated vascular relaxation, we investigated the effects of high glucose on NO production, and the possible alterations of signalling pathways implicated in this scenario. NO production and intracellular Ca(2+) levels ([Ca(2+)](i)) were assessed using the fluorescent probes 4,5-diaminofluorescein diacetate and fura-2 respectively. Exposure of cultured bovine aortic endothelial cells to high glucose for 5 or 10 days significantly reduced NO production induced by bradykinin (but not by Ca(2+) ionophore) in a time- and dose-dependent manner. This was probably due to an attenuation in bradykinin-induced elevations of [Ca(2+)](i) under these conditions, since a close correlation between [Ca(2+)](i) increases and NO generation was observed in intact bovine aortic endothelial cells. Both bradykinin-promoted intracellular Ca(2+) mobilisation and extracellular Ca(2+) entry were affected. Moreover, bradykinin-induced formation of Ins(1,4,5)P(3), a phospholipase C product leading to increases in [Ca(2+)](i), was also inhibited following high glucose culture. This abnormality was not attributable to a decrease in inositol phospholipids, but possibly to a reduction in the number of bradykinin receptors. The alterations in NO production, the increases in [Ca(2+)](i), and the bradykinin receptor number due to high glucose could be largely reversed by protein kinase C inhibitors and D: -alpha-tocopherol (antioxidant). Chronic exposure to high glucose reduces NO generation in endothelial cells, probably by impairing phospholipase-C-mediated Ca(2+) signalling due to excess protein kinase C activation. This defect in NO release may contribute to the diminished endothelium

  16. Stabilization of mismatch repair gene PMS2 by glycogen synthase kinase 3beta is implicated in the treatment of cervical carcinoma.

    Science.gov (United States)

    Zhang, Yuan; Shu, Yi Min; Wang, Shu Fang; Da, Bang Hong; Wang, Ze Hua; Li, Hua Bin

    2010-02-23

    PMS2 expression loss was reported in a variety of human. However, its importance has not been fully understood in cervical carcinoma. The aim of this study was to determine the expression of PMS2 in cervical carcinoma and evaluate the significance of mismatch repair gene PMS2 regulated by glycogen synthase kinase 3beta (GSK-3beta) in chemosensitivity. We examined PMS2 and phosphorylated GSK-3beta(s9) expression in cervical carcinoma tissues using immunohistochemical staining. Furthermore, we detected PMS2 expression in HeLa cells and evaluate the interaction with GSK-3beta after transfection with GSK-3beta by small interference RNA (siRNA), co-immunoprecipitation and immunoblotting. We also evaluated the effect of PMS2 transfection on HeLa cells' chemosensitivity to cisplatin treatment. We found significant downregulation of PMS2 in cervical carcinoma, which was negatively associated with phosphorylated GSK-3beta (s9). Furthermore, we demonstrated GSK-3beta transfection was able to interact with PMS2 and enhance PMS2 production in HeLa cells, and increased PMS2 production was responsible for enhanced chemosensitivity. Our results provide the evidence that stabilization of PMS2 production by GSK-3beta was important to improve chemosensitization, indicating the significance of GSK-3beta-related PMS2 downregulation in the development of cervical carcinoma and in developing a potential strategy for chemotherapy.

  17. Stabilization of mismatch repair gene PMS2 by glycogen synthase kinase 3β is implicated in the treatment of cervical carcinoma

    Directory of Open Access Journals (Sweden)

    Wang Ze

    2010-02-01

    Full Text Available Abstract Background PMS2 expression loss was reported in a variety of human. However, its importance has not been fully understood in cervical carcinoma. The aim of this study was to determine the expression of PMS2 in cervical carcinoma and evaluate the significance of mismatch repair gene PMS2 regulated by glycogen synthase kinase 3β (GSK-3β in chemosensitivity. Methods We examined PMS2 and phosphorylated GSK-3β(s9 expression in cervical carcinoma tissues using immunohistochemical staining. Furthermore, we detected PMS2 expression in HeLa cells and evaluate the interaction with GSK-3β after transfection with GSK-3β by small interference RNA (siRNA, co-immunoprecipitation and immunoblotting. We also evaluated the effect of PMS2 transfection on HeLa cells' chemosensitivity to cisplatin treatment. Results We found significant downregulation of PMS2 in cervical carcinoma, which was negatively associated with phosphorylated GSK-3β (s9. Furthermore, we demonstrated GSK-3β transfection was able to interact with PMS2 and enhance PMS2 production in HeLa cells, and increased PMS2 production was responsible for enhanced chemosensitivity. Conclusions Our results provide the evidence that stabilization of PMS2 production by GSK-3β was important to improve chemosensitization, indicating the significance of GSK-3β-related PMS2 downregulation in the development of cervical carcinoma and in developing a potential strategy for chemotherapy.

  18. Stabilization of mismatch repair gene PMS2 by glycogen synthase kinase 3β is implicated in the treatment of cervical carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yuan [Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China); Shu, Yi Min [Allergy and Cancer Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080 (China); Wang, Shu Fang [Department of Pathology, Baylor College of Medicine, Houston, TX 77030 (United States); Da, Bang Hong; Wang, Ze Hua [Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China); Li, Hua Bin [Allergy and Cancer Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080 (China); Department of Medicine, Feinberg Medical School, Northwestern University, Chicago, IL 60611 (United States)

    2010-02-23

    PMS2 expression loss was reported in a variety of human. However, its importance has not been fully understood in cervical carcinoma. The aim of this study was to determine the expression of PMS2 in cervical carcinoma and evaluate the significance of mismatch repair gene PMS2 regulated by glycogen synthase kinase 3β (GSK-3β) in chemosensitivity. We examined PMS2 and phosphorylated GSK-3β(s9) expression in cervical carcinoma tissues using immunohistochemical staining. Furthermore, we detected PMS2 expression in HeLa cells and evaluate the interaction with GSK-3β after transfection with GSK-3β by small interference RNA (siRNA), co-immunoprecipitation and immunoblotting. We also evaluated the effect of PMS2 transfection on HeLa cells' chemosensitivity to cisplatin treatment. We found significant downregulation of PMS2 in cervical carcinoma, which was negatively associated with phosphorylated GSK-3β (s9). Furthermore, we demonstrated GSK-3β transfection was able to interact with PMS2 and enhance PMS2 production in HeLa cells, and increased PMS2 production was responsible for enhanced chemosensitivity. Our results provide the evidence that stabilization of PMS2 production by GSK-3β was important to improve chemosensitization, indicating the significance of GSK-3β-related PMS2 downregulation in the development of cervical carcinoma and in developing a potential strategy for chemotherapy.

  19. Stabilization of mismatch repair gene PMS2 by glycogen synthase kinase 3β is implicated in the treatment of cervical carcinoma

    Science.gov (United States)

    2010-01-01

    Background PMS2 expression loss was reported in a variety of human. However, its importance has not been fully understood in cervical carcinoma. The aim of this study was to determine the expression of PMS2 in cervical carcinoma and evaluate the significance of mismatch repair gene PMS2 regulated by glycogen synthase kinase 3β (GSK-3β) in chemosensitivity. Methods We examined PMS2 and phosphorylated GSK-3β(s9) expression in cervical carcinoma tissues using immunohistochemical staining. Furthermore, we detected PMS2 expression in HeLa cells and evaluate the interaction with GSK-3β after transfection with GSK-3β by small interference RNA (siRNA), co-immunoprecipitation and immunoblotting. We also evaluated the effect of PMS2 transfection on HeLa cells' chemosensitivity to cisplatin treatment. Results We found significant downregulation of PMS2 in cervical carcinoma, which was negatively associated with phosphorylated GSK-3β (s9). Furthermore, we demonstrated GSK-3β transfection was able to interact with PMS2 and enhance PMS2 production in HeLa cells, and increased PMS2 production was responsible for enhanced chemosensitivity. Conclusions Our results provide the evidence that stabilization of PMS2 production by GSK-3β was important to improve chemosensitization, indicating the significance of GSK-3β-related PMS2 downregulation in the development of cervical carcinoma and in developing a potential strategy for chemotherapy. PMID:20178594

  20. Stabilization of mismatch repair gene PMS2 by glycogen synthase kinase 3β is implicated in the treatment of cervical carcinoma

    International Nuclear Information System (INIS)

    Zhang, Yuan; Shu, Yi Min; Wang, Shu Fang; Da, Bang Hong; Wang, Ze Hua; Li, Hua Bin

    2010-01-01

    PMS2 expression loss was reported in a variety of human. However, its importance has not been fully understood in cervical carcinoma. The aim of this study was to determine the expression of PMS2 in cervical carcinoma and evaluate the significance of mismatch repair gene PMS2 regulated by glycogen synthase kinase 3β (GSK-3β) in chemosensitivity. We examined PMS2 and phosphorylated GSK-3β(s9) expression in cervical carcinoma tissues using immunohistochemical staining. Furthermore, we detected PMS2 expression in HeLa cells and evaluate the interaction with GSK-3β after transfection with GSK-3β by small interference RNA (siRNA), co-immunoprecipitation and immunoblotting. We also evaluated the effect of PMS2 transfection on HeLa cells' chemosensitivity to cisplatin treatment. We found significant downregulation of PMS2 in cervical carcinoma, which was negatively associated with phosphorylated GSK-3β (s9). Furthermore, we demonstrated GSK-3β transfection was able to interact with PMS2 and enhance PMS2 production in HeLa cells, and increased PMS2 production was responsible for enhanced chemosensitivity. Our results provide the evidence that stabilization of PMS2 production by GSK-3β was important to improve chemosensitization, indicating the significance of GSK-3β-related PMS2 downregulation in the development of cervical carcinoma and in developing a potential strategy for chemotherapy

  1. The PH Domain of PDK1 Exhibits a Novel, Phospho-Regulated Monomer-Dimer Equilibrium With Important Implications for Kinase Domain Activation: Single Molecule and Ensemble Studies†

    Science.gov (United States)

    Ziemba, Brian P.; Pilling, Carissa; Calleja, Véronique; Larijani, Banafshé; Falke, Joseph J.

    2013-01-01

    Phosphoinositide-Dependent Kinase-1 (PDK1) is an essential master kinase recruited to the plasma membrane by the binding of its C-terminal PH domain to the signaling lipid phosphatidylinositol-3,4-5-trisphosphate (PIP3). Membrane binding leads to PDK1 phospho-activation, but despite the central role of PDK1 in signaling and cancer biology this activation mechanism remains poorly understood. PDK1 has been shown to exist as a dimer in cells, and one crystal structure of its isolated PH domain exhibits a putative dimer interface. It has been proposed that phosphorylation of PH domain residue T513 (or the phospho-mimetic T513E mutation) may regulate a novel PH domain dimer-monomer equilibrium, thereby converting an inactive PDK1 dimer to an active monomer. However, the oligomeric state(s) of the PH domain on the membrane have not yet been determined, nor whether a negative charge at position 513 is sufficient to regulate its oligomeric state. The present study investigates the binding of purified WT and T513E PDK1 PH domains to lipid bilayers containing the PIP3 target lipid, using both single molecule and ensemble measurements. Single molecule analysis of the brightness of fluorescent PH domain shows that the PIP3-bound WT PH domain on membranes is predominantly dimeric, while the PIP3-bound T513E PH domain is monomeric, demonstrating that negative charge at the T513 position is sufficient to dissociate the PH domain dimer and is thus likely to play a central role in PDK1 monomerization and activation. Single molecule analysis of 2-D diffusion of PH domain-PIP3 complexes reveals that the dimeric WT PH domain diffuses at the same rate a single lipid molecule, indicating that only one of its two PIP3 binding sites is occupied and there is little protein penetration into the bilayer as observed for other PH domains. The 2-D diffusion of T513E PH domain is slower, suggesting the negative charge disrupts local structure in a way that enables greater protein insertion into

  2. Increased rho kinase activity in mononuclear cells of dialysis and stage 3-4 chronic kidney disease patients with left ventricular hypertrophy: Cardiovascular risk implications.

    Science.gov (United States)

    Calò, Lorenzo A; Vertolli, Ugo; Pagnin, Elisa; Ravarotto, Verdiana; Davis, Paul A; Lupia, Mario; Naso, Elena; Maiolino, Giuseppe; Naso, Agostino

    2016-03-01

    Cardiovascular disease (CVD) is the leading cause of excess mortality in chronic kidney disease (CKD) and dialysis patients (DP) who have higher prevalence of left ventricular hypertrophy (LVH), the strongest predictor of CV events. Rho kinase (ROCK) activation is linked in hypertensive patients to cardiac remodeling while ROCK inhibition suppresses cardiomyocyte hypertrophy and, in a human clinical condition opposite to hypertension, its downregulation associates with lack of CV remodeling. Information on ROCK activation-LVH link in CKD and DP is lacking. Mononuclear cells (PBMCs) MYPT-1 phosphorylation, a marker of ROCK activity, and the effect of fasudil, a ROCK inhibitor, on MYPT-1 phosphorylation were assessed in 23 DPs, 13 stage 3-4 CKD and 36 healthy subjects (HS) by Western blot. LV mass was assessed by M-mode echocardiography. DP and CKD had higher MYPT-1 phosphorylation compared to HS (p<0.001 and p=0.003). Fasudil (500 and 1000μM) dose dependently reduced MYPT-1 phosphorylation in DP (p<0.01). DP had higher LV mass than CKD (p<0.001). MYPT-1 phosphorylation was higher in patients with LVH (p=0.009) and correlated with LV mass both in DP and CKD with LVH (p<0.001 and p=0.006). In DP and CKD, ROCK activity tracks with LVH. This ROCK activation-LVH link provided in these CVD high-risk patients along with similar findings in hypertensive patients and added to opposite findings in a human model opposite to hypertension and in type 2 diabetic patients, identify ROCK activation as a potential LVH marker and provide further rationale for ROCK activation inhibition as target of therapy in CVD high-risk patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Sequence analysis and characterization of pyruvate kinase from Clonorchis sinensis, a 53.1-kDa homopentamer, implicated immune protective efficacy against clonorchiasis

    Directory of Open Access Journals (Sweden)

    Tingjin Chen

    2017-11-01

    Full Text Available Abstract Background Clonorchis sinensis, the causative agent of clonorchiasis, is classified as one of the most neglected tropical diseases and affects more than 15 million people globally. This hepatobiliary disease is highly associated with cholangiocarcinoma. As key molecules in the infectivity and subsistence of trematodes, glycolytic enzymes have been targets for drug and vaccine development. Clonorchis sinensis pyruvate kinase (CsPK, a crucial glycolytic enzyme, was characterized in this research. Results Differences were observed in the sequences and spatial structures of CsPK and PKs from humans, rats, mice and rabbits. CsPK possessed a characteristic active site signature (IKLIAKIENHEGV and some unique sites but lacked the N-terminal domain. The predicted subunit molecular mass (Mr of CsPK was 53.1 kDa. Recombinant CsPK (rCsPK was a homopentamer with a Mr. of approximately 290 kDa by both native PAGE and gel filtration chromatography. Significant differences in the protein and mRNA levels of CsPK were observed among four life stages of C. sinensis (egg, adult worm, excysted metacercaria and metacercaria, suggesting that these developmental stages may be associated with diverse energy demands. CsPK was widely distributed in adult worms. Moreover, an intense Th1-biased immune response was persistently elicited in rats immunized with rCsPK. Also, rat anti-rCsPK sera suppressed C. sinensis adult subsistence both in vivo and in vitro. Conclusions The sequences and spatial structures, molecular mass, and expression profile of CsPK have been characterized. rCsPK was indicated to be a homopentamer. Rat anti-rCsPK sera suppressed C. sinensis adult subsistence both in vivo and in vitro. CsPK is worthy of further study as a promising target for drug and vaccine development.

  4. Sequence analysis and characterization of pyruvate kinase from Clonorchis sinensis, a 53.1-kDa homopentamer, implicated immune protective efficacy against clonorchiasis.

    Science.gov (United States)

    Chen, Tingjin; Jiang, Hongye; Sun, Hengchang; Xie, Zhizhi; Ren, Pengli; Zhao, Lu; Dong, Huimin; Shi, Mengchen; Lv, Zhiyue; Wu, Zhongdao; Li, Xuerong; Yu, Xinbing; Huang, Yan; Xu, Jin

    2017-11-09

    Clonorchis sinensis, the causative agent of clonorchiasis, is classified as one of the most neglected tropical diseases and affects more than 15 million people globally. This hepatobiliary disease is highly associated with cholangiocarcinoma. As key molecules in the infectivity and subsistence of trematodes, glycolytic enzymes have been targets for drug and vaccine development. Clonorchis sinensis pyruvate kinase (CsPK), a crucial glycolytic enzyme, was characterized in this research. Differences were observed in the sequences and spatial structures of CsPK and PKs from humans, rats, mice and rabbits. CsPK possessed a characteristic active site signature (IKLIAKIENHEGV) and some unique sites but lacked the N-terminal domain. The predicted subunit molecular mass (Mr) of CsPK was 53.1 kDa. Recombinant CsPK (rCsPK) was a homopentamer with a Mr. of approximately 290 kDa by both native PAGE and gel filtration chromatography. Significant differences in the protein and mRNA levels of CsPK were observed among four life stages of C. sinensis (egg, adult worm, excysted metacercaria and metacercaria), suggesting that these developmental stages may be associated with diverse energy demands. CsPK was widely distributed in adult worms. Moreover, an intense Th1-biased immune response was persistently elicited in rats immunized with rCsPK. Also, rat anti-rCsPK sera suppressed C. sinensis adult subsistence both in vivo and in vitro. The sequences and spatial structures, molecular mass, and expression profile of CsPK have been characterized. rCsPK was indicated to be a homopentamer. Rat anti-rCsPK sera suppressed C. sinensis adult subsistence both in vivo and in vitro. CsPK is worthy of further study as a promising target for drug and vaccine development.

  5. High levels of inactive thymidine kinase 1 polypeptide detected in sera from dogs with solid tumours by immunoaffinity methods: implications for in vitro diagnostics.

    Science.gov (United States)

    Kiran Kumar, J; Sharif, H; Westberg, S; von Euler, H; Eriksson, S

    2013-09-01

    Determination of serum thymidine kinase 1 (STK1) activity has been used as a proliferation marker for neoplastic diseases in both human and veterinary medicine. The purpose of this study was to determine STK1 activity and enzyme levels in different dog tumours. Serum samples from three dogs with leukaemia, five with lymphoma, 21 with solid tumours and 18 healthy dogs were analyzed for STK1 activity, using an optimized [(3)H]-deoxythymidine (dThd) phosphorylation assay, and for STK1 protein levels using an immunoaffinity/western blot assay. STK1 activity in dogs with haematological tumours was significantly higher than in the solid tumour and healthy dog groups (mean ± standard deviation [SD] = 65 ± 79, 1.1 ± 0.5, and 1.0 ± 0.4 pmol/min/mL, respectively). Serum samples were analyzed after immunoaffinity isolation by western blot and the TK1 26 kDa band intensities quantified revealing that concentrations were significantly higher in dogs with haematological tumours and solid tumours compared to healthy dogs (mean ± SD=33 ± 12, 30 ± 13, and 10 ± 5 ng/mL, respectively). Pre-incubation with the reducing agent dithioerythritol (DTE) showed a decrease in STK1 activity and protein levels in most samples, but an increase of about 20% in sera from healthy dogs and from those with haematological malignancies. Compared to animals with solid tumours, the specific STK1 activity (nmol [(3)H]-deoxythymidine monophosphate (dTMP)/min/mg of TK1 protein of 26 kDa) was 30-fold higher in haematological malignancies and 2.5-fold higher in healthy dogs, respectively. The results demonstrate that there is a large fraction of inactive TK1 protein, particularly in sera from dogs with solid tumours. The findings are important in the use of STK1 as a biomarker. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Perianal atypical leiomyoma: A case report.

    Science.gov (United States)

    Sun, Pingliang; Ou, Hailing; Huang, Shen; Wei, Longxiang; Zhang, Sen; Liu, Jiali; Geng, Shuguang; Yang, Kun

    2017-12-01

    Reports on perianal atypical leiomyoma, a perianal tumor, are rare. We confirmed a perianal atypical leiomyoma by its clinical presentation, magnetic resonance imaging findings, and immunohistochemistry. A 28-year-old female with a perianal mass found more than 4 years ago. The 5cm_4cm_4cm sized mass was located on the left side of the anus and vagina; The magnetic resonance imaging (MRI) scan revealed: A 4.1cm × 5.2cm × 4.9cm sized round mass was observed on the left side of the circumference. Perianal atypical leiomyoma. anal peripheral mass resection was performed under lumbar anesthesia. The postoperative course was uneventful, healing, the patient was discharged. Perianal atypical leiomyomas are benign tumors, but with the clinically atypical leiomyoma, it is sometimes difficult to distinguish between potential malignant smooth muscle tumors,and there may be malignant changes. Surgery should ensure complete resection, and to avoid postoperative recurrence, there should be a regular follow-up.

  7. ATYPICAL ANTIPSYCHOTICS USE IN CHILDREN AND ADOLESCENTS

    Directory of Open Access Journals (Sweden)

    Nataša Potočnik-Dajčman

    2002-06-01

    Full Text Available Background. Classical antipsychotics – neuroleptics are one of the most frequently prescribed psychotropic drugs in child psychiatry. Atypical antipsychotics are used for the same indications – psychotic (schizophrenia as well as unpsychotic disorders (pervasive developmental disorders, mood disorders, conduct disorders and tics disorders. It is surprising that the studies on their use with regard to this age group are rather rare. They are carried out on a small number of samples and only exceptionally double blind. This article summarizes published clinical experience with atypical antipsychotics in children and adolescents. A short overview of pharmacodynamics, pharmacokinetics and side effects is given. Schizophrenia and pervasive developmental disorders are major indications for use of atypical antipsychotics in children and adolescents, but they have also been successfully used for other disorders such as aggressive behaviour, tics and anorexia nervosa.Conclusions. With better side-effect profile, some of the atypical antipsychotics are expected to be doctrinally recognised as the first-line treatment for childhood schizophrenia and pervasive developmental disorders. However, more long-term studies carried out on a larger sample are needed. Atypical antipsychotics are already used in everyday practice as first-line treatment of childhood and adolescents schizophrenia.

  8. [Atypical reaction to anesthesia in Duchenne/Becker muscular dystrophy].

    Science.gov (United States)

    Silva, Helga Cristina Almeida da; Hiray, Marcia; Vainzof, Mariz; Schmidt, Beny; Oliveira, Acary Souza Bulle; Amaral, José Luiz Gomes do

    2017-05-31

    Duchenne/Becker muscular dystrophy affects skeletal muscles and leads to progressive muscle weakness and risk of atypical anesthetic reactions following exposure to succinylcholine or halogenated agents. The aim of this report is to describe the investigation and diagnosis of a patient with Becker muscular dystrophy and review the care required in anesthesia. Male patient, 14 years old, referred for hyperCKemia (chronic increase of serum creatine kinase levels - CK), with CK values of 7,779-29,040IU.L -1 (normal 174IU.L -1 ). He presented with a discrete delay in motor milestones acquisition (sitting at 9 months, walking at 18 months). He had a history of liver transplantation. In the neurological examination, the patient showed difficulty in walking on one's heels, myopathic sign (hands supported on the thighs to stand), high arched palate, calf hypertrophy, winged scapulae, global muscle hypotonia and arreflexia. Spirometry showed mild restrictive respiratory insufficiency (forced vital capacity: 77% of predicted). The in vitro muscle contracture test in response to halothane and caffeine was normal. Muscular dystrophy analysis by Western blot showed reduced dystrophin (20% of normal) for both antibodies (C and N-terminal), allowing the diagnosis of Becker muscular dystrophy. On preanesthetic assessment, the history of delayed motor development, as well as clinical and/or laboratory signs of myopathy, should encourage neurological evaluation, aiming at diagnosing subclinical myopathies and planning the necessary care to prevent anesthetic complications. Duchenne/Becker muscular dystrophy, although it does not increase susceptibility to MH, may lead to atypical fatal reactions in anesthesia. Copyright © 2017 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  9. Enhanced expression of a calcium-dependent protein kinase

    Indian Academy of Sciences (India)

    Among the downstream targets of calcium in plants, calcium-dependent protein kinases (CDPKs) form an interesting class of kinases which are activated by calcium binding. They have been implicated in a diverse array of responses to hormonal and environmental stimuli. In order to dissect the role of CDPKs in the moss ...

  10. Thymidine kinases in archaea

    DEFF Research Database (Denmark)

    Clausen, A.R.; Matakos, A.; Sandrini, Michael

    2006-01-01

    Twenty-six fully sequenced archaeal genomes were searched for genes coding for putative deoxyribonucleoside kinases (dNKs). We identified only 5 human-like thymidine kinase 1 genes (TK1s) and none for non-TK1 kinases. Four TK1s were identified in the Euryarchaea and one was found in the Crenarcha...

  11. Kinase impact assessment in the landscape of fusion genes that retain kinase domains: a pan-cancer study

    Science.gov (United States)

    Kim, Pora; Jia, Peilin; Zhao, Zhongming

    2018-01-01

    Abstract Assessing the impact of kinase in gene fusion is essential for both identifying driver fusion genes (FGs) and developing molecular targeted therapies. Kinase domain retention is a crucial factor in kinase fusion genes (KFGs), but such a systematic investigation has not been done yet. To this end, we analyzed kinase domain retention (KDR) status in chimeric protein sequences of 914 KFGs covering 312 kinases across 13 major cancer types. Based on 171 kinase domain-retained KFGs including 101 kinases, we studied their recurrence, kinase groups, fusion partners, exon-based expression depth, short DNA motifs around the break points and networks. Our results, such as more KDR than 5′-kinase fusion genes, combinatorial effects between 3′-KDR kinases and their 5′-partners and a signal transduction-specific DNA sequence motif in the break point intronic sequences, supported positive selection on 3′-kinase fusion genes in cancer. We introduced a degree-of-frequency (DoF) score to measure the possible number of KFGs of a kinase. Interestingly, kinases with high DoF scores tended to undergo strong gene expression alteration at the break points. Furthermore, our KDR gene fusion network analysis revealed six of the seven kinases with the highest DoF scores (ALK, BRAF, MET, NTRK1, NTRK3 and RET) were all observed in thyroid carcinoma. Finally, we summarized common features of ‘effective’ (highly recurrent) kinases in gene fusions such as expression alteration at break point, redundant usage in multiple cancer types and 3′-location tendency. Collectively, our findings are useful for prioritizing driver kinases and FGs and provided insights into KFGs’ clinical implications. PMID:28013235

  12. Atypical Rulings of the Indonesian Constitutional Court

    Directory of Open Access Journals (Sweden)

    Bisariyadi

    2016-08-01

    Full Text Available In deciding judicial review cases, the Court may issue rulings that is not in accordance to what is stipulated in the Constitutional Court Law (Law Number 8 Year 2011. Atypical rulings means that the court may reconstruct a provision, delay the legislation/rulings enactment or give instruction to lawmakers. In addition, the court also introduce the “conditionally (unconstitutional” concept. This essay attempts to identify and classify these atypical rulings, including conditionally (un constitutional rulings, by examined the constitutional court judicial review rulings from 2003 to 2015. This study will provide a ground work for advance research on typical rulings by the Indonesian constitutional court.

  13. Atypical visual loss in giant cell arteritis

    DEFF Research Database (Denmark)

    Thystrup, Jan Deichmann; Knudsen, G M; Mogensen, A M

    1994-01-01

    Three patients with atypical ocular involvement due to histologically verified giant cell arteritis are reported. Prior to diagnosis, the first patient had periods of amaurosis fugax. He presented with normal vision. In spite of high-dose systemic corticosteroid therapy, he became blind in the te......Three patients with atypical ocular involvement due to histologically verified giant cell arteritis are reported. Prior to diagnosis, the first patient had periods of amaurosis fugax. He presented with normal vision. In spite of high-dose systemic corticosteroid therapy, he became blind...

  14. Dysfunctional metacognition and drive for thinness in typical and atypical anorexia nervosa.

    Science.gov (United States)

    Davenport, Emily; Rushford, Nola; Soon, Siew; McDermott, Cressida

    2015-01-01

    Anorexia nervosa is complex and difficult to treat. In cognitive therapies the focus has been on cognitive content rather than process. Process-oriented therapies may modify the higher level cognitive processes of metacognition, reported as dysfunctional in adult anorexia nervosa. Their association with clinical features of anorexia nervosa, however, is unclear. With reclassification of anorexia nervosa by DSM-5 into typical and atypical groups, comparability of metacognition and drive for thinness across groups and relationships within groups is also unclear. Main objectives were to determine whether metacognitive factors differ across typical and atypical anorexia nervosa and a non-clinical community sample, and to explore a process model by determining whether drive for thinness is concurrently predicted by metacognitive factors. Women receiving treatment for anorexia nervosa (n = 119) and non-clinical community participants (n = 100), aged between 18 and 46 years, completed the Eating Disorders Inventory (3(rd) Edition) and Metacognitions Questionnaire (Brief Version). Body Mass Index (BMI) of 18.5 kg/m(2) differentiated between typical (n = 75) and atypical (n = 44) anorexia nervosa. Multivariate analyses of variance and regression analyses were conducted. Metacognitive profiles were similar in both typical and atypical anorexia nervosa and confirmed as more dysfunctional than in the non-clinical group. Drive for thinness was concurrently predicted in the typical patients by the metacognitive factors, positive beliefs about worry, and need to control thoughts; in the atypical patients by negative beliefs about worry and, inversely, by cognitive self-consciousness, and in the non-clinical group by cognitive self-consciousness. Despite having a healthier weight, the atypical group was as severely affected by dysfunctional metacognitions and drive for thinness as the typical group. Because metacognition concurrently predicted drive for thinness

  15. Protein trans-splicing of multiple atypical split inteins engineered from natural inteins.

    Directory of Open Access Journals (Sweden)

    Ying Lin

    Full Text Available Protein trans-splicing by split inteins has many uses in protein production and research. Splicing proteins with synthetic peptides, which employs atypical split inteins, is particularly useful for site-specific protein modifications and labeling, because the synthetic peptide can be made to contain a variety of unnatural amino acids and chemical modifications. For this purpose, atypical split inteins need to be engineered to have a small N-intein or C-intein fragment that can be more easily included in a synthetic peptide that also contains a small extein to be trans-spliced onto target proteins. Here we have successfully engineered multiple atypical split inteins capable of protein trans-splicing, by modifying and testing more than a dozen natural inteins. These included both S1 split inteins having a very small (11-12 aa N-intein fragment and S11 split inteins having a very small (6 aa C-intein fragment. Four of the new S1 and S11 split inteins showed high efficiencies (85-100% of protein trans-splicing both in E. coli cells and in vitro. Under in vitro conditions, they exhibited reaction rate constants ranging from ~1.7 × 10(-4 s(-1 to ~3.8 × 10(-4 s(-1, which are comparable to or higher than those of previously reported atypical split inteins. These findings should facilitate a more general use of trans-splicing between proteins and synthetic peptides, by expanding the availability of different atypical split inteins. They also have implications on understanding the structure-function relationship of atypical split inteins, particularly in terms of intein fragment complementation.

  16. Atypically presenting kaposiform hemangioendothelioma of the knee: ultrasound findings.

    Science.gov (United States)

    Erdem Toslak, Iclal; Stegman, Matthew; Reiter, Michael P; Barkan, Güliz A; Borys, Dariusz; Lim-Dunham, Jennifer E

    2018-04-10

    Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor of early childhood and infancy. Kasabach-Merritt phenomenon, a common complication of KHE, is characterized by life-threatening thrombocytopenia, hemolytic anemia, and consumption coagulopathy. There may be atypical cases that do not present with Kasabach-Merritt phenomenon and do have atypical imaging findings. Knowledge of atypical imaging features may assist radiologists in identifying KHE. In this report, we present a 4-year-old case of KHE with atypical ultrasound findings.

  17. Damage-induced DNA replication stalling relies on MAPK-activated protein kinase 2 activity

    DEFF Research Database (Denmark)

    Köpper, Frederik; Bierwirth, Cathrin; Schön, Margarete

    2013-01-01

    knockdown of the MAP kinase-activated protein kinase 2 (MK2), a kinase currently implicated in p38 stress signaling and G2 arrest. Depletion or inhibition of MK2 also protected cells from DNA damage-induced cell death, and mice deficient for MK2 displayed decreased apoptosis in the skin upon UV irradiation...

  18. Atypical Pyoderma Gangrenosum Mimicking an Infectious Process

    Directory of Open Access Journals (Sweden)

    Derek To

    2014-01-01

    Full Text Available We present a patient with atypical pyoderma gangrenosum (APG, which involved the patient’s arm and hand. Hemorrhagic bullae and progressive ulcerations were initially thought to be secondary to an infectious process, but a biopsy revealed PG. Awareness of APG by infectious disease services may prevent unnecessary use of broad-spectrum antibiotics.

  19. Atypical pyoderma gangrenosum mimicking an infectious process.

    Science.gov (United States)

    To, Derek; Wong, Aaron; Montessori, Valentina

    2014-01-01

    We present a patient with atypical pyoderma gangrenosum (APG), which involved the patient's arm and hand. Hemorrhagic bullae and progressive ulcerations were initially thought to be secondary to an infectious process, but a biopsy revealed PG. Awareness of APG by infectious disease services may prevent unnecessary use of broad-spectrum antibiotics.

  20. Cohort study of atypical pressure ulcers development.

    Science.gov (United States)

    Jaul, Efraim

    2014-12-01

    Atypical pressure ulcers (APU) are distinguished from common pressure ulcers (PU) with both unusual location and different aetiology. The occurrence and attempts to characterise APU remain unrecognised. The purpose of this cohort study was to analyse the occurrence of atypical location and the circumstances of the causation, and draw attention to the prevention and treatment by a multidisciplinary team. The cohort study spanned three and a half years totalling 174 patients. The unit incorporates two weekly combined staff meetings. One concentrates on wound assessment with treatment decisions made by the physician and nurse, and the other, a multidisciplinary team reviewing all patients and coordinating treatment. The main finding of this study identified APU occurrence rate of 21% within acquired PU over a three and a half year period. Severe spasticity constituted the largest group in this study and the most difficult to cure wounds, located in medial aspects of knees, elbows and palms. Medical devices caused the second largest occurrence of atypical wounds, located in the nape of the neck, penis and nostrils. Bony deformities were the third recognisable atypical wound group located in shoulder blades and upper spine. These three categories are definable and time observable. APU are important to be recognisable, and can be healed as well as being prevented. The prominent role of the multidisciplinary team is primary in identification, prevention and treatment. © 2013 The Authors. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

  1. Non-diabetic atypical necrobiosis lipoidica

    Directory of Open Access Journals (Sweden)

    Mittal R

    1994-01-01

    Full Text Available One 8 year female child had asymptomatic, anaesthetic, hypohidrotic, atrophic, yellowish, waxy plaque on the front of left thigh since 2 months. No nerve thickening was observed clinically or histopathologically. Hyperkeratosis, follicular keratosis, epidermal atrophy, degeneration of collagen, mononuclear granulomas and perivascular mononuclear infiltrate confirmed the clinical diagnosis of atypical necrobiosis lipoidica.

  2. Atypical fractures on long term bisphosphonates therapy.

    LENUS (Irish Health Repository)

    Hussein, W

    2011-01-01

    Bisphosphonates reduce fractures risk in patients with osteoporosis. A new pattern of fractures is now being noted in patients on prolonged bisphosphonate therapy. We report a case of an atypical femoral fracture with preceding pain and highlight the characteristics of these fractures.

  3. Diabetic muscle infarction: atypical MR appearance

    International Nuclear Information System (INIS)

    Sharma, P.; Mangwana, S.; Kapoor, R.K.

    2000-01-01

    We describe a case of diabetic muscle infarction which had atypical features of hyperintensity of the affected muscle on T1-weighted images. Biopsy was performed which revealed diffuse extensive hemorrhage within the infarcted muscle. We believe increased signal intensity on T1-weighted images should suggest hemorrhage within the infarcted muscle. (orig.)

  4. Atypical Food Packaging Affects The Persuasive Impact of Product Claims

    NARCIS (Netherlands)

    van Ooijen, M.L.; Fransen, P.W.J.; Verlegh, P.W.J.; Smit, E.G.

    2016-01-01

    Atypical food packaging draws attention in the retail environment, and therefore increases product salience. However, until now, no research has focused on how atypical packaging affects the persuasive impact of other food information. In the present study, we propose that atypical packaging

  5. Atypical food packaging affects the persuasive impact of product claims

    NARCIS (Netherlands)

    van Ooijen, I.; Fransen, M.L.; Verlegh, P.W.J.; Smit, E.G.

    Atypical food packaging draws attention in the retail environment, and therefore increases product sal- ience. However, until now, no research has focused on how atypical packaging affects the persuasive impact of other food information. In the present study, we propose that atypical packaging

  6. IMPLICATIONS OF MOUTH BREATHING AND ATYPICAL SWALLOWING IN BODY POSTURE

    Directory of Open Access Journals (Sweden)

    Veronique Sousa

    2017-07-01

    Conclusion: Statistically significant associations were established between the breathing pattern and the horizontal alignment of acromions, as well as the horizontal and vertical alignment of the head; between the pattern of breathing and swallowing with occlusal relationship anteroposterior and occlusal relationship vertical and also between breathing pattern and swallowing with digital sucking habits and pacifier use.

  7. Specific involvement of atypical PKCζ/PKMζ in spinal persistent nociceptive processing following peripheral inflammation in rat

    Directory of Open Access Journals (Sweden)

    Marchand Fabien

    2011-11-01

    Full Text Available Abstract Background Central sensitization requires the activation of various intracellular signalling pathways within spinal dorsal horn neurons, leading to a lowering of activation threshold and enhanced responsiveness of these cells. Such plasticity contributes to the manifestation of chronic pain states and displays a number of features of long-term potentiation (LTP, a ubiquitous neuronal mechanism of increased synaptic strength. Here we describe the role of a novel pathway involving atypical PKCζ/PKMζ in persistent spinal nociceptive processing, previously implicated in the maintenance of late-phase LTP. Results Using both behavioral tests and in vivo electrophysiology in rats, we show that inhibition of this pathway, via spinal delivery of a myristoylated protein kinase C-ζ pseudo-substrate inhibitor, reduces both pain-related behaviors and the activity of deep dorsal horn wide dynamic range neurons (WDRs following formalin administration. In addition, Complete Freund's Adjuvant (CFA-induced mechanical and thermal hypersensitivity was also reduced by inhibition of PKCζ/PKMζ activity. Importantly, this inhibition did not affect acute pain or locomotor behavior in normal rats and interestingly, did not inhibited mechanical allodynia and hyperalgesia in neuropathic rats. Pain-related behaviors in both inflammatory models coincided with increased phosphorylation of PKCζ/PKMζ in dorsal horn neurons, specifically PKMζ phosphorylation in formalin rats. Finally, inhibition of PKCζ/PKMζ activity decreased the expression of Fos in response to formalin and CFA in both superficial and deep laminae of the dorsal horn. Conclusions These results suggest that PKCζ, especially PKMζ isoform, is a significant factor involved in spinal persistent nociceptive processing, specifically, the manifestation of chronic pain states following peripheral inflammation.

  8. Prognostic significance of atypical papillary urothelial hyperplasia.

    Science.gov (United States)

    Swierczynski, Sharon L; Epstein, Jonathan I

    2002-05-01

    Typical papillary hyperplasia, a recently recognized precursor lesion to low-grade papillary urothelial neoplasms, consists of undulating folds of cytologically benign urothelium. Well-developed, branching fibrovascular cores of a papillary neoplasm are not evident. We have noted lesions with the architectural pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia. We identified 15 cases of atypical papillary hyperplasia (13 males, 2 females, age 55 to 92) with overlying urothelium showing cytologic atypia. Of these cases, 8 (53%) were received in consultation. Of the 15 cases, 8 exhibited overlying flat carcinoma in situ (CIS), 4 had overlying dysplasia, and 3 were transitional between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia. Of these cases, 5 patients had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Concurrent to the diagnosis of atypical papillary hyperplasia, there were 25 different urothelial lesions: CIS (n = 11), papilloma (n = 1), papillary neoplasm of low malignant potential with CIS (n = 1), high-grade papillary urothelial carcinoma (n = 10; 3 with CIS), small-cell carcinoma (n = 1), and infiltrating urothelial carcinoma (n = 1). Of 11 patients with known prior history, 2 had 12 prior urothelial neoplasms (9 low-grade papillary neoplasms, 2 papillary urothelial neoplasms of low malignant potential, and 1 high-grade papillary cancer). Of 10 patients with atypical papillary hyperplasia and a minimum of 1 year of follow-up, 9 had 19 recurrences: CIS (n = 4), papilloma (n = 1), papillary neoplasm of low malignant potential (n = 1), infiltrating urothelial carcinoma (n = 3; 1 with CIS), and high-grade papillary urothelial carcinoma (n = 10; 5 with invasion and 2 with CIS). Whether the papillary hyperplasia had overlying CIS or dysplasia did not affect the correlation with urothelial neoplasms. Immunohistochemical analysis

  9. Primary atypical sacral meningioma- not always benign

    International Nuclear Information System (INIS)

    Bhadra, A.K.; Casey, A.T.H.; Saifuddin, A.; Briggs, T.W.

    2007-01-01

    We present a case of an atypical recurrent meningioma of the sacrum with pulmonary metastasis in a 31-year-old man. He presented with deep-seated buttock pain and urinary hesitancy for 3 months. MRI revealed a lesion occupying the central and left side of the sacral canal at the S1-S2 level. Surgical excision of the lesion via a posterior approach was undertaken, and the patient became symptom-free post-operatively. Histology confirmed atypical meningioma. Eight months later he re-presented with similar symptoms, and MRI confirmed local recurrence. The patient underwent left hemisacrectomy. Six months later he again presented with low back pain and MRI confirmed a second local recurrence. A CT scan of the chest showed multiple lung metastases. The patient died of a severe chest infection 18 months later. (orig.)

  10. Atypical femoral fractures related to bisphosphonate therapy

    Directory of Open Access Journals (Sweden)

    Tarun Pankaj Jain

    2012-01-01

    Full Text Available Bisphosphonates (BP are a commonly prescribed class of drugs for the prevention of osteoporosis-related fractures. Paradoxically, however, they have recently been linked to atypical fractures in the shaft of the femur. Since many physicians including radiologists, are not aware of this entity, the incidence is likely underreported. These fractures usually occur in the sub-trochanteric region of the femur in the setting of low-energy trauma. It starts as a fracture line involving the lateral cortex and then progresses medially to give rise to a complete fracture. The fracture line is usually transverse, and there is a medial spike associated with a complete fracture. These fractures can be bilateral. Awareness of these atypical fractures and their radiological appearance should enable their early and accurate detection and thus lead to specific treatment.

  11. Primary lateral sclerosis mimicking atypical parkinsonism

    DEFF Research Database (Denmark)

    Norlinah, Ibrahim M; Bhatia, Kailash P; Østergaard, Karen

    2007-01-01

    of the atypical parkinsonian syndromes. Here we describe five patients initially referred with a diagnosis of levodopa-unresponsive atypical parkinsonism (n = 4) or primary progressive multiple sclerosis (n = 1), but subsequently found to have features consistent with PLS instead. Onset age varied from 49 to 67......Primary lateral sclerosis (PLS), the upper motor neurone variant of motor neurone disease, is characterized by progressive spinal or bulbar spasticity with minimal motor weakness. Rarely, PLS may present with clinical features resembling parkinsonism resulting in occasional misdiagnosis as one...... in all patients. Anterior horn cell involvement developed in three cases. Early gait disturbances resulting in falls were seen in all patients and none of them responded to dopaminergic medications. Two patients underwent dopamine transporter (DaT) SPECT scanning with normal results. Other features...

  12. Herpes zoster - typical and atypical presentations.

    Science.gov (United States)

    Dayan, Roy Rafael; Peleg, Roni

    2017-08-01

    Varicella- zoster virus infection is an intriguing medical entity that involves many medical specialties including infectious diseases, immunology, dermatology, and neurology. It can affect patients from early childhood to old age. Its treatment requires expertise in pain management and psychological support. While varicella is caused by acute viremia, herpes zoster occurs after the dormant viral infection, involving the cranial nerve or sensory root ganglia, is re-activated and spreads orthodromically from the ganglion, via the sensory nerve root, to the innervated target tissue (skin, cornea, auditory canal, etc.). Typically, a single dermatome is involved, although two or three adjacent dermatomes may be affected. The lesions usually do not cross the midline. Herpes zoster can also present with unique or atypical clinical manifestations, such as glioma, zoster sine herpete and bilateral herpes zoster, which can be a challenging diagnosis even for experienced physicians. We discuss the epidemiology, pathophysiology, diagnosis and management of Herpes Zoster, typical and atypical presentations.

  13. Recurrent conjunctival atypical fibroxanthoma in Pigmentosum Xeroderma.

    Science.gov (United States)

    Cerdà-Ibáñez, M; Barreiro-González, A; Barranco González, H; Aviñó Martínez, J; Évole-Buselli, M; Harto-Castaño, M Á

    2018-02-01

    A 7 year-old boy with Xeroderma Pigmentosum (XP) and who presents a recurrent conjunctival atypical fibroxanthoma after two surgeries. This is the third procedure and the patient is treated with a surgical excision of the tumour and cryotherapy at the surgical bed. Due to the risk of recurrence, topical Mitomycin C 0,02% was added at post-operative care achieving a good clinical outcome. Surgical exeresis with cryotherapy and topical Mitomycin C is an effective treatment for a case of an atypical fibroxanthoma with a high potential for recurrence and invasion. An ophthalmologic follow-up is required for these patients, as well as general paediatric care and support aids. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. Primary atypical sacral meningioma- not always benign

    Energy Technology Data Exchange (ETDEWEB)

    Bhadra, A.K.; Casey, A.T.H.; Saifuddin, A.; Briggs, T.W. [Royal National Orthopaedic Hospital, Stanmore, London (United Kingdom)

    2007-06-15

    We present a case of an atypical recurrent meningioma of the sacrum with pulmonary metastasis in a 31-year-old man. He presented with deep-seated buttock pain and urinary hesitancy for 3 months. MRI revealed a lesion occupying the central and left side of the sacral canal at the S1-S2 level. Surgical excision of the lesion via a posterior approach was undertaken, and the patient became symptom-free post-operatively. Histology confirmed atypical meningioma. Eight months later he re-presented with similar symptoms, and MRI confirmed local recurrence. The patient underwent left hemisacrectomy. Six months later he again presented with low back pain and MRI confirmed a second local recurrence. A CT scan of the chest showed multiple lung metastases. The patient died of a severe chest infection 18 months later. (orig.)

  15. [Psychotic forms of atypical autism in children].

    Science.gov (United States)

    Simashkova, N V

    2006-01-01

    The aim of the study was to determine clinical borders of psychotic forms of atypical autism in children, its psychopathological and age-specific manifestations as well as nosological peculiarities and to specify its pathogenetic features. Eighty patients with childhood endogenous autism, Rett syndrome, fragile X syndrome, Down syndrome have been studied during 14 years. The study showed that psychoses similar by symptoms and course, which are characterized by attacks and regressive-catatonic disorders, may develop in the course of atypical autism. These psychoses develop on the background of dysontogenesis with consequent replacement of the following stages: autistic, regressive, catatonic, with returning to the autistic stage between attacks. Psychopathological similarity of these psychoses in different disorders correlated with EEG changes of the same type (appearance of the marked I-rhythm at the regressive stage of psychosis).

  16. Atypical retroperitoneal extension of iliopsoas bursitis

    International Nuclear Information System (INIS)

    Coulier, B.; Cloots, V.

    2003-01-01

    We report two rare cases of iliopsoas bursitis extending into the retroperitoneal space. The first lesion contained much gas, mimicking a retroperitoneal abscess, and the second was responsible for atypical inguinal pain. The diagnosis was made by contrast-enhanced CT in both cases and arthrography in the first case. Iliopsoas bursitis in these two patients, it is hypothesized, extended into the retroperitoneum, at least in part, by way of intraneural or perineural structures. (orig.)

  17. Atypical retroperitoneal extension of iliopsoas bursitis

    Energy Technology Data Exchange (ETDEWEB)

    Coulier, B.; Cloots, V. [Department of Diagnostic Imaging, Cliniques St. Luc, Rue St Luc 8, 5004, Bouge, Namur (Belgium)

    2003-05-01

    We report two rare cases of iliopsoas bursitis extending into the retroperitoneal space. The first lesion contained much gas, mimicking a retroperitoneal abscess, and the second was responsible for atypical inguinal pain. The diagnosis was made by contrast-enhanced CT in both cases and arthrography in the first case. Iliopsoas bursitis in these two patients, it is hypothesized, extended into the retroperitoneum, at least in part, by way of intraneural or perineural structures. (orig.)

  18. Aspects of atypical degenerative lesions of vertebrae

    International Nuclear Information System (INIS)

    Battikha, J.G.; Garcia, J.F.; Wettstein, P.

    1981-01-01

    Over the last 20 years, several authors have reported aspects of degenerative disease of the vertebral column with irregularity and sclerosis of the margins of the vertebral bodies [2, 4, 7-9, 13, 15, 17]. Twenty cases of such atypical degenerative vertebral lesions have been studied over a two year period and their radiological characteristics have been compared with vertebral lesions of infective origin and in the rheumatoid disorders. (orig.)

  19. Atypical Localized Rheumatoid Nodule: Case Report

    Directory of Open Access Journals (Sweden)

    KORHAN BARIS BAYRAM

    2015-01-01

    Full Text Available Rheumatoid nodules can be seen in about 30% of patiens with rheumatoid arthritis. They are occasionally localized subcutaneous, but they can rarely seen in visceral organs. Their appearance can be confused with many clinical conditions when they have atypical localizations. To exclude the presence of a malignancy, these lesions should always be investigated. We aimed to discuss a patient with rheumatoid nodule localized in close neighborhood of hyoid bone, presumed as malignancy.

  20. Typical and atypical presentations of aspergilloma

    International Nuclear Information System (INIS)

    Villajos, M.; Darnell, A.; Gallardo, X.; Castaner, E.; Mata, J. M.; Paedavila, E.

    1999-01-01

    To show the different forms of radiological presentations of aspergilloma, emphasizing the importance of recognizing the atypical forms. The explorations of 11 patients with aspergilloma were examined retrospectively between 1993 and 1997. These patients were studied using conventional X-rays and computed tomography (CT): Typical and atypical radiological findings were observed. In two patients, who presented recurrent hemoptysis, a percutaneous installation of amphotericin B was carried out with tomographic control. Out of the 11 patients, two were female and nine male. In eight of the cases the radiological findings showed an intercavity injury with different evolutionary forms, while in three of the cases there was a progressive pleural swelling. In the two patients treated pertinaciously, no significant radiological changes were observed, however, neither of them showed hemoptysis again. The pleural swelling adjacent to the cavity and/or the swelling of the cavity wall are atypical radiological presentations of the aspergilloma, that can accompany or precede the appearance of this illness. (Author) 7 refs

  1. Muscle phosphorylase kinase deficiency

    DEFF Research Database (Denmark)

    Preisler, N; Orngreen, M C; Echaniz-Laguna, A

    2012-01-01

    To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD).......To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD)....

  2. Flat epithelial atypia and atypical ductal hyperplasia: carcinoma underestimation rate.

    Science.gov (United States)

    Ingegnoli, Anna; d'Aloia, Cecilia; Frattaruolo, Antonia; Pallavera, Lara; Martella, Eugenia; Crisi, Girolamo; Zompatori, Maurizio

    2010-01-01

    This study was carried out to determine the underestimation rate of carcinoma upon surgical biopsy after a diagnosis of flat epithelial atypia and atypical ductal hyperplasia and 11-gauge vacuum-assisted breast biopsy. A retrospective review was conducted of 476 vacuum-assisted breast biopsy performed from May 2005 to January 2007 and a total of 70 cases of atypia were identified. Fifty cases (71%) were categorized as pure atypical ductal hyperplasia, 18 (26%) as pure flat epithelial atypia and two (3%) as concomitant flat epithelial atypia and atypical ductal hyperplasia. Each group were compared with the subsequent open surgical specimens. Surgical biopsy was performed in 44 patients with atypical ductal hyperplasia, 15 patients with flat epithelial atypia, and two patients with flat epithelial atypia and atypical ductal hyperplasia. Five cases of atypical ductal hyperplasia were upgraded to ductal carcinoma in situ, three cases of flat epithelial atypia yielded one ductal carcinoma in situ and two cases of invasive ductal carcinoma, and one case of flat epithelial atypia/atypical ductal hyperplasia had invasive ductal carcinoma. The overall rate of malignancy was 16% for atypical ductal hyperplasia (including flat epithelial atypia/atypical ductal hyperplasia patients) and 20% for flat epithelial atypia. The presence of flat epithelial atypia and atypical ductal hyperplasia at biopsy requires careful consideration, and surgical excision should be suggested.

  3. Soluble CD40 ligand stimulates CD40-dependent activation of the β2 integrin Mac-1 and protein kinase C zeda (PKCζ in neutrophils: implications for neutrophil-platelet interactions and neutrophil oxidative burst.

    Directory of Open Access Journals (Sweden)

    Rong Jin

    Full Text Available Recent work has revealed an essential involvement of soluble CD40L (sCD40L in inflammation and vascular disease. Activated platelets are the major source of sCD40L, which has been implicated in platelet and leukocyte activation, although its exact functional impact on leukocyte-platelet interactions and the underlying mechanisms remain undefined. We aimed to determine the impact and the mechanisms of sCD40L on neutrophils. We studied neutrophil interactions with activated, surface-adherent platelets as a model for leukocyte recruitment to the sites of injury. Our data show that CD40L contributes to neutrophil firm adhesion to and transmigration across activated surface-adherent platelets, possibly through two potential mechanisms. One involves the direct interaction of ligand-receptor (CD40L-CD40, i.e., platelet surface CD40L interaction with neutrophil CD40; another involves an indirect mechanism, i.e. soluble CD40L stimulates activation of the leukocyte-specific β2 integrin Mac-1 in neutrophils and thereby further promotes neutrophil adhesion and migration. Activation of the integrin Mac-1 is known to be critical for mediating neutrophil adhesion and migration. sCD40L activated Mac-1 in neutrophils and enhanced neutrophil-platelet interactions in wild-type neutrophils, but failed to elicit such responses in CD40-deficient neutrophils. Furthermore, our data show that the protein kinase C zeta (PKCζ is critically required for sCD40L-induced Mac-1 activation and neutrophil adhesive function. sCD40L strongly stimulated the focal clustering of Mac-1 (CD11b and the colocalization of Mac-1 with PKCζ in wild-type neutrophils, but had minimal effect in CD40-deficient neutrophils. Blocking PKCζ completely inhibited sCD40L-induced neutrophil firm adhesion. Moreover, sCD40L strongly stimulates neutrophil oxidative burst via CD40-dependent activation of PI3K/NF-KB, but independent of Mac-1 and PKCζ. These findings may contribute to a better

  4. Atypical Pneumonia: Updates on Legionella, Chlamydophila, and Mycoplasma Pneumonia.

    Science.gov (United States)

    Sharma, Lokesh; Losier, Ashley; Tolbert, Thomas; Dela Cruz, Charles S; Marion, Chad R

    2017-03-01

    Community-acquired pneumonia (CAP) has multiple causes and is associated with illness that requires admission to the hospital and mortality. The causes of atypical CAP include Legionella species, Chlamydophila, and Mycoplasma. Atypical CAP remains a diagnostic challenge and, therefore, likely is undertreated. This article reviews the advancements in the evaluation and treatment of patients and discusses current conflicts and controversies of atypical CAP. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Atypical Teratoid Rhabdoid Tumor: Current Therapy and Future Directions

    Energy Technology Data Exchange (ETDEWEB)

    Ginn, Kevin F.; Gajjar, Amar, E-mail: amar.gajjar@stjude.org [Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, TN (United States)

    2012-09-12

    Atypical teratoid rhabdoid tumors (ATRTs) are rare central nervous system tumors that comprise approximately 1–2% of all pediatric brain tumors; however, in patients less than 3 years of age this tumor accounts for up to 20% of cases. ATRT is characterized by loss of the long arm of chromosome 22 which results in loss of the hSNF5/INI-1 gene. INI1, a member of the SWI/SNF chromatin remodeling complex, is important in maintenance of the mitotic spindle and cell cycle control. Overall survival in ATRT is poor with median survival around 17 months. Radiation is an effective component of therapy but is avoided in patients younger than 3 years of age due to long term neurocognitive sequelae. Most long term survivors undergo radiation therapy as a part of their upfront or salvage therapy, and there is a suggestion that sequencing the radiation earlier in therapy may improve outcome. There is no standard curative chemotherapeutic regimen, but anecdotal reports advocate the use of intensive therapy with alkylating agents, high-dose methotrexate, or therapy that includes high-dose chemotherapy with stem cell rescue. Due to the rarity of this tumor and the lack of randomized controlled trials it has been challenging to define optimal therapy and advance treatment. Recent laboratory investigations have identified aberrant function and/or regulation of cyclin D1, aurora kinase, and insulin-like growth factor pathways in ATRT. There has been significant interest in identifying and testing therapeutic agents that target these pathways.

  6. Atypical calcific tendinitis with cortical erosions

    International Nuclear Information System (INIS)

    Kraemer, E.J.; El-Khoury, G.Y.

    2000-01-01

    Objective. To present and discuss six cases of calcific tendinitis in atypical locations (one at the insertion of the pectoralis major and five at the insertion of the gluteus maximus).Patients and results. All cases were associated with cortical erosions, and five had soft tissue calcifications. The initial presentation was confusing and the patients were suspected of having infection or neoplastic disease.Conclusion. Calcific tendinitis is a self-limiting condition. It is important to recognize the imaging features of this condition to avoid unnecessary investigation and surgery. (orig.)

  7. Autosomal dominant craniometaphyseal dysplasia with atypical features.

    Science.gov (United States)

    McKay, D R; Fialkov, J A

    2002-03-01

    Craniometaphyseal dysplasia (CMD) is a rare genetic disorder of bone modelling characterised by hyperostosis and sclerosis of the craniofacial bones, and abnormal modelling of the metaphyses. Clinically, autosomal dominant (AD) CMD is characterised by facial distortion and cranial-nerve compression. The goals of surgical treatment for AD CMD are cosmetic recontouring of the sclerotic craniofacial bones, correction of nasal obstruction and correction or prevention of neurological manifestations. We describe the successful correction of AD CMD craniofacial manifestations in an individual with atypical findings, and outline an approach for correcting the craniofacial deformities associated with this rare disorder. Copyright 2002 The British Association of Plastic Surgeons.

  8. Wilson’s disease: Atypical imaging features

    Directory of Open Access Journals (Sweden)

    Venugopalan Y Vishnu

    2016-10-01

    Full Text Available Wilson’s disease is a genetic movement disorder with characteristic clinical and imaging features. We report a 17- year-old boy who presented with sialorrhea, hypophonic speech, paraparesis with repeated falls and recurrent seizures along with cognitive decline. He had bilateral Kayser Flescher rings. Other than the typical features of Wilson’s disease in cranial MRI, there were extensive white matter signal abnormalities (T2 and FLAIR hyperintensities and gyriform contrast enhancement which are rare imaging features in Wilson's disease. A high index of suspicion is required to diagnose Wilson’s disease when atypical imaging features are present.

  9. Viral pneumonias: Typical and atypical findings

    International Nuclear Information System (INIS)

    Westhoff-Bleck, M.; Bleck, J.S.; Schirg, E.

    1987-01-01

    The clinical and radiological features of viral pneumonias are summarized and discussed. Although viral infections of the lung belong to atypical pneumonias they demonstrate not always the radiographic pattern of an interstitial pneumonia. Characteristic radiographic findings are quite rare. In most cases the microbial etiology cannot be predicted from chest radiographs. The appearance varies depending on the virulence of the organism and the resistence of the host. In this regard knowledge of epidemiological data as well as patients condition and underlying disease is of utmost importance. Differentiation between community- and hospital-acquired infection may be very helpful. (orig.) [de

  10. Tumor-induced osteomalacia (TIO): atypical presentation.

    Science.gov (United States)

    Khaliq, Waseem; Cheripalli, Praveen; Tangella, Krishnarao

    2011-05-01

    Tumor-induced osteomalacia is a rare acquired condition characterized by phosphaturia, hypophosphatemia and osteomalacia. We report an unusual presentation in a 15-year-old healthy male with a two-week history of cough and chest pain. The chest radiograph showed right middle lobe opacity and chest CT revealed a mass in the extra pleural space. A biopsy showed chondro-myxoidstroma with osteoid formation. Diagnosis was confirmed with the above findings and hypophosphatemia. The patient's symptoms resolved after complete surgical excision of the mass. Tumor-induced osteomalacia, although a rare disorder, can be a diagnostic challenge, especially in patients presenting with atypical symptoms.

  11. Pyruvate kinase blood test

    Science.gov (United States)

    ... medlineplus.gov/ency/article/003357.htm Pyruvate kinase blood test To use the sharing features on this page, ... energy when oxygen levels are low. How the Test is Performed A blood sample is needed. In the laboratory, white blood ...

  12. SH2/SH3 adaptor proteins can link tyrosine kinases to a Ste20-related protein kinase, HPK1.

    Science.gov (United States)

    Anafi, M; Kiefer, F; Gish, G D; Mbamalu, G; Iscove, N N; Pawson, T

    1997-10-31

    Ste20-related protein kinases have been implicated as regulating a range of cellular responses, including stress-activated protein kinase pathways and the control of cytoskeletal architecture. An important issue involves the identities of the upstream signals and regulators that might control the biological functions of mammalian Ste20-related protein kinases. HPK1 is a protein-serine/threonine kinase that possesses a Ste20-like kinase domain, and in transfected cells activates a protein kinase pathway leading to the stress-activated protein kinase SAPK/JNK. Here we have investigated candidate upstream regulators that might interact with HPK1. HPK1 possesses an N-terminal catalytic domain and an extended C-terminal tail with four proline-rich motifs. The SH3 domains of Grb2 bound in vitro to specific proline-rich motifs in the HPK1 tail and functioned synergistically to direct the stable binding of Grb2 to HPK1 in transfected Cos1 cells. Epidermal growth factor (EGF) stimulation did not affect the binding of Grb2 to HPK1 but induced recruitment of the Grb2.HPK1 complex to the autophosphorylated EGF receptor and to the Shc docking protein. Several activated receptor and cytoplasmic tyrosine kinases, including the EGF receptor, stimulated the tyrosine phosphorylation of the HPK1 serine/threonine kinase. These results suggest that HPK1, a mammalian Ste20-related protein-serine/threonine kinase, can potentially associate with protein-tyrosine kinases through interactions mediated by SH2/SH3 adaptors such as Grb2. Such interaction may provide a possible mechanism for cross-talk between distinct biochemical pathways following the activation of tyrosine kinases.

  13. Structural Bioinformatics and Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions: Towards Allosteric Inhibition of Protein Kinases by Targeting the Hsp90-Cdc37 Chaperone Machinery

    Directory of Open Access Journals (Sweden)

    Gennady Verkhivker

    2013-11-01

    Full Text Available A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding structure and function of molecular chaperones, the molecular mechanisms and guiding principles of kinase recruitment to the chaperone system are lacking quantitative characterization. Structural and thermodynamic characterization of Hsp90-Cdc37 binding with protein kinase clients by modern experimental techniques is highly challenging, owing to a transient nature of chaperone-mediated interactions. In this work, we used experimentally-guided protein docking to probe the allosteric nature of the Hsp90-Cdc37 binding with the cyclin-dependent kinase 4 (Cdk4 kinase clients. The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cdc37 targeting of the N-terminal kinase lobe. The interactions of Hsp90 with the C-terminal kinase lobe may provide additional “molecular brakes” that can lock (or unlock kinase from the system during client loading (release stages. The results of this study support a central role of the Cdc37 chaperone in recognition and recruitment of the kinase clients. Structural analysis may have useful implications in developing strategies for allosteric inhibition of protein kinases by targeting the Hsp90-Cdc37 chaperone machinery.

  14. Experimental transmission of atypical scrapie to sheep

    Directory of Open Access Journals (Sweden)

    Spiropoulos John

    2007-08-01

    Full Text Available Abstract Background Active surveillance for transmissible spongiform encephalopathies in small ruminants has been an EU regulatory requirement since 2002. A number of European countries have subsequently reported cases of atypical scrapie, similar to previously published cases from Norway, which have pathological and molecular features distinct from classical scrapie. Most cases have occurred singly in flocks, associated with genotypes considered to be more resistant to classical disease. Experimental transmissibility of such isolates has been reported in certain ovinised transgenic mice, but has not previously been reported in the natural host. Information on the transmissibility of this agent is vital to ensuring that disease control measures are effective and proportionate. Results This report presents the successful experimental transmission, in 378 days, of atypical scrapie to a recipient sheep of homologous genotype with preservation of the pathological and molecular characteristics of the donor. This isolate also transmitted to ovinised transgenic mice (Tg338 with a murine phenotype indistinguishable from that of Nor 98. Conclusion This result strengthens the opinion that these cases result from a distinct strain of scrapie agent, which is potentially transmissible in the natural host under field conditions.

  15. Atypical Celiac Disease: From Recognizing to Managing

    Directory of Open Access Journals (Sweden)

    B. Admou

    2012-01-01

    Full Text Available The nonclassic clinical presentation of celiac disease (CD becomes increasingly common in physician’s daily practice, which requires an awareness of its many clinical faces with atypical, silent, and latent forms. Besides the common genetic background (HLA DQ2/DQ8 of the disease, other non-HLA genes are now notably reported with a probable association to atypical forms. The availability of high-sensitive and specific serologic tests such as antitissue transglutuminase, antiendomysium, and more recent antideamidated, gliadin peptide antibodies permits to efficiently uncover a large portion of the submerged CD iceberg, including individuals having conditions associated with a high risk of developing CD (type 1 diabetes, autoimmune diseases, Down syndrome, family history of CD, etc., biologic abnormalities (iron deficiency anemia, abnormal transaminase levels, etc., and extraintestinal symptoms (short stature, neuropsychiatric disorders, alopecia, dental enamel hypoplasia, recurrent aphtous stomatitis, etc.. Despite the therapeutic alternatives currently in developing, the strict adherence to a GFD remains the only effective and safe therapy for CD.

  16. Prevalence of atypical swallowing: a kinesiographic study.

    Science.gov (United States)

    Monaco, A; Cattaneo, R; Spadaro, A; Marchetti, E; Barone, A

    2006-12-01

    The aim of this study was to investigate the prevalence of kinesiographic coincidence between the most cranial position during deglutition of mandible and habitual occlusal position and to evaluate the distribution of clinical diagnosis according to the kinesiographic pattern of deglutition. 201 random patients in waiting list for dental treatment and classified as orthodontic patients, prosthetic patients, TMD patients and control patients, were evaluated. Kinesiographic records were acquired using K7I and positioning a magnetic sensor frame integral with the head and with the sensory field balanced on an artificial magnet adhering to the mucosa covering the roots of the lower mandibular incisors. The kinesiographic occlusal position was compared to the kinesiographic most cranial position of the mandible during swallowing. 99 patients displayed a discrepancy between the most cranial position during swallowing and the occlusal position. 102 patients did not show any discrepancy. In this group the kinesiographic most cranial position during swallowing coincided with the occlusal position. The finding suggests that computerised kinesiography could be useful to study deglutition, detecting in a reliable way the movement pattern. Atypical deglutition seems to be less atypical than previously though in dental patient population and, despite these data confirm its correlation with malocclusion, we noted an inverse correlation with necessity of prosthetic treatment and no higher prevalence in TMD patients.

  17. Atypical subtrochanteric and diaphyseal femoral fractures

    DEFF Research Database (Denmark)

    Shane, Elizabeth; Burr, David; Abrahamsen, Bo

    2014-01-01

    Bisphosphonates (BPs) and denosumab reduce the risk of spine and nonspine fractures. Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on denosumab, but they also occur in patients with no exp......Bisphosphonates (BPs) and denosumab reduce the risk of spine and nonspine fractures. Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on denosumab, but they also occur in patients...... with no exposure to these drugs. In this report, we review studies on the epidemiology, pathogenesis, and medical management of AFFs, published since 2010. This newer evidence suggests that AFFs are stress or insufficiency fractures. The original case definition was revised to highlight radiographic features...... a minor to a major feature. The association with specific diseases and drug exposures was removed from the minor features, because it was considered that these associations should be sought rather than be included in the case definition. Studies with radiographic review consistently report significant...

  18. Intraocular lens calculations in atypical eyes

    Directory of Open Access Journals (Sweden)

    Aazim A Siddiqui

    2017-01-01

    Full Text Available Cataract surgery is the most performed surgical procedure in the field of ophthalmology. The process of intraocular lens (IOL calculations is a critical step to achieving successful outcomes. Many IOL formulae exist to guide surgeons through the difficult process of picking the most appropriate lens to achieve a certain target refraction. However, these formulae reach within 0.50 diopters of the target refraction only 75% of the time, leaving 25% of the eyes with a significant refractive surprise. A literature review was performed to investigate all the relevant published material on the history, progress, and recent advancements of IOL calculations. Based on this review, the appropriate history, evolution, progress, limitations, and recent advancements are analyzed and explained. Although the modern IOL formulae and biometric devices perform well for average eyes, they are suboptimal for eyes with atypical biometric parameters and also those that are postrefractive and keratoconic. There has not been a single, perfect formula that can resolve the complexities of this process. Various methods of formula optimization and newer generation of IOL formulae and devices may hold the key to improving outcomes in both typical and atypical eyes. These solutions minimize refractive error by introducing new input parameters and complex mathematical techniques to better estimate postoperative lens position.

  19. An atypical case of Reye's syndrome

    International Nuclear Information System (INIS)

    Maehara, Fumiaki; Goto, Katsuya; Okudera, Toshio; Mitsudome, Akihisa; Hara, Kunio; Shiraishi, Masayuki

    1982-01-01

    An atypical case of Reye's syndrome was reported with emphasis on usefulness of CT for the diagnosis and follow-up study of this disease. The patient was a 13-month-old girl who had been transferred to our hospital because of status epilepticus, a comatous state and a high temperature. She was diagnosed as having Reye's syndrome according to data of liver function tests, findings in CSF and body CT which revealed swelling of the liver with diminished attenuation value suggesting fatty infiltration. However, there were atypical features in this patient: epileptic seizures since age 5 months, no vomiting at the time of onset and no evidence of brain swelling on CT in acute phase. She was discharged 2 months later with impaired neuropsychological functions of marked degree. When she was 2 year-old, she again went into status epilepticus, was comatous and had a high temperature. She was dead when she arrived at emergency room of our hospital. Autopsy findings revealed features of Reye's syndrome as follows: abundant accumulation of small fat droplets without nuclear displacement in the liver, fatty infiltration in the kidney and myocardium, and mild swelling in the cerebral cortex with marked ventricular dilatation. The possibility of recurrence of Reye's syndrome was discussed based on the clinical and autopsy findings. The value of CT in the diagnosis and the follow-up study of this disease was emphasized. (author)

  20. Stress-induced activation of protein kinase CK2 by direct interaction with p38 mitogen-activated protein kinase

    DEFF Research Database (Denmark)

    Sayed, M; Kim, S O; Salh, B S

    2000-01-01

    Protein kinase CK2 has been implicated in the regulation of a wide range of proteins that are important in cell proliferation and differentiation. Here we demonstrate that the stress signaling agents anisomycin, arsenite, and tumor necrosis factor-alpha stimulate the specific enzyme activity of CK2...... in the human cervical carcinoma HeLa cells by up to 8-fold, and this could be blocked by the p38 MAP kinase inhibitor SB203580. We show that p38alpha MAP kinase, in a phosphorylation-dependent manner, can directly interact with the alpha and beta subunits of CK2 to activate the holoenzyme through what appears...

  1. Anti-glycophorin C induces mitochondrial membrane depolarization and a loss of extracellular regulated kinase 1/2 protein kinase activity that is prevented by pretreatment with cytochalasin D: implications for hemolytic disease of the fetus and newborn caused by anti-Ge3.

    Science.gov (United States)

    Micieli, Jonathan A; Wang, Duncheng; Denomme, Gregory A

    2010-08-01

    Anti-glycophorin C (GPC), blood group antibodies of which cause hemolytic disease of the fetus and newborn (HDFN), is a potent inhibitor of erythroid progenitor cell growth. The cellular mechanism for growth inhibition has not been characterized. K562 cells were incubated in the presence of either anti-GPC, an immunoglobulin G isotype control, an inhibitor of actin polymerization called cytochalasin D with anti-GPC, or cytochalasin D alone. The JC-1 cationic dye was used to detect mitochondrial depolarization and the activity of the mitogen-activated protein kinases was assessed by Western blotting. Anti-GPC inhibits the activity of extracellular regulated kinase (ERK)1/2 within 10 minutes but does not alter the activity of p38 or c-Jun N-terminal kinase. After 24 hours there was a significant loss of mitochondrial membrane potential compared to isotype control–treated cells. Both the ERK1/2 inhibition and the loss of mitochondrial potential were prevented by pretreatment with cytochalasin D. A cell surface antibody can cause anemia by altering the signaling pathways in erythroid cells by promoting depolarization of mitochondria via cytoskeletal rearrangement. The observation that neonates with anti-GPC HDFN are unresponsive to erythropoietin can be explained by the antibody inhibiting a protein kinase through which this hematopoietic growth factor achieves its effects.

  2. Homozygous TREM2 mutation in a family with atypical frontotemporal dementia.

    Science.gov (United States)

    Le Ber, Isabelle; De Septenville, Anne; Guerreiro, Rita; Bras, José; Camuzat, Agnès; Caroppo, Paola; Lattante, Serena; Couarch, Philippe; Kabashi, Edor; Bouya-Ahmed, Kawtar; Dubois, Bruno; Brice, Alexis

    2014-10-01

    TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p.Thr66Met heterozygous mutation in a new consanguineous Italian family. Two sibs had early onset autosomal recessive FTLD without severe bone disorders. Atypical signs were present in this family: early parietal and hippocampus involvement, parkinsonism, epilepsy, and corpus callosum thickness on brain magnetic resonance imaging. This study further demonstrates the implication of TREM2 mutations in FTLD phenotypes. It illustrates the variability of bone phenotype and underlines the frequency of atypical signs in TREM2 carriers. This and previous studies evidence that TREM2 mutation screening should be limited to autosomal recessive FTLD with atypical phenotypes characterized by: (1) a very young age at onset (20-50 years); (2) early parietal and hippocampal deficits; (3) the presence of seizures and parkinsonism; (4) suggestive extensive white matter lesions and corpus callosum thickness on brain magnetic resonance imaging. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. 123I-IMP SPECT studies in schizophrenia and atypical psychosis

    International Nuclear Information System (INIS)

    Hayashi, Takuji; Suga, Hidemichi

    1993-01-01

    According to the classification of Mitsuda, 23 patients with endogenous psychosis aged 40 years or younger, presenting with hallucination and delusion, were classified as having schizophrenia (n=12) or atypical psychosis (n=11). These patients were studied by single photon emission computed tomography (SPECT) with N-isopropyl-p-I-123-iodoamphetamine (I-123 IMP). Sixteen healthy persons served as controls. Early and delayed SPECT images were obtained 30 min and 4 hr, respectively, after intravenous injection of I-123 IMP. The group of schizophrenic patients had markedly decreased uptake of I-123 in the basal ganglia, as well as the right temporal and left occipital areas on both early and delayed images. In the group of atypical psychosis patients, however, decreased uptake of I-123 was noted in both the right basal ganglia and left occipital area on early images, but none of such findings were seen on delayed images. Regarding the uptake ratio in the frontal area on both early and delayed images, there were significant differences between the two groups. These findings have important implications for the different etiology of both disease types: not only functional disturbance in the frontal area but also irreversible changes may be involved in the occurrence of schizophrenia, and functional disturbance particularly in the right basal ganglia may be involved in the occurrence of atypical psychosis. (N.K.)

  4. The phonological memory profile of preschool children who make atypical speech sound errors.

    Science.gov (United States)

    Waring, Rebecca; Eadie, Patricia; Rickard Liow, Susan; Dodd, Barbara

    2018-01-01

    Previous research indicates that children with speech sound disorders (SSD) have underlying phonological memory deficits. The SSD population, however, is diverse. While children who make consistent atypical speech errors (phonological disorder/PhDis) are known to have executive function deficits in rule abstraction and cognitive flexibility, little is known about their memory profile. Sixteen monolingual preschool children with atypical speech errors (PhDis) were matched individually to age-and-gender peers with typically developing speech (TDS). The two groups were compared on forward recall of familiar words (pointing response), reverse recall of familiar words (pointing response), and reverse recall of digits (spoken response) and a receptive vocabulary task. There were no differences between children with TDS and children with PhDis on forward recall or vocabulary tasks. However, children with TDS significantly outperformed children with PhDis on the two reverse recall tasks. Findings suggest that atypical speech errors are associated with impaired phonological working memory, implicating executive function impairment in specific subtypes of SSD.

  5. [sup 123]I-IMP SPECT studies in schizophrenia and atypical psychosis

    Energy Technology Data Exchange (ETDEWEB)

    Hayashi, Takuji; Suga, Hidemichi (Aichi Medical University, Nagakute (Japan))

    1993-05-01

    According to the classification of Mitsuda, 23 patients with endogenous psychosis aged 40 years or younger, presenting with hallucination and delusion, were classified as having schizophrenia (n=12) or atypical psychosis (n=11). These patients were studied by single photon emission computed tomography (SPECT) with N-isopropyl-p-I-123-iodoamphetamine (I-123 IMP). Sixteen healthy persons served as controls. Early and delayed SPECT images were obtained 30 min and 4 hr, respectively, after intravenous injection of I-123 IMP. The group of schizophrenic patients had markedly decreased uptake of I-123 in the basal ganglia, as well as the right temporal and left occipital areas on both early and delayed images. In the group of atypical psychosis patients, however, decreased uptake of I-123 was noted in both the right basal ganglia and left occipital area on early images, but none of such findings were seen on delayed images. Regarding the uptake ratio in the frontal area on both early and delayed images, there were significant differences between the two groups. These findings have important implications for the different etiology of both disease types: not only functional disturbance in the frontal area but also irreversible changes may be involved in the occurrence of schizophrenia, and functional disturbance particularly in the right basal ganglia may be involved in the occurrence of atypical psychosis. (N.K.).

  6. Genetics Home Reference: atypical hemolytic-uremic syndrome

    Science.gov (United States)

    ... Kidney Diseases: Kidney Failure: Choosing a Treatment That's Right for You Educational Resources (6 links) Disease InfoSearch: Hemolytic uremic syndrome, atypical MalaCards: genetic atypical hemolytic-uremic syndrome Merck Manual Consumer Version: Overview of Anemia Merck Manual Consumer Version: ...

  7. Atypical relapse of hemolytic uremic syndrome after transplantation

    NARCIS (Netherlands)

    Olie, Karolien H.; Florquin, Sandrine; Groothoff, Jaap W.; Verlaak, René; Strain, Lisa; Goodship, Timothy H. J.; Weening, Jan J.; Davin, Jean-Claude

    2004-01-01

    Atypical hemolytic uremic syndrome (HUS) frequently leads to end-stage renal failure and can relapse after transplantation. A 12-year-old girl presenting with familial atypical HUS with a factor H mutation was successfully transplanted 6 years after a first transplant that had failed because of

  8. Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment

    Science.gov (United States)

    ... teratoid/rhabdoid tumor. There is no standard staging system for central nervous system atypical teratoid/rhabdoid tumor. The extent or spread ... different types of treatment for patients with central nervous system atypical teratoid/rhabdoid tumor. Different types of treatment ...

  9. 'Atypical' bacteria are a common cause of community-acquired ...

    African Journals Online (AJOL)

    Objectives. To assess the proportion of cases of community· acquired pneumonia caused by 'atypical' bacteria, inclUding the recently discovered Chlamydia pneumoniae, and to compare the clinical, radiographic and laboratory features of patients with and without 'atypical' bacteria. Methods. A prospective serological ...

  10. Typical and Atypical Dementia Family Caregivers: Systematic and Objective Comparisons

    Science.gov (United States)

    Nichols, Linda O.; Martindale-Adams, Jennifer; Burns, Robert; Graney, Marshall J.; Zuber, Jeffrey

    2011-01-01

    This systematic, objective comparison of typical (spouse, children) and atypical (in-law, sibling, nephew/niece, grandchild) dementia family caregivers examined demographic, caregiving and clinical variables. Analysis was of 1,476 caregivers, of whom 125 were atypical, from the Resources for Enhancing Alzheimer's Caregivers Health (REACH I and II)…

  11. Atypical MRI features in soft-tissue arteriovenous malformation: a novel imaging appearance with radiologic-pathologic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Patel, Anand S. [University of California, San Francisco, Department of Radiology and Biomedical Imaging, San Francisco, CA (United States); University of California, San Francisco, Department of Interventional Radiology, San Francisco, CA (United States); Schulman, Joshua M.; Ruben, Beth S. [University of California, San Francisco, Departments of Pathology and Dermatology, San Francisco, CA (United States); Hoffman, William Y. [University of California, San Francisco, Department of Plastic Surgery, Birthmarks and Vascular Anomalies Clinic, San Francisco, CA (United States); Dowd, Christopher F. [University of California, San Francisco, Department of Interventional Neuroradiology, Birthmarks and Vascular Anomalies Clinic, San Francisco, CA (United States); Frieden, Ilona J. [University of California, San Francisco, Department of Dermatology, Birthmarks and Vascular Anomalies Clinic, San Francisco, CA (United States); Hess, Christopher P. [University of California, San Francisco, Department of Neuroradiology, Birthmarks and Vascular Anomalies Clinic, San Francisco, CA (United States)

    2015-09-15

    The absence of a discrete mass, surrounding signal abnormality and solid enhancement are imaging features that have traditionally been used to differentiate soft-tissue arteriovenous malformations from vascular tumors on MRI. We have observed that these findings are not uncommon in arteriovenous malformations, which may lead to misdiagnosis or inappropriate treatment. To estimate the frequency of atypical MRI features in soft-tissue arteriovenous malformations and assess their relationship to lesion size, location, tissue type involved and vascular architecture. Medical records, MRI and histopathology were reviewed in consecutive patients with soft-tissue arteriovenous malformations in a multidisciplinary vascular anomalies clinic. Arteriovenous malformations were divided into those with and without atypical MRI findings (perilesional T2 signal abnormality, enhancement and/or a soft-tissue mass). Lesion location, size, tissue involved and vascular architecture were also compared between groups. Tissue stains were reviewed in available biopsy or resection specimens to assess relationships between MRI findings and histopathology. Thirty patients with treatment-naive arteriovenous malformations were included. Fifteen lesions demonstrated atypical MRI. There was no difference in age, gender, lesion size or involved body part between the groups. However, more than half of the atypical lesions demonstrated multicompartmental involvement, and tiny intralesional flow voids were more common in atypical arteriovenous malformations. Histopathology also differed in atypical cases, showing densely packed endothelial cells with connective tissue architectural distortion and edema. Arteriovenous malformations may exhibit features of a vascular tumor on MRI, particularly when multicompartmental and/or containing tiny internal vessels. These features are important to consider in suspected fast-flow vascular malformations and may have implications with respect to their treatment

  12. [Atypical cerebellar neurocytoma resembling a hemangioblastoma. A case report].

    Science.gov (United States)

    Lista Martínez, Olalla; Rivas López, Luis Alfredo; Pombo Otero, Jorge Francisco; Amaro Cendón, Santiago; Bravo García, Christian; Villa Fernández, Juan Manuel

    2014-01-01

    Through August 2013, 105 cases of intracranial extraventricular neurocytoma (EVN) had been described; 6% were located in cerebellum and 22% were atypical EVN. A rare morphologic form of neurocytoma, atypical EVN has had only 24 cases reported to date. Its prognosis is poorer than the typical central neurocytoma. This case report describes an atypical cerebellar EVN, a form that has not been reported yet, hence the interest of this article. We emphasise its cystic nature and mural nodule, in an infrequent presentation. EVN are low-incidence tumours that we need to take into consideration when making the differential diagnosis of cystic cerebellar lesions with mural nodule. Given that the prognosis of atypical EVNs depends on the atypical nature and on the grade of resection, medical follow up has to be more constant, due to the greater degree of recurrence. Copyright © 2013 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

  13. A phenotype of atypical apraxia of speech in a family carrying SQSTM1 mutation.

    Science.gov (United States)

    Boutoleau-Bretonnière, Claire; Camuzat, Agnès; Le Ber, Isabelle; Bouya-Ahmed, Kawtar; Guerreiro, Rita; Deruet, Anne-Laure; Evrard, Christelle; Bras, José; Lamy, Estelle; Auffray-Calvier, Elisabeth; Pallardy, Amandine; Hardy, John; Brice, Alexis; Derkinderen, Pascal; Vercelletto, Martine

    2015-01-01

    SQSTM1 mutations, coding for the p62 protein, were identified as a monogenic cause of Paget disease of bone and of amyotrophic lateral sclerosis. More recently, SQSTM1 mutations were identified in few families with frontotemporal dementia. We report a new family carrying SQSTM1 mutation and presenting with a clinical phenotype of speech apraxia or atypical behavioral disorders, associated with early visuo-contructional deficits. This study further supports the implication of SQSTM1 in frontotemporal dementia, and enlarges the phenotypic spectrum associated with SQSTM1 mutations.

  14. An Atypical Porencephalic Cyst Manifesting as a Simple Partial Seizure: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Abdulaziz Ibrahim Al Thafar

    2017-01-01

    Full Text Available Background. Porencephaly is an extremely rare neurological disease characterized by the presence of solitary or multiple degenerative cerebrospinal fluid (CSF cavities within the brain parenchyma. Case Report. We describe a case involving a 23-year-old male who presented with involuntary movements of the left upper limb of 6 months’ duration. A diagnosis of porencephaly was confirmed by magnetic resonance imaging (MRI. Conclusion. The rarity of occurrence and atypical presentation of such a lesion present a challenge to clinicians. Little is known about the pathogenesis and appropriate management of porencephaly. Further studies of the implications of porencephaly for neurodevelopment and behavior are needed.

  15. Imaging the neurobiological substrate of atypical depression by SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Pagani, Marco [Institute of Cognitive Sciences and Technologies, CNR, Rome (Italy); Karolinska University Hospital, Department of Nuclear Medicine, Stockholm (Sweden); Salmaso, Dario [Institute of Cognitive Sciences and Technologies, CNR, Rome (Italy); Nardo, Davide [University of Rome La Sapienza, Department of Psychology, Rome (Italy); Jonsson, Cathrine; Larsson, Stig A. [Karolinska University Hospital, Department of Nuclear Medicine, Stockholm (Sweden); Jacobsson, Hans [Karolinska University Hospital, Department of Radiology, Stockholm (Sweden); Gardner, Ann [Karolinska University Hospital Huddinge, Karolinska Institutet, Department of Clinical Neuroscience, Section of Psychiatry, Stockholm (Sweden)

    2007-01-15

    Neurobiological abnormalities underlying atypical depression have previously been suggested. The purpose of this study was to explore differences at functional brain imaging between depressed patients with and without atypical features and healthy controls. Twenty-three out-patients with chronic depressive disorder recruited from a service for patients with audiological symptoms were investigated. Eleven fulfilled the DSM-IV criteria for atypical depression (mood reactivity and at least two of the following: weight gain, hypersomnia, leaden paralysis and interpersonal rejection sensitivity). Twenty-three healthy subjects served as controls. Voxel-based analysis was applied to explore differences in {sup 99m}Tc-HMPAO uptake between groups. Patients in the atypical group had a higher prevalence of bilateral hearing impairment and higher depression and somatic distress ratings at the time of SPECT. Significantly higher tracer uptake was found bilaterally in the atypical group as compared with the non-atypicals in the sensorimotor (Brodmann areas, BA1-3) and premotor cortex in the superior frontal gyri (BA6), in the middle frontal cortex (BA8), in the parietal associative cortex (BA5, BA7) and in the inferior parietal lobule (BA40). Significantly lower tracer distribution was found in the right hemisphere in the non-atypicals compared with the controls in BA6, BA8, BA44, BA45 and BA46 in the frontal cortex, in the orbito-frontal cortex (BA11, BA47), in the postcentral parietal cortex (BA2) and in the multimodal association parietal cortex (BA40). The differences found between atypical and non-atypical depressed patients suggest different neurobiological substrates in these patient groups. The putative links with the clinical features of atypical depression are discussed. These findings encourage the use of functional neuroimaging in psychiatric disorders. (orig.)

  16. Imaging the neurobiological substrate of atypical depression by SPECT

    International Nuclear Information System (INIS)

    Pagani, Marco; Salmaso, Dario; Nardo, Davide; Jonsson, Cathrine; Larsson, Stig A.; Jacobsson, Hans; Gardner, Ann

    2007-01-01

    Neurobiological abnormalities underlying atypical depression have previously been suggested. The purpose of this study was to explore differences at functional brain imaging between depressed patients with and without atypical features and healthy controls. Twenty-three out-patients with chronic depressive disorder recruited from a service for patients with audiological symptoms were investigated. Eleven fulfilled the DSM-IV criteria for atypical depression (mood reactivity and at least two of the following: weight gain, hypersomnia, leaden paralysis and interpersonal rejection sensitivity). Twenty-three healthy subjects served as controls. Voxel-based analysis was applied to explore differences in 99m Tc-HMPAO uptake between groups. Patients in the atypical group had a higher prevalence of bilateral hearing impairment and higher depression and somatic distress ratings at the time of SPECT. Significantly higher tracer uptake was found bilaterally in the atypical group as compared with the non-atypicals in the sensorimotor (Brodmann areas, BA1-3) and premotor cortex in the superior frontal gyri (BA6), in the middle frontal cortex (BA8), in the parietal associative cortex (BA5, BA7) and in the inferior parietal lobule (BA40). Significantly lower tracer distribution was found in the right hemisphere in the non-atypicals compared with the controls in BA6, BA8, BA44, BA45 and BA46 in the frontal cortex, in the orbito-frontal cortex (BA11, BA47), in the postcentral parietal cortex (BA2) and in the multimodal association parietal cortex (BA40). The differences found between atypical and non-atypical depressed patients suggest different neurobiological substrates in these patient groups. The putative links with the clinical features of atypical depression are discussed. These findings encourage the use of functional neuroimaging in psychiatric disorders. (orig.)

  17. The diagnosis and management of pre-invasive breast disease: Pathology of atypical lobular hyperplasia and lobular carcinoma in situ

    International Nuclear Information System (INIS)

    Simpson, Peter T; Gale, Theodora; Fulford, Laura G; Reis-Filho, Jorge S; Lakhani, Sunil R

    2003-01-01

    The term lobular neoplasia refers to a spectrum of lesions featuring atypical lobular hyperplasia and lobular carcinoma in situ (LCIS). The histopathological characteristics of these lesions are well documented. What is less well understood is the management implications of a patient diagnosed with LCIS; treatment regimes vary and are somewhat controversial. LCIS is now considered a risk factor and a non-obligate precursor for the subsequent development of invasive cancer

  18. An atypical case of Noonan syndrome with mutation diagnosed by targeted exome sequencing

    Directory of Open Access Journals (Sweden)

    Jinsup Kim

    2017-09-01

    Full Text Available Noonan syndrome (NS is a genetic disorder caused by autosomal dominant inheritance and is characterized by a distinctive facial appearance, short stature, chest deformity, and congenital heart disease. In individuals with NS, germline mutations have been identified in several genes involved in the RAS/mitogen-activated protein kinase signal transduction pathway. Because of its clinical and genetic heterogeneity, the conventional diagnostic protocol with Sanger sequencing requires a multistep approach. Therefore, molecular genetic diagnosis using targeted exome sequencing (TES is considered a less expensive and faster method, particularly for patients who do not fulfill the clinical diagnostic criteria of NS. In this case, the patient showed short stature, dysmorphic facial features suggestive of NS, feeding intolerance, cryptorchidism, and intellectual disability in early childhood. At the age of 16, the patient still showed extreme short stature with delayed puberty and characteristic facial features suggestive of NS. Although the patient had no cardiac problems or chest wall deformities, which are commonly present in NS and are major concerns for patients and clinicians, the patient showed several other characteristic clinical features of NS. Considering the possibility of a genetic disorder, including NS, a molecular genetic study with TES was performed. With TES analysis, we detected a pathogenic variant of c.458A > T in KRAS in this patient with atypical NS phenotype and provided appropriate clinical management and genetic counseling. The application of TES enables accurate molecular diagnosis of patients with nonspecific or atypical features in genetic diseases with several responsible genes, such as NS.

  19. Phosphorylation of the Yeast Choline Kinase by Protein Kinase C

    Science.gov (United States)

    Choi, Mal-Gi; Kurnov, Vladlen; Kersting, Michael C.; Sreenivas, Avula; Carman, George M.

    2005-01-01

    The Saccharomyces cerevisiae CKI1-encoded choline kinase catalyzes the committed step in phosphatidylcholine synthesis via the Kennedy pathway. The enzyme is phosphorylated on multiple serine residues, and some of this phosphorylation is mediated by protein kinase A. In this work, we examined the hypothesis that choline kinase is also phosphorylated by protein kinase C. Using choline kinase as a substrate, protein kinase C activity was dose- and time-dependent, and dependent on the concentrations of choline kinase (Km = 27 μg/ml) and ATP (Km = 15 μM). This phosphorylation, which occurred on a serine residue, was accompanied by a 1.6-fold stimulation of choline kinase activity. The synthetic peptide SRSSS25QRRHS (Vmax/Km = 17.5 mM-1 μmol min-1 mg-1) that contains the protein kinase C motif for Ser25 was a substrate for protein kinase C. A Ser25 to Ala (S25A) mutation in choline kinase resulted in a 60% decrease in protein kinase C phosphorylation of the enzyme. Phosphopeptide mapping analysis of the S25A mutant enzyme confirmed that Ser25 was a protein kinase C target site. In vivo, the S25A mutation correlated with a decrease (55%) in phosphatidylcholine synthesis via the Kennedy pathway whereas an S25D phosphorylation site mimic correlated with an increase (44%) in phosphatidylcholine synthesis. Whereas the S25A (protein kinase C site) mutation did not affect the phosphorylation of choline kinase by protein kinase A, the S30A (protein kinase A site) mutation caused a 46% reduction in enzyme phosphorylation by protein kinase C. A choline kinase synthetic peptide (SQRRHS30LTRQ) containing Ser30 was a substrate (Vmax/Km = 3.0 mM−1 μmol min−1 mg−1) for protein kinase C. Comparison of phosphopeptide maps of the wild type and S30A mutant choline kinase enzymes phosphorylated by protein kinase C confirmed that Ser30 was also a target site for protein kinase C. PMID:15919656

  20. Anorexia Nervosa/Atypical Anorexia Nervosa.

    Science.gov (United States)

    Moskowitz, Lindsay; Weiselberg, Eric

    2017-04-01

    Anorexia nervosa has the highest mortality rate among all psychiatric illnesses, as it can result in significant psychopathology along with life-threatening medical complications. Atypical anorexia nervosa is a new variant described in the latest DSM edition, which has much in common with anorexia nervosa and also can result in significant morbidity and mortality. The evolution of the criteria for these illnesses is reviewed, and the two are compared and contrasted in this article. Important labs to monitor for in those with these illnesses, along with an emphasis on the monitoring of vital signs and weight, are reviewed here. The necessity for close psychiatric monitoring of safety concerns, including suicidal thoughts, is also stressed. The etiology and the treatment of these illnesses are reviewed from a biopsychosocial approach; and lastly, the prognosis of these illnesses is discussed. Copyright © 2017. Published by Elsevier Inc.

  1. Extensive hypertrophic lupus erythematosus: Atypical presentation

    Directory of Open Access Journals (Sweden)

    Tarun Narang

    2012-01-01

    Full Text Available Lupus erythematosus (LE is a disease with a wide spectrum of cutaneous and systemic manifestations. Clinical features of patients with LE show a great variation, and for this reason it is difficult to develop a unifying concept of this disease. Our objective is to present a case of hypertrophic LE with atypical morphology and extensive involvement, who responded favorably to isotretinoin. Diagnosis of hypertrophic lupus erythematosus (HLE was confirmed by characteristic histopathological findings. Combination therapy with isotretinoin and hydroxychloroquine resulted in flattening and repression of previously refractory skin lesions. Sometimes, HLE lesions may present a diagnostic and therapeutic dilemma. In long standing lesions, squamous cell carcinoma may arise. Therefore, HLE requires adequate therapy with clinical and histopathological follow up.

  2. Atypical fibroxanthoma on a bald scalp.

    Science.gov (United States)

    Nakai, Noriaki; Takenaka, Hideya; Kishimoto, Saburo

    2005-10-01

    We present the clinical, histopathological and immunohistochemical findings of an atypical fibroxanthoma (AFX) on the bald scalp of an 81-year-old French man who had worked at a private high school in Japan as a janitor for over 40 years. The patient had a history of basal cell carcinoma on the nape, and chronic solar radiation seemed to be a predisposing factor in the pathogenesis of this association. This case showed the typical clinical and histopathological characteristics of AFX, and the immunohistochemical results suggested differentiation of histiocytes and myofibroblasts. The AFX was completely resected, and the patient has not had tumor recurrence or metastasis for over four postoperative years. This case therefore provides further support to the theory that AFX displays a clinically benign course, even though it is essentially a malignant tumor histologically located in the dermis. Therefore, we must excise AFX completely with great care and perform regular physical examinations for several years after operation.

  3. Refractory Rheumatic Disorder: Atypical Postpregnancy Osteoporosis

    Directory of Open Access Journals (Sweden)

    Cindy Mourgues

    2015-01-01

    Full Text Available This is a case report on a young patient with severe osteoporosis that was initially revealed when she presented with polyarthralgia during her second pregnancy. Postpartum, the pain increased and her X-ray did not show any abnormalities. A bone scintigraphy was performed. It indicated an inflammatory rheumatic disorder. Six months after partum, an investigation of right coxalgia revealed a spontaneous basicervical fracture. Given the persistent polyarthralgia, the patient underwent a new scintigraphy, which revealed areas of what looked to be old rib and L1 fractures. A subsequent full body magnetic resonance imaging (MRI scan revealed signal abnormalities that could indicate multiple lower limb bone fractures. Despite exhaustive biological, radiological, and histological testing, no secondary cause for the osteoporosis was found. The patient was started on teriparatide. We finally concluded that, despite the atypical presentation, the patient was suffering from postpregnancy osteoporosis. It is possible that the frequency of occurrence of this still poorly understood disease is underestimated.

  4. Therapeutic drug monitoring of atypical antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Grundmann Milan

    2014-12-01

    Full Text Available Schizophrenia is a severe psychiatric disorder often associated with cognitive impairment and affective, mainly depressive, symptoms. Antipsychotic medication is the primary intervention for stabilization of acute psychotic episodes and prevention of recurrences and relapses in patients with schizophrenia. Typical antipsychotics, the older class of antipsychotic agents, are currently used much less frequently than newer atypical antipsychotics. Therapeutic drug monitoring (TDM of antipsychotic drugs is the specific method of clinical pharmacology, which involves measurement of drug serum concentrations followed by interpretation and good cooperation with the clinician. TDM is a powerful tool that allows tailor-made treatment for the specific needs of individual patients. It can help in monitoring adherence, dose adjustment, minimizing the risk of toxicity and in cost-effectiveness in the treatment of psychiatric disorders. The review provides complex knowledge indispensable to clinical pharmacologists, pharmacists and clinicians for interpretation of TDM results.

  5. A bone fide atypical fibroxanthoma of penis

    Directory of Open Access Journals (Sweden)

    Roberto Cuomo

    2014-01-01

    Full Text Available Malignant mesenchymal tumors of the penis are very rare and they have vascular origin. We present a case of a 71-year-old man with a painless nodule of 2.0 cm in diameter located in the penile foreskin. There was no history of urinary or sexually transmitted disease. An excisional biopsy revealed a markedly pleomorphic sarcoma resembling atypical fibroxanthoma (AFX associated with a squamous cell carcinoma in situ. The patient refused a wide re-excision and was free of disease after 36 months. Because the different therapeutic management and prognosis, differential diagnosis should be made with sarcomatoid squamous cell carcinoma and melanoma: A diagnosis of AFX or malignant fibrous histiocytoma may be considered only after the complete exclusion of these two entities.

  6. An atypical presentation of amoebic hepatic abscess

    International Nuclear Information System (INIS)

    Crespo Ramírez, Eduardo; Ruz Hernández, Mario; Guanche Garcell, Humberto; Castañeda Hernández, Mirtha

    2015-01-01

    Introduction: amoebic hepatic abscess is the extraintestinal manifestation of an infection by entamoeba histolytica. Estimations are made that 10% of the world population has been infected by the parasite, being more frequent in tropical regions, where overcrowding and bad sanitary conditions occur. Africa, Latin America, Southeast Asian and India have considerable health problems, resulting from this disease. In Cuba amoebiasis has been proved not to be one of the most frequent parasitism cases. Case presentation: male patient of age 48 years and of Indian nationality, presenting clinical findings, which proves a unique lesion in the right liver lobule, diagnosed by ultrasound scan and nuclear magnetic resonance. The presence is confirmed of serum antibodies against entamoeba histolytica. Treatment with metronidazole produced clinical and radiological improvement. Conclusions: atypical clinical presentation constitutes a remarkable element worthy considered in daily clinical practice. (author)

  7. Atypical features of hyperthyroidism in Blacks

    International Nuclear Information System (INIS)

    Kalk, W.J.

    1980-01-01

    Hyperthyroidism is reportedly uncommon in the indigenous populations of Africa. The presenting symptoms volunteered, the symptoms elicited by direct questioning, and the results of physical examination were therefore prospectively compared in 60 Black and 56 White patients with thyrotoxicosis attending a single thyroid clinic. Fewer Blacks than Whites volunteered information about weight loss, while more Blacks complained only of the presence of a goitre. A 'chance' diagnosis of hyperthyroidism was made more frequently in Blacks. Symptomatology elicited by direct questioning and findings on physical examination were generally similar in each group, except that Blacks presented more frequently with complicated disease (cardiac failure and overt myopathy) and infiltrative ophthalmopathy. The frequency with which hyperthyroidism presents 'atypically' in Black compared with White patients may reflect educational, socio-economic and cultural differences in the Black and White populations, and may partly explain the infrequency with which this disease is diagnosed in Blacks

  8. Enterococcus faecalis phosphomevalonate kinase

    Science.gov (United States)

    Doun, Stephanie S.; Burgner, John W.; Briggs, Scott D.; Rodwell, Victor W.

    2005-01-01

    The six enzymes of the mevalonate pathway of isopentenyl diphosphate biosynthesis represent potential for addressing a pressing human health concern, the development of antibiotics against resistant strains of the Gram-positive streptococci. We previously characterized the first four of the mevalonate pathway enzymes of Enterococcus faecalis, and here characterize the fifth, phosphomevalonate kinase (E.C. 2.7.4.2). E. faecalis genomic DNA and the polymerase chain reaction were used to clone DNA thought to encode phosphomevalonate kinase into pET28b(+). Double-stranded DNA sequencing verified the sequence of the recombinant gene. The encoded N-terminal hexahistidine-tagged protein was expressed in Escherichia coli with induction by isopropylthiogalactoside and purified by Ni++ affinity chromatography, yield 20 mg protein per liter. Analysis of the purified protein by MALDI-TOF mass spectrometry established it as E. faecalis phosphomevalonate kinase. Analytical ultracentrifugation revealed that the kinase exists in solution primarily as a dimer. Assay for phosphomevalonate kinase activity used pyruvate kinase and lactate dehydrogenase to couple the formation of ADP to the oxidation of NADH. Optimal activity occurred at pH 8.0 and at 37°C. The activation energy was ~5.6 kcal/mol. Activity with Mn++, the preferred cation, was optimal at about 4 mM. Relative rates using different phosphoryl donors were 100 (ATP), 3.6 (GTP), 1.6 (TTP), and 0.4 (CTP). Km values were 0.17 mM for ATP and 0.19 mM for (R,S)-5-phosphomevalonate. The specific activity of the purified enzyme was 3.9 μmol substrate converted per minute per milligram protein. Applications to an immobilized enzyme bioreactor and to drug screening and design are discussed. PMID:15802646

  9. A case of atypical progressive supranuclear palsy

    Directory of Open Access Journals (Sweden)

    Spaccavento S

    2013-12-01

    Full Text Available Simona Spaccavento, Marina Del Prete, Angela Craca, Anna Loverre IRCCS Salvatore Maugeri Foundation, Cassano Murge, Bari, Italy Background: Progressive supranuclear palsy (PSP is a neurodegenerative extrapyramidal syndrome. Studies have demonstrated that PSP can present clinically as an atypical dementing syndrome dominated by a progressive apraxia of speech (AOS and aphasia. Aim: We aimed to investigate the clinical presentation of PSP, using a comprehensive multidimensional evaluation, and the disease response to various pharmacological treatments. Methods: A 72-year-old right-handed male, with 17 years education, who first presented with aphasia, AOS, depression, apathy, and postural instability at 69 years; a complete neuropsychological evaluation, tapping the different cognitive domains, was performed. Results: Testing revealed a moderate global cognitive deficit (Mini-Mental State Examination test score =20, low memory test scores (story recall, Rey’s 15-word Immediate and Delayed Recall, and poor phonemic and semantic fluency. The patient’s language was characterized by AOS, with slow speech rate, prolonged intervals between syllables and words, decreased articulatory accuracy, sound distortions, and anomia. Behavioral changes, such as depression, anxiety, apathy, and irritability, were reported. The neurological examination revealed supranuclear vertical gaze palsy, poor face miming, and a mild balance deficit. Magnetic resonance imaging showed only widespread cortical atrophy. Single photon emission computed tomography demonstrated left > right frontotemporal cortical abnormalities. After 6 months, a further neuropsychological assessment showed a progression in cognitive deficits, with additional attention deficits. The patient reported frequent falls, but the neurological deficits remained unchanged. Neuroimaging tests showed the same brain involvement. Conclusion: Our case highlights the heterogeneity of the clinical features in

  10. Atypical Neurotransmitters and the Neurobiology of Depression.

    Science.gov (United States)

    Joca, Samia Regiane; Moreira, Fabricio Araujo; Wegener, Gregers

    2015-01-01

    Since the first report that the mechanism of action of antidepressants involves the facilitation of monoaminergic neurotransmission in the brain in the 1960s, the leading hypothesis about the neurobiology of depression has been the so called "monoaminergic hypothesis". However, a growing body of evidence from the last two decades also supports important involvement of non-monoaminergic mechanisms in the neurobiology of depression and antidepressant action. The discovery of nitric oxide (NO) and endocannabinoid signaling in the brain during the 1990s challenged the wellestablished criteria of classical neurotransmission. These transmitters are synthesized and released on demand by the postsynaptic neurons, and may act as a retrograde messenger on the presynaptic terminal, modulating neurotransmitter release. These unconventional signaling mechanisms and the important role as neural messengers have classified NO and endocannabinoids as atypical neurotransmitters. They are able to modulate neural signaling mediated by the main conventional neurotransmitters systems in the brain, including the monoaminergic, glutamatergic and GABAergic signaling systems. This review aims at discussing the fundamental aspects of NO- and endocannabinoid-mediated signaling in the brain, and how they can be related to the neurobiology of depression. Both preclinical and clinical evidence supporting the involvement of these atypical neurotransmitters in the neurobiology of depression, and in the antidepressant effects are presented here. The evidence is discussed on basis of their ability to modulate different neurotransmitter systems in the brain, including monoaminergic and glutamatergic ones. A better comprehension of NO and endocannabinoid signaling mechanisms in the neurobiology depression could provide new avenues for the development of novel non-monoamine based antidepressants.

  11. From Phosphosites to Kinases

    DEFF Research Database (Denmark)

    Munk, Stephanie; Refsgaard, Jan C; Olsen, Jesper V

    2016-01-01

    Kinases play a pivotal role in propagating the phosphorylation-mediated signaling networks in living cells. With the overwhelming quantities of phosphoproteomics data being generated, the number of identified phosphorylation sites (phosphosites) is ever increasing. Often, proteomics investigations...... sequence motifs, mostly based on large scale in vivo and in vitro experiments. The context of the kinase and the phosphorylated proteins in a biological system is equally important for predicting association between the enzymes and substrates, an aspect that is also being tackled with available...

  12. Detection of hypoglycin A in the seeds of sycamore (Acer pseudoplatanus) and box elder (A. negundo) in New Zealand; the toxin associated with cases of equine atypical myopathy.

    Science.gov (United States)

    McKenzie, R K; Hill, F I; Habyarimana, J A; Boemer, F; Votion, D M

    2016-05-01

    During April and May 2014 four horses aged between 5 months and 9 years, located in the Canterbury, Marlborough and Southland regions, presented with a variety of clinical signs including recumbency, stiffness, lethargy, dehydration, depression, and myoglobinuria suggestive of acute muscle damage. Two horses were subjected to euthanasia and two recovered. In all cases seeds of sycamore maple (Acer pseudoplatanus) or box elder (A. negundo) were present in the area where the horse had been grazing. The samaras (seeds) of some Acer spp. may contain hypoglycin A, that has been associated with cases of atypical myopathy in Europe and North America. To determine if hypoglycin A is present in the samaras of Acer spp. in New Zealand, samples were collected from trees throughout the country that were associated with historical and/or current cases of atypical myopathy, and analysed for hypoglycin A. Serum samples from the four cases and four unaffected horses were analysed for the presence of hypoglycin A, profiles of acylcarnitines (the definitive diagnosis for atypical myopathy) and activities of creatine kinase and aspartate aminotransferase.Markedly elevated serum activities of creatine kinase and aspartate aminotransferase, and increased concentrations of selected acylcarnitines were found in the case horses. Hypoglycin A was detected in the serum of those horses but not in the healthy controls. Hypoglycin A was detected in 10/15 samples of samaras from sycamore maple and box elder from throughout New Zealand. Cases of atypical myopathy were diagnosed on properties where samaras containing hypoglycin A were also found. Sycamore and box elder trees in New Zealand are a source of hypoglycin A associated with the development of atypical myopathy. If pastured horses present with clinical and biochemical signs of severe muscle damage then the environment should be checked for the presence of these trees. Horses should be prevented from grazing samaras from Acer spp. in the

  13. Atypical chemokine receptors in cancer: friends or foes?

    Science.gov (United States)

    Massara, Matteo; Bonavita, Ornella; Mantovani, Alberto; Locati, Massimo; Bonecchi, Raffaella

    2016-06-01

    The chemokine system is a fundamental component of cancer-related inflammation involved in all stages of cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical chemokine receptors are a new, emerging class of regulators of the chemokine system. They control chemokine bioavailability by scavenging, transporting, or storing chemokines. They can also regulate the activity of canonical chemokine receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity. Here, we summarize recent results about the role of these receptors (atypical chemokine receptor 1/Duffy antigen receptor for chemokine, atypical chemokine receptor 2/D6, atypical chemokine receptor 3/CXC-chemokine receptor 7, and atypical chemokine receptor 4/CC-chemokine receptor-like 1) on the tumorigenesis process, indicating that their effects are strictly dependent on the cell type on which they are expressed and on their coexpression with other chemokine receptors. Indeed, atypical chemokine receptors inhibit tumor growth and progression through their activity as negative regulators of chemokine bioavailability, whereas, on the contrary, they can promote tumorigenesis when they regulate the signaling of other chemokine receptors, such as CXC-chemokine receptor 4. Thus, atypical chemokine receptors are key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies. © Society for Leukocyte Biology.

  14. Malignant atypical cell in urine cytology: a diagnostic dilemma

    Directory of Open Access Journals (Sweden)

    Kakkar Nandita

    2006-01-01

    Full Text Available Abstract Aims The aim of this study was to find out the characteristic morphology of malignant atypical cells which were missed on routine cytology of urine. Materials and methods In this retrospective study, we examined detailed cytomorphology of 18 cases of atypical urinary cytology which were missed on routine examination and were further proved on histopathology as transitional cell carcinoma (TCC of bladder. The cytological features of these cases were compared with 10 cases of benign urine samples. Results There were 11 cases of high grade TCC and 7 cases of low grade TCC on histopathology of the atypical urine samples. Necrosis in the background and necrosed papillae were mostly seen in malignant atypical cells. The comet cells and cells with India ink nuclei (single cells with deep black structure-less nuclei were only observed in malignant atypical cells. The most consistent features in malignant atypical cells were: i high nuclear and cytoplasmic (N/C ratio ii nuclear pleomorphism iii nuclear margin irregularity iv hyperchromasia and v chromatin abnormalities Conclusion The present study emphasizes that nuclear features such as high N/C ratio, hyperchromasia and chromatin abnormalities are particularly useful for assessing the malignant atypical cells. Other cytological features such as comet cells and cells with India ink nuclei are also helpful for diagnosis but have limited value because they are less frequently seen.

  15. Src family kinases in chronic kidney disease.

    Science.gov (United States)

    Wang, Jun; Zhuang, Shougang

    2017-09-01

    Src family kinases (SFKs) belong to nonreceptor protein tyrosine kinases and have been implicated in the regulation of numerous cellular processes, including cell proliferation, differentiation, migration and invasion, and angiogenesis. The role and mechanisms of SFKs in tumorgenesis have been extensively investigated, and some SFK inhibitors are currently under clinical trials for tumor treatment. Recent studies have also demonstrated the importance of SFKs in regulating the development of various fibrosis-related chronic diseases (e.g., idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, and systemic sclerosis). In this article, we summarize the roles of SFKs in various chronic kidney diseases, including glomerulonephritis, diabetic nephropathy, human immunodeficiency virus-associated nephropathy, autosomal dominant form of polycystic kidney disease, and obesity-associated kidney disease, and discuss the mechanisms involved. Copyright © 2017 the American Physiological Society.

  16. Ror receptor tyrosine kinases: orphans no more.

    Science.gov (United States)

    Green, Jennifer L; Kuntz, Steven G; Sternberg, Paul W

    2008-11-01

    Receptor tyrosine kinase-like orphan receptor (Ror) proteins are a conserved family of tyrosine kinase receptors that function in developmental processes including skeletal and neuronal development, cell movement and cell polarity. Although Ror proteins were originally named because the associated ligand and signaling pathway were unknown, recent studies in multiple species have now established that Ror proteins are Wnt receptors. Depending on the cellular context, Ror proteins can either activate or repress transcription of Wnt target genes and can modulate Wnt signaling by sequestering Wnt ligands. New evidence implicates Ror proteins in planar cell polarity, an alternative Wnt pathway. Here, we review the progress made in understanding these mysterious proteins and, in particular, we focus on their function as Wnt receptors.

  17. Atypical real estate objects: legal regime and control system

    Directory of Open Access Journals (Sweden)

    Voskresenskaya Elena

    2017-01-01

    Full Text Available The legal concept of immovable things raises controversy in legal practice. Determining and understanding the definition of real estate, the complexity and diversity of these objects, a growing appearance of so-called atypical properties (such as sport stadiums, roads, boreholes, analyzing legislation and judicial practice of this field – all these issues call for a deep study of this topic. There is a conflicting arbitration practice, the subject of which is the learning of the legal nature of atypical real estate (for instance, asphalt playgrounds, car parks, fences, wells. The object of the research is the learning of the legal status of atypical real estate.

  18. Radiographic differentiation of atypical tuberculosis from mycobacterium tuberculosis

    International Nuclear Information System (INIS)

    Tarver, R.D.; Pearcy, E.A.; Conces, D.J. Jr.; Mathur, P.N.

    1987-01-01

    The chest radiographs of 95 patients with the new diagnosis of atypical turberculosis were reviewed to determine if any significant differences between atypical tuberculosis and that caused by Mycobacterium tuberculosis could be discerned. Findings included upper lobe involvement in B4 of the 95 patients and cavities in 76, with nearly equal groups having no, moderate, or extensive surrounding alveolar disease. Nodules were common; in six patients a nodule was the sole manifestation of disease. Adenopathy was seen in 12 of the 95 patients, atlectasis in 45, pleural thickening in 90, and effusions in three. These radiographic findings did not allow the radiographic differentiation of atypical tuberculosis from Mycobacterium tuberculosis infection

  19. Kinase Associated-1 Domains Drive MARK/PAR1 Kinases to Membrane Targets by Binding Acidic Phospholipids

    Energy Technology Data Exchange (ETDEWEB)

    Moravcevic, Katarina; Mendrola, Jeannine M.; Schmitz, Karl R.; Wang, Yu-Hsiu; Slochower, David; Janmey, Paul A.; Lemmon, Mark A. (UPENN-MED)

    2011-09-28

    Phospholipid-binding modules such as PH, C1, and C2 domains play crucial roles in location-dependent regulation of many protein kinases. Here, we identify the KA1 domain (kinase associated-1 domain), found at the C terminus of yeast septin-associated kinases (Kcc4p, Gin4p, and Hsl1p) and human MARK/PAR1 kinases, as a membrane association domain that binds acidic phospholipids. Membrane localization of isolated KA1 domains depends on phosphatidylserine. Using X-ray crystallography, we identified a structurally conserved binding site for anionic phospholipids in KA1 domains from Kcc4p and MARK1. Mutating this site impairs membrane association of both KA1 domains and intact proteins and reveals the importance of phosphatidylserine for bud neck localization of yeast Kcc4p. Our data suggest that KA1 domains contribute to coincidence detection, allowing kinases to bind other regulators (such as septins) only at the membrane surface. These findings have important implications for understanding MARK/PAR1 kinases, which are implicated in Alzheimer's disease, cancer, and autism.

  20. Manganese- and 1-methyl-4-phenylpyridinium-induced neurotoxicity display differences in morphological, electrophysiological and genome-wide alterations: implications for idiopathic Parkinson's disease.

    Science.gov (United States)

    Mythri, Rajeswara Babu; Raghunath, Narayana Reddy; Narwade, Santosh Chandrakant; Pandareesh, Mirazkar Dasharatha Rao; Sabitha, Kollarkandi Rajesh; Aiyaz, Mohamad; Chand, Bipin; Sule, Manas; Ghosh, Krittika; Kumar, Senthil; Shankarappa, Bhagyalakshmi; Soundararajan, Soundarya; Alladi, Phalguni Anand; Purushottam, Meera; Gayathri, Narayanappa; Deobagkar, Deepti Dileep; Laxmi, Thenkanidiyoor Rao; Srinivas Bharath, Muchukunte Mukunda

    2017-11-01

    Idiopathic Parkinson's disease and manganese-induced atypical parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the Parkinson's disease toxin 1-methyl-4-phenylpyridinium ion (MPP + ) and manganese (Mn), followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP + and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~ 93%) with slow discharge rates (0-5 Hz). While MPP + exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High-throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP + and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-signal transducer and activator of transcription pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the Janus kinase-signal transducer and activator of transcription pathway. We conclude that idiopathic Parkinson's disease and atypical parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution

  1. Regulation of hematopoietic cell function by protein tyrosine kinase-encoding oncogenes, a review

    NARCIS (Netherlands)

    Punt, C. J.

    1992-01-01

    Tyrosine phosphorylation of proteins by protein tyrosine kinases (PTKs) is an important mechanism in the regulation of various cellular processes such as proliferation, differentiation, and transformation. Accumulating data implicate PTKs as essential intermediates in the transduction of

  2. Aripiprazole versus other atypical antipsychotics for schizophrenia

    Science.gov (United States)

    Komossa, Katja; Rummel-Kluge, Christine; Schmid, Franziska; Hunger, Heike; Schwarz, Sandra; El-Sayeh, Hany George G; Kissling, Werner; Leucht, Stefan

    2014-01-01

    Background In many countries of the industrialised world second generation (atypical) antipsychotics have become first line drug treatments for people with schizophrenia. The question as to whether, and if so how much, the effects of the various second generation antipsychotics differ is a matter of debate. In this review we examine how the efficacy and tolerability of aripiprazole differs from that of other second generation antipsychotics. Objectives To evaluate the effects of aripiprazole compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. Search methods We searched the Cochrane Schizophrenia Group Trials Register (March 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. Selection criteria We included all randomised trials comparing oral aripiprazole with oral forms of amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychoses. Data collection and analysis We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (MD) again based on a random-effects model. Main results The review currently includes four trials with 1404 participants on two out of eight possible comparisons - aripiprazole versus olanzapine and aripiprazole versus risperidone. The overall number of participants leaving the studies early was considerable (38.5%), limiting the validity of the findings, but with no significant differences between groups. Aripiprazole was less efficacious than olanzapine in terms of the general mental state (PANSS total score: n=794, 2 RCTs, MD 4.96 CI 1.85 to 8.06), but it was associated with fewer side

  3. [Apropos of atypical melancholia with Sustiva (efavirenz)].

    Science.gov (United States)

    Lang, J P; Halleguen, O; Picard, A; Lang, J M; Danion, J M

    2001-01-01

    The treatment of HIV infection has changed dramatically in recent years as a result of the development of new drugs which allows a variety of multitherapy combinations more adapted to patients' needs and thereby improving compliance. Efavirenz is a non-nucleoside reverse transcriptase inhibitor. In addition to a potent antiretroviral activity, efavirenz is an easy-to-take drug with once-daily dosing and is usually well tolerated. Efavirenz, however, may induce psychic alterations which are variable and atypical in both their clinical presentation and severity. As early as the first days of treatment, efavirenz may provoke surprising phenomena such as nightmares, vivid dreams, hallucinations or illusions, and twilight states. Depersonalization and derealization episodes, personality alterations, stream of thought troubles and unusual thought contents, atypical depression and cognitive disorders have also been observed. These phenomena may occur either early or later on treatment. The prevalence of severe psychic disorders is less than 5%, but they are often responsible for harmful treatment discontinuations. Psychiatric side effects are heterogeneous and probably not related to pre-existing psychologic weakness. We do not have enough data to evaluate these side effects and their etiopathogeny. The drug could act directly on the central nervous system since it crosses the blood-brain barrier, on the serotoninergic and dopaminergic systems. Some authors have compared efavirenz-induced psychic effects to those associated with LSD and found structural similarities between the two molecules. However, the heterogeneity and low prevalence of the psychiatric side effects of efavirenz suggest and individual sensitivity. In order to improve patient care, a better clinical approach, neuropsychological evaluation, and functional brain imagery should be used to progress in the analysis and comprehension of these disorders. We discuss in this paper the case of Mister H. This HIV

  4. A novel CDKL5 mutation in a Japanese patient with atypical Rett syndrome.

    Science.gov (United States)

    Christianto, Antonius; Katayama, Syouichi; Kameshita, Isamu; Inazu, Tetsuya

    2016-08-01

    Rett syndrome (RTT) is a severe X-linked dominant inheritance disorder with a wide spectrum of clinical manifestations. Mutations in Methyl CpG binding protein 2 (MECP2), Cyclin dependent kinase-like 5 (CDKL5) and Forkhead box G1 (FOXG1) have been associated with classic and/or variant RTT. This study was conducted to identify the responsible gene(s) in atypical RTT patient, and to examine the effect of the mutation on protein function. DNA sequence analysis showed a novel heterozygous mutation in CDKL5 identified as c.530A>G which resulted in an amino acid substitution at position 177, from tyrosine to cysteine. Genotyping analysis indicated that the mutation was not merely a single nucleotide polymorphism (SNP). We also revealed that patient's blood lymphocytes had random X-chromosome inactivation (XCI) pattern. Further examination by bioinformatics analysis demonstrated the mutation caused damage or deleterious in its protein. In addition, we demonstrated in vitro kinase assay of mutant protein showed impairment of its activity. Taken together, the results suggested the mutant CDKL5 was responsible for the disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Aurora B kinase inhibition in mitosis: strategies for optimising the use of aurora kinase inhibitors such as AT9283.

    Science.gov (United States)

    Curry, Jayne; Angove, Hayley; Fazal, Lynsey; Lyons, John; Reule, Matthias; Thompson, Neil; Wallis, Nicola

    2009-06-15

    Aurora kinases play a key role in regulating mitotic division and are attractive oncology targets. AT9283, a multi-targeted kinase inhibitor with potent activity against Aurora A and B kinases, inhibited growth and survival of multiple solid tumor cell lines and was efficacious in mouse xenograft models. AT9283-treatment resulted in endoreduplication and ablation of serine-10 histone H3 phosphorylation in both cells and tumor samples, confirming that in these models it acts as an Aurora B kinase inhibitor. In vitro studies demonstrated that exposure to AT9283 for one complete cell cycle committed an entire population of p53 checkpoint-compromised cells (HCT116) to multinucleation and death whereas treatment of p53 checkpoint-competent cells (HMEC, A549) for a similar length of time led to a reversible arrest of cells with 4N DNA. Further studies in synchronized cell populations suggested that exposure to AT9283 during mitosis was critical for optimal cytotoxicity. We therefore investigated ways in which these properties might be exploited to optimize the efficacy and therapeutic index of Aurora kinase inhibitors for p53 checkpoint compromised tumors in vivo. Combining Aurora B kinase inhibition with paclitaxel, which arrests cells in mitosis, in a xenograft model resulted in promising efficacy without additional toxicity. These findings have implications for optimizing the efficacy of Aurora kinase inhibitors in clinical practice.

  6. Delayed Recurrence of Atypical Pulmonary Carcinoid Cluster: A Rare Occurrence

    Directory of Open Access Journals (Sweden)

    Salim Surani

    2014-01-01

    Full Text Available Carcinoid is one of the most common tumors of the gastrointestinal tract followed by the tracheobronchial tree. Bronchial carcinoid compromises 20% of total carcinoid and accounts for 1–5% of pulmonary malignancies. Carcinoid can be typical or atypical, with atypical carcinoid compromises 10% of the carcinoid tumors. Carcinoid usually presents as peripheral lung lesion or solitary endobronchial abnormality. Rarely it can present as multiple endobronchial lesion. We hereby present a rare case of an elderly gentleman who had undergone resection of right middle and lower lobe of lung for atypical carcinoid. Seven years later he presented with cough. CT scan of chest revealed right hilar mass. Flexible bronchoscopy revealed numerous endobronchial polypoid lesions in the tracheobronchial tree. Recurrent atypical carcinoid was then confirmed on biopsy.

  7. The Use of Electroconvulsive Therapy in Atypical Psychotic Presentations

    Science.gov (United States)

    Vasu, Devi

    2007-01-01

    Convulsive therapy and its progeny, electroconvulsive therapy (ECT), were originally used for the treatment of catatonic schizophrenia, and there is little doubt that ECT remains an effective intervention for the treatment of schizophrenia. However, current practice tends to favor the use of ECT in severe or treatment refractory affective disorders, and its use in schizophrenia and other nonaffective (atypical) psychotic disorders has become controversial. Case reports have suggested a role for ECT in two specific atypical psychotic disorders: Cotard's syndrome and cycloid psychosis. In this article, we review the atypical psychotic disorders and report a series of five case examples that signify the role of ECT in atypical psychotic presentations, particularly when the symptoms resemble those found in Cotard's syndrome and cycloid psychosis. PMID:20428309

  8. Animal behavior models of the mechanisms underlying antipsychotic atypicality.

    NARCIS (Netherlands)

    Geyer, M.A.; Ellenbroek, B.A.

    2003-01-01

    This review describes the animal behavior models that provide insight into the mechanisms underlying the critical differences between the actions of typical vs. atypical antipsychotic drugs. Although many of these models are capable of differentiating between antipsychotic and other psychotropic

  9. Atypical mitochondrial inheritance patterns in eukaryotes.

    Science.gov (United States)

    Breton, Sophie; Stewart, Donald T

    2015-10-01

    Mitochondrial DNA (mtDNA) is predominantly maternally inherited in eukaryotes. Diverse molecular mechanisms underlying the phenomenon of strict maternal inheritance (SMI) of mtDNA have been described, but the evolutionary forces responsible for its predominance in eukaryotes remain to be elucidated. Exceptions to SMI have been reported in diverse eukaryotic taxa, leading to the prediction that several distinct molecular mechanisms controlling mtDNA transmission are present among the eukaryotes. We propose that these mechanisms will be better understood by studying the deviations from the predominating pattern of SMI. This minireview summarizes studies on eukaryote species with unusual or rare mitochondrial inheritance patterns, i.e., other than the predominant SMI pattern, such as maternal inheritance of stable heteroplasmy, paternal leakage of mtDNA, biparental and strictly paternal inheritance, and doubly uniparental inheritance of mtDNA. The potential genes and mechanisms involved in controlling mitochondrial inheritance in these organisms are discussed. The linkage between mitochondrial inheritance and sex determination is also discussed, given that the atypical systems of mtDNA inheritance examined in this minireview are frequently found in organisms with uncommon sexual systems such as gynodioecy, monoecy, or andromonoecy. The potential of deviations from SMI for facilitating a better understanding of a number of fundamental questions in biology, such as the evolution of mtDNA inheritance, the coevolution of nuclear and mitochondrial genomes, and, perhaps, the role of mitochondria in sex determination, is considerable.

  10. Atypical handedness in mesial temporal lobe epilepsy.

    Science.gov (United States)

    Doležalová, Irena; Schachter, Steven; Chrastina, Jan; Hemza, Jan; Hermanová, Markéta; Rektor, Ivan; Pažourková, Marta; Brázdil, Milan

    2017-07-01

    The main aim of our study was to investigate the handedness of patients with mesial temporal lobe epilepsy (MTLE). We also sought to identify clinical variables that correlated with left-handedness in this population. Handedness (laterality quotient) was assessed in 73 consecutive patients with MTLE associated with unilateral hippocampal sclerosis (HS) using the Edinburgh Handedness Inventory. Associations between right- and left-handedness and clinical variables were investigated. We found that 54 (74.0%) patients were right-handed, and 19 (26%) patients were left-handed. There were 15 (36.6%) left-handed patients with left-sided seizure onset compared to 4 (12.5%) left-handed patients with right-sided seizure onset (p=0.030). Among patients with left-sided MTLE, age at epilepsy onset was significantly correlated with handedness (8years of age [median; min-max 0.5-17] in left-handers versus 15years of age [median; min-max 3-30] in right-handers (p<0.001). Left-sided MTLE is associated with atypical handedness, especially when seizure onset occurs during an active period of brain development, suggesting a bi-hemispheric neuroplastic process for establishing motor dominance in patients with early-onset left-sided MTLE. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. The neurogenetics of atypical parkinsonian disorders.

    Science.gov (United States)

    Fogel, Brent L; Clark, Mary C; Geschwind, Daniel H

    2014-04-01

    Although classic Parkinson disease is the disorder most commonly associated with the clinical feature of parkinsonism, there is in fact a broader spectrum of disease represented by a collection of phenotypically similar neurodegenerative conditions that mimic many of its core features. These atypical parkinsonian disorders most commonly include progressive supranuclear palsy and corticobasal degeneration, disorders both associated with frontotemporal dementia, as well as multiple system atrophy and dementia with Lewy bodies. Although the clinical distinction of these disorders still remains a challenge to physicians, recent advances in genetics are poised to tease apart the differences. Insights into the molecular etiologies underlying these conditions will improve diagnosis, yield a better understanding of the underlying disease pathology, and ultimately lend stimulation to the development of potential treatments. At the same time, the wide range of phenotypes observed from mutations in a single gene warrants broad testing facilitated by advances in DNA sequencing. These expanding genomic approaches, ranging from the use of next-generation sequencing to identify causative or risk-associated gene variations to the study of epigenetic modification linking human genetics to environmental factors, are poised to lead the field into a new age of discovery. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  12. Persistent consequences of atypical early number concepts

    Directory of Open Access Journals (Sweden)

    Michèle M. M. Mazzocco

    2013-09-01

    Full Text Available How does symbolic number knowledge performance help identify young children at risk for poor mathematics achievement outcomes? In research and practice, classification of mathematics learning disability (MLD, or dyscalculia is typically based on composite scores from broad measures of mathematics achievement. These scores do predict later math achievement levels, but do not specify the nature of math difficulties likely to emerge among students at greatest risk for long-term mathematics failure. Here we report that gaps in 2nd and 3rd graders’ number knowledge predict specific types of errors made on math assessments at Grade 8. Specifically, we show that early whole number misconceptions predict slower and less accurate performance, and atypical computational errors, on Grade 8 arithmetic tests. We demonstrate that basic number misconceptions can be detected by idiosyncratic responses to number knowledge items, and that when such misconceptions are evident during primary school they persist throughout the school age years, with variable manifestation throughout development. We conclude that including specific qualitative assessments of symbolic number knowledge in primary school may provide greater specificity of the types of difficulties likely to emerge among students at risk for poor mathematics outcomes.

  13. Atypical moral judgment following traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Angelica Muresan

    2012-07-01

    Full Text Available Previous research has shown an association between emotions, particularly social emotions, and moral judgments. Some studies suggested an association between blunted emotion and the utilitarian moral judgments observed in patients with prefrontal lesions. In order to investigate how prefrontal brain damage affects moral judgment, we asked a sample of 29 TBI patients (12 females and 17 males and 41 healthy participants (16 females and 25 males to judge 22 hypothetical dilemmas split into three different categories (non-moral, impersonal and personal moral. The TBI group presented a higher proportion of affirmative (utilitarian responses for personal moral dilemmas when compared to controls, suggesting an atypical pattern of utilitarian judgements. We also found a negative association between the performance on recognition of social emotions and the proportion of affirmative responses on personal moral dilemmas. These results suggested that the preference for utilitarian responses in this type of dilemmas is accompanied by difficulties in social emotion recognition. Overall, our findings suggest that deontological moral judgments are associated with normal social emotion processing and that frontal lobe plays an important role in both emotion and moral judgment.

  14. Atypical Presentation of Traumatic Aortic Injury

    Directory of Open Access Journals (Sweden)

    Andrew Fu Wah Ho

    2014-01-01

    Full Text Available Background. Blunt thoracic aorta injury (BAI is second only to head injury as cause of mortality in blunt trauma. While most patients do not survive till arrival at the hospital, for the remainder, prompt diagnosis and treatment greatly improve outcomes. We report an atypical presentation of BAI, highlighting the diagnostic challenges of this condition in the emergency department. Case Presentation. A previously well 25-year-old male presented 15 hours after injury hemodynamically stable with delirium. There were no signs or symptoms suggestive of BAI. Sonography showed small bilateral pleural effusions. Chest radiograph showed a normal mediastinum. Eventually, CT demonstrated a contained distal aortic arch disruption. The patient underwent percutaneous endovascular thoracic aortic repair and recovered well. Conclusion. This catastrophic lesion may present with few reliable signs and symptoms; hence, a high index of suspicion is crucial for early diagnosis and definitive surgical management. This paper discusses the diagnostic utility of clinical features, injury mechanism, and radiographic modalities. Consideration of mechanism of injury, clinical features, and chest radiograph findings should prompt advanced chest imaging.

  15. Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era.

    Directory of Open Access Journals (Sweden)

    Zafar Iqbal

    Full Text Available BACKGROUND: BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients. METHODS: We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. RESULTS: Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8-48, all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation. CONCLUSION: Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid

  16. Stereological estimation of nuclear volume in benign and atypical meningiomas

    DEFF Research Database (Denmark)

    Madsen, C; Schrøder, H D

    1993-01-01

    A stereological estimation of nuclear volume in benign and atypical meningiomas was made. The aim was to investigate whether this method could discriminate between these two meningeal neoplasms. The difference was significant and it was moreover seen that there was no overlap between the two groups....... The results demonstrate that atypical meningiomas can be distinguished from benign meningiomas by an objective stereological estimation of nuclear volume....

  17. Atypical presentation of macrophagic myofasciitis 10 years post vaccination.

    LENUS (Irish Health Repository)

    Ryan, Aisling M

    2012-02-03

    Macrophagic myofasciitis (MMF) is an uncommon inflammatory disorder of muscle believed to be due to persistence of vaccine-derived aluminium hydroxide at the site of injection. The condition is characterised by diffuse myalgias, arthralgia and fatigue. We describe a patient with histologically confirmed MMF whose presentation was atypical with left chest and upper limb pain beginning more than 10 years post vaccination. Treatment with steroids led to symptomatic improvement. Although rare, clinicians should consider MMF in cases of atypical myalgia.

  18. Atypical meningococcal meningitis with rashless presentation:A case report

    Institute of Scientific and Technical Information of China (English)

    Sunita; Singh Manpreet; Kapoor Dheeraj

    2012-01-01

    Meningococcal disease is the major health problem in developing world. The clinical presentation is varied, ranging from transient fever and bacteraemia to fulminant disease with death ensuing within hours of the onset of clinical symptoms. The classical clinical manifestations of meningococcal disease have been well described, but atypical presentations if unrecognized, may lead to a delay in treatment and fatal outcome. We here report a case presented with atypical presentation of meningococcal meningitis without classical rash, which was diagnosed and managed successfully.

  19. Globalization and deregulation: does flexicuritiy protect atypically employed?

    OpenAIRE

    Seifert, Hartmut; Tangian, Andranik S.

    2006-01-01

    "Hitherto, discussion of flexicurity has focused on normal employment (permanent full-time), with atypical work receiving only cursory attention. Nevertheless, the most affected are just atypically employed (= other than normally employed). To monitor effects of flexicurity policies in Europe, flexicurity indices are constructed from: (a) scores of the strictness of employment protection legislation provided by the OECD, (b) qualitative juridical data on social security benefits (unemployment...

  20. Atypical Focal Osteomyelitis as Initial Manifestation of AIDS

    OpenAIRE

    A. Akiki; Y. Bilde

    2011-01-01

    Persistent pain development after a skeletal contusion rarely poses the diagnosis of osteomyelitis. We report the case of a fibular head contusion as an initial manifestation of a focal abscess development in a healthy young patient. The traditional treatment of surgical drainage revealed the presence of an atypical Mycobacterium haemophilum isolates in the abscess. This lead to further investigations that concluded and established the diagnosis of AIDS. Conclusion. Isolation of an atypical M...

  1. Generic penetration in the retail atypical antipsychotic market.

    Science.gov (United States)

    Lenderts, Susan; Kalali, Amir H; Buckley, Peter

    2010-03-01

    In this article, we explore the penetration of generic atypical antipsychotics in the United States market before and after the availability of generic risperidone in July 2008. Analysis suggests that, overall, generic penetration into the atypical antipsychotic market has grown from approximately three percent in January 2008 to more than 25 percent in December 2009. Similar trends are uncovered when branded and generic prescriptions are analyzed by specialty.

  2. An Atypical Case of Pityriasis Rosea Gigantea after Influenza Vaccination

    Directory of Open Access Journals (Sweden)

    Dimitrios Papakostas

    2014-04-01

    Full Text Available Pityriasis rosea is a common erythematosquamous eruption, typically presenting along the cleavage lines of the skin. A wide spectrum of atypical manifestations may challenge even the most experienced physician. Here we report a rare case of a suberythrodermic pityriasis rosea with gigantic plaques after an influenza vaccination, and we discuss the possible triggers of atypical manifestations of such a common dermatological disease in the setting of an altered immunity.

  3. Tyrosine kinases in rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Kobayashi Akiko

    2011-08-01

    Full Text Available Abstract Rheumatoid arthritis (RA is an inflammatory, polyarticular joint disease. A number of cellular responses are involved in the pathogenesis of rheumatoid arthritis, including activation of inflammatory cells and cytokine expression. The cellular responses involved in each of these processes depends on the specific signaling pathways that are activated; many of which include protein tyrosine kinases. These pathways include the mitogen-activated protein kinase pathway, Janus kinases/signal transducers and activators transcription pathway, spleen tyrosine kinase signaling, and the nuclear factor κ-light-chain-enhancer of activated B cells pathway. Many drugs are in development to target tyrosine kinases for the treatment of RA. Based on the number of recently published studies, this manuscript reviews the role of tyrosine kinases in the pathogenesis of RA and the potential role of kinase inhibitors as new therapeutic strategies of RA.

  4. Atypical sonographic patterns of fibroadenoma of the breast : pathologic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Kook, Shin Ho; Kim, Myung Sook; Pae, Won Kil [Kangbuk Samsung Hospital, Sungkyunkwan Univ. College of Medicine, Seoul (Korea, Republic of)

    1999-03-01

    To correlate the atypical sonographic patterns of fibroadenoma of the breast with the pathologic findings. Among 203 surgically proven 43 which were sonographically atypical fibroadenomas, were retrospectively reviewed. The diagnostic criteria for atypical variety, as seen on sonography, were an ill-defined margin, microlobulated or irregular shape, heterogeneous internal echo-pattern, posterior shadowing, microcalcification, and clefts. The atypical sonographic patterns of these 43 fibroadenomas were analysed and compared with the pathologic findings. Among 43 lesions, ill-defined margins or irregular shapes were seen in 15 cases, heterogeneous internal echo-patterns in 27, posterior attenuation in nine, and clefts in seven. Thirty-seven (86%) of the 43 were predominantly ductal or had a mixed ductal and stromal component. Eleven (73.3%) of fifteen ill-defined margin or irregular shaped lesions were caused by interdigitation of surrounding normal breast parenchyma and mass. Twenty two (81.5%) of 27 heterogeneous internal echo-pat-terns were related to dilated ducts, phyllodes features, collagen bundles, adenosis, microcalcification, or fat vacuoles. Eight (88.9%) of nine posterior attenuations were caused by collagen bundles, microcalcification, ductal proliferation or dilatation. All seven cases showing clefts revealed phyllodes features and dilated ducts. Most atypical fibroadenomas had a predominantly ductal or mixed component. Ill-defined margin or irregular shape was mainly due to interdigitation of normal surrounding parenchyma. Variable histologic features were related to the heterogeneous internal echo-pattern, posterior shadowing, and the clefts revealed by atypical sonographic findings.

  5. Atypical sonographic patterns of fibroadenoma of the breast : pathologic correlation

    International Nuclear Information System (INIS)

    Kook, Shin Ho; Kim, Myung Sook; Pae, Won Kil

    1999-01-01

    To correlate the atypical sonographic patterns of fibroadenoma of the breast with the pathologic findings. Among 203 surgically proven 43 which were sonographically atypical fibroadenomas, were retrospectively reviewed. The diagnostic criteria for atypical variety, as seen on sonography, were an ill-defined margin, microlobulated or irregular shape, heterogeneous internal echo-pattern, posterior shadowing, microcalcification, and clefts. The atypical sonographic patterns of these 43 fibroadenomas were analysed and compared with the pathologic findings. Among 43 lesions, ill-defined margins or irregular shapes were seen in 15 cases, heterogeneous internal echo-patterns in 27, posterior attenuation in nine, and clefts in seven. Thirty-seven (86%) of the 43 were predominantly ductal or had a mixed ductal and stromal component. Eleven (73.3%) of fifteen ill-defined margin or irregular shaped lesions were caused by interdigitation of surrounding normal breast parenchyma and mass. Twenty two (81.5%) of 27 heterogeneous internal echo-pat-terns were related to dilated ducts, phyllodes features, collagen bundles, adenosis, microcalcification, or fat vacuoles. Eight (88.9%) of nine posterior attenuations were caused by collagen bundles, microcalcification, ductal proliferation or dilatation. All seven cases showing clefts revealed phyllodes features and dilated ducts. Most atypical fibroadenomas had a predominantly ductal or mixed component. Ill-defined margin or irregular shape was mainly due to interdigitation of normal surrounding parenchyma. Variable histologic features were related to the heterogeneous internal echo-pattern, posterior shadowing, and the clefts revealed by atypical sonographic findings

  6. Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia.

    Science.gov (United States)

    Roth Flach, Rachel J; Danai, Laura V; DiStefano, Marina T; Kelly, Mark; Menendez, Lorena Garcia; Jurczyk, Agata; Sharma, Rohit B; Jung, Dae Young; Kim, Jong Hun; Kim, Jason K; Bortell, Rita; Alonso, Laura C; Czech, Michael P

    2016-07-29

    Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced β cell mass, fewer proliferating β cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase Map4k4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from β cells in mice. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Atypical antipsychotics in bipolar disorder: systematic review of randomised trials

    Directory of Open Access Journals (Sweden)

    Moore R Andrew

    2007-08-01

    Full Text Available Abstract Background Atypical antipsychotics are increasingly used for treatment of mental illnesses like schizophrenia and bipolar disorder, and considered to have fewer extrapyramidal effects than older antipsychotics. Methods We examined efficacy in randomised trials of bipolar disorder where the presenting episode was either depression, or manic/mixed, comparing atypical antipsychotic with placebo or active comparator, examined withdrawals for any cause, or due to lack of efficacy or adverse events, and combined all phases for adverse event analysis. Studies were found through systematic search (PubMed, EMBASE, Cochrane Library, and data combined for analysis where there was clinical homogeneity, with especial reference to trial duration. Results In five trials (2,206 patients participants presented with a depressive episode, and in 25 trials (6,174 patients the presenting episode was manic or mixed. In 8-week studies presenting with depression, quetiapine and olanzapine produced significantly better rates of response and symptomatic remission than placebo, with NNTs of 5–6, but more adverse event withdrawals (NNH 12. With mania or mixed presentation atypical antipsychotics produced significantly better rates of response and symptomatic remission than placebo, with NNTs of about 5 up to six weeks, and 4 at 6–12 weeks, but more adverse event withdrawals (NNH of about 22 in studies of 6–12 weeks. In comparisons with established treatments, atypical antipsychotics had similar efficacy, but significantly fewer adverse event withdrawals (NNT to prevent one withdrawal about 10. In maintenance trials atypical antipsychotics had significantly fewer relapses to depression or mania than placebo or active comparator. In placebo-controlled trials, atypical antipsychotics were associated with higher rates of weight gain of ≥7% (mainly olanzapine trials, somnolence, and extrapyramidal symptoms. In active controlled trials, atypical antipsychotics

  8. Regulation of Autophagy by Kinases

    International Nuclear Information System (INIS)

    Sridharan, Savitha; Jain, Kirti; Basu, Alakananda

    2011-01-01

    Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated protein kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets

  9. Regulation of Autophagy by Kinases

    Energy Technology Data Exchange (ETDEWEB)

    Sridharan, Savitha; Jain, Kirti; Basu, Alakananda, E-mail: alakananda.basu@unthsc.edu [Department of Molecular Biology and Immunology, Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX 76107 (United States)

    2011-06-09

    Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated protein kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets.

  10. Regulation of Autophagy by Kinases

    Science.gov (United States)

    Sridharan, Savitha; Jain, Kirti; Basu, Alakananda

    2011-01-01

    Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated protein kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets. PMID:24212825

  11. Regulation of Autophagy by Kinases

    Directory of Open Access Journals (Sweden)

    Savitha Sridharan

    2011-06-01

    Full Text Available Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK and protein kinase C that are often deregulated in cancer and are important therapeutic targets.

  12. Amisulpride versus other atypical antipsychotics for schizophrenia

    Science.gov (United States)

    Komossa, Katja; Rummel-Kluge, Christine; Hunger, Heike; Schmid, Franziska; Schwarz, Sandra; da Mota Neto, Joaquim I Silveira; Kissling, Werner; Leucht, Stefan

    2014-01-01

    Background In many countries of the industrialised world second generation (atypical) antipsychotics have become first line drug treatments for people with schizophrenia. The question as to whether, and if so how much, the effects of the various second generation antipsychotics differ is a matter of debate. In this review we examine how the efficacy and tolerability of amisulpride differs from that of other second generation antipsychotics. Objectives To evaluate the effects of amisulpride compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. Search methods We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CINAHL, EMBASE, MEDLINE and PsycINFO. We updated this search in July 2012 and added 47 new trials to the awaiting classification section. Selection criteria We included randomised, at least single-blind, trials comparing oral amisulpride with oral forms of aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychoses. Data collection and analysis We extracted data independently. For continuous data we calculated weighted mean differences (MD), for dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. Main results The review currently includes ten short to medium term trials with 1549 participants on three comparisons: amisulpride versus olanzapine, risperidone and ziprasidone. The overall attrition rate was considerable (34.7%) with no significant difference between groups. Amisulpride was similarly effective as olanzapine and risperidone and more effective than ziprasidone (leaving the study early due to inefficacy: n=123, 1 RCT, RR 0.21 CI 0.05 to 0.94, NNT 8 CI 5 to 50

  13. Association between GRB2/Sos and insulin receptor substrate 1 is not sufficient for activation of extracellular signal-regulated kinases by interleukin-4: implications for Ras activation by insulin.

    Science.gov (United States)

    Pruett, W; Yuan, Y; Rose, E; Batzer, A G; Harada, N; Skolnik, E Y

    1995-03-01

    Insulin receptor substrate 1 (IRS-1) mediates the activation of a variety of signaling pathways by the insulin and insulin-like growth factor 1 receptors by serving as a docking protein for signaling molecules with SH2 domains. We and others have shown that in response to insulin stimulation IRS-1 binds GRB2/Sos and have proposed that this interaction is important in mediating Ras activation by the insulin receptor. Recently, it has been shown that the interleukin (IL)-4 receptor also phosphorylates IRS-1 and an IRS-1-related molecule, 4PS. Unlike insulin, however, IL-4 fails to activate Ras, extracellular signal-regulated kinases (ERKs), or mitogen-activated protein kinases. We have reconstituted the IL-4 receptor into an insulin-responsive L6 myoblast cell line and have shown that IRS-1 is tyrosine phosphorylated to similar degrees in response to insulin and IL-4 stimulation in this cell line. In agreement with previous findings, IL-4 failed to activate the ERKs in this cell line or to stimulate DNA synthesis, whereas the same responses were activated by insulin. Surprisingly, IL-4's failure to activate ERKs was not due to a failure to stimulate the association of tyrosine-phosphorylated IRS-1 with GRB2/Sos; the amounts of GRB2/Sos associated with IRS-1 were similar in insulin- and IL-4-stimulated cells. Moreover, the amounts of phosphatidylinositol 3-kinase activity associated with IRS-1 were similar in insulin- and IL-4-stimulated cells. In contrast to insulin, however, IL-4 failed to induce tyrosine phosphorylation of Shc or association of Shc with GRB2. Thus, ERK activation correlates with Shc tyrosine phosphorylation and formation of an Shc/GRB2 complex. Thus, ERK activation correlates with Shc tyrosine phosphorylation and formation of an Shc/GRB2 complex. Previous studies have indicated that activation of ERks in this cell line is dependent upon Ras since a dominant-negative Ras (Asn-17) blocks ERK activation by insulin. Our findings, taken in the context

  14. Physical and Psychological Morbidity in Adolescents With Atypical Anorexia Nervosa.

    Science.gov (United States)

    Sawyer, Susan M; Whitelaw, Melissa; Le Grange, Daniel; Yeo, Michele; Hughes, Elizabeth K

    2016-04-01

    Adolescents with atypical anorexia nervosa (AN) have lost significant weight but are not underweight. This study aimed to describe the physical and psychological morbidity of adolescents diagnosed with atypical AN, and to compare them with underweight adolescents with AN. All first presentations of atypical AN (n = 42) and full-threshold AN (n = 118) to a specialist pediatric eating disorder program between July 2010 and June 2014 were examined. Diagnosis was assessed by using the Eating Disorder Examination and anthropometric measurement. Psychological morbidity measures included eating and weight concerns, bingeing, purging, compulsive exercise, and psychiatric comorbidity. Compared with AN, more adolescents with atypical AN were premorbidly overweight or obese (71% vs 12%). They had lost more weight (17.6 kg vs 11.0 kg) over a longer period (13.3 vs 10.2 months). There was no significant difference in the frequency of bradycardia (24% vs 33%;) or orthostatic instability (43% vs 38%). We found no evidence of a difference in frequency of psychiatric comorbidities (38% vs 45%) or suicidal ideation (43% vs 39%). Distress related to eating and body image was more severe in atypical AN. Atypical AN considerably affects physical and psychological functioning, despite adolescents presenting within or above the normal weight range. There was little evidence that the morbidity of adolescents with atypical AN was any less severe than that of adolescents with full-threshold AN. The findings support the need for vigilance around weight loss in adolescents, regardless of body size. Copyright © 2016 by the American Academy of Pediatrics.

  15. Bacterial Protein-Tyrosine Kinases

    DEFF Research Database (Denmark)

    Shi, Lei; Kobir, Ahasanul; Jers, Carsten

    2010-01-01

    in exopolysaccharide production, virulence, DNA metabolism, stress response and other key functions of the bacterial cell. BY-kinases act through autophosphorylation (mainly in exopolysaccharide production) and phosphorylation of other proteins, which have in most cases been shown to be activated by tyrosine......Bacteria and Eukarya share essentially the same family of protein-serine/threonine kinases, also known as the Hanks-type kinases. However, when it comes to protein-tyrosine phosphorylation, bacteria seem to have gone their own way. Bacterial protein-tyrosine kinases (BY-kinases) are bacterial...... and highlighted their importance in bacterial physiology. Having no orthologues in Eukarya, BY-kinases are receiving a growing attention from the biomedical field, since they represent a particularly promising target for anti-bacterial drug design....

  16. Identification of methylenecyclopropyl acetic acid in serum of European horses with atypical myopathy.

    Science.gov (United States)

    Votion, D-M; van Galen, G; Sweetman, L; Boemer, F; de Tullio, P; Dopagne, C; Lefère, L; Mouithys-Mickalad, A; Patarin, F; Rouxhet, S; van Loon, G; Serteyn, D; Sponseller, B T; Valberg, S J

    2014-03-01

    It is hypothesised that European atypical myopathy (AM) has a similar basis as seasonal pasture myopathy in North America, which is now known to be caused by ingestion of hypoglycin A contained in seeds from the tree Acer negundo. Serum from horses with seasonal pasture myopathy contained the conjugated toxic metabolite of hypoglycin A, methylenecyclopropyl acetic acid (MCPA). Retrospective study on archived samples. 1) To determine whether MCPA-carnitine was present in serum of European horses confirmed to have AM; 2) to determine whether Acer negundo or related Acer species were present on AM pastures in Europe. Concentrations of MCPA-carnitine were analysed in banked serum samples of 17 AM horses from Europe and 3 diseased controls (tetanus, neoplasia and exertional rhabdomyolysis) using tandem mass spectrometry. Atypical myopathy was diagnosed by characteristic serum acylcarnitine profiles. Pastures of 12 AM farms were visited by experienced botanists and plant species were documented. Methylenecyclopropyl acetic acid-carnitine at high concentrations (20.39 ± 17.24 nmol/l; range 0.95-57.63 nmol/l; reference: <0.01 nmol/l) was identified in serum of AM but not disease controls (0.00 ± 0.00 nmol/l). Acer pseudoplatanus but not Acer negundo was present on all AM farms. Atypical myopathy in Europe, like seasonal pasture myopathy in North America, is highly associated with the toxic metabolite of hypoglycin A, MCPA-carnitine. This finding coupled with the presence of a tree of which seeds are known to also contain hypoglycin A indicates that ingestion of Acer pseudoplatanus is the probable cause of AM. This finding has major implications for the prevention of AM. © 2013 EVJ Ltd.

  17. Tracing the associations between sex, the atypical and the combined atypical-melancholic depression subtypes: A path analysis.

    Science.gov (United States)

    Rodgers, Stephanie; Vandeleur, Caroline L; Ajdacic-Gross, Vladeta; Aleksandrowicz, Aleksandra A; Strippoli, Marie-Pierre F; Castelao, Enrique; Glaus, Jennifer; Lasserre, Aurélie M; Müller, Mario; Rössler, Wulf; Angst, Jules; Preisig, Martin

    2016-01-15

    Numerous studies have examined determinants leading to preponderance of women in major depressive disorder (MDD), which is particularly accentuated for the atypical depression subtype. It is thus of interest to explore the specific indirect effects influencing the association between sex and established depression subtypes. The data of 1624 subjects with a lifetime diagnosis of MDD derived from the population-based PsyCoLaus data were used. An atypical (n=256), a melancholic (n=422), a combined atypical and melancholic features subtype (n=198), and an unspecified MDD group (n=748) were constructed according to the DSM-IV specifiers. Path models with direct and indirect effects were applied to the data. Partial mediation of the female-related atypical and combined atypical-melancholic depression subtypes was found. Early anxiety disorders and high emotion-orientated coping acted as mediating variables between sex and the atypical depression subtype. In contrast, high Body Mass Index (BMI) served as a suppression variable, also concerning the association between sex and the combined atypical-melancholic subtype. The latter association was additionally mediated by an early age of MDD onset and early/late anxiety disorders. The use of cross-sectional data does not allow causal conclusions. This is the first study that provides evidence for a differentiation of the general mechanisms explaining sex differences of overall MDD by depression subtypes. Determinants affecting the pathways begin early in life. Since some of them are primarily of behavioral nature, the present findings could be a valuable target in mental health care. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase.

    Science.gov (United States)

    Gajiwala, Ketan S; Grodsky, Neil; Bolaños, Ben; Feng, Junli; Ferre, RoseAnn; Timofeevski, Sergei; Xu, Meirong; Murray, Brion W; Johnson, Ted W; Stewart, Al

    2017-09-22

    The receptor tyrosine kinase family consisting of Tyro3, Axl, and Mer (TAM) is one of the most recently identified receptor tyrosine kinase families. TAM receptors are up-regulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination. To this end, using differential scanning fluorimetry and hydrogen-deuterium exchange mass spectrometry, we show here that a lower stability and greater dynamic nature of the Axl kinase domain may account for its poor crystallizability. We present the first structural characterization of the Axl kinase domain in complex with a small-molecule macrocyclic inhibitor. The Axl crystal structure revealed two distinct conformational states of the enzyme, providing a first glimpse of what an active TAM receptor kinase may look like and suggesting a potential role for the juxtamembrane region in enzyme activity. We noted that the ATP/inhibitor-binding sites of the TAM members closely resemble each other, posing a challenge for the design of a selective inhibitor. We propose that the differences in the conformational dynamics among the TAM family members could potentially be exploited to achieve inhibitor selectivity for targeted receptors. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Atypical E2f functions are critical for pancreas polyploidization.

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    Ramadhan B Matondo

    Full Text Available The presence of polyploid cells in the endocrine and exocrine pancreas has been reported for four decades. In rodents, pancreatic polyploidization is initiated after weaning and the number of polyploid cells increases with age. Surprisingly the molecular regulators and biological functions of polyploidization in the pancreas are still unknown. We discovered that atypical E2f activity is essential for polyploidization in the pancreas, using an inducible Cre/LoxP approach in new-born mice to delete ubiquitously the atypical E2f transcription factors, E2f7 and E2f8. In contrast to its critical role in embryonic survival, conditional deletion of both of both atypical E2fs in newborn mice had no impact on postnatal survival and mice lived until old age. However, deficiency of E2f7 or E2f8 alone was sufficient to suppress polyploidization in the pancreas and associated with only a minor decrease in blood serum levels of glucose, insulin, amylase and lipase under 4 hours starvation condition compared to wildtype littermates. In mice with fewer pancreatic polyploid cells that were fed ad libitum, no major impact on hormones or enzymes levels was observed. In summary, we identified atypical E2fs to be essential for polyploidization in the pancreas and discovered that postnatal induced loss of both atypical E2fs in many organs is compatible with life until old age.

  20. Atypical E2f functions are critical for pancreas polyploidization.

    Science.gov (United States)

    Matondo, Ramadhan B; Moreno, Eva; Toussaint, Mathilda J M; Tooten, Peter C J; van Essen, Saskia C; van Liere, Elsbeth A; Youssef, Sameh A; Bongiovanni, Laura; de Bruin, Alain

    2018-01-01

    The presence of polyploid cells in the endocrine and exocrine pancreas has been reported for four decades. In rodents, pancreatic polyploidization is initiated after weaning and the number of polyploid cells increases with age. Surprisingly the molecular regulators and biological functions of polyploidization in the pancreas are still unknown. We discovered that atypical E2f activity is essential for polyploidization in the pancreas, using an inducible Cre/LoxP approach in new-born mice to delete ubiquitously the atypical E2f transcription factors, E2f7 and E2f8. In contrast to its critical role in embryonic survival, conditional deletion of both of both atypical E2fs in newborn mice had no impact on postnatal survival and mice lived until old age. However, deficiency of E2f7 or E2f8 alone was sufficient to suppress polyploidization in the pancreas and associated with only a minor decrease in blood serum levels of glucose, insulin, amylase and lipase under 4 hours starvation condition compared to wildtype littermates. In mice with fewer pancreatic polyploid cells that were fed ad libitum, no major impact on hormones or enzymes levels was observed. In summary, we identified atypical E2fs to be essential for polyploidization in the pancreas and discovered that postnatal induced loss of both atypical E2fs in many organs is compatible with life until old age.

  1. Ichthyosiform mycosis fungoides with alopecia and atypical membranous nephropathy

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    Qiang Zhou

    2011-01-01

    Full Text Available We describe here a rare case of variant of mycosis fungoides (MF: ichthyosiform MF with alopecia and atypical membranous nephropathy. The diagnosis was made based on the following findings: generalized ichthyosis-like eruption, alopecia, enlarged superficial lymph nodes, proteinuria, and hematuria, the histological features of the skin biopsy from both ichthyotic and alopecic lesions with immunohistochemical staining, and the renal biopsy examination with immunofluorescence. The histological examination of ichthyotic and alopecic lesions displayed a predominant infiltration of atypical lymphocytes in the upper dermis with the characteristics of epidermotropism and folliculotropism. Immunohistochemical studies demonstrated that most infiltrated atypical lymphocytes were CD3, CD4, and CD45RO positive, whereas negative for CD5, CD7, CD20, CD30, and CD56. A renal biopsy examination revealed atypical membranous nephropathy with deposition of immunoglobulin G (IgG, IgM, IgA, C1q, and C3. In this case atypical membranous nephropathy was involved, which is very uncommon and has never been presented in the literature to date. Although ichthyosiform MF usually features a relatively favorable course, diffuse alopecia and the renal involvement in this case might indicate aggressive disease and poor prognosis.

  2. Sertindole versus other atypical antipsychotics for schizophrenia

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    Komossa, Katja; Rummel-Kluge, Christine; Hunger, Heike; Schwarz, Sandra; Schmid, Franziska; Lewis, Ruth; Kissling, Werner; Leucht, Stefan

    2014-01-01

    Background In many countries of the industrialised world second generation (atypical) antipsychotics have become the first line drug treatment for people with schizophrenia. The question as to whether and, if so, how much the effects of the various second generation antipsychotics differ is a matter of debate. Objectives To evaluate the effects of sertindole compared with other second generation antipsychotics for people with schizophrenia and schizophrenia-like psychosis. Search methods We searched the Cochrane Schizophrenia Group Trials Register (April 2007) and ClinicalTrials.gov (February 2009). Selection criteria We included all randomised trials comparing oral sertindole with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone or zotepine for people with schizophrenia or schizophrenia-like psychosis. Data collection and analysis We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated weighted mean differences (WMD) again based on a random-effects model. Main results The review currently includes two short-term low-quality randomised trials (total n=508) both comparing sertindole with risperidone. One third of participants left the studies early (2 RCTs, n=504, RR 1.23 CI 0.94 to 1.60). There was no difference in efficacy (2 RCTs, n=493, WMD PANSS total change from baseline 1.98 CI −8.24 to 12.20). Compared with relatively high doses of risperidone (between 4 and 12 mg/day), sertindole produced significantly less akathisia and parkinsonism (1 RCT, n=321, RR 0.24 CI 0.09 to 0.69, NNT 14, CI 8 to 100). Sertindole produced more cardiac effects (2 RCTs, n=508, RR QTc prolongation 4.86 CI 1.94 to 12.18), weight change (2 RCTs, n=328, WMD 0.99 CI 0.12 to 1.86) and male sexual dysfunction (2 RCTs, n=437, RR 2.90 CI 1.32 to 6.35, NNH 13 CI 8 to 33

  3. Characterization of the autophagy marker protein Atg8 reveals atypical features of autophagy in Plasmodium falciparum.

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    Rahul Navale

    Full Text Available Conventional autophagy is a lysosome-dependent degradation process that has crucial homeostatic and regulatory functions in eukaryotic organisms. As malaria parasites must dispose a number of self and host cellular contents, we investigated if autophagy in malaria parasites is similar to the conventional autophagy. Genome wide analysis revealed a partial autophagy repertoire in Plasmodium, as homologs for only 15 of the 33 yeast autophagy proteins could be identified, including the autophagy marker Atg8. To gain insights into autophagy in malaria parasites, we investigated Plasmodium falciparum Atg8 (PfAtg8 employing techniques and conditions that are routinely used to study autophagy. Atg8 was similarly expressed and showed punctate localization throughout the parasite in both asexual and sexual stages; it was exclusively found in the pellet fraction as an integral membrane protein, which is in contrast to the yeast or mammalian Atg8 that is distributed among cytosolic and membrane fractions, and suggests for a constitutive autophagy. Starvation, the best known autophagy inducer, decreased PfAtg8 level by almost 3-fold compared to the normally growing parasites. Neither the Atg8-associated puncta nor the Atg8 expression level was significantly altered by treatment of parasites with routinely used autophagy inhibitors (cysteine (E64 and aspartic (pepstatin protease inhibitors, the kinase inhibitor 3-methyladenine, and the lysosomotropic agent chloroquine, indicating an atypical feature of autophagy. Furthermore, prolonged inhibition of the major food vacuole protease activity by E64 and pepstatin did not cause accumulation of the Atg8-associated puncta in the food vacuole, suggesting that autophagy is primarily not meant for degradative function in malaria parasites. Atg8 showed partial colocalization with the apicoplast; doxycycline treatment, which disrupts apicoplast, did not affect Atg8 localization, suggesting a role, but not exclusive, in

  4. A Novel Atypical PKC-Iota Inhibitor, Echinochrome A, Enhances Cardiomyocyte Differentiation from Mouse Embryonic Stem Cells.

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    Kim, Hyoung Kyu; Cho, Sung Woo; Heo, Hye Jin; Jeong, Seung Hun; Kim, Min; Ko, Kyung Soo; Rhee, Byoung Doo; Mishchenko, Natalia P; Vasileva, Elena A; Fedoreyev, Sergey A; Stonik, Valentin A; Han, Jin

    2018-06-02

    Echinochrome A (EchA) is a marine bioproduct extracted from sea urchins having antioxidant, antimicrobial, anti-inflammatory, and chelating effects, and is the active component of the clinical drug histochrome. We investigated the potential use of Ech A for inducing cardiomyocyte differentiation from mouse embryonic stem cells (mESCs). We also assessed the effects of Ech A on mitochondrial mass, inner membrane potential (Δψm), reactive oxygen species generation, and levels of Ca 2+ . To identify the direct target of Ech A, we performed in vitro kinase activity and surface plasmon resonance binding assays. Ech A dose-dependently enhanced cardiomyocyte differentiation with higher beating rates. Ech A (50 μM) increased the mitochondrial mass and membrane potential but did not alter the mitochondrial superoxide and Ca 2+ levels. The in vitro kinase activity of the atypical protein kinase C-iota (PKCι) was significantly decreased by 50 μM of Ech A with an IC 50 for PKCι activity of 107 μM. Computational protein-ligand docking simulation results suggested the direct binding of Ech A to PKCι, and surface plasmon resonance confirmed the direct binding with a low K D of 6.3 nM. Therefore, Ech A is a potential drug for enhancing cardiomyocyte differentiation from mESCs through direct binding to PKCι and inhibition of its activity.

  5. Impact of side-effects of atypical antipsychotics on non-compliance, relapse and cost.

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    Mortimer, A; Williams, P; Meddis, D

    2003-01-01

    Atypical antipsychotics generally have milder side-effects than conventional antipsychotics, but also differ among themselves in this respect. This study aimed to compare the impact of different side-effect profiles of individual atypical antipsychotics on non-compliance, relapse and cost in schizophrenia. A state-transition model was built using literature data supplemented by expert opinion. The model found that quetiapine and ziprasidone were similar in estimated non-compliance and relapse rates. Olanzapine and risperidone had higher estimated non-compliance and relapse rates, and incremental, 1-year, per-patient direct costs, using US-based cost data, of approximately $530 (95% confidence interval [CI] approximately $275, $800), and approximately $485 (95% CI approximately $235, $800), respectively, compared with quetiapine. Incremental costs attributable to different side-effect profiles were highly significant. This study shows that differing side-effect profiles of the newer antipsychotic agents are likely to lead to different compliance rates, and consequent variation in relapse rates. The cost implications of these heterogenous clinical outcomes are substantial.

  6. Disinhibited social engagement in postinstitutionalized children: differentiating normal from atypical behavior.

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    Lawler, Jamie M; Hostinar, Camelia E; Mliner, Shanna B; Gunnar, Megan R

    2014-05-01

    The most commonly reported socially aberrant behavior in postinstitutionalized (PI) children is disinhibited social engagement (DSE; also known as indiscriminate friendliness). There is no gold standard for measurement of this phenomenon nor agreement on how to differentiate it from normative behavior. We adopted a developmental psychopathology approach (Cicchetti, 1984) to study this phenomenon by comparing it to normative social development and by studying its patterns over time in 50 newly adopted PI children (16-36 months at adoption) compared with 41 children adopted early from foster care overseas and 47 nonadopted (NA) controls. Using coded behavioral observations of the child's interaction with an unfamiliar adult, atypical behaviors were differentiated from normative behaviors. Principal components analysis identified two dimensions of social disinhibition. The nonphysical social dimension (e.g., initiations, proximity) showed wide variation in NA children and is therefore considered a typical form of sociability. Displays of physical contact and intimacy were rare in NA children, suggesting that they represent an atypical pattern of behavior. Both adopted groups demonstrated more physical DSE behavior than NA children. There were no group differences on the nonphysical factor, and it increased over time in all groups. Implications for understanding the etiology of DSE and future directions are discussed.

  7. Risperidone versus other atypical antipsychotics for schizophrenia

    Science.gov (United States)

    Komossa, Katja; Rummel-Kluge, Christine; Schwarz, Sandra; Schmid, Franziska; Hunger, Heike; Kissling, Werner; Leucht, Stefan

    2014-01-01

    Background In many countries of the industrialised world second-generation (“atypical”) antipsychotics (SGAs) have become the first line drug treatment for people with schizophrenia. The question as to whether and if so how much the effects of the various SGAs differ is a matter of debate. In this review we examined how the efficacy and tolerability of risperidone differs from that of other SGAs. Objectives To evaluate the effects of risperidone compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychosis. Search methods 1. Electronic searching We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. 2. Reference searching We inspected the references of all identified studies for more trials. 3. Personal contact We contacted the first author of each included study for missing information. 4. Drug companies We contacted the manufacturers of all atypical antipsychotics included for additional data. Selection criteria We included all randomised, blinded trials comparing oral risperidone with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis. Data collection and analysis We extracted data independently. For dichotomous data we calculated risk ratio (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD), again based on a random-effects model. Main results The review currently includes 45 blinded RCTs with 7760 participants. The number of RCTs available for each comparison varied: four studies compared risperidone with amisulpride, two with aripiprazole, 11 with clozapine, 23 with olanzapine, eleven with

  8. Atypical pyoderma gangrenosum in a patient with osteomyelofibrosis

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    Živanović Dubravka

    2007-01-01

    Full Text Available Background. Atypical forms of pyoderma gangrenosum generally appear on the upper extremities; most frequently they are associated with myeloproliferative disorders, including osteomyelofibrosis. A response to systemic steroids is more pronounced than in classical form. Sometimes it may be the first sign of an underlying malignancy. Case report. We reported a patient with atypical pyoderma gangrenosum developed during the course of a myeloid malignancy - osteomyelofibrosis. The lesions occurred after a minor trauma. Painful blistering plaques, with an elevated, bluish-gray border were located on the dorsal aspect of hands. No skin malignancy was found. The lesions resolved rapidly to systemic steroids. Conclusion. Considering the unusual clinical presentation which makes the diagnosis difficult, as well as the fact that atypical forms of pyoderma gangrenosum can be the first sign of malignancies, especially myeloproliferative ones, recognizing this entity enables timely guiding future investigations toward their prompt detection.

  9. Atypical language representation in children with intractable temporal lobe epilepsy.

    Science.gov (United States)

    Maulisova, Alice; Korman, Brandon; Rey, Gustavo; Bernal, Byron; Duchowny, Michael; Niederlova, Marketa; Krsek, Pavel; Novak, Vilem

    2016-05-01

    This study evaluated language organization in children with intractable epilepsy caused by temporal lobe focal cortical dysplasia (FCD) alone or dual pathology (temporal lobe FCD and hippocampal sclerosis, HS). We analyzed clinical, neurological, fMRI, neuropsychological, and histopathologic data in 46 pediatric patients with temporal lobe lesions who underwent excisional epilepsy surgery. The frequency of atypical language representation was similar in both groups, but children with dual pathology were more likely to be left-handed. Atypical receptive language cortex correlated with lower intellectual capacity, verbal abstract conceptualization, receptive language abilities, verbal working memory, and a history of status epilepticus but did not correlate with higher seizure frequency or early seizure onset. Histopathologic substrate had only a minor influence on neuropsychological status. Greater verbal comprehension deficits were noted in children with atypical receptive language representation, a risk factor for cognitive morbidity. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Atypical femur fractures associated with bisphosphonates: from prodrome to resolution

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    Braulio Sastre-Jala

    2015-10-01

    Full Text Available Atypical fractures related to the prolonged use of bisphosphonates are caused by low energy mechanisms and are characterized by oblique and transverse lines and frequent bilateralism. We present a clinical case of a patient who we believe illustrates, both in clinical and radiological aspects, the new definition of atypical femur fracture related to treatment using bisphosphonates treated conservatively and successfully with discharge and teriparatide 20 mcg/80 mcl s.c./24h. The appearance of painful symptoms in the upper thigh, especially if bilateral, in patients treated with bisphosphonates for long periods of time, makes it necessary to dismiss bone lesions that might otherwise suggest atypical fracture. In those cases where the fracture is incomplete, restoring bone metabolism through the administration of teriparatide 20 mcg/80 mcl s.c./24h could prevent displaced fractures.

  11. Atypical presentation of HELLP syndrome: clinical case report

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    Juan Manuel Tobar Parra

    2017-12-01

    Full Text Available Objective: To describe a case of HELLP syndrome with atypical presentation form. Background: HELLP syndrome is a complication of preeclampsia, characterized by: haemolysis, elevation of liver enzymes and thrombocytopenia; Can present atypical, without hypertension or proteinuria, 10-20% of the cases. Case report: 38 year old female patient, with a pregnancy of 38.5 weeks of gestation, treated at the Hospital Universitario San José de Popayán (Colombia. Atypical HELLP syndrome is diagnosed in a pregnant woman with thrombocytopenia, impaired liver enzymes, but no evidence of proteinuria or hypertension. Gestation is terminated by cesarean section and magnesium sulfate is given for 24 hours, with adequate post-surgical evolution, clinical improvement of the symptomatology presented, normalization of liver enzymes and platelet elevation. Conclusion: Knowledge of this syndrome, although of rare occurrence, allows a fast action, an effective diagnosis and treatment, to avoid morbidity and greater maternal fetal mortality.

  12. Computerized tomography findings on schizophrenia and atypical psychosis

    International Nuclear Information System (INIS)

    Hayashi, Takuji; Watanabe, Toyonobu; Kito, Hiroshi; Sekine, Takeo

    1988-01-01

    The brain CTs of 54 endogenous psychotics (27 males, 27 females) who were less than 40 years of age and were first adimitted in Aichi Medical University from 1982 to 1986, and 20 controls (10 males, 10 females) were examined. Using Mitsuda's classification, we devided all the cases into 29 schizophrenics (18 males, 11 females) and 25 atypical psychotics (9 males, 16 females). In order to investigate the differences of CT findings between the two patient groups, the 3rd ventricle index (the ratio of 3rd ventricle width to the internal diameter of the skull), Evans'ratio, lateral ventricle brain ratio (VBR), Sylvian fissure to brain ratio, 4th ventricle to cerebellum ratio were determined. Schizophrenics had larger 3rd and lateral ventricles as well as Sylvian fissures when compared to controls, but atypical psychotics had not. Moreover, schizophrenics had larger 3rd and lateral ventricle than atypical psychotics. But in widths of Sylvian fissures there was no statistical significant difference between the two groups. Ventricle enlargements of schizophrenics did not correlate with duration of illness as well as age, and were not results of prior psychiatric treatment such as medication and EST. Therefore the following is suggested that, this abnormal CT findings predate the onset of schizophrenic psychoses. In atypical psychotics the changes of Sylvian fissures correlated with duration of illness, but not with age. Such observations may possibly suggest that recurrence of the illness might finally attain irreversible changes even in atypical psychotics. Finally, the heterogeneity of schizophrenia and the independence of atypical psychosis were also discussed. (author) 53 refs

  13. The Efficacy of Acute Electroconvulsive Therapy in Atypical Depression

    Science.gov (United States)

    Husain, Mustafa M.; McClintock, Shawn M.; Rush, A. John; Knapp, Rebecca G.; Fink, Max; Rummans, Teresa A.; Rasmussen, Keith; Claassen, Cynthia; Petrides, Georgios; Biggs, Melanie M.; Mueller, Martina; Sampson, Shirlene; Bailine, Samuel H.; Lisanby, Sarah H.; Kellner, Charles H.

    2013-01-01

    Objective This study examined the characteristics and outcomes of patients with major depressive disorder (MDD), with or without atypical features, who were treated with acute bilateral electroconvulsive therapy (ECT). Method Analyses were conducted with 489 patients who met DSM-IV criteria for MDD. Subjects were identified as typical or atypical on the basis of the Structured Clinical Interview for DSM-IV obtained at baseline prior to ECT. Depression symptom severity was measured by the 24-item Hamilton Rating Scale for Depression (HAM-D24) and the 30-item Inventory of Depressive Symptomatology–Self-Report (IDS-SR30). Remission was defined as at least a 60% decrease from baseline in HAM-D24 score and a total score of 10 or below on the last 2 consecutive HAM-D24 ratings. The randomized controlled trial was performed from 1997 to 2004. Results The typical (N = 453) and atypical (N = 36) groups differed in several sociodemographic and clinical variables including gender (p = .0071), age (p = .0005), treatment resistance (p = .0014), and age at first illness onset (p < .0001) and onset of current episode (p = .0008). Following an acute course of bilateral ECT, a considerable portion of both the typical (67.1%) and the atypical (80.6%) groups reached remission. The atypical group was 2.6 (95% CI = 1.1 to 6.2) times more likely to remit than the typical group after adjustment for age, psychosis, gender, clinical site, and depression severity based on the HAM-D24. Conclusion Acute ECT is an efficacious treatment for depressed patients with typical or atypical symptom features. PMID:18278988

  14. Sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase C (PKC)-mediated activation of cAMP-response element-binding protein (CREB): implications for Alzheimer disease therapy.

    Science.gov (United States)

    Corbett, Grant T; Roy, Avik; Pahan, Kalipada

    2013-03-22

    Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are believed to be genuine molecular mediators of neuronal growth and homeostatic synapse activity. However, levels of these neurotrophic factors decrease in different brain regions of patients with Alzheimer disease (AD). Induction of astrocytic neurotrophin synthesis is a poorly understood phenomenon but represents a plausible therapeutic target because neuronal neurotrophin production is aberrant in AD and other neurodegenerative diseases. Here, we delineate that sodium phenylbutyrate (NaPB), a Food and Drug Administration-approved oral medication for hyperammonemia, induces astrocytic BDNF and NT-3 expression via the protein kinase C (PKC)-cAMP-response element-binding protein (CREB) pathway. NaPB treatment increased the direct association between PKC and CREB followed by phosphorylation of CREB (Ser(133)) and induction of DNA binding and transcriptional activation of CREB. Up-regulation of markers for synaptic function and plasticity in cultured hippocampal neurons by NaPB-treated astroglial supernatants and its abrogation by anti-TrkB blocking antibody suggest that NaPB-induced astroglial neurotrophins are functionally active. Moreover, oral administration of NaPB increased the levels of BDNF and NT-3 in the CNS and improved spatial learning and memory in a mouse model of AD. Our results highlight a novel neurotrophic property of NaPB that may be used to augment neurotrophins in the CNS and improve synaptic function in disease states such as AD.

  15. [Auricular sporotrichosis. Atypical case report simulating bacterial cellulitis].

    Science.gov (United States)

    Ochoa-Reyes, Juan; Ramos-Martínez, Ernesto; Treviño-Rangel, Rogelio; González, Gloria M; Bonifaz, Alexandro

    Sporotrichosis is the most common subcutaneous or implantation mycosis in Mexico. The case of a preauricular cutaneous-fixed sporotrichosis simulating atypical bacterial cellulitis is reported in an elderly patient with no history of trauma. The biopsy showed a suppurative granuloma with scarce yeast. Sporothrix schenckii was identified in the culture and confirmed by molecular biology. She was treated with itraconazole and a clinical and mycological cure was obtained. The case of atypical presentation is presented, coming from a semi-arid zone with extreme weather.

  16. Atypical Neuroleptic Malignant Syndrome Associated with Use of Clozapine

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    Quevedo-Florez Leonardo

    2017-01-01

    Full Text Available The Neuroleptic Malignant Syndrome (NMS is a medical emergency of infrequent presentation in the emergency department, which is associated with the use of psychiatric drugs, such as typical and atypical antipsychotics. Our case addresses a 55-year-old patient diagnosed with undifferentiated schizophrenia for 10 years, who had been receiving clozapine and clonazepam as part of their treatment. This patient presents the symptoms of Neuroleptic Malignant Syndrome without fever, which improves with treatment especially with the withdrawal of clozapine. In the absence of fever and clinical improvement, the patient is considered to have an atypical presentation of this disease.

  17. Medicolegal aspects of atypical firearm injuries: a case report.

    Science.gov (United States)

    Gürses, Murat Serdar; Akan, Okan; Eren, Bülent; Durak, Dilek; Türkmen, Nursel; Cetin, Selçuk

    2014-01-01

    Our case was a twenty year-old man, who was injured during the military duty with G3 infantry rifle in the training area. An atypical firearm entry wound on the left side of sternum which was 4.5 cm in diameter, and was surrounded by six irregular skin burn wounds by a flash-suppressor and a 0.7 cm diameter firearm exit wound at space on the left midscapular line. Our case emphasizes that the interpretation of properties of these atypical firearm entry wounds need to be carefully assessed by physicians.

  18. Zotepine versus other atypical antipsychotics for schizophrenia

    Science.gov (United States)

    Subramanian, Selvizhi; Rummel-Kluge, Christine; Hunger, Heike; Schmid, Franziska; Schwarz, Sandra; Kissling, Werner; Leucht, Stefan; Komossa, Katja

    2014-01-01

    Background In many parts of the world, particularly in industrialised countries, second generation (atypical) antipsychotic drugs have become first line treatment for people suffering from schizophrenia. The question as to whether the effects of various second generation antipsychotic drugs differ is a matter of debate. Objectives To evaluate the effects of zotepine compared with other second generation antipsychotic drugs for people suffering from schizophrenia and schizophrenia-like psychoses. Search methods We searched the Cochrane Schizophrenia Group Trials Register (November 2009), inspected references of all identified studies for further trials and contacted authors of trials for additional information. Selection criteria We included only randomised clinical controlled trials that compared zotepine with any forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole or ziprasidone in people suffering from only schizophrenia or schizophrenia-like psychoses. Data collection and analysis SS and KK extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated weighted mean differences (MD) again based on a random-effects model. Main results We included three studies (total n=289; 2 RCTs zotepine vs clozapine; 1 RCT zotepine vs clozapine vs risperidone (at 4 mg, 8 mg doses) vs remoxipride. All studies were of limited methodological quality. When zotepine was compared with clozapine, it was clozapine that was found to be more effective in terms of global state (n=59, 1 RCT, RR No clinically significant response 8.23 CI 1.14 to 59.17). Mental state scores also favoured clozapine (n=59, 1 RCT, MD average score (BPRS total, high = poor) 6.00 CI 2.17 to 9.83) and there was less use of antiparkinson medication in the clozapine group (n=116, 2 RCTs, RR 20.96 CI 2.89 to 151.90). In the

  19. Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains.

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    Travis W Bainbridge

    Full Text Available Receptor tyrosine kinase-like orphan receptors (ROR 1 and 2 are atypical members of the receptor tyrosine kinase (RTK family and have been associated with several human diseases. The vertebrate RORs contain an ATP binding domain that deviates from the consensus amino acid sequence, although the impact of this deviation on catalytic activity is not known and the kinase function of these receptors remains controversial. Recently, ROR2 was shown to signal through a Wnt responsive, β-catenin independent pathway and suppress a canonical Wnt/β-catenin signal. In this work we demonstrate that both ROR1 and ROR2 kinase domains are catalytically deficient while CAM-1, the C. elegans homolog of ROR, has an active tyrosine kinase domain, suggesting a divergence in the signaling processes of the ROR family during evolution. In addition, we show that substitution of the non-consensus residues from ROR1 or ROR2 into CAM-1 and MuSK markedly reduce kinase activity, while restoration of the consensus residues in ROR does not restore robust kinase function. We further demonstrate that the membrane-bound extracellular domain alone of either ROR1 or ROR2 is sufficient for suppression of canonical Wnt3a signaling, and that this domain can also enhance Wnt5a suppression of Wnt3a signaling. Based on these data, we conclude that human ROR1 and ROR2 are RTK-like pseudokinases.

  20. An Atypical HNF4A Mutation Which Does Not Conform to the Classic Presentation of HNF4A-MODY

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    Andrew J. Spiro

    2018-01-01

    Full Text Available Objective. To present the case of an atypical Hepatocyte Nuclear Factor 4 Alpha (HNF4A mutation that is not consistent with the classically published presentation of HNF4A-Mature Onset Diabetes of the Young (MODY. Methods. Clinical presentation and literature review. Results. A 43-year-old nonobese man was referred to the endocrinology clinic for evaluation of elevated fasting blood glucose (FBG measurements. Laboratory review revealed prediabetes and hypertriglyceridemia for the previous decade. Testing of autoantibodies for type 1 diabetes was negative. Genetic testing showed an autosomal dominant, heterozygous missense mutation (c.991C>T; p.Arg331Cys in the HNF4A gene, which is correlated with HNF4A-MODY. Phenotypically, patients with an HNF4A-MODY tend to have early-onset diabetes, microvascular complications, low triglyceride levels, increased birth weight, fetal macrosomia, and less commonly neonatal hyperinsulinemic hypoglycemia. The patient did not demonstrate any of these features but instead presented with late-onset diabetes, an elevated triglyceride level, and a normal birth weight. Conclusion. Our patient likely represents an atypical variant of HNF4A-MODY with a milder clinical presentation. Patients with atypical, less-severe presentations of HNF4A-MODY may be largely undiagnosed or misdiagnosed, but identification is important due to implications for treatment, pregnancy, and screening of family members.

  1. The psychopharmacology of aggressive behavior: a translational approach: part 2: clinical studies using atypical antipsychotics, anticonvulsants, and lithium.

    Science.gov (United States)

    Comai, Stefano; Tau, Michael; Pavlovic, Zoran; Gobbi, Gabriella

    2012-04-01

    Patients experiencing mental disorders are at an elevated risk for developing aggressive behavior. In the past 10 years, the psychopharmacological treatment of aggression has changed dramatically owing to the introduction of atypical antipsychotics on the market and the increased use of anticonvulsants and lithium in the treatment of aggressive patients.This review (second of 2 parts) uses a translational medicine approach to examine the neurobiology of aggression, discussing the major neurotransmitter systems implicated in its pathogenesis (serotonin, glutamate, norepinephrine, dopamine, and γ-aminobutyric acid) and the neuropharmacological rationale for using atypical antipsychotics, anticonvulsants, and lithium in the therapeutics of aggressive behavior. A critical review of all clinical trials using atypical antipsychotics (aripiprazole, clozapine, loxapine, olanzapine, quetiapine, risperidone, ziprasidone, and amisulpride), anticonvulsants (topiramate, valproate, lamotrigine, and gabapentin), and lithium are presented. Given the complex, multifaceted nature of aggression, a multifunctional combined therapy, targeting different receptors, seems to be the best strategy for treating aggressive behavior. This therapeutic strategy is supported by translational studies and a few human studies, even if additional randomized, double-blind, clinical trials are needed to confirm the clinical efficacy of this framework.

  2. Receptor-interacting protein (RIP) kinase family

    OpenAIRE

    Zhang, Duanwu; Lin, Juan; Han, Jiahuai

    2010-01-01

    Receptor-interacting protein (RIP) kinases are a group of threonine/serine protein kinases with a relatively conserved kinase domain but distinct non-kinase regions. A number of different domain structures, such as death and caspase activation and recruitment domain (CARD) domains, were found in different RIP family members, and these domains should be keys in determining the specific function of each RIP kinase. It is known that RIP kinases participate in different biological processes, incl...

  3. Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates

    DEFF Research Database (Denmark)

    Hoffman, Nolan J; Parker, Benjamin L; Chaudhuri, Rima

    2015-01-01

    -intensity exercise bout, revealing 1,004 unique exercise-regulated phosphosites on 562 proteins. These included substrates of known exercise-regulated kinases (AMPK, PKA, CaMK, MAPK, mTOR), yet the majority of kinases and substrate phosphosites have not previously been implicated in exercise signaling. Given...

  4. A child with myoclonus-dystonia (DYT11) misdiagnosed as atypical opsoclonus myoclonus syndrome

    DEFF Research Database (Denmark)

    Drivenes, Bergitte; Born, Alfred Peter; Ek, Jakob

    2015-01-01

    INTRODUCTION: DYT11 is an autosomal dominant inherited movement disorder characterized by myoclonus and dystonia. CLINICAL PRESENTATION: We present a case with atypical symptoms and with episodes of ataxia and myoclonus preceded by infections. Atypical presentation of opsoclonus myoclonus syndrom...

  5. Atypical Presentation of Herpes Simplex Virus Type 2 Infection Refractory to Treatment With Acyclovir in 2 Hematologic Patients.

    Science.gov (United States)

    Nieto Rodríguez, D; Sendagorta Cudós, E; Rueda Carnero, J M; Herranz Pinto, P

    2017-12-01

    Herpesvirus infections are not uncommon in hematologic patients. Our first patient, diagnosed with chronic lymphatic leukemia, presented extensive genital herpes infection refractory to treatment with acyclovir and with a partial response to foscarnet, which had to be withdrawn due to systemic adverse effects. The second patient, diagnosed with follicular Hodgkin lymphoma, presented hypertrophic herpes infection refractory to treatment with acyclovir but that responded to intralesional cidofovir and topical imiquimod. As in other immunodepressed patients, herpesvirus infection in hematologic patients can present atypical manifestations, as well as resistance to treatments that act via the viral thymidine kinase. A high level of clinical suspicion is therefore needed to make an early diagnosis, together with extensive knowledge of the different treatments available. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  6. A naturally occurring cowpox virus with an ectromelia virus A-type inclusion protein gene displays atypical A-type inclusions.

    Science.gov (United States)

    Okeke, Malachy Ifeanyi; Hansen, Hilde; Traavik, Terje

    2012-01-01

    Human orthopoxvirus (OPV) infections in Europe are usually caused by cowpox virus (CPXV). The genetic heterogeneity of CPXVs may in part be due to recombination with other OPV species. We describe the characterization of an atypical CPXV (CPXV-No-H2) isolated from a human patient in Norway. CPXV-No-H2 was characterized on the basis of A-type inclusion (ATI) phenotype as well as the DNA region containing the p4c and atip open reading frames. CPXV-No-H2 produced atypical V(+/) ATI, in which virions are on the surface of ATI but not within the ATI matrix. Phylogenetic analysis showed that the atip gene of CPXV-No-H2 clustered closely with that of ectromelia virus (ECTV) with a bootstrap support of 100% whereas its p4c gene is diverged compared to homologues in other OPV species. By recombination analysis we identified a putative crossover event at nucleotide 147, downstream the start of the atip gene. Our results suggest that CPXV-No-H2 originated from a recombination between CPXV and ECTV. Our findings are relevant to the evolution of OPVs. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Relationships between atypical sensory processing patterns, maladaptive behaviour and maternal stress in Spanish children with autism spectrum disorder.

    Science.gov (United States)

    Nieto, C; López, B; Gandía, H

    2017-12-01

    This study investigated sensory processing in a sample of Spanish children with autism spectrum disorder (ASD). Specifically, the study aimed to explore (1) the prevalence and distribution of atypical sensory processing patterns, (2) the relationship between adaptive and maladaptive behaviour with atypical sensory processing and (3) the possible relationship between sensory subtype and maternal stress. The short sensory profile 2 (Dunn 2014) and the vineland adaptive behavior scale (Sparrow et al. 1984) were administered to examine the sensory processing difficulties and maladaptive behaviours of 45 children with ASD aged 3 to 14; their mothers also completed the parenting stress index-short form (Abidin 1995). Atypical sensory features were found in 86.7% of the children; avoider and sensor being the two most common patterns. No significant relationship was found between atypical sensory processing and adaptive behaviour. However, the analysis showed a strong relationship between sensory processing and maladaptive behaviour. Both maladaptive behaviour and sensory processing difficulties correlated significantly with maternal stress although maternal stress was predicted only by the sensory variable, and in particular by the avoider pattern. The findings suggest that sensory features in ASD may be driving the high prevalence of parental stress in carers. They also suggest that the effect on parental stress that has been attributed traditionally to maladaptive behaviours may be driven by sensory difficulties. The implications of these findings are discussed in relation to the development of interventions and the need to explore contextual and cultural variables as possible sources of variability. © 2017 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

  8. Atypical radiation response of SCID cells

    Science.gov (United States)

    Chawapun, Nisa

    Murine SCID (severe combined immune deficiency) cells are well known for their defect in DNA double-strand break repair and in variable(diversity)joining [V(D)J] recombination due to a mutation in a catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). As a consequence, scid cells are hypersensitive to ionizing radiation. The present study showed that asynchronous populations of scid cells were about two-fold more sensitive than Balb/c with respect to cell killing and the defect in scid cells was corrected by complementation with human chromosome 8. Analysis of the survival of synchronized populations as a function of the cell cycle revealed that while scid cells were hypersensitive in all cell cycle phases compared to wild-type cells, this hypersensitivity is even more pronounced in G1 phase. The hypersensitivity reduced as the cells progressed into S phase suggested that homologous recombination repair plays a role. The results imply that there are at least two pathways for the repair of DSB DNA, consistent with a model previously proposed by others. The scid cells were also more sensitive to UVC light (254 nm) killing as compared to wild type cells by clonogenic survival. Using a host cell reactivation (HCR) assay to study the nucleotide excision repair (NER) which is the major repair pathway for UV-photoproducts, the results showed that NER in scid cells was not as efficient as CB- 17. This suggests that DNA-PK is involved in NER as well as non-homologous end-joining (NHEJ) DSB repair which is responsible for ionizing radiation sensitivity in scid cells. Repair in scid cells was not totally absent as shown by low dose rate sparing of cell killing after exposure to 137Cs γ-rays at dose rate of 0.6 cGy/h, 1.36 cGy/h, 6 cGy/h as compared to high dose rate at 171 cGy/min, although this phenomenon could be explained partly by proliferation. However, for radiation induced transformation, no significant dose rate effect was seen. A plot of transformation

  9. Synapses of Amphids Defective (SAD-A) Kinase Promotes Glucose-stimulated Insulin Secretion through Activation of p21-activated Kinase (PAK1) in Pancreatic β-Cells*

    Science.gov (United States)

    Nie, Jia; Sun, Chao; Faruque, Omar; Ye, Guangming; Li, Jia; Liang, Qiangrong; Chang, Zhijie; Yang, Wannian; Han, Xiao; Shi, Yuguang

    2012-01-01

    The p21-activated kinase-1 (PAK1) is implicated in regulation of insulin exocytosis as an effector of Rho GTPases. PAK1 is activated by the onset of glucose-stimulated insulin secretion (GSIS) through phosphorylation of Thr-423, a major activation site by Cdc42 and Rac1. However, the kinase(s) that phosphorylates PAK1 at Thr-423 in islet β-cells remains elusive. The present studies identified SAD-A (synapses of amphids defective), a member of AMP-activated protein kinase-related kinases exclusively expressed in brain and pancreas, as a key regulator of GSIS through activation of PAK1. We show that SAD-A directly binds to PAK1 through its kinase domain. The interaction is mediated by the p21-binding domain (PBD) of PAK1 and requires both kinases in an active conformation. The binding leads to direct phosphorylation of PAK1 at Thr-423 by SAD-A, triggering the onset of GSIS from islet β-cells. Consequently, ablation of PAK1 kinase activity or depletion of PAK1 expression completely abolishes the potentiating effect of SAD-A on GSIS. Consistent with its role in regulating GSIS, overexpression of SAD-A in MIN6 islet β-cells significantly stimulated cytoskeletal remodeling, which is required for insulin exocytosis. Together, the present studies identified a critical role of SAD-A in the activation of PAK1 during the onset of insulin exocytosis. PMID:22669945

  10. Synapses of amphids defective (SAD-A) kinase promotes glucose-stimulated insulin secretion through activation of p21-activated kinase (PAK1) in pancreatic β-Cells.

    Science.gov (United States)

    Nie, Jia; Sun, Chao; Faruque, Omar; Ye, Guangming; Li, Jia; Liang, Qiangrong; Chang, Zhijie; Yang, Wannian; Han, Xiao; Shi, Yuguang

    2012-07-27

    The p21-activated kinase-1 (PAK1) is implicated in regulation of insulin exocytosis as an effector of Rho GTPases. PAK1 is activated by the onset of glucose-stimulated insulin secretion (GSIS) through phosphorylation of Thr-423, a major activation site by Cdc42 and Rac1. However, the kinase(s) that phosphorylates PAK1 at Thr-423 in islet β-cells remains elusive. The present studies identified SAD-A (synapses of amphids defective), a member of AMP-activated protein kinase-related kinases exclusively expressed in brain and pancreas, as a key regulator of GSIS through activation of PAK1. We show that SAD-A directly binds to PAK1 through its kinase domain. The interaction is mediated by the p21-binding domain (PBD) of PAK1 and requires both kinases in an active conformation. The binding leads to direct phosphorylation of PAK1 at Thr-423 by SAD-A, triggering the onset of GSIS from islet β-cells. Consequently, ablation of PAK1 kinase activity or depletion of PAK1 expression completely abolishes the potentiating effect of SAD-A on GSIS. Consistent with its role in regulating GSIS, overexpression of SAD-A in MIN6 islet β-cells significantly stimulated cytoskeletal remodeling, which is required for insulin exocytosis. Together, the present studies identified a critical role of SAD-A in the activation of PAK1 during the onset of insulin exocytosis.

  11. Giant atypical ossifying fibromyxoid tumour of the calf

    International Nuclear Information System (INIS)

    Harish, Srinivasan; Polson, Alexander; Griffiths, Meryl; Morris, Paul; Malata, Charles; Bearcroft, Philip W.P.

    2006-01-01

    We present a case of giant atypical ossifying fibromyxoid tumour (OFMT) of soft tissue, occurring in the calf, in a 77-year-old woman. The patient presented with a history of bleeding ulcer over a calf lump that had been present for over 4 years. Clinical presentation, radiological features and histopathologic findings are described, and the relevant literature is reviewed. (orig.)

  12. Clinical features of Friedreich's ataxia: classical and atypical phenotypes.

    Science.gov (United States)

    Parkinson, Michael H; Boesch, Sylvia; Nachbauer, Wolfgang; Mariotti, Caterina; Giunti, Paola

    2013-08-01

    One hundred and fifty years since Nikolaus Friedreich's first description of the degenerative ataxic syndrome which bears his name, his description remains at the core of the classical clinical phenotype of gait and limb ataxia, poor balance and coordination, leg weakness, sensory loss, areflexia, impaired walking, dysarthria, dysphagia, eye movement abnormalities, scoliosis, foot deformities, cardiomyopathy and diabetes. Onset is typically around puberty with slow progression and shortened life-span often related to cardiac complications. Inheritance is autosomal recessive with the vast majority of cases showing an unstable intronic GAA expansion in both alleles of the frataxin gene on chromosome 9q13. A small number of cases are caused by a compound heterozygous expansion with a point mutation or deletion. Understanding of the underlying molecular biology has enabled identification of atypical phenotypes with late onset, or atypical features such as retained reflexes. Late-onset cases tend to have slower progression and are associated with smaller GAA expansions. Early-onset cases tend to have more rapid progression and a higher frequency of non-neurological features such as diabetes, cardiomyopathy, scoliosis and pes cavus. Compound heterozygotes, including those with large deletions, often have atypical features. In this paper, we review the classical and atypical clinical phenotypes of Friedreich's ataxia. © 2013 International Society for Neurochemistry.

  13. Exploring Atypical Verb+Noun Combinations in Learner Technical Writing

    Science.gov (United States)

    Luzon Marco, Maria Jose

    2011-01-01

    Professional and academic discourse is characterised by a specific phraseology, which usually poses problems for students. This paper investigates atypical verb+noun collocations in a corpus of English technical writing of Spanish students. I focus on the type of verbs that most frequently occurred in these awkward or questionable combinations and…

  14. Use of atypical antipsychotics in nursing homes and pharmaceutical marketing.

    Science.gov (United States)

    Pimentel, Camilla B; Donovan, Jennifer L; Field, Terry S; Gurwitz, Jerry H; Harrold, Leslie R; Kanaan, Abir O; Lemay, Celeste A; Mazor, Kathleen M; Tjia, Jennifer; Briesacher, Becky A

    2015-02-01

    To describe the current extent and type of pharmaceutical marketing in nursing homes (NHs) in one state and to provide preliminary evidence for the potential influence of pharmaceutical marketing on the use of atypical antipsychotics in NHs. Nested mixed-methods, cross-sectional study of NHs in a cluster randomized trial. Forty-one NHs in Connecticut. NH administrators, directors of nursing, and medical directors (n = 93, response rate 75.6%). Quantitative data, including prescription drug dispensing data (September 2009-August 2010) linked with Nursing Home Compare data (April 2011), were used to determine facility-level prevalence of atypical antipsychotic use, facility-level characteristics, NH staffing, and NH quality. Qualitative data, including semistructured interviews and surveys of NH leaders conducted in the first quarter of 2011, were used to determine encounters with pharmaceutical marketing. Leadership at 46.3% of NHs (n = 19) reported pharmaceutical marketing encounters, consisting of educational training, written and Internet-based materials, and sponsored training. No association was detected between level of atypical antipsychotic prescribing and reports of any pharmaceutical marketing by at least one NH leader. NH leaders frequently encounter pharmaceutical marketing through a variety of ways, although the impact on atypical antipsychotic prescribing is unclear. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

  15. Laparoscopic diagnostic findings in atypical intestinal malrotation in ...

    African Journals Online (AJOL)

    We present our experience with laparoscopic management of atypical presentations of intestinal malrotation in children, describing laparoscopic findings in these ... Thirty-six patients (90%) were found to have definite laparoscopic findings in the form of markedly dilated stomach and first part of duodenum, ectopic site of ...

  16. Characterization of atypical Aeromonas salmonicida by different methods

    DEFF Research Database (Denmark)

    Austin, B.; Austin, D.A.; Dalsgaard, Inger

    1998-01-01

    Fifty two isolates of atypical Aeromonas salmonicida, recovered from a wide range of hosts and geographical locations, were heterogeneous in terms of molecular and phenotypic characteristics, and represented taxa which could not be accommodated by the current classification of four subspecies...

  17. Early Freezing of Gait: Atypical versus Typical Parkinson Disorders

    Directory of Open Access Journals (Sweden)

    Abraham Lieberman

    2015-01-01

    Full Text Available In 18 months, 850 patients were referred to Muhammad Ali Parkinson Center (MAPC. Among them, 810 patients had typical Parkinson disease (PD and 212 had PD for ≤5 years. Among the 212 patients with early PD, 27 (12.7% had freezing of gait (FOG. Forty of the 850 had atypical parkinsonism. Among these 40 patients, all of whom had symptoms for ≤5 years, 12 (30.0% had FOG. FOG improved with levodopa in 21/27 patients with typical PD but did not improve in the 12 patients with atypical parkinsonism. FOG was associated with falls in both groups of patients. We believe that FOG unresponsive to levodopa in typical PD resembles FOG in atypical parkinsonism. We thus compared the 6 typical PD patients with FOG unresponsive to levodopa plus the 12 patients with atypical parkinsonism with the 21 patients with typical PD responsive to levodopa. We compared them by tests of locomotion and postural stability. Among the patients with FOG unresponsive to levodopa, postural stability was more impaired than locomotion. This finding leads us to believe that, in these patients, postural stability, not locomotion, is the principal problem underlying FOG.

  18. Peritoneal Dialysis-Related Peritonitis: Atypical and Resistant Organisms

    NARCIS (Netherlands)

    Cho, Yeoungjee; Struijk, Dirk Gijsbert

    2017-01-01

    Peritoneal dialysis (PD)-related peritonitis remains to be one of the most frequent and serious complications of PD. In this study, existing literature has been reviewed on PD peritonitis caused by atypical organisms and antibiotic resistant organisms and their impact on patient outcomes. Although

  19. Stereological estimation of nuclear volume in benign and atypical meningiomas

    DEFF Research Database (Denmark)

    Madsen, C; Schrøder, H D

    1993-01-01

    A stereological estimation of nuclear volume in benign and atypical meningiomas was made. The aim was to investigate whether this method could discriminate between these two meningeal neoplasms. The difference was significant and it was moreover seen that there was no overlap between the two groups...

  20. Educational Needs and Causes of False Diagnosis of Atypical ...

    African Journals Online (AJOL)

    Erah

    The entity of atypical squamous cells of undetermined significance (ASCUS) in The Bethesda System 2001 for reporting cervical cytology is characterized by equivocal diagnosis, poor reproducibility and debatable management. This retrospective study was done to analyse the causes of false ASCUS if any and identify the ...

  1. Renal cell carcinoma: an atypical case containing fat

    International Nuclear Information System (INIS)

    Saez Castan, J.; Perez Paya, F.; Ramon Sanchez, J.; Rausell Felix, M.; Alpera Tenza, M.; Orti Tarazona, C.

    1995-01-01

    An atypical form of presentation of renal cell carcinoma is reported. The lesion contained fat collections, an exceptional findings in these neoplasms. We describe the intravenous urography, ultrasound and CT images, as well as the preoperative follow-up using CT, performed 11 months after the first study. 11 refs

  2. Olfactory and imaging features in atypical Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Huihong Zhang

    2018-02-01

    Full Text Available Cognition and speech disorders are the most common symptoms of dementia in neurodegenerative disease. Here, we present a detailed clinical evaluation of a case of logopenic variant of primary progressive aphasia (lv-PPA, an atypical form of Alzheimer disease (AD, including cognitive testing over time, brain imaging, electrophysiology, and tests of olfactory function.

  3. Atypical retinal pigment epithelial defects with retained photoreceptor layers

    DEFF Research Database (Denmark)

    Giannakaki-Zimmermann, Helena; Querques, Giuseppe; Munch, Inger Christine

    2017-01-01

    BACKGROUND: To report patients with age-related macular degeneration and atypical central retinal pigment epithelium (RPE) defects not attributable to geographic atrophy (GA) or RPE-tears with overlying preserved photoreceptor layers. METHODS: Multimodal imaging case-series evaluating the course...

  4. Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130Cas.

    Science.gov (United States)

    Polte, T R; Hanks, S K

    1995-11-07

    The focal adhesion kinase (FAK) has been implicated in integrin-mediated signaling events and in the mechanism of cell transformation by the v-Src and v-Crk oncoproteins. To gain further insight into FAK signaling pathways, we used a two-hybrid screen to identify proteins that interact with mouse FAK. The screen identified two proteins that interact with FAK via their Src homology 3 (SH3) domains: a v-Crk-associated tyrosine kinase substrate (Cas), p130Cas, and a still uncharacterized protein, FIPSH3-2, which contains an SH3 domain closely related to that of p130Cas. These SH3 domains bind to the same proline-rich region of FAK (APPKPSR) encompassing residues 711-717. The mouse p130Cas amino acid sequence was deduced from cDNA clones, revealing an overall high degree of similarity to the recently reported rat sequence. Coimmunoprecipitation experiments confirmed that p130Cas and FAK are associated in mouse fibroblasts. The stable interaction between p130Cas and FAK emerges as a likely key element in integrin-mediated signal transduction and further represents a direct molecular link between the v-Src and v-Crk oncoproteins. The Src family kinase Fyn, whose Src homology 2 (SH2) domain binds to the major FAK autophosphorylation site (tyrosine 397), was also identified in the two-hybrid screen.

  5. Understanding A-type supergiants. I. Ultraviolet and visible spectral atlas of A-type supergiants

    CERN Document Server

    Verdugo, E; Gómez de Castro, A I

    1999-01-01

    This paper is the first of a series whose aim is to perform a systematic study of A-type supergiant atmospheres and winds. Here we present a spectral atlas of 41 A-supergiants observed by us in high and medium resolution in the visible and ultraviolet. The atlas consists of profiles of the H alpha , H beta , H gamma , H delta , H epsilon , Ca II (H and K), Na I (D1 and D2), Mg II/sub 4481/, Mg II uv1 and Fe II uv1, uv2, uv3, uv62, uv63, uv161 lines for 41 stars with spectral types ranging from B9 to A9 and luminosity classes Ia, Iab and Ib, and provides the basic data for a thoughtful study of these stars. The overall characteristics of the sample as well as the data reduction procedures are described. We also present some examples of spectral variability. Figures 1-3 are only available in electronic form at http://www.edpsciences.com. (27 refs).

  6. Glutamatergic neurotransmission modulation and the mechanisms of antipsychotic atypicality.

    Science.gov (United States)

    Heresco-Levy, Uriel

    2003-10-01

    The neurotransmission mediated by the excitatory amino acids (EAA) glutamate (GLU) and aspartate is of interest to the pharmacotherapy of psychosis due to its role in neurodevelopment and neurotoxicity, its complex interactions with dopaminergic and other neurotransmitter systems and its pivotal importance in recent models of schizophrenia. Accumulating evidence indicates that modulation of glutamatergic neurotransmission may play an important role in the mechanisms of action of atypical antipsychotic drugs. The principles of the phencyclidine (PCP) model of schizophrenia suggest that conventional neuroleptics cannot counteract all aspects of schizophrenia symptomatology, while a more favorable outcome, including anti-negative and cognitive symptoms effects, would be expected with the use of treatment modalities targeting glutamatergic neurotransmission. Clozapine and other presently used atypical antipsychotics differ from conventional neuroleptics in the way they affect various aspects of glutamatergic receptors function. In this context, a specific hypothesis suggesting an agonistic role of clozapine at the N-methyl-D-aspartate (NMDA) subtype of GLU receptors has been postulated. Furthermore, the results of the first generation of clinical trials with glycine (GLY) site agonists of the NMDA receptor in schizophrenia suggest that this type of compounds (1) have efficacy and side effects profiles different than those of conventional neuroleptics and (2) differ in their synergic effects when used in addition to conventional neuroleptics versus clozapine and possibly additional atypical antipsychotics. These findings (1) bring further support to the hypothesis that glutamatergic effects may play an important role in the mechanism of action of atypical antipsychotics, (2) help explain the unique clinical profile of clozapine, and (3) suggest that GLY site agonists of the NMDA receptor may represent a new class of atypical antipsychotic medication. Future research in

  7. Lipoma arborescens: Comparison of typical and atypical disease presentations

    International Nuclear Information System (INIS)

    Howe, B.M.; Wenger, D.E.

    2013-01-01

    Aim: To determine whether the aetiology differed between typical cases of lipoma arborescens with unilateral knee involvement and atypical cases involving joints other than the knee, polyarticular disease, and disease outside of the knee joint. Materials and methods: Cases of lipoma arborescens involving the knee joint were evaluated for the distribution of the disease and severity of degenerative arthritis. Joints other than the knee were evaluated for the presence and severity of degenerative arthritis, and the distribution was classified as either intra-articular, extra-articular, or both. Clinical history was reviewed for patient age at presentation, a history of inflammatory arthritis, diabetes mellitus, and known steroid use. Fisher's exact test was used to determine whether there was a statistically significant difference between typical and atypical presentations of the disease. Results: Lipoma arborescens was identified in 45 joints in 39 patients. Twenty-eight patients were classified as “typical” and 11 patients had “atypical” disease. There was no significant difference in age at presentation, presence of degenerative arthritis, or known inflammatory arthritis when comparing typical and atypical presentations of the disease. Conclusion: Twenty-eight percent of patients in the present study had atypical presentation of lipoma arborescens with multifocal lipoma arborescens or disease in joints other than the knee. There was no significant difference in age at presentation, presence of degenerative arthritis, or known inflammatory arthritis when comparing typical and atypical presentations of the disease. Of the 39 patients, only three had no evidence of degenerative arthritis, which suggests that many cases of lipoma arborescens are secondary to chronic reactive change in association with degenerative arthritis

  8. Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth.

    Science.gov (United States)

    Koo, Junghui; Yue, Ping; Gal, Anthony A; Khuri, Fadlo R; Sun, Shi-Yong

    2014-05-01

    mTOR kinase inhibitors that target both mTORC1 and mTORC2 are being evaluated in cancer clinical trials. Here, we report that glycogen synthase kinase-3 (GSK3) is a critical determinant for the therapeutic response to this class of experimental drugs. Pharmacologic inhibition of GSK3 antagonized their suppressive effects on the growth of cancer cells similarly to genetic attenuation of GSK3. Conversely, expression of a constitutively activated form of GSK3β sensitized cancer cells to mTOR inhibition. Consistent with these findings, higher basal levels of GSK3 activity in a panel of human lung cancer cell lines correlated with more efficacious responses. Mechanistic investigations showed that mTOR kinase inhibitors reduced cyclin D1 levels in a GSK3β-dependent manner, independent of their effects on suppressing mTORC1 signaling and cap binding. Notably, selective inhibition of mTORC2 triggered proteasome-mediated cyclin D1 degradation, suggesting that mTORC2 blockade is responsible for GSK3-dependent reduction of cyclin D1. Silencing expression of the ubiquitin E3 ligase FBX4 rescued this reduction, implicating FBX4 in mediating this effect of mTOR inhibition. Together, our findings define a novel mechanism by which mTORC2 promotes cell growth, with potential implications for understanding the clinical action of mTOR kinase inhibitors. ©2014 AACR.

  9. Basic residues in the 74-83 and 191-198 segments of protein kinase CK2 catalytic subunit are implicated in negative but not in positive regulation by the beta-subunit

    DEFF Research Database (Denmark)

    Sarno, S; Vaglio, P; Marin, O

    1997-01-01

    by the beta-subunit many fold more than that of alpha wild type, while extrastimulation by beta mutant D55L56E57A, observable with alpha wild type, is abolished with these mutants. These data support the conclusion that down regulation by the acidic residues clustered in the N-terminal moiety of beta...... is mediated by basic residues in the 74-83 and in the 191-198 sequences of the alpha-subunit. These are also implicated in substrate recognition consistent with the concept that the N-terminal acidic region of the beta subunit operates as a pseudosubstrate. In contrast, another CK2alpha mutant, V66A, is more...

  10. Akt1/protein kinase Bα is critical for ischemic and VEGF-mediated angiogenesis

    OpenAIRE

    Ackah, Eric; Yu, Jun; Zoellner, Stefan; Iwakiri, Yasuko; Skurk, Carsten; Shibata, Rei; Ouchi, Noriyuki; Easton, Rachael M.; Galasso, Gennaro; Birnbaum, Morris J.; Walsh, Kenneth; Sessa, William C.

    2005-01-01

    Akt, or protein kinase B, is a multifunctional serine-threonine protein kinase implicated in a diverse range of cellular functions including cell metabolism, survival, migration, and gene expression. However, the in vivo roles and effectors of individual Akt isoforms in signaling are not explicitly clear. Here we show that the genetic loss of Akt1, but not Akt2, in mice results in defective ischemia and VEGF-induced angiogenesis as well as severe peripheral vascular disease. Akt1 knockout (Ak...

  11. The Rho kinases I and II regulate different aspects of myosin II activity

    DEFF Research Database (Denmark)

    Yoneda, Atsuko; Multhaupt, Hinke A B; Couchman, John R

    2005-01-01

    The homologous mammalian rho kinases (ROCK I and II) are assumed to be functionally redundant, based largely on kinase construct overexpression. As downstream effectors of Rho GTPases, their major substrates are myosin light chain and myosin phosphatase. Both kinases are implicated in microfilament...... bundle assembly and smooth muscle contractility. Here, analysis of fibroblast adhesion to fibronectin revealed that although ROCK II was more abundant, its activity was always lower than ROCK I. Specific reduction of ROCK I by siRNA resulted in loss of stress fibers and focal adhesions, despite...

  12. Role of the mixed-lineage protein kinase pathway in the metabolic stress response to obesity

    OpenAIRE

    Kant, Shashi; Barrett, Tamera; Vertii, Anastassiia; Noh, Yun Hee; Jung, Dae Young; Kim, Jason K.; Davis, Roger J.

    2013-01-01

    Saturated free fatty acid (FFA) is implicated in the metabolic response to obesity. In vitro studies indicate that FFA signaling may be mediated by the mixed-lineage protein kinase (MLK) pathway that activates cJun NH2-terminal kinase (JNK). Here, we examined the role of the MLK pathway in vivo using a mouse model of diet-induced obesity. The ubiquitously expressed MLK2 and MLK3 protein kinases have partially redundant functions. We therefore compared wild-type and compound mutant mice that l...

  13. Atypical epithelial hyperplasia of the breast: state of the art.

    Science.gov (United States)

    Dion, Ludivine; Racin, Adelaïde; Brousse, Susie; Beltjens, Françoise; Cauchois, Aurélie; Levêque, Jean; Coutant, Charles; Lavoué, Vincent

    2016-09-01

    Atypical epithelial hyperplasia (AEH) of the breast is considered benign histological lesions with breast cancer risk. This review focuses on clinical signification and management of AEH that remains controversial. A review of published studies was performed using medline database. In this review, we fully describe the current evidence available. In particular, we describe 1) data from immunohistochemistry and molecular studies that suggest AEH is a precursor of breast cancer; 2) epidemiological studies demonstrate low rate of breast cancer in women with AEH; 3) surgical excision is necessary after diagnosis of AEH, such as lobular carcinoma in situ or atypical ductal hyperplasia, on core needle biopsy; 4) although current recommendations are evolving to fewer (if not no) excisions for flat epithelial with atypia and classic lobular neoplasia found on percutaneous biopsy (without radiologic indications for excision). Expert commentary: HEA management steel need prospective evidences, but recent retrospective data give some clue for less invasive management for some of HEA.

  14. Acute Zonal Occult Outer Retinopathy with Atypical Findings

    Directory of Open Access Journals (Sweden)

    Dimitrios Karagiannis

    2014-01-01

    Full Text Available Background. To report a case of acute zonal occult outer retinopathy (AZOOR with atypical electrophysiology findings. Case Presentation. A 23-year-old-female presented with visual acuity deterioration in her right eye accompanied by photopsia bilaterally. Corrected distance visual acuity at presentation was 20/50 in the right eye and 20/20 in the left eye. Fundus examination was unremarkable. Visual field (VF testing revealed a large scotoma. Pattern and full-field electroretinograms (PERG and ERG revealed macular involvement associated with generalized retinal dysfunction. Electrooculogram (EOG light rise and the Arden ratio were within normal limits bilaterally. The patient was diagnosed with AZOOR due to clinical findings, visual field defect, and ERG findings. Conclusion. This is a case of AZOOR with characteristic VF defects and clinical symptoms presenting with atypical EOG findings.

  15. Behavioural relevance of atypical language lateralization in healthy subjects.

    Science.gov (United States)

    Knecht, S; Dräger, B; Flöel, A; Lohmann, H; Breitenstein, C; Deppe, M; Henningsen, H; Ringelstein, E B

    2001-08-01

    In most humans, language is lateralized to the left side of the brain. It has been speculated that this hemispheric specialization is a prerequisite for the full realization of linguistic potential. Using standardized questionnaires and performance measures, we attempted to determine if there are behavioural correlates of atypical, i.e. right-hemispheric and bilateral, language lateralization. The side and degree of language lateralization were determined by measuring the hemispheric perfusion differences by functional transcranial Doppler ultrasonography during a word generation task in healthy volunteers. Subjects with left (n = 264), bilateral (n = 31) or right (n = 31) hemisphere language representation did not differ significantly with respect to mastery of foreign languages, academic achievement, artistic talents, verbal fluency or (as assessed in a representative subgroup) in intelligence or speed of linguistic processing. These findings suggest that atypical hemispheric specialization for language, i.e. right-hemisphere or bilateral specialization, is not associated with major impairments of linguistic faculties in otherwise healthy subjects.

  16. Atypical form of cat scratch disease in immunocompetent patient

    Directory of Open Access Journals (Sweden)

    Kojić Miroslav

    2013-01-01

    Full Text Available Introduction. Cat scratch disease (CSD is an acute infectious disease with benign course caused by the bacteria Bartonella henselae. Clinically, it is usually manifested as regional lymphadenopathy and mild infective syndrome. Rare forms of the disease which usually occur in immunocompromised presons are: encephalitis, transverse myelitis, neuroretinitis, granulomatosus conjunctivitis, arthritis, hepatitis etc. Case report. We presented an atypical form of cat scratch disease in a young immunocompetent female person. The disease was manifested with prolonged fever, rash, purulent lymphadenitis and hepatitis. The diagnosis was based on characteristic patohystological finding and exclusion of the other causes of lymphadenopathy. The patient was treated by antibiotics for a few weeks, with surgical incision and drainage of the purulent lymphadenitis. Conclusion. Atypical forms of CSD could be an important differential-diagnostic problem, especially if there is no opportunity for serological confirmation of the disease.

  17. Atypical Kawasaki Disease Presenting as Intestinal Pseudo-obstruction

    Directory of Open Access Journals (Sweden)

    Mao-Meng Tiao

    2006-01-01

    Full Text Available Intestinal pseudo-obstruction in atypical Kawasaki disease (KD is rare. A boy aged 2 years and 6 months presented with a 7-day history of fever, coffee-ground vomit, and abdominal pain. Abdominal radiography and ultrasound showed a dilated duodenum. Peeling of the skin on his fingers and toes developed on hospitalization day 9. Echocardiogram revealed right and left coronary artery dilatation compatible with KD. He was treated with 2 g/kg intravenous immunoglobulin (IVIG, with rapid resolution of fever and relief of abdominal pain. Follow-up abdominal radiography and ultrasound showed improvement of bowel dilatation. This case illustrates that atypical KD can present with intestinal pseudo-obstruction. A high index of suspicion is required for early diagnosis, and prompt treatment with IVIG is recommended.

  18. Atypical cross talk between mentalizing and mirror neuron networks in autism spectrum disorder.

    Science.gov (United States)

    Fishman, Inna; Keown, Christopher L; Lincoln, Alan J; Pineda, Jaime A; Müller, Ralph-Axel

    2014-07-01

    immature or aberrant developmental processes in 2 brain networks involved in understanding of others, a domain of impairment in ASD. Further, robust links with sociocommunicative symptoms of ASD implicate atypically increased ToM-MNS connectivity in social deficits observed in ASD.

  19. Liquid scintillation: Sample preparation and counting atypical emissions

    International Nuclear Information System (INIS)

    Anon.

    1991-01-01

    Liquid scintillation sample preparation has the most published information but the least amount of definitive technical direction because the chemical and physical nature of the samples from biological investigations varies widely. This chapter discusses the following related topics: Aqueous Samples; Tissue Solubilizers; Absorption of 14 CO 2 ; Sample Combustion Methods; Heterogeneous Systems; Sample Preparation Problems (colored samples, chemiluminescence, photoluminescence, static electricity); Counting Various Types of Emitters; Counting Atypical Emissions. 2 refs., 2 figs

  20. Endoscopic management of pancreatic pseudocysts at atypical locations.

    Science.gov (United States)

    Bhasin, Deepak Kumar; Rana, Surinder Singh; Nanda, Mohit; Chandail, Vijant Singh; Masoodi, Ibrahim; Kang, Mandeep; Kalra, Navin; Sinha, Saroj Kant; Nagi, Birinder; Singh, Kartar

    2010-05-01

    There is paucity of data on endoscopic management of pseudocysts at atypical locations. We evaluated the efficacy of endoscopic transpapillary nasopancreatic drain (NPD) placement in the management of pseudocysts of pancreas at atypical locations. Eleven patients with pseudocysts at atypical locations were treated with attempted endoscopic transpapillary nasopancreatic drainage. On endoscopic retrograde pancreatography (ERP), a 5-F NPD was placed across/near the site of duct disruption. Three patients each had mediastinal, intrahepatic, and intra/perisplenic pseudocysts and one patient each had renal and pelvic pseudocyst. Nine patients had chronic pancreatitis whereas two patients had acute pancreatitis. The size of the pseudocysts ranged from 2 to 15 cm. On ERP, the site of ductal disruption was in the body of pancreas in five patients (45.4%), and tail of pancreas in six patients (54.6%). All the patients had partial disruption of pancreatic duct. The NPD was successfully placed across the disruption in 10 of the 11 patients (90.9%) and pseudocysts resolved in 4-8 weeks. One of the patients developed fever, 5 days after the procedure, which was successfully treated by intravenous antibiotics. In another patient, NPD became blocked 12 days after the procedure and was successfully opened by aspiration. The NPD slipped out in one of the patient with splenic pseudocyst and was replaced with a stent. There was no recurrence of symptoms or pseudocysts during follow-up of 3-70 months. Pancreatic pseudocysts at atypical locations with ductal communication and partial ductal disruption that is bridged by NPD can also be effectively treated with endoscopic transpapillary NPD placement.

  1. Idiopathic Atypical Haemolytic Uraemic Syndrome presenting with acute dystonia

    LENUS (Irish Health Repository)

    Maduemem, Rizwan K E

    2017-09-01

    Hemolytic Uremic Syndrome (HUS), a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. The atypical HUS (aHUS) results from over activation of complement system with formation of micro thrombi and damage to endothelial cells resulting in renal impairment in 50 % and death in 25 %, commonly in untreated patients. We report an intriguing case of aHUS presenting with acute onset of movement disorder and fluctuating delirium.

  2. Atypical Eating Attitudes and Behaviors in Thai Medical Students

    OpenAIRE

    Jarurin Pitanupong; Chonnakarn Jatchavala

    2017-01-01

    Objective: To determine the prevalence, and associated factors of atypical eating attitudes and behaviors in Thai medical students. Methods: A cross-sectional survey examined the eating abnormalities in Thai medical students, conducted in 2014. Research assistants collected data by using; self-reported questionnaires using The Eating Attitudes Test-26 (EAT-26 Thai Version). The statistical analysis used R-program for qualitative variables and logistic regression was applied to ...

  3. Atypical Eating Attitudes and Behaviors in Thai Medical Students

    Directory of Open Access Journals (Sweden)

    Jarurin Pitanupong

    2017-01-01

    Full Text Available Objective: To determine the prevalence, and associated factors of atypical eating attitudes and behaviors in Thai medical students. Methods: A cross-sectional survey examined the eating abnormalities in Thai medical students, conducted in 2014. Research assistants collected data by using; self-reported questionnaires using The Eating Attitudes Test-26 (EAT-26 Thai Version. The statistical analysis used R-program for qualitative variables and logistic regression was applied to determine the correlation and P-value. Results: 141 Thai, medical students (15.9% were reported to have atypical attitudes towards eating, and displayed abnormal eating behaviors. There was no statistically significant correlation of attitude towards eating, and their current eating behaviors according to the medical students’ gender, year of studying and Grade Point Average. However, their eating attitudes and behaviors were, associated with Body Mass index. Normal weight (BMI 18.5- 23.49 and overweight (BMI 23.5-39.9 groups could increase by 2.2 (95% CI =1.2, 4.3 and 2.3 (95% CI=1.1, 4.8 times risk depending on atypical eating attitudes and abnormal eating behaviors respectively, when compared with the underweight group (BMI<18.5. Conclusion: There was no correlated difference in concerns to the Thai medical student’s abnormal eating habits, with gender, years of their study and Grade Point Average. Only normal to over-weight BMI were associated. Overweight male, medical students significantly represented more atypical attitudes towards eating and behaviors than other groups in this population. These results may reveal the changing trends of eating attitudes and behaviors due to the current ideal body image of being more muscular. However, prospective studies are still needed.

  4. Retail Bank Interest Rate Pass-Through; Is Chile Atypical?

    OpenAIRE

    Alessandro Rebucci; Marco A Espinosa-Vega

    2003-01-01

    This paper investigates empirically the pass-through of money market interest rates to retail banking interest rates in Chile, the United States, Canada, Australia, New Zealand, and five European countries. Overall, Chile's pass-through does not appear atypical. Based on a standard error-correction model, we find that, as in most countries considered, Chile's measured pass-through is incomplete. But Chile's pass-through is also faster than in many other countries considered and is comparable ...

  5. Atypical arteriole anastomoses for fingertip replantations under digital block.

    Science.gov (United States)

    Koshima, Isao

    2008-01-01

    Reconstructive microsurgery is now in a new stage of supermicrosurgery. With this technique, very tiny (0.3mm) vascular anastomoses are possible. In this paper, we describe two cases of successful fingertip replantations employing arteriole (terminal branch of digital artery) anastomoses, the arteriole graft being obtained from the same fingertip defect, reverse arteriole flow to subdermal venule, and delayed venular drainage for venous congestion. These atypical tiny vascular anastomoses were successfully carried out under digital block.

  6. Long-term Deformation Measurements of Atypical Roof Timber Structures

    Directory of Open Access Journals (Sweden)

    Jiří Bureš

    2014-06-01

    Full Text Available The paper includes conclusions from evaluation of results obtained from long-termmeasuring of innovative atypical roof timber structures. Based on the results ofmeasurements of vertical and horizontal deformation components it is possible to analyzethe real behavior of structures in given conditions. By assessing deformations in variousstages, including particularly external and internal environment temperatures, relative airhumidity and moisture content of wood, decisive parameters for real structure behaviorcan be established. The data are processed from period 2001 – 2013.

  7. Costovertebral joint dysfunction: another misdiagnosed cause of atypical chest pain.

    Science.gov (United States)

    Arroyo, J. F.; Jolliet, P.; Junod, A. F.

    1992-01-01

    The diagnostic work-up of atypical chest pain frequently leads to invasive procedures. However, this painful symptomatology can sometimes be of benign origin and respond to simple therapeutic manoeuvres. A number of musculoskeletal conditions such as costovertebral joint dysfunctions should be carefully considered. We report five cases in which patient discomfort and high costs could have been avoided if awareness of these conditions had led to a correct diagnosis upon initial physical examination. PMID:1448407

  8. Atypical spatiotemporal signatures of working memory brain processes in autism.

    Science.gov (United States)

    Urbain, C M; Pang, E W; Taylor, M J

    2015-08-11

    Working memory (WM) impairments may contribute to the profound behavioural manifestations in children with autism spectrum disorder (ASD). However, previous behavioural results are discrepant as are the few functional magnetic resonance imaging (fMRI) results collected in adults and adolescents with ASD. Here we investigate the precise temporal dynamics of WM-related brain activity using magnetoencephalography (MEG) in 20 children with ASD and matched controls during an n-back WM task across different load levels (1-back vs 2-back). Although behavioural results were similar between ASD and typically developing (TD) children, the between-group comparison performed on functional brain activity showed atypical WM-related brain processes in children with ASD compared with TD children. These atypical responses were observed in the ASD group from 200 to 600 ms post stimulus in both the low- (1-back) and high- (2-back) memory load conditions. During the 1-back condition, children with ASD showed reduced WM-related activations in the right hippocampus and the cingulate gyrus compared with TD children who showed more activation in the left dorso-lateral prefrontal cortex and the insulae. In the 2-back condition, children with ASD showed less activity in the left insula and midcingulate gyrus and more activity in the left precuneus than TD children. In addition, reduced activity in the anterior cingulate cortex was correlated with symptom severity in children with ASD. Thus, this MEG study identified the precise timing and sources of atypical WM-related activity in frontal, temporal and parietal regions in children with ASD. The potential impacts of such atypicalities on social deficits of autism are discussed.

  9. Understanding the Uncanny: Both Atypical Features and Category Ambiguity Provoke Aversion toward Humanlike Robots

    Directory of Open Access Journals (Sweden)

    Megan K. Strait

    2017-08-01

    Full Text Available Robots intended for social contexts are often designed with explicit humanlike attributes in order to facilitate their reception by (and communication with people. However, observation of an “uncanny valley”—a phenomenon in which highly humanlike entities provoke aversion in human observers—has lead some to caution against this practice. Both of these contrasting perspectives on the anthropomorphic design of social robots find some support in empirical investigations to date. Yet, owing to outstanding empirical limitations and theoretical disputes, the uncanny valley and its implications for human-robot interaction remains poorly understood. We thus explored the relationship between human similarity and people's aversion toward humanlike robots via manipulation of the agents' appearances. To that end, we employed a picture-viewing task (Nagents = 60 to conduct an experimental test (Nparticipants = 72 of the uncanny valley's existence and the visual features that cause certain humanlike robots to be unnerving. Across the levels of human similarity, we further manipulated agent appearance on two dimensions, typicality (prototypic, atypical, and ambiguous and agent identity (robot, person, and measured participants' aversion using both subjective and behavioral indices. Our findings were as follows: (1 Further substantiating its existence, the data show a clear and consistent uncanny valley in the current design space of humanoid robots. (2 Both category ambiguity, and more so, atypicalities provoke aversive responding, thus shedding light on the visual factors that drive people's discomfort. (3 Use of the Negative Attitudes toward Robots Scale did not reveal any significant relationships between people's pre-existing attitudes toward humanlike robots and their aversive responding—suggesting positive exposure and/or additional experience with robots is unlikely to affect the occurrence of an uncanny valley effect in humanoid robotics

  10. Understanding the Uncanny: Both Atypical Features and Category Ambiguity Provoke Aversion toward Humanlike Robots.

    Science.gov (United States)

    Strait, Megan K; Floerke, Victoria A; Ju, Wendy; Maddox, Keith; Remedios, Jessica D; Jung, Malte F; Urry, Heather L

    2017-01-01

    Robots intended for social contexts are often designed with explicit humanlike attributes in order to facilitate their reception by (and communication with) people. However, observation of an "uncanny valley"-a phenomenon in which highly humanlike entities provoke aversion in human observers-has lead some to caution against this practice. Both of these contrasting perspectives on the anthropomorphic design of social robots find some support in empirical investigations to date. Yet, owing to outstanding empirical limitations and theoretical disputes, the uncanny valley and its implications for human-robot interaction remains poorly understood. We thus explored the relationship between human similarity and people's aversion toward humanlike robots via manipulation of the agents' appearances. To that end, we employed a picture-viewing task ( N agents = 60) to conduct an experimental test ( N participants = 72) of the uncanny valley's existence and the visual features that cause certain humanlike robots to be unnerving. Across the levels of human similarity, we further manipulated agent appearance on two dimensions, typicality (prototypic, atypical, and ambiguous) and agent identity (robot, person), and measured participants' aversion using both subjective and behavioral indices. Our findings were as follows: (1) Further substantiating its existence, the data show a clear and consistent uncanny valley in the current design space of humanoid robots. (2) Both category ambiguity, and more so, atypicalities provoke aversive responding, thus shedding light on the visual factors that drive people's discomfort. (3) Use of the Negative Attitudes toward Robots Scale did not reveal any significant relationships between people's pre-existing attitudes toward humanlike robots and their aversive responding-suggesting positive exposure and/or additional experience with robots is unlikely to affect the occurrence of an uncanny valley effect in humanoid robotics. This work furthers

  11. Increasing use of atypical antipsychotics and anticonvulsants during pregnancy.

    Science.gov (United States)

    Epstein, Richard A; Bobo, William V; Shelton, Richard C; Arbogast, Patrick G; Morrow, James A; Wang, Wei; Chandrasekhar, Rameela; Cooper, William O

    2013-07-01

    To quantify maternal use of atypical antipsychotics, typical antipsychotics, anticonvulsants, and lithium during pregnancy. Tennessee birth and death records were linked to Tennessee Medicaid data to conduct a retrospective cohort study of 296,817 women enrolled in Tennessee Medicaid throughout pregnancy who had a live birth or fetal death from 1985 to 2005. During the study time period, the adjusted rate of use of any study medication during pregnancy increased from nearly 14 to 31 per 1000 pregnancies (β = 0.08, 95% CI = 0.07, 0.09). Significant increases were reported in use of anticonvulsants alone among mothers with pain and other psychiatric disorders, atypical antipsychotics alone among mothers with bipolar disorders, schizophrenia, unipolar depressive disorders, and other psychiatric disorders, and more than one studied medication for mothers with epilepsy, pain disorders, bipolar disorders, unipolar depressive disorders, and other psychiatric disorders. Significant decreases were reported in use of lithium alone and typical antipsychotics alone for all clinically meaningful diagnosis groups. There was a substantial increase in use of atypical antipsychotics alone, anticonvulsants alone, and medications from multiple studied categories among Tennessee Medicaid-insured pregnant women during the study period. Further examination of the maternal and fetal consequences of exposure to these medications during pregnancy is warranted. Copyright © 2012 John Wiley & Sons, Ltd.

  12. Increasing use of atypical antipsychotics and anticonvulsants during pregnancy

    Science.gov (United States)

    Epstein, Richard A.; Bobo, William V.; Shelton, Richard C.; Arbogast, Patrick G.; Morrow, James A.; Wang, Wei; Chandrasekhar, Rameela; Cooper, William O.

    2013-01-01

    Purpose To quantify maternal use of atypical antipsychotics, typical antipsychotics, anticonvulsants and lithium during pregnancy. Methods Tennessee birth and death records were linked to Tennessee Medicaid data to conduct a retrospective cohort study of 296,817 women enrolled in Tennessee Medicaid throughout pregnancy who had a live birth or fetal death from 1985 to 2005. Results During the study time period, the adjusted rate of use of any study medication during pregnancy increased from nearly 14 to 31 per 1,000 pregnancies (β = 0.08, 95% CI = 0.07, 0.09). Significant increases were reported in use of anticonvulsants alone among mothers with pain and other psychiatric disorders, atypical antipsychotics alone among mothers with bipolar disorders, schizophrenia, unipolar depressive disorders, and other psychiatric disorders, and more than one studied medication for mothers with epilepsy, pain disorders, bipolar disorders, unipolar depressive disorders, and other psychiatric disorders. Significant decreases were reported in use of lithium alone and typical antipsychotics alone for all clinically meaningful diagnosis groups. Conclusions There was a substantial increase in use of atypical antipsychotics alone, anticonvulsants alone, and medications from multiple studied categories among Tennessee Medicaid-insured pregnant women during the study period. Further examination of the maternal and fetal consequences of exposure to these medications during pregnancy is warranted. PMID:23124892

  13. Atypical resource allocation may contribute to many aspects of autism

    Directory of Open Access Journals (Sweden)

    Emily J. Goldknopf

    2013-12-01

    Full Text Available Based on a review of the literature and on reports by people with autism, this paper suggests that atypical resource allocation is a factor that contributes to many aspects of autism spectrum conditions, including difficulties with language and social cognition, atypical sensory and attentional experiences, executive and motor challenges, and perceptual and conceptual strengths and weaknesses. Drawing upon resource theoretical approaches that suggest that perception, cognition, and action draw upon multiple pools of resources, the approach states that compared with resources in typical cognition, resources in autism are narrowed or reduced, especially in people with strong sensory symptoms. In narrowed attention, resources are restricted to smaller areas and to fewer modalities, stages of processing, and cognitive processes than in typical cognition; resources may be more intense than in typical cognition. In reduced attentional capacity, overall resources are reduced; resources may be restricted to fewer modalities, stages of processing, and cognitive processes than in typical cognition, or the amount of resources allocated to each area or process may be reduced. Possible neural bases of the hypothesized atypical resource allocation, relations to other approaches, limitations, and tests of the hypotheses are discussed.

  14. Atypical Rocky Mountain spotted fever with polyarticular arthritis.

    Science.gov (United States)

    Chaudhry, Muhammad A; Scofield, Robert Hal

    2013-11-01

    Rocky Mountain spotted fever (RMSF) is an acute, serious tick borne illness caused by Rickettsia rickettsi. Frequently, RMSF is manifested by headache, a typical rash and fever but atypical disease is common, making diagnosis difficult. Inflammatory arthritis as a manifestation is rare. The purpose of this study is to describe a patient with serologically proven RMSF who presented in an atypical manner with inflammatory arthritis of the small joints of the hands and to review the previously reported patients with rickettsial infection and inflammatory arthritis. An 18-year-old woman presented with a rash that began on the distal extremities and spread centrally, along with hand pain and swelling. She had tenderness and swelling of the metacarpophlangeal joints on examination in addition to an erythematosus macular rash and occasional fever. Acute and convalescent serology demonstrated R rickettsi infection. She was successfully treated with doxycycline. Inflammatory arthritis is a rare manifestation of RMSF or other rickettsial infection with 8 previously reported patients, only 1 of whom had RMSF. Physician must have a high index of suspicion for RMSF because of atypical presentations.

  15. CT and MRI diagnosis of posterior fossa atypical ependymoma

    International Nuclear Information System (INIS)

    Yu Bolang; Zhang Ming; Luo Lin; Wang Shijie; Zhu Liping

    2000-01-01

    Objective: To analyse the CT and MRI features of posterior fossa atypical ependymoma. Methods: Sixteen cases of posterior fossa atypical ependymoma proved by surgery and pathology had CT and (or) MRI scanning. There were 11 males and 5 females. The age ranged from 17 to 46 (mean, 31.2). Twelve cases ranged from 20 to 40 years old. the main symptoms of all cases were dizziness, unsteady walking and vomiting. Results: The locations of all cases were cerebellum (12 cases), vermis (3 cases) and cerebellopontile angle (1 cases). Fifteen cases were solid with multiple cystic changes and 1 case in the cerebellopontile angle was cystic. The tumor was usually close to the surface of cerebellum with rather extensive connection with dura mater or tentorium. Calcifications were shown in 3 cases. The tumors revealed inhomogeneous density on CT scan and inhomogeneous intensity on MRI. Mild inhomogeneous enhancement was shown in most cases, while intense irregular enhancement in the others. Conclusions: The characteristic findings of the posterior fossa atypical ependymoma ependymoma were cerebellar intraparenchymatous multiple small cystic changes within solid tumor in most cases and inhomogeneous density and intensity on CT and MRI. The differential diagnosis is meningioma, metastasis and acoustic schwannoma

  16. Extracutaneous atypical syphilis in HIV-infected patients.

    Science.gov (United States)

    Prieto, Paula; Imaz, Arkaitz; Calatayud, Laura; García, Olga; Saumoy, María; Podzamczer, Daniel

    2017-12-07

    We describe a series of cases of syphilis with atypical extracutaneous clinical presentation diagnosed in HIV-infected patients. Retrospective observational study. All cases of syphilis diagnosed in HIV-infected patients during the period between June 2013 and June 2016 in a tertiary hospital of the Barcelona metropolitan area were analysed. A total of 71 cases of syphilis were diagnosed, 32 of them presenting with clinical signs or symptoms. Seven of these cases (9.8% of the total and 21.8% of the symptomatic cases) had atypical presentations with extracutaneous involvement: ocular (4), gastric (1), multiple hepatic abscesses (1) and generalised adenopathies (1). Patients were treated with intramuscular or intravenous penicillin and the clinical and serological evolution was good in all of them. Extracutaneous atypical clinical presentations were observed in 21.8% of symptomatic cases of syphilis in HIV+ patients with ocular involvement being the most freqent. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  17. Evidence for Broadening Criteria for Atypical Depression Which May Define a Reactive Depressive Disorder

    Directory of Open Access Journals (Sweden)

    Brett Silverstein

    2015-01-01

    Full Text Available Objective. Arguing that additional symptoms should be added to the criteria for atypical depression. Method. Published research articles on atypical depression are reviewed. Results. (1 The original studies upon which the criteria for atypical depression were based cited fatigue, insomnia, pain, and loss of weight as characteristic symptoms. (2 Several studies of DSM depressive criteria found patients with atypical depression to exhibit high levels of insomnia, fatigue, and loss of appetite/weight. (3 Several studies have found atypical depression to be comorbid with headaches, bulimia, and body image issues. (4 Most probands who report atypical depression meet criteria for “somatic depression,” defined as depression associated with several of disordered eating, poor body image, headaches, fatigue, and insomnia. The gender difference in prevalence of atypical depression results from its overlap with somatic depression. Somatic depression is associated with psychosocial measures related to gender, linking it with the descriptions of atypical depression as “reactive” appearing in the studies upon which the original criteria for atypical depression were based. Conclusion. Insomnia, disordered eating, poor body image, and aches/pains should be added as criteria for atypical depression matching criteria for somatic depression defining a reactive depressive disorder possibly distinct from endogenous melancholic depression.

  18. Evidence for Broadening Criteria for Atypical Depression Which May Define a Reactive Depressive Disorder.

    Science.gov (United States)

    Silverstein, Brett; Angst, Jules

    2015-01-01

    Objective. Arguing that additional symptoms should be added to the criteria for atypical depression. Method. Published research articles on atypical depression are reviewed. Results. (1) The original studies upon which the criteria for atypical depression were based cited fatigue, insomnia, pain, and loss of weight as characteristic symptoms. (2) Several studies of DSM depressive criteria found patients with atypical depression to exhibit high levels of insomnia, fatigue, and loss of appetite/weight. (3) Several studies have found atypical depression to be comorbid with headaches, bulimia, and body image issues. (4) Most probands who report atypical depression meet criteria for "somatic depression," defined as depression associated with several of disordered eating, poor body image, headaches, fatigue, and insomnia. The gender difference in prevalence of atypical depression results from its overlap with somatic depression. Somatic depression is associated with psychosocial measures related to gender, linking it with the descriptions of atypical depression as "reactive" appearing in the studies upon which the original criteria for atypical depression were based. Conclusion. Insomnia, disordered eating, poor body image, and aches/pains should be added as criteria for atypical depression matching criteria for somatic depression defining a reactive depressive disorder possibly distinct from endogenous melancholic depression.

  19. Inhibiting Src family tyrosine kinase activity blocks glutamate signalling to ERK1/2 and Akt/PKB but not JNK in cultured striatal neurones.

    Science.gov (United States)

    Crossthwaite, Andrew J; Valli, Haseeb; Williams, Robert J

    2004-03-01

    Glutamate receptor activation of mitogen-activated protein (MAP) kinase signalling cascades has been implicated in diverse neuronal functions such as synaptic plasticity, development and excitotoxicity. We have previously shown that Ca2+-influx through NMDA receptors in cultured striatal neurones mediates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt/protein kinase B (PKB) through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. Exposing neurones to the Src family tyrosine kinase inhibitor PP2, but not the inactive analogue PP3, inhibited NMDA receptor-induced phosphorylation of ERK1/2 and Akt/PKB in a concentration-dependent manner, and reduced cAMP response element-binding protein (CREB) phosphorylation. To establish a link between Src family tyrosine kinase-mediated phosphorylation and PI 3-kinase signalling, affinity precipitation experiments were performed with the SH2 domains of the PI 3-kinase regulatory subunit p85. This revealed a Src-dependent phosphorylation of a focal adhesion kinase (FAK)-p85 complex on glutamate stimulation. Demonstrating that PI3-kinase is not ubiquitously involved in NMDA receptor signal transduction, the PI 3-kinase inhibitors wortmannin and LY294002 did not prevent NMDA receptor Ca2+-dependent phosphorylation of c-Jun N-terminal kinase 1/2 (JNK1/2). Further, inhibiting Src family kinases increased NMDA receptor-dependent JNK1/2 phosphorylation, suggesting that Src family kinase-dependent cascades may physiologically limit signalling to JNK. These results demonstrate that Src family tyrosine kinases and PI3-kinase are pivotal regulators of NMDA receptor signalling to ERK/Akt and JNK in striatal neurones.

  20. Chitin and stress induced protein kinase activation

    DEFF Research Database (Denmark)

    Kenchappa, Chandra Shekar; Azevedo da Silva, Raquel; Bressendorff, Simon

    2017-01-01

    The assays described here are pertinent to protein kinase studies in any plant. They include an immunoblot phosphorylation/activation assay and an in-gel activity assay for MAP kinases (MPKs) using the general protein kinase substrate myelin basic protein. They also include a novel in-gel peptide...... substrate assay for Snf1-related kinase family 2 members (SnRK2s). This kinase family-specific assay overcomes some limitations of in-gel assays and permits the identification of different types of kinase activities in total protein extracts....

  1. Higher protein kinase C ζ in fatty rat liver and its effect on insulin actions in primary hepatocytes.

    Directory of Open Access Journals (Sweden)

    Wei Chen

    Full Text Available We previously showed the impairment of insulin-regulated gene expression in the primary hepatocytes from Zucker fatty (ZF rats, and its association with alterations of hepatic glucose and lipid metabolism. However, the molecular mechanism is unknown. A preliminary experiment shows that the expression level of protein kinase C ζ (PKCζ, a member of atypical PKC family, is higher in the liver and hepatocytes of ZF rats than that of Zucker lean (ZL rats. Herein, we intend to investigate the roles of atypical protein kinase C in the regulation of hepatic gene expression. The insulin-regulated hepatic gene expression was evaluated in ZL primary hepatocytes treated with atypical PKC recombinant adenoviruses. Recombinant adenovirus-mediated overexpression of PKCζ, or the other atypical PKC member PKCι/λ, alters the basal and impairs the insulin-regulated expressions of glucokinase, sterol regulatory element-binding protein 1c, the cytosolic form of phosphoenolpyruvate carboxykinase, the catalytic subunit of glucose 6-phosphatase, and insulin like growth factor-binding protein 1 in ZL primary hepatocytes. PKCζ or PKCι/λ overexpression also reduces the protein level of insulin receptor substrate 1, and the insulin-induced phosphorylation of AKT at Ser473 and Thr308. Additionally, PKCι/λ overexpression impairs the insulin-induced Prckz expression, indicating the crosstalk between PKCζ and PKCι/λ. We conclude that the PKCζ expression is elevated in hepatocytes of insulin resistant ZF rats. Overexpressions of aPKCs in primary hepatocytes impair insulin signal transduction, and in turn, the down-stream insulin-regulated gene expression. These data suggest that elevation of aPKC expression may contribute to the hepatic insulin resistance at gene expression level.

  2. Relationships among Sensory Responsiveness, Anxiety, and Ritual Behaviors in Children with and without Atypical Sensory Responsiveness.

    Science.gov (United States)

    Bart, Orit; Bar-Shalita, Tami; Mansour, Hanin; Dar, Reuven

    2017-08-01

    To explore relationships between sensory responsiveness, anxiety, and ritual behaviors in boys with typical and atypical sensory responsiveness. Forty-eight boys, ages 5-9 participated in the study (28 boys with atypical sensory responsiveness and 20 controls). Atypical sensory responsiveness was defined as a score of ≤154 on the Short Sensory Profile. Parents completed the Sensory Profile, the Screen for Child Anxiety Related Emotional Disorders, and the Childhood Routines Inventory. Children with atypical sensory responsiveness had significantly higher levels of anxiety and a higher frequency of ritual behaviors than controls. Atypical sensory responsiveness was significantly related to both anxiety and ritual behaviors, with anxiety mediating the relationship between sensory modulation and ritual behaviors. The findings elucidate the potential consequences of atypical sensory responsiveness and could support the notion that ritual behaviors develop as a coping mechanism in response to anxiety stemming from primary difficulty in modulating sensory input.

  3. Non-Viral Deoxyribonucleoside Kinases

    DEFF Research Database (Denmark)

    Christiansen, Louise Slot; Munch-Petersen, Birgitte; Knecht, Wolfgang

    2015-01-01

    Deoxyribonucleoside kinases (dNKs) phosphorylate deoxyribonucleosides to their corresponding monophosphate compounds. dNks also phosphorylate deoxyribonucleoside analogues that are used in the treatment of cancer or viral infections. The study of the mammalian dNKs has therefore always been of gr...

  4. K63-Linked Ubiquitination in Kinase Activation and Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Guocan [Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Gao, Yuan [Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX (United States); Li, Liren [Department of Genomic Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Jin, Guoxiang; Cai, Zhen [Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX (United States); Chao, Jui-I [Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan (China); Lin, Hui-Kuan, E-mail: hklin@mdanderson.org [Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX (United States)

    2012-01-31

    Ubiquitination has been demonstrated to play a pivotal role in multiple biological functions, which include cell growth, proliferation, apoptosis, DNA damage response, innate immune response, and neuronal degeneration. Although the role of ubiquitination in targeting proteins for proteasome-dependent degradation have been extensively studied and well-characterized, the critical non-proteolytic functions of ubiquitination, such as protein trafficking and kinase activation, involved in cell survival and cancer development, just start to emerge, In this review, we will summarize recent progresses in elucidating the non-proteolytic function of ubiquitination signaling in protein kinase activation and its implications in human cancers. The advancement in the understanding of the novel functions of ubiquitination in signal transduction pathways downstream of growth factor receptors may provide novel paradigms for the treatment of human cancers.

  5. K63-Linked Ubiquitination in Kinase Activation and Cancer

    International Nuclear Information System (INIS)

    Wang, Guocan; Gao, Yuan; Li, Liren; Jin, Guoxiang; Cai, Zhen; Chao, Jui-I; Lin, Hui-Kuan

    2012-01-01

    Ubiquitination has been demonstrated to play a pivotal role in multiple biological functions, which include cell growth, proliferation, apoptosis, DNA damage response, innate immune response, and neuronal degeneration. Although the role of ubiquitination in targeting proteins for proteasome-dependent degradation have been extensively studied and well-characterized, the critical non-proteolytic functions of ubiquitination, such as protein trafficking and kinase activation, involved in cell survival and cancer development, just start to emerge, In this review, we will summarize recent progresses in elucidating the non-proteolytic function of ubiquitination signaling in protein kinase activation and its implications in human cancers. The advancement in the understanding of the novel functions of ubiquitination in signal transduction pathways downstream of growth factor receptors may provide novel paradigms for the treatment of human cancers.

  6. Investigating the role of RIO protein kinases in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Tasha K Mendes

    Full Text Available RIO protein kinases (RIOKs are a relatively conserved family of enzymes implicated in cell cycle control and ribosomal RNA processing. Despite their functional importance, they remain a poorly understood group of kinases in multicellular organisms. Here, we show that the C. elegans genome contains one member of each of the three RIOK sub-families and that each of the genes coding for them has a unique tissue expression pattern. Our analysis showed that the gene encoding RIOK-1 (riok-1 was broadly and strongly expressed. Interestingly, the intestinal expression of riok-1 was dependent upon two putative binding sites for the oxidative and xenobiotic stress response transcription factor SKN-1. RNA interference (RNAi-mediated knock down of riok-1 resulted in germline defects, including defects in germ line stem cell proliferation, oocyte maturation and the production of endomitotic oocytes. Taken together, our findings indicate new functions for RIOK-1 in post mitotic tissues and in reproduction.

  7. Outcomes of photorefractive keratectomy in patients with atypical topography.

    Science.gov (United States)

    Movahedan, Hossein; Namvar, Ehsan; Farvardin, Mohsen

    2017-11-01

    Photorefractive keratectomy (PRK) is at risk of serious complications such as corneal ectasia, which can reduce corrected distance visual acuity. The rate of complications of PRK is higher in patients with atypical topography. To determine the outcomes of photorefractive keratectomy in patients with atypical topography. This cross-sectional study was done in 2015 in Shiraz in Iran. We included 85 eyes in this study. The samples were selected using a simple random sampling method. All patients were under evaluation for uncorrected distance visual acuity, corrected distance visual acuity, manifest refraction, corneal topography, central corneal thickness using pentacam, slit-lamp microscopy, and detailed fondus evaluation. The postoperative examination was done 1-7 years after surgery. Data were analyzed using IBM SPSS 21.0 version. To analyze the data, descriptive statistics (frequency, percentage, mean, and standard deviation), chi-square, and independent samples t-test were used. We studied 85 eyes. Among the patients, 23 (27.1%) were male and 62 (72.9%) were female. Mean age of the participants was 28.25±5.55 years. Mean postoperative refraction was - 0.37±0.55 diopters. Keratoconus or corneal ectasia was not reported in any patient in this study. There was no statistically significant difference between SI index before and after operation (p=0.736). Mean preoperative refraction was -3.84 ± 1.46 diopters in males and -4.20±1.96 diopters in females; thus there was not statistically significant difference (p = 0.435). PRK is a safe and efficient photorefractive surgery and is associated with low complication rate in patients with atypical topography.

  8. Atypical Clinical Manifestations of Graves' Disease: An Analysis in Depth

    Science.gov (United States)

    Hegazi, Mohamed Osama; Ahmed, Sherif

    2012-01-01

    Over the past few decades, there has been an increase in the number of reports about newly recognized (atypical or unusual) manifestations of Graves' disease (GD), that are related to various body systems. One of these manifestations is sometimes the main presenting feature of GD. Some of the atypical manifestations are specifically related to GD, while others are also similarly seen in patients with other forms of hyperthyroidism. Lack of knowledge of the association between these findings and GD may lead to delay in diagnosis, misdiagnosis, or unnecessary investigations. The atypical clinical presentations of GD include anemia, vomiting, jaundice, and right heart failure. There is one type of anemia that is not explained by any of the known etiological factors and responds well to hyperthyroidism treatment. This type of anemia resembles anemia of chronic disease and may be termed GD anemia. Other forms of anemia that are associated with GD include pernicious anemia, iron deficiency anemia of celiac disease, and autoimmune hemolytic anemia. Vomiting has been reported as a presenting feature of Graves' disease. Some cases had the typical findings of hyperthyroidism initially masked, and the vomiting did not improve until hyperthyroidism has been detected and treated. Hyperthyroidism may present with jaundice, and on the other hand, deep jaundice may develop with the onset of overt hyperthyroidism in previously compensated chronic liver disease patients. Pulmonary hypertension is reported to be associated with GD and to respond to its treatment. GD-related pulmonary hypertension may be so severe to produce isolated right-sided heart failure that is occasionally found as the presenting manifestation of GD. PMID:22132347

  9. Atypical lymphocytes in malaria mimicking dengue infection in Thailand

    Directory of Open Access Journals (Sweden)

    Polrat Wilairatana

    2010-09-01

    Full Text Available Polrat Wilairatana1, Noppadon Tangpukdee1, Sant Muangnoicharoen1, Srivicha Krudsood2, Shigeyuki Kano31Department of Clinical Tropical Medicine, 2Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; 3Department of Tropical Medicine and Malaria, Research Institute, National Center for Global Health and Medicine, Tokyo, JapanAbstract: Patients with uncomplicated falciparum or vivax malaria usually present with acute febrile illness and thrombocytopenia similar to dengue infection. We retrospectively studied atypical lymphocytes (AL and atypical lymphocytosis (ALO, defined as AL > 5% of total white blood cells in 1310 uncomplicated malaria patients. In 718 falciparum malaria patients, AL and ALO on day 0 were found in 53.2% and 5.7% of the patients, respectively, with median AL on admission of 1% (range 0%–10%, whereas in 592 vivax malaria patients, AL and ALO on day 0 were found in 55.4% and 9.5% of the patients, respectively, with median AL on admission of 1% (range 0%–14%. After antimalarial treatment, AL and ALO declined in both falciparum and vivax malaria. However, AL and ALO remained in falciparum malaria on days 7, 14, and 21, whereas AL and ALO remained in vivax malaria on days 7, 14, 21, and 28. In both falciparum and vivax malaria patients, there was a positive correlation between AL and total lymphocytes, but a negative correlation between AL and highest fever on admission, white blood cells, and neutrophils, eosinophils, and platelets (P < 0.05. In conclusion, AL or ALO may be found in uncomplicated falciparum and vivax malaria mimicking dengue infection. In tropical countries where both dengue and malaria are endemic, presence of AL or ALO in any acute febrile patients with thrombocytopenia (similar to the findings in dengue malaria could not be excluded. Particularly if the patients have risk of malaria infection, confirmative microscopic examination for malaria should be carried out

  10. Amide proton transfer imaging for differentiation of benign and atypical meningiomas

    Energy Technology Data Exchange (ETDEWEB)

    Joo, Bio [The Armed Forces Capital Hospital, Department of Radiology, Seongnam, Gyeonggi-do (Korea, Republic of); Han, Kyunghwa; Choi, Yoon Seong; Lee, Seung-Koo [Yonsei University College of Medicine, Department of Radiology and Research Institute of Radiological Science, College of Medicine, Seoul (Korea, Republic of); Ahn, Sung Soo [Yonsei University College of Medicine, Department of Radiology and Research Institute of Radiological Science, College of Medicine, Seoul (Korea, Republic of); Yonsei University, Department of Radiology, College of Medicine, Seoul (Korea, Republic of); Chang, Jong Hee; Kang, Seok-Gu [Yonsei University College of Medicine, Department of Neurosurgery, Seoul (Korea, Republic of); Kim, Se Hoon [Yonsei University College of Medicine, Department of Pathology, Seoul (Korea, Republic of); Zhou, Jinyuan [Johns Hopkins University School of Medicine, Division of MRI Research, Department of Radiology, Baltimore, MD (United States)

    2018-01-15

    To investigate the difference in amide proton transfer (APT)-weighted signals between benign and atypical meningiomas and determine the value of APT imaging for differentiating the two. Fifty-seven patients with pathologically diagnosed meningiomas (benign, 44; atypical, 13), who underwent preoperative MRI with APT imaging between December 2014 and August 2016 were included. We compared normalised magnetisation transfer ratio asymmetry (nMTR{sub asym}) values between benign and atypical meningiomas on APT-weighted images. Conventional MRI features were qualitatively assessed. Both imaging features were evaluated by multivariable logistic regression analysis. The discriminative value of MRI with and without nMTR{sub asym} was evaluated. The nMTR{sub asym} of atypical meningiomas was significantly greater than that of benign meningiomas (2.46% vs. 1.67%; P < 0.001). In conventional MR images, benign and atypical meningiomas exhibited significant differences in maximum tumour diameter, non-skull base location, and heterogeneous enhancement. On multivariable logistic regression analysis, high nMTR{sub asym} was an independent predictor of atypical meningiomas (adjusted OR, 11.227; P = 0.014). The diagnostic performance of MRI improved with nMTR{sub asym} for predicting atypical meningiomas. Atypical meningiomas exhibited significantly higher APT-weighted signal intensities than benign meningiomas. The discriminative value of conventional MRI improved significantly when combined with APT imaging for diagnosis of atypical meningioma. (orig.)

  11. Protein kinase CK2 in human diseases

    DEFF Research Database (Denmark)

    Guerra, Barbara; Issinger, Olaf-Georg

    2008-01-01

    Protein kinase CK2 (formerly referred to as casein kinase II) is an evolutionary conserved, ubiquitous protein kinase. There are two paralog catalytic subunits, i.e. alpha (A1) and alpha' (A2). The alpha and alpha' subunits are linked to two beta subunits to produce a heterotetrameric structure...

  12. A family of congenital hepatic fibrosis and atypical retinitis pigmentosa

    Directory of Open Access Journals (Sweden)

    Sunil Pawar

    2015-11-01

    Full Text Available Congenital hepatic fibrosis is a rare cause of portal hypertension and esophageal varices in children. We report cases of siblings with biopsy proven congenital hepatic fibrosis and with atypical retinitis pigmentosa. They presented with repeated episodes of jaundice along with progressive decrease of vision in night. They had hepatosplenomegaly and portal hypertension with esophageal varices. One of the siblings had a large regenerating nodule replacing the entire right lobe of the liver and other one developed repeated hematemesis. This constellation of diagnosis belongs to the ciliopathy group of disorders. The spectrum of ciliopathy disorders has been evolving, and it varies from mild to severe manifestations.

  13. Atypical presentation of posterior reversible encephalopathy syndrome: Two cases

    Directory of Open Access Journals (Sweden)

    Nishant Kumar

    2018-01-01

    Full Text Available Posterior reversible encephalopathy syndrome (PRES is a clinico-neuroradiological entity, first described in 1996. It is commonly associated with systemic hypertension, intake of immunosuppressant drugs, sepsis and eclampsia and preeclampsia. Headache, alteration in consciousness, visual disturbances and seizures are common manifestations of PRES. Signs of pyramidal tract involvement and motor dysfunction are uncommon clinical findings. However, clinical presentation is not diagnostic. On neuroimaging, lesions are characteristically found in parieto occipital region of the brain due to vasogenic edema. We report two cases of PRES with atypical clinical presentation-one which was suggestive of neurocysticercosis and the other in which agitation and opisthotonic posture were predominant features.

  14. Atypical presentation of sporotrichosis: report of three cases

    Directory of Open Access Journals (Sweden)

    Melissa Orzechowski Xavier

    2013-01-01

    Full Text Available Sporotrichosis occurs after fungal implantation of Sporothrix spp. in the skin, and is the main subcutaneous mycosis in Latin America. Here we describe three atypical cases of the disease. The first case report an extra-cutaneous occurrence of the disease with joint infection; the second one describes a patient with bilateral lymphocutaneous form of sporotrichosis; and the third shows a zoonotic cutaneous case with the development of an erythema nodosum as a hypersensitivity reaction. These cases show the disease importance on the region and the necessity of fungal culture to the diagnosis confirmation.

  15. [Anxiety driven atypical eating disorder in the course of phenylketonuria].

    Science.gov (United States)

    Rapps, Nora; Mack, Isabelle; Herrmann-Werner, Anne; Zipfel, Stephan; Teufel, Martin

    2015-07-01

    Phenylketonuria is the most common genetic disease in amino acid metabolism. We report the case of a 22-year old patient with phenylketonuria and psychological symptoms. After early treatment, phenylalanine levels had been controlled and were within target area. Clinical interview and psychometrics showed atypical eating disorder and anxiety disorder. Possible toxic effects and psychological factors may play a role in pathogenesis. Most likely the frequency of eating disorders and anxiety disorders in phenylketonuria is underestimated. © Georg Thieme Verlag KG Stuttgart · New York.

  16. THE ROLE OF ATYPICAL ANTIPSYCHOTIC DECREASING AGGRESIVENESS IN SCHIZOPHRENIA

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    Juvita Novia Anggraini Maria

    2013-03-01

    Full Text Available Schizophrenia is a psychiatry disorder accompanying by alteration of mind-set, perception,  thought, and behavior. Symptom of schizophrenia can be positive symptom and negative symptom. The positive symptom often became a fear for the others, that is aggresiveness as violance, suicide, ang homicide. Aggresiveness divided in five category, that is impulsivity, affective instability, anxiety/hyperarousal, cognitive disorganization, predatory/planned aggression. Pharmacology theraphy is a choice in decreasing aggresiveness in schizophrenia. Atypical antipsychotic theraphy indicate higher effectivity and fewer side effect than conventional antipsychotic.

  17. Lipomatosis of the sciatic nerve: typical and atypical MRI features

    International Nuclear Information System (INIS)

    Wong, Bernadette Zhi Ying; Amrami, Kimberly K.; Wenger, Doris E.; Dyck, P. James B.; Scheithauer, Bernd W.; Spinner, Robert J.

    2006-01-01

    Lipomatosis of nerve, also known as fibrolipomatous hamartoma, is a rare condition of nerve, usually affecting the median nerve. The MRI appearance is characteristic. We describe two cases of lipomatosis of nerve involving the sciatic nerve, an extremely unusual location for this lesion, in patients with sciatic neuropathy. These cases share the typical features previously described in the literature for other nerves, but also contain atypical features not previously highlighted, relating to the variability in distribution and extent of the fatty deposition. Recognition of the MRI appearance of this entity is important in order to avoid unnecessary attempts at surgical resection of this lesion. (orig.)

  18. A case of unilateral atypical orofacial pain with Eagle's syndrome

    Directory of Open Access Journals (Sweden)

    G V Sowmya

    2016-01-01

    Full Text Available Eagle's syndrome is not an uncommon condition, but less known to physicians, where an elongated styloid process or calcified stylohyoid ligament compresses the adjacent anatomical structures leading to orofacial pain. Diagnosis is made with appropriate radiological examination. Nonsurgical treatment options include reassurance, analgesia, and anti.inflammatory medications; and the surgical option includes a transoral or external approach. Here, we present a case report of a male patient, of age38 years, with a chief complaint of unilateral atypical orofacial pain on the right side of his face radiating to the neck region, for the last two months.

  19. Atypical Primary Cutaneous Rosai Dorfman Disease: A Case Report.

    Science.gov (United States)

    Kinio, Anna E; Sawchuk, Michael A; Pratt, Melanie

    Rosai Dorfman disease (RDD) is a rare disorder that typically presents with bilateral cervical lymphadenopathy and follows a benign course. We present a case of late-onset atypical primary cutaneous RDD that is resistant to treatment modalities described in the literature. Case report. An 84-year-old woman presented with a 7-year history of cutaneous lesions histologically consistent with RDD. She later failed initial treatments of acitretin and thalidomide. Physicians must be aware of unusual presentations of RDD. Also, further treatment options must be explored for patients resistant to classical management of RDD.

  20. Atypical Gastric Ulcer in an Elderly Cocaine User

    Directory of Open Access Journals (Sweden)

    Vinaya Gaduputi

    2013-01-01

    Full Text Available Cocaine or Benzoylmethylecgonine is an alkaloid extracted from the leaves of the Erythroxylon plant, which can cause gastrointestinal ischemia from severe arterial vasoconstriction via stimulation of alpha-adrenergic receptors in the gastric and mesenteric arteries. We report this case of a 65-year-old man who presented with a single massive ulcer at the incisura of the stomach as a result of cocaine use. The size and location of this ulcer were atypical and illustrate the potential for serious gastrointestinal manifestations from cocaine use.

  1. Atypical Papular Purpuric Eruption Induced by Parvovirus B19 Infection

    Directory of Open Access Journals (Sweden)

    Şeyma Kayalı

    2016-03-01

    Full Text Available Parvovirus B19 infection’s most common dermatological manifestation is erythema infectiosum as also known the fifth disease. Rare clinical presentations of parvovirus B 19 like papulopurpuric gloves and socks syndrome and acropetechial syndrome has also been described re­cently. This study presents report of a case with atypical feature and distribution of rash due to parvovirus B19 in­fection. We want to emphasize that pediatricians should consider parvovirus B19 infection of any patient who has leukopenia presenting with petechial/purpuric eruption of an unclear origin.

  2. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase.

    Science.gov (United States)

    Stoyanov, B; Volinia, S; Hanck, T; Rubio, I; Loubtchenkov, M; Malek, D; Stoyanova, S; Vanhaesebroeck, B; Dhand, R; Nürnberg, B

    1995-08-04

    Phosphoinositide-3 kinase activity is implicated in diverse cellular responses triggered by mammalian cell surface receptors and in the regulation of protein sorting in yeast. Receptors with intrinsic and associated tyrosine kinase activity recruit heterodimeric phosphoinositide-3 kinases that consist of p110 catalytic subunits and p85 adaptor molecules containing Src homology 2 (SH2) domains. A phosphoinositide-3 kinase isotype, p110 gamma, was cloned and characterized. The p110 gamma enzyme was activated in vitro by both the alpha and beta gamma subunits of heterotrimeric guanosine triphosphate (GTP)-binding proteins (G proteins) and did not interact with p85. A potential pleckstrin homology domain is located near its amino terminus. The p110 gamma isotype may link signaling through G protein-coupled receptors to the generation of phosphoinositide second messengers phosphorylated in the D-3 position.

  3. The molecular architecture of human N-acetylgalactosamine kinase.

    Science.gov (United States)

    Thoden, James B; Holden, Hazel M

    2005-09-23

    Galactokinase plays a key role in normal galactose metabolism by catalyzing the conversion of alpha-d-galactose to galactose 1-phosphate. Within recent years, the three-dimensional structures of human galactokinase and two bacterial forms of the enzyme have been determined. Originally, the gene encoding galactokinase in humans was mapped to chromosome 17. An additional gene, encoding a protein with sequence similarity to galactokinase, was subsequently mapped to chromosome 15. Recent reports have shown that this second gene (GALK2) encodes an enzyme with greater activity against GalNAc than galactose. This enzyme, GalNAc kinase, has been implicated in a salvage pathway for the reutilization of free GalNAc derived from the degradation of complex carbohydrates. Here we report the first structural analysis of a GalNAc kinase. The structure of the human enzyme was solved in the presence of MnAMPPNP and GalNAc or MgATP and GalNAc (which resulted in bound products in the active site). The enzyme displays a distinctly bilobal appearance with its active site wedged between the two domains. The N-terminal region is dominated by a seven-stranded mixed beta-sheet, whereas the C-terminal motif contains two layers of anti-parallel beta-sheet. The overall topology displayed by GalNAc kinase places it into the GHMP superfamily of enzymes, which generally function as small molecule kinases. From this investigation, the geometry of the GalNAc kinase active site before and after catalysis has been revealed, and the determinants of substrate specificity have been defined on a molecular level.

  4. Autoregulation of kinase dephosphorylation by ATP binding in AGC protein kinases.

    Science.gov (United States)

    Chan, Tung O; Pascal, John M; Armen, Roger S; Rodeck, Ulrich

    2012-02-01

    AGC kinases, including the three Akt (protein kinase B) isoforms, protein kinase A (PKA) and all protein kinase C (PKC) isoforms, require activation loop phosphorylation (threonine 308 in Akt1) as well as phosphorylation of a C-terminal residue (serine 473 in Akt1) for catalytic activity and phosphorylation of downstream targets. Conversely, phosphatases reverse these phosphorylations. Virtually all cellular processes are affected by AGC kinases, a circumstance that has led to intense scrutiny of the molecular mechanisms that regulate phosphorylation of these kinases. Here, we review a new layer of control of phosphorylation in Akt, PKA and PKC pointing to ATP binding pocket occupancy as a means to decelerate dephosphorylation of these and, potentially, other kinases. This additional level of kinase regulation opens the door to search for new functional motifs for the rational design of non- ATP-competitive kinase inhibitors that discriminate within and between protein kinase families.

  5. Autoregulation of kinase dephosphorylation by ATP binding to AGC protein kinases

    Science.gov (United States)

    Pascal, John M; Armen, Roger S

    2012-01-01

    AGC kinases, including the three Akt (protein kinase B) isoforms, protein kinase A (PKA) and all protein kinase C (PKC) isoforms, require activation loop phosphorylation (threonine 308 in Akt1) as well as phosphorylation of a C-terminal residue (serine 473 in Akt1) for catalytic activity and phosphorylation of downstream targets. Conversely, phosphatases reverse these phosphorylations. Virtually all cellular processes are affected by AGC kinases, a circumstance that has led to intense scrutiny of the molecular mechanisms that regulate phosphorylation of these kinases. Here, we review a new layer of control of phosphorylation in Akt, PKA and PKC pointing to ATP binding pocket occupancy as a means to decelerate dephosphorylation of these and, potentially, other kinases. This additional level of kinase regulation opens the door to search for new functional motifs for the rational design of non-ATP-competitive kinase inhibitors that discriminate within and between protein kinase families. PMID:22262182

  6. Src kinase regulation by phosphorylation and dephosphorylation

    International Nuclear Information System (INIS)

    Roskoski, Robert

    2005-01-01

    Src and Src-family protein-tyrosine kinases are regulatory proteins that play key roles in cell differentiation, motility, proliferation, and survival. The initially described phosphorylation sites of Src include an activating phosphotyrosine 416 that results from autophosphorylation, and an inhibiting phosphotyrosine 527 that results from phosphorylation by C-terminal Src kinase (Csk) and Csk homologous kinase. Dephosphorylation of phosphotyrosine 527 increases Src kinase activity. Candidate phosphotyrosine 527 phosphatases include cytoplasmic PTP1B, Shp1 and Shp2, and transmembrane enzymes include CD45, PTPα, PTPε, and PTPλ. Dephosphorylation of phosphotyrosine 416 decreases Src kinase activity. Thus far PTP-BL, the mouse homologue of human PTP-BAS, has been shown to dephosphorylate phosphotyrosine 416 in a regulatory fashion. The platelet-derived growth factor receptor protein-tyrosine kinase mediates the phosphorylation of Src Tyr138; this phosphorylation has no direct effect on Src kinase activity. The platelet-derived growth factor receptor and the ErbB2/HER2 growth factor receptor protein-tyrosine kinases mediate the phosphorylation of Src Tyr213 and activation of Src kinase activity. Src kinase is also a substrate for protein-serine/threonine kinases including protein kinase C (Ser12), protein kinase A (Ser17), and CDK1/cdc2 (Thr34, Thr46, and Ser72). Of the three protein-serine/threonine kinases, only phosphorylation by CDK1/cdc2 has been demonstrated to increase Src kinase activity. Although considerable information on the phosphoprotein phosphatases that catalyze the hydrolysis of Src phosphotyrosine 527 is at hand, the nature of the phosphatases that mediate the hydrolysis of phosphotyrosine 138 and 213, and phosphoserine and phosphothreonine residues has not been determined

  7. Myosin light chain kinase regulates synaptic plasticity and fear learning in the lateral amygdala.

    Science.gov (United States)

    Lamprecht, R; Margulies, D S; Farb, C R; Hou, M; Johnson, L R; LeDoux, J E

    2006-01-01

    Learning and memory depend on signaling molecules that affect synaptic efficacy. The cytoskeleton has been implicated in regulating synaptic transmission but its role in learning and memory is poorly understood. Fear learning depends on plasticity in the lateral nucleus of the amygdala. We therefore examined whether the cytoskeletal-regulatory protein, myosin light chain kinase, might contribute to fear learning in the rat lateral amygdala. Microinjection of ML-7, a specific inhibitor of myosin light chain kinase, into the lateral nucleus of the amygdala before fear conditioning, but not immediately afterward, enhanced both short-term memory and long-term memory, suggesting that myosin light chain kinase is involved specifically in memory acquisition rather than in posttraining consolidation of memory. Myosin light chain kinase inhibitor had no effect on memory retrieval. Furthermore, ML-7 had no effect on behavior when the training stimuli were presented in a non-associative manner. Anatomical studies showed that myosin light chain kinase is present in cells throughout lateral nucleus of the amygdala and is localized to dendritic shafts and spines that are postsynaptic to the projections from the auditory thalamus to lateral nucleus of the amygdala, a pathway specifically implicated in fear learning. Inhibition of myosin light chain kinase enhanced long-term potentiation, a physiological model of learning, in the auditory thalamic pathway to the lateral nucleus of the amygdala. When ML-7 was applied without associative tetanic stimulation it had no effect on synaptic responses in lateral nucleus of the amygdala. Thus, myosin light chain kinase activity in lateral nucleus of the amygdala appears to normally suppress synaptic plasticity in the circuits underlying fear learning, suggesting that myosin light chain kinase may help prevent the acquisition of irrelevant fears. Impairment of this mechanism could contribute to pathological fear learning.

  8. EGFR kinase-dependent and kinase-independent roles in clear cell renal cell carcinoma.

    Science.gov (United States)

    Cossu-Rocca, Paolo; Muroni, Maria R; Sanges, Francesca; Sotgiu, Giovanni; Asunis, Anna; Tanca, Luciana; Onnis, Daniela; Pira, Giovanna; Manca, Alessandra; Dore, Simone; Uras, Maria G; Ena, Sara; De Miglio, Maria R

    2016-01-01

    -dependent and kinase-independent functions, both potentially involved in CCRCC progression. These results might have important implications on therapeutic approaches to CCRCC, since the disruption of the interaction between EGFR/SGLT1, mediated by anti-EGFR antibodies and/or SGLT1 inhibitors, might constitute a novel therapeutic target for CCRCC treatment, and new clinical trials should be evaluated on the basis of this therapeutic proposal.

  9. Protein kinase C-related kinase 1 and 2 play an essential role in thromboxane-mediated neoplastic responses in prostate cancer

    OpenAIRE

    O'Sullivan, Aine G.; Mulvaney, Eamon P.; Hyland, Paula B.; Kinsella, B. Therese

    2015-01-01

    The prostanoid thromboxane (TX) A2 is increasingly implicated in neoplastic progression, including prostate cancer (PCa). Mechanistically, we recently identified protein kinase C-related kinase (PRK) 1 as a functional interactant of both the TP? and TP? isoforms of the human T prostanoid receptor (TP). The interaction with PRK1 was not only essential for TP?/TP?-induced PCa cell migration but also enabled the TXA2-TP axis to induce phosphorylation of histone H3 at Thr11 (H3Thr11), an epigenet...

  10. The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction

    NARCIS (Netherlands)

    Green, J.; Nusse, R.; van Amerongen, R.

    2014-01-01

    Receptor tyrosine kinases of the Ryk and Ror families were initially classified as orphan receptors because their ligands were unknown. They are now known to contain functional extracellular Wnt-binding domains and are implicated in Wnt-signal transduction in multiple species. Although their

  11. Kinase cogs go forward and reverse in the Wnt signaling machine.

    Science.gov (United States)

    Dale, Trevor

    2006-01-01

    An important link between Wnt binding at the cell surface and nuclear -catenin-TCF-dependent transcription has been made with the identification of kinases that promote the association of the Wnt receptor and -catenin turnover complexes. Surprisingly, the enzymes implicated had previously been suggested to inhibit rather than promote Wnt signaling.

  12. Creatine kinase and blood pressure: Clinical and therapeutic implications

    NARCIS (Netherlands)

    Oudman, I.

    2013-01-01

    Hypertension affects more than one billion people worldwide and is one of the most powerful contributors to cardiovascular morbidity and mortality. Black people of African descent are more often affected by the disease. One of the biological factors contributing to this difference is the enzyme

  13. The influence of atypical antipsychotic drugs on sexual function

    Directory of Open Access Journals (Sweden)

    Just MJ

    2015-07-01

    Full Text Available Marek J Just Department of General and Endocrine Surgery, Piekary Medical Centre, Piekary Slaskie, Poland Abstract: Human sexuality is contingent upon many biological and psychological factors. Such factors include sexual drive (libido, physiological arousal (lubrication/erection, orgasm, and ejaculation, as well as maintaining normal menstrual cycle. The assessment of sexual dysfunction can be difficult due to the intimate nature of the problem and patients’ unwillingness to discuss it. Also, the problem of dysfunction is often overlooked by doctors. Atypical antipsychotic treatment is a key component of mental disorders’ treatment algorithms recommended by the National Institute of Health and Clinical Excellence, the American Psychiatric Association, and the British Society for Psychopharmacology. The relationship between atypical antipsychotic drugs and sexual dysfunction is mediated in part by antipsychotic blockade of pituitary dopamine D2 receptors increasing prolactin secretion, although direct correlations have not been established between raised prolactin levels and clinical symptoms. Variety of mechanisms are likely to contribute to antipsychotic-related sexual dysfunction, including hyperprolactinemia, sedation, and antagonism of a number of neurotransmitter receptors (α-adrenergic, dopaminergic, histaminic, and muscarinic. Maintaining normal sexual function in people treated for mental disorders can affect their quality of life, mood, self-esteem, attitude toward taking medication, and compliance during therapy. Keywords: schizophrenia, galactorrhea, hyperprolactinemia, mood disorders, anorgasmia

  14. Atypical mycobacterial infection resembles sporotrichosis in elderly patient

    Directory of Open Access Journals (Sweden)

    Siti Nurani Fauziah

    2018-04-01

    Full Text Available Atypical mycobacterial (AM infection is caused by Mycobacterium species other than M.tuberculosis. AM skin infection has clinical manifestations that resemble M. tuberculosis infection and deep fungal infection. Laboratory workup is necessary to confirm the diagnosis. An 83-year old female came with a painful lump and swelling on her right lower extremity since three months before admission. Physical examination revealed a plaque consisting, of multiple erythematous and hyperpigmented papules and nodules, diffuse erythematous lesion, and shallow ulcers partially covered with pus and crust. Histopathological features showed tuberculoid granuloma. Direct test and periodic acid-Schiff (PAS staining of the skin biopsy found no fungal element nor acid-fast bacilli (AFB. Culture and polymerase chain reaction (PCR of M. tuberculosis were negative. The working diagnosis was atypical mycobacterial infection and treatment with 450 mg rifampicin and 100 mg minocycline daily were administered accordingly. In two months observation following the treatment, the pain was no longer exist, the ulcers were completely healed, and some nodules were in the process of healing Among other Mycobacterium spp, M.marinum is the most common cause of AM infrections. Clinical manifestation of M. marinum infection may present as solitary or multiple nodules on the hands, feet, elbows and knees with sporotrichoid spreading patern. The diagnosis of AM was established based on clinical and laboratory examination. The diagnosis was also confirmed by good clinical response to minocycline and rifampicin.

  15. Atypical hemispheric dominance for attention: functional MRI topography.

    Science.gov (United States)

    Flöel, Agnes; Jansen, Andreas; Deppe, Michael; Kanowski, Martin; Konrad, Carsten; Sommer, Jens; Knecht, Stefan

    2005-09-01

    The right hemisphere is predominantly involved in tasks associated with spatial attention. However, left hemispheric dominance for spatial attention can be found in healthy individuals, and both spatial attention and language can be lateralized to the same hemisphere. Little is known about the underlying regional distribution of neural activation in these 'atypical' individuals. Previously a large number of healthy subjects were screened for hemispheric dominance of visuospatial attention and language, using functional Doppler ultrasonography. From this group, subjects were chosen who were 'atypical' for hemispheric dominance of visuospatial attention and language, and their pattern of brain activation was studied with functional magnetic resonance imaging during a task probing spatial attention. Right-handed subjects with the 'typical' pattern of brain organization served as control subjects. It was found that subjects with an inverted lateralization of language and spatial attention (language right, attention left) recruited left-hemispheric areas in the attention task, homotopic to those recruited by control subjects in the right hemisphere. Subjects with lateralization of both language and attention to the right hemisphere activated an attentional network in the right hemisphere that was comparable to control subjects. The present findings suggest that not the hemispheric side, but the intrahemispheric pattern of activation is the distinct feature for the neural processes underlying language and attention.

  16. Current status of atypical antipsychotics for the treatment of fibromyalgia.

    Science.gov (United States)

    Rico-Villademoros, F; Calandre, E P; Slim, M

    2014-06-01

    The treatment of fibromyalgia requires pharmacological and nonpharmacological therapies. The pharmacological treatment of fibromyalgia is limited to a few drugs that have been demonstrated to be moderately effective in some but not all dimensions of the disease. Therefore, the search for new drugs to treat this condition is warranted. Atypical antipsychotics offered an attractive alternative because they had been shown to be active against several key symptoms of fibromyalgia. The results of open-label studies, however, appear to indicate that atypical antipsychotics are poorly tolerated in patients with fibromyalgia, and only quetiapine XR has been studied in randomized controlled trials. Quetiapine XR has demonstrated effectiveness in treating comorbid major depression, anxiety and sleep disturbance. However, in two randomized controlled trials, quetiapine XR was not differentiated from placebo and failed to demonstrate noninferiority to amitriptyline in terms of improving overall symptomatology. The effect of quetiapine XR on pain and its usefulness as part of a combination pharmacological regimen should be further evaluated. Overall, the use of quetiapine (initiated at a low dose and slowly titrated) in fibromyalgia should be limited to patients with comorbid major depression or patients who are currently receiving other treatments and have unresolved and disabling depressive and/or anxiety symptoms. Copyright 2014 Prous Science, S.A.U. or its licensors. All rights reserved.

  17. Benign occipital lobe seizures: Natural progression and atypical evolution

    Directory of Open Access Journals (Sweden)

    Prithika Chary

    2013-01-01

    Full Text Available Benign occipital seizure syndromes are benign childhood epilepsy syndromes and are mainly of two types, Panayiotopoulos syndrome, an autonomic epilepsy and idiopathic childhood occipital epilepsy of Gastaut (ICOE-G including the idiopathic photosensitive occipital lobe epilepsy. Although both these types are categorized as occipital seizures, they are distinct in presentation and management. They can also be tricky to diagnose as visual symptoms may not always be the presenting feature and it is also not very easy to elicit visual hallucinations during history taking. These seizures have a good response to treatment; however, there could be atypical evolution and refractoriness to treatment especially with ICOE-G. We describe three children who presented with visual and non-visual symptoms and the electroencephalography (EEG in all the three cases showed occipital paroxysms. We have emphasized the clues in the clinical history and EEG leading to the diagnosis of these distinct epilepsy syndromes. We have also discussed the natural course of these epilepsy syndromes with some atypical evolution, which clinicians need to be aware of during treatment of these children.

  18. Benign occipital lobe seizures: Natural progression and atypical evolution.

    Science.gov (United States)

    Chary, Prithika; Rajendran, Bhuvaneshwari

    2013-10-01

    Benign occipital seizure syndromes are benign childhood epilepsy syndromes and are mainly of two types, Panayiotopoulos syndrome, an autonomic epilepsy and idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) including the idiopathic photosensitive occipital lobe epilepsy. Although both these types are categorized as occipital seizures, they are distinct in presentation and management. They can also be tricky to diagnose as visual symptoms may not always be the presenting feature and it is also not very easy to elicit visual hallucinations during history taking. These seizures have a good response to treatment; however, there could be atypical evolution and refractoriness to treatment especially with ICOE-G. We describe three children who presented with visual and non-visual symptoms and the electroencephalography (EEG) in all the three cases showed occipital paroxysms. We have emphasized the clues in the clinical history and EEG leading to the diagnosis of these distinct epilepsy syndromes. We have also discussed the natural course of these epilepsy syndromes with some atypical evolution, which clinicians need to be aware of during treatment of these children.

  19. Atypical dermatophilosis of sheep in Kenya : clinical communication

    Directory of Open Access Journals (Sweden)

    J.K. Wabacha

    2007-06-01

    Full Text Available An outbreak of an atypical form of ovine dermatophilosis affecting the lips and muzzle with a very high morbidity in weaners and hoggets in Kenya is reported. Clinical diagnosis of ovine dermatophilosis was made and confirmed by direct microscopic examination as well as isolation and identification of Dermatophilus congolensis from scab material from the affected sheep. The morbidity rate within the flock was 31.8 % (237 / 745 with 98.3 % (233 / 237 of the affected sheep being weaners and hoggets. No fatalities were recorded. The lesions, confined in the lips and the muzzle, were swelling of both the upper and lower lips, circumscribed lumps in the skin of both the upper and lower lips, oedema of the head and the submandibular area and scabs and crusts on the lips and muzzle. Within 1 week following treatment with long acting oxytetracycline (20 % at a rate of 20 mg/kg body weight, intramuscularly and a topical application of oxytetracycline spray, lumps regressed in size and were covered by dark-brown scabs. Removal of the dark-brown scabs revealed erythematous areas covered with purulent material and horny erythematous projections (papillae projecting from the surfaces. Within the 2nd week, the horny erythematous projections formed greyish scabs, which later peeled off leaving alopaecic areas around the lips. The paper highlights atypical dermatophilosis of sheep and we believe that this is the first published report of an outbreak of ovine dermatophilosis in Kenya.

  20. Typical and atypical clinical presentation of uterine myomas

    Directory of Open Access Journals (Sweden)

    Wen-Hsiang Su

    2012-10-01

    Full Text Available Myoma is the most common benign neoplasm that can occur in the female reproductive system, most frequently seen in women in their 50s. Although the majority of myomas are asymptomatic, some patients have symptoms and/or signs of varying degrees. Typical myoma-related symptoms or signs include: (1 menstrual disturbances like menorrhagia, dysmenorrhea and intermenstrual bleeding, (2 pelvic pain unrelated to menstruation, (3 compression symptoms, similar to a sensation of bloatedness, urinary frequency and constipation, (4 subfertility status such as recurrent abortion, preterm labor, dystocia with an increased incidence of Cesarean section, and postpartum hemorrhage, and (5 cosmetic problems due to increased abdominal girth However, there are undoubtedly some clinical presentations secondary to uterine myomas are not so specific, such as: (1 uncommon compression-related symptoms, (2 cardiac symptom and atypical symptoms secondary to vascular involvement or dissemination, (3 abdominal symptoms mimicking pelvic carcinomatosis, (4 dyspnea, (5 pruritus, (6 hiccup or internal bleeding, and (7 vaginal protruding mass or uterine inversion. Familiarization with these symptoms and awareness of other unusual or atypical presentations of uterine myomas will remind clinical practitioners of their significance, and of the necessity of follow-up examinations and individualized management to fit the needs and childbirth desires of the patients.

  1. Breast Metastases from Extramammary Malignancies: Typical and Atypical Ultrasound Features

    Energy Technology Data Exchange (ETDEWEB)

    Mun, Sung Hee [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710 (Korea, Republic of); Department of Radiology, Catholic University of Daegu College of Medicine, Daegu 712-702 (Korea, Republic of); Ko, Eun Young; Han, Boo-Kyung; Shin, Jung Hee [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710 (Korea, Republic of); Kim, Suk Jung [Department of Radiology, Inje University College of Medicine, Busan Paik Hospital, Busan 614-735 (Korea, Republic of); Cho, Eun Yoon [Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710 (Korea, Republic of)

    2014-07-01

    Breast metastases from extramammary malignancies are uncommon. The most common sources are lymphomas/leukemias and melanomas. Some of the less common sources include carcinomas of the lung, ovary, and stomach, and infrequently, carcinoid tumors, hypernephromas, carcinomas of the liver, tonsil, pleura, pancreas, cervix, perineum, endometrium and bladder. Breast metastases from extramammary malignancies have both hematogenous and lymphatic routes. According to their routes, there are common radiological features of metastatic diseases of the breast, but the features are not specific for metastases. Typical ultrasound (US) features of hematogenous metastases include single or multiple, round to oval shaped, well-circumscribed hypoechoic masses without spiculations, calcifications, or architectural distortion; these masses are commonly located superficially in subcutaneous tissue or immediately adjacent to the breast parenchyma that is relatively rich in blood supply. Typical US features of lymphatic breast metastases include diffusely and heterogeneously increased echogenicities in subcutaneous fat and glandular tissue and a thick trabecular pattern with secondary skin thickening, lymphedema, and lymph node enlargement. However, lesions show variable US features in some cases, and differentiation of these lesions from primary breast cancer or from benign lesions is difficult. In this review, we demonstrate various US appearances of breast metastases from extramammary malignancies as typical and atypical features, based on the results of US and other imaging studies performed at our institution. Awareness of the typical and atypical imaging features of these lesions may be helpful to diagnose metastatic lesions of the breast.

  2. Time course of lung function changes in atypical pneumonia.

    Science.gov (United States)

    Benusiglio, L N; Stalder, H; Junod, A F

    1980-01-01

    We measured pulmonary function in each of 21 patients suffering from "atypical", non-bacterial pneumonia during the acute illness and during convalescence (two to 18 months) to study the course and the nature of functional impairment at different stages of the disease. In six patients, no aetiological agent was found. An aetiological agent was identified in 15 of the patients: Mycoplasma pneumoniae (seven patients), influenza A (three patients), parainfluenza 3 (one patient), varicella (two patients), Q fever (one patient), coxsackie B3 (one patient). At the time of admission we observed a restrictive pattern in 52%, an obstructive pattern (decreased FEV1/FVC ratio) in 52% abnormalities in distribution of ventilation (abnormal slope of phase 3) in 63%, and abnormalities in gas exchange (increased AaDO2) in 75% of the patients. The frequency of abnormalities in these pulmonary function tests decreased dramatically after two to four weeks and nearly disappeared in most patients during convalescence. The only major residual abnormality was a decreased FEV1/FVC ratio in five subjects, four of whom were smokers. However, when MMEF and V75 were measured at this stage, their average value for all the groups of patients with the exclusion of the Mycoplasma pneumoniae group, was markedly reduced. These data suggest that small airways involvement can be demonstrated during the convalescence of patients recovering from various types of atypical pneumonia other than those caused by Mycoplasma pneumoniae. PMID:7444825

  3. Atypical antipsychotics in the treatment of early-onset schizophrenia

    Directory of Open Access Journals (Sweden)

    Hrdlicka M

    2015-04-01

    Full Text Available Michal Hrdlicka, Iva Dudova Department of Child Psychiatry, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic Abstract: Atypical antipsychotics (AAPs have been successfully used in early-onset schizophrenia (EOS. This review summarizes the randomized, double-blind, controlled studies of AAPs in EOS, including clozapine, risperidone, olanzapine, aripiprazole, paliperidone, quetiapine, and ziprasidone. No significant differences in efficacy between AAPs were found, with the exception of clozapine and ziprasidone. Clozapine demonstrated superior efficacy in treatment-resistant patients with EOS, whereas ziprasidone failed to demonstrate efficacy in the treatment of EOS. Our review also focuses on the onset of action and weight gain associated with AAPs. The data on onset of action of AAPs in pediatric psychiatry are scanty and inconsistent. Olanzapine appears to cause the most significant weight gain in patients with EOS, while ziprasidone and aripiprazole seem to cause the least. Keywords: early-onset schizophrenia, atypical antipsychotics, efficacy, onset of action, weight gain

  4. Breast Metastases from Extramammary Malignancies: Typical and Atypical Ultrasound Features

    International Nuclear Information System (INIS)

    Mun, Sung Hee; Ko, Eun Young; Han, Boo-Kyung; Shin, Jung Hee; Kim, Suk Jung; Cho, Eun Yoon

    2014-01-01

    Breast metastases from extramammary malignancies are uncommon. The most common sources are lymphomas/leukemias and melanomas. Some of the less common sources include carcinomas of the lung, ovary, and stomach, and infrequently, carcinoid tumors, hypernephromas, carcinomas of the liver, tonsil, pleura, pancreas, cervix, perineum, endometrium and bladder. Breast metastases from extramammary malignancies have both hematogenous and lymphatic routes. According to their routes, there are common radiological features of metastatic diseases of the breast, but the features are not specific for metastases. Typical ultrasound (US) features of hematogenous metastases include single or multiple, round to oval shaped, well-circumscribed hypoechoic masses without spiculations, calcifications, or architectural distortion; these masses are commonly located superficially in subcutaneous tissue or immediately adjacent to the breast parenchyma that is relatively rich in blood supply. Typical US features of lymphatic breast metastases include diffusely and heterogeneously increased echogenicities in subcutaneous fat and glandular tissue and a thick trabecular pattern with secondary skin thickening, lymphedema, and lymph node enlargement. However, lesions show variable US features in some cases, and differentiation of these lesions from primary breast cancer or from benign lesions is difficult. In this review, we demonstrate various US appearances of breast metastases from extramammary malignancies as typical and atypical features, based on the results of US and other imaging studies performed at our institution. Awareness of the typical and atypical imaging features of these lesions may be helpful to diagnose metastatic lesions of the breast

  5. Signaling network of the Btk family kinases.

    Science.gov (United States)

    Qiu, Y; Kung, H J

    2000-11-20

    The Btk family kinases represent new members of non-receptor tyrosine kinases, which include Btk/Atk, Itk/Emt/Tsk, Bmx/Etk, and Tec. They are characterized by having four structural modules: PH (pleckstrin homology) domain, SH3 (Src homology 3) domain, SH2 (Src homology 2) domain and kinase (Src homology 1) domain. Increasing evidence suggests that, like Src-family kinases, Btk family kinases play central but diverse modulatory roles in various cellular processes. They participate in signal transduction in response to virtually all types of extracellular stimuli which are transmitted by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen-receptors and integrins. They are regulated by many non-receptor tyrosine kinases such as Src, Jak, Syk and FAK family kinases. In turn, they regulate many of major signaling pathways including those of PI3K, PLCgamma and PKC. Both genetic and biochemical approaches have been used to dissect the signaling pathways and elucidate their roles in growth, differentiation and apoptosis. An emerging new role of this family of kinases is cytoskeletal reorganization and cell motility. The physiological importance of these kinases was amply demonstrated by their link to the development of immunodeficiency diseases, due to germ-line mutations. The present article attempts to review the structure and functions of Btk family kinases by summarizing our current knowledge on the interacting partners associated with the different modules of the kinases and the diverse signaling pathways in which they are involved.

  6. Receptor-interacting protein (RIP) kinase family

    Science.gov (United States)

    Zhang, Duanwu; Lin, Juan; Han, Jiahuai

    2010-01-01

    Receptor-interacting protein (RIP) kinases are a group of threonine/serine protein kinases with a relatively conserved kinase domain but distinct non-kinase regions. A number of different domain structures, such as death and caspase activation and recruitment domain (CARD) domains, were found in different RIP family members, and these domains should be keys in determining the specific function of each RIP kinase. It is known that RIP kinases participate in different biological processes, including those in innate immunity, but their downstream substrates are largely unknown. This review will give an overview of the structures and functions of RIP family members, and an update of recent progress in RIP kinase research. PMID:20383176

  7. MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA-Dependent Mechanism.

    Directory of Open Access Journals (Sweden)

    Laura P Bernard

    Full Text Available The Par1 kinases, also known as microtubule affinity-regulating kinases (MARKs, are important for the establishment of cell polarity from worms to mammals. Dysregulation of these kinases has been implicated in autism, Alzheimer's disease and cancer. Despite their important function in health and disease, it has been unclear how the activity of MARK/Par1 is regulated by signals from cell surface receptors. Here we show that MARK/Par1 is activated downstream of NMDA receptors in primary hippocampal neurons. Further, we show that this activation is dependent on protein kinase A (PKA, through the phosphorylation of Ser431 of Par4/LKB1, the major upstream kinase of MARK/Par1. Together, our data reveal a novel mechanism by which MARK/Par1 is activated at the neuronal synapse.

  8. Oncoprotein protein kinase antibody kit

    Science.gov (United States)

    Karin, Michael [San Diego, CA; Hibi, Masahiko [San Diego, CA; Lin, Anning [La Jolla, CA

    2008-12-23

    An isolated polypeptide (JNK) characterized by having a molecular weight of 46 kD as determined by reducing SDS-PAGE, having serine and threonine kinase activity, phosphorylating the c-Jun N-terminal activation domain and polynucleotide sequences and method of detection of JNK are provided herein. JNK phosphorylates c-Jun N-terminal activation domain which affects gene expression from AP-1 sites.

  9. Thymidine kinase diversity in bacteria

    DEFF Research Database (Denmark)

    Sandrini, Michael; Clausen, A.R.; Munch-Petersen, B.

    2006-01-01

    Thymidine kinases (TKs) appear to be almost ubiquitous and are found in nearly all prokaryotes, eukaryotes, and several viruses. They are the key enzymes in thymidine salvage and activation of several anti-cancer and antiviral drugs. We show that bacterial TKs can be subdivided into 2 groups. The....... The TKs from Gram-positive bacteria are more closely related to the eukaryotic TK1 enzymes than are TKs from Gram-negative bacteria....

  10. Direct gaze elicits atypical activation of the theory-of-mind network in autism spectrum conditions.

    Science.gov (United States)

    von dem Hagen, Elisabeth A H; Stoyanova, Raliza S; Rowe, James B; Baron-Cohen, Simon; Calder, Andrew J

    2014-06-01

    Eye contact plays a key role in social interaction and is frequently reported to be atypical in individuals with autism spectrum conditions (ASCs). Despite the importance of direct gaze, previous functional magnetic resonance imaging in ASC has generally focused on paradigms using averted gaze. The current study sought to determine the neural processing of faces displaying direct and averted gaze in 18 males with ASC and 23 matched controls. Controls showed an increased response to direct gaze in brain areas implicated in theory-of-mind and gaze perception, including medial prefrontal cortex, temporoparietal junction, posterior superior temporal sulcus region, and amygdala. In contrast, the same regions showed an increased response to averted gaze in individuals with an ASC. This difference was confirmed by a significant gaze direction × group interaction. Relative to controls, participants with ASC also showed reduced functional connectivity between these regions. We suggest that, in the typical brain, perceiving another person gazing directly at you triggers spontaneous attributions of mental states (e.g. he is "interested" in me), and that such mental state attributions to direct gaze may be reduced or absent in the autistic brain.

  11. Multimodal imaging of temporal processing in typical and atypical language development.

    Science.gov (United States)

    Kovelman, Ioulia; Wagley, Neelima; Hay, Jessica S F; Ugolini, Margaret; Bowyer, Susan M; Lajiness-O'Neill, Renee; Brennan, Jonathan

    2015-03-01

    New approaches to understanding language and reading acquisition propose that the human brain's ability to synchronize its neural firing rate to syllable-length linguistic units may be important to children's ability to acquire human language. Yet, little evidence from brain imaging studies has been available to support this proposal. Here, we summarize three recent brain imaging (functional near-infrared spectroscopy (fNIRS), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG)) studies from our laboratories with young English-speaking children (aged 6-12 years). In the first study (fNIRS), we used an auditory beat perception task to show that, in children, the left superior temporal gyrus (STG) responds preferentially to rhythmic beats at 1.5 Hz. In the second study (fMRI), we found correlations between children's amplitude rise-time sensitivity, phonological awareness, and brain activation in the left STG. In the third study (MEG), typically developing children outperformed children with autism spectrum disorder in extracting words from rhythmically rich foreign speech and displayed different brain activation during the learning phase. The overall findings suggest that the efficiency with which left temporal regions process slow temporal (rhythmic) information may be important for gains in language and reading proficiency. These findings carry implications for better understanding of the brain's mechanisms that support language and reading acquisition during both typical and atypical development. © 2014 New York Academy of Sciences.

  12. Atypical frontal-posterior synchronization of Theory of Mind regions in autism during mental state attribution.

    Science.gov (United States)

    Kana, Rajesh K; Keller, Timothy A; Cherkassky, Vladimir L; Minshew, Nancy J; Just, Marcel Adam

    2009-01-01

    This study used fMRI to investigate the functioning of the Theory of Mind (ToM) cortical network in autism during the viewing of animations that in some conditions entailed the attribution of a mental state to animated geometric figures. At the cortical level, mentalizing (attribution of metal states) is underpinned by the coordination and integration of the components of the ToM network, which include the medial frontal gyrus, the anterior paracingulate, and the right temporoparietal junction. The pivotal new finding was a functional underconnectivity (a lower degree of synchronization) in autism, especially in the connections between frontal and posterior areas during the attribution of mental states. In addition, the frontal ToM regions activated less in participants with autism relative to control participants. In the autism group, an independent psychometric assessment of ToM ability and the activation in the right temporoparietal junction were reliably correlated. The results together provide new evidence for the biological basis of atypical processing of ToM in autism, implicating the underconnectivity between frontal regions and more posterior areas.

  13. Familial Atypical Hemolytic Uremic Syndrome: A Review of Its Genetic and Clinical Aspects

    Directory of Open Access Journals (Sweden)

    Fengxiao Bu

    2012-01-01

    Full Text Available Atypical hemolytic uremic syndrome (aHUS is a rare renal disease (two per one million in the USA characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Both sporadic (80% of cases and familial (20% of cases forms are recognized. The study of familial aHUS has implicated genetic variation in multiple genes in the complement system in disease pathogenesis, helping to define the mechanism whereby complement dysregulation at the cell surface level leads to both sporadic and familial disease. This understanding has culminated in the use of Eculizumab as first-line therapy in disease treatment, significantly changing the care and prognosis of affected patients. However, even with this bright outlook, major challenges remain to understand the complexity of aHUS at the genetic level. It is possible that a more detailed picture of aHUS can be translated to an improved understanding of disease penetrance, which is highly variable, and response to therapy, both in the short and long terms.

  14. Structural and biochemical analysis of atypically low dephosphorylating activity of human dual-specificity phosphatase 28.

    Directory of Open Access Journals (Sweden)

    Bonsu Ku

    Full Text Available Dual-specificity phosphatases (DUSPs constitute a subfamily of protein tyrosine phosphatases, and are intimately involved in the regulation of diverse parameters of cellular signaling and essential biological processes. DUSP28 is one of the DUSP subfamily members that is known to be implicated in the progression of hepatocellular and pancreatic cancers, and its biological functions and enzymatic characteristics are mostly unknown. Herein, we present the crystal structure of human DUSP28 determined to 2.1 Å resolution. DUSP28 adopts a typical DUSP fold, which is composed of a central β-sheet covered by α-helices on both sides and contains a well-ordered activation loop, as do other enzymatically active DUSP proteins. The catalytic pocket of DUSP28, however, appears hardly accessible to a substrate because of the presence of nonconserved bulky residues in the protein tyrosine phosphatase signature motif. Accordingly, DUSP28 showed an atypically low phosphatase activity in the biochemical assay, which was remarkably improved by mutations of two nonconserved residues in the activation loop. Overall, this work reports the structural and biochemical basis for understanding a putative oncological therapeutic target, DUSP28, and also provides a unique mechanism for the regulation of enzymatic activity in the DUSP subfamily proteins.

  15. Early Cretaceous MORB-type basalt and A-type rhyolite in northern Tibet: Evidence for ridge subduction in the Bangong-Nujiang Tethyan Ocean

    Science.gov (United States)

    Fan, Jian-Jun; Li, Cai; Sun, Zhen-Ming; Xu, Wei; Wang, Ming; Xie, Chao-Ming

    2018-04-01

    New zircon U-Pb ages, major- and trace-element data, and Hf isotopic compositions are presented for bimodal volcanic rocks of the Zhaga Formation (ZF) in the western-middle segment of the Bangong-Nujiang suture zone (BNSZ), northern Tibet. The genesis of these rocks is described, and implications for late-stage evolution of the Bangong-Nujiang Tethyan Ocean (BNTO) are considered. Detailed studies show that the ZF bimodal rocks, which occur as layers within a typical bathyal to abyssal flysch deposit, comprise MORB-type basalt that formed at a mid-ocean ridge, and low-K calc-alkaline A-type rhyolite derived from juvenile crust. The combination of MORB-type basalt, calc-alkaline A-type rhyolite, and bathyal to abyssal flysch deposits in the ZF leads us to propose that they formed as a result of ridge subduction. The A-type ZF rhyolites yield LA-ICP-MS zircon U-Pb ages of 118-112 Ma, indicating formation during the Early Cretaceous. Data from the present study, combined with regional geological data, indicate that the BNTO underwent conversion from ocean opening to ocean closure during the Late Jurassic-Early Cretaceous. The eastern segment of the BNTO closed during this period, while the western and western-middle segments were still at least partially open and active during the Early Cretaceous, accompanied by ridge subduction within the Bangong-Nujiang Tethyan Ocean.

  16. Cognitive Function and Depression in Symptom Resolution in Schizophrenia Patients Treated with an Atypical Antipsychotic

    Science.gov (United States)

    Stip, Emmanuel; Mancini-Marie, Adham

    2004-01-01

    Objective: To investigate which cognitive and affective features contribute most to responder/non-responder group separation during a switching trial with atypical antipsychotic. Design: A prospective open trial with an atypical antipsychotic (olanzapine). Patients: One hundred and thirty-four patients meeting diagnostic criteria for…

  17. Self-limiting atypical antipsychotics-induced edema: Clinical cases and systematic review

    OpenAIRE

    Musa Usman Umar; Aminu Taura Abdullahi

    2016-01-01

    A number of atypical antipsychotics have been associated with peripheral edema. The exact cause is not known. We report two cases of olanzapine-induced edema and a brief review of atypical antipsychotic-induced edema, possible risk factors, etiology, and clinical features. The recommendation is given on different methods of managing this side effect.

  18. Self-limiting Atypical Antipsychotics-induced Edema: Clinical Cases and Systematic Review.

    Science.gov (United States)

    Umar, Musa Usman; Abdullahi, Aminu Taura

    2016-01-01

    A number of atypical antipsychotics have been associated with peripheral edema. The exact cause is not known. We report two cases of olanzapine-induced edema and a brief review of atypical antipsychotic-induced edema, possible risk factors, etiology, and clinical features. The recommendation is given on different methods of managing this side effect.

  19. Self-limiting Atypical Antipsychotics-induced Edema: Clinical Cases and Systematic Review

    Science.gov (United States)

    Umar, Musa Usman; Abdullahi, Aminu Taura

    2016-01-01

    A number of atypical antipsychotics have been associated with peripheral edema. The exact cause is not known. We report two cases of olanzapine-induced edema and a brief review of atypical antipsychotic-induced edema, possible risk factors, etiology, and clinical features. The recommendation is given on different methods of managing this side effect. PMID:27335511

  20. Childhood Atypical Teratoid/Rhabdoid Tumor Treatment (PDQ®)—Patient Version

    Science.gov (United States)

    Atypical teratoid/rhabdoid tumor (AT/RT) is a fast-growing tumor of the brain or spinal cord. Treatment may include surgery, radiation therapy, and chemotherapy. Get information about the symptoms, diagnosis, prognosis, and treatment of newly diagnosed and recurrent childhood atypical teratoid/rhabdoid tumors in this expert-reviewed summary.

  1. Atypical Speech and Language Development: A Consensus Study on Clinical Signs in the Netherlands

    Science.gov (United States)

    Visser-Bochane, Margot I.; Gerrits, Ellen; van der Schans, Cees P.; Reijneveld, Sijmen A.; Luinge, Margreet R.

    2017-01-01

    Background: Atypical speech and language development is one of the most common developmental difficulties in young children. However, which clinical signs characterize atypical speech-language development at what age is not clear. Aim: To achieve a national and valid consensus on clinical signs and red flags (i.e. most urgent clinical signs) for…

  2. Atypical bulimia nervosa in a male patient of rural north-east India

    Directory of Open Access Journals (Sweden)

    Manabendra Makhal

    2014-01-01

    Full Text Available Eating disorders such as bulimia nervosa rarely seem to manifest in males from non-Western cultures like India, but occur infrequently in milder forms with fewer symptoms as atypical bulimia nervosa. This report describes a male case of bulimia nervosa from rural area of India presenting with atypical features. He was treated successfully with fluoxetine and cognitive behavioural therapy.

  3. Atypical imaging of spinal tuberculosis: a case report and review of ...

    African Journals Online (AJOL)

    ... is a rare imaging manifestation and diagnosis was confirmed by pathology after the surgery. Therefore atypical imaging is often appeared in clinical practice and it is meaningful and necessary for the diagnosis of atypical spinal tuberculosis combined with multiple organ tuberculosis. Pan African Medical Journal 2016; 24 ...

  4. A critical analysis of the new equal pay provisions relating to atypical ...

    African Journals Online (AJOL)

    Keywords: Equal pay; Labour Relations Act; equal pay for atypical employees; atypical employment; sections 198A-198D of the Labour Relations Act; Agency Workers Regulations 2010; Fixed-term Employees (Prevention of Less Favourable Treatment) Regulations 2002; Part-time Workers (Prevention of Less Favourable ...

  5. The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain

    DEFF Research Database (Denmark)

    Appel, Camilla Kristine; Gallego-Pedersen, Simone; Andersen, Line

    2017-01-01

    Pain is a severe and debilitating complication of metastatic bone cancer. Current analgesics do not provide sufficient pain relief for all patients, creating a great need for new treatment options. The Src kinase, a non-receptor protein tyrosine kinase, is implicated in processes involved in cancer......-induced bone pain, including cancer growth, osteoclastic bone degradation and nociceptive signalling. Here we investigate the role of dasatinib, an oral Src kinase family and Bcr-Abl tyrosine kinase inhibitor, in an animal model of cancer-induced bone pain. Daily administration of dasatinib (15 mg/kg, p...

  6. A proteomic approach for comprehensively screening substrates of protein kinases such as Rho-kinase.

    Directory of Open Access Journals (Sweden)

    Mutsuki Amano

    Full Text Available BACKGROUND: Protein kinases are major components of signal transduction pathways in multiple cellular processes. Kinases directly interact with and phosphorylate downstream substrates, thus modulating their functions. Despite the importance of identifying substrates in order to more fully understand the signaling network of respective kinases, efficient methods to search for substrates remain poorly explored. METHODOLOGY/PRINCIPAL FINDINGS: We combined mass spectrometry and affinity column chromatography of the catalytic domain of protein kinases to screen potential substrates. Using the active catalytic fragment of Rho-kinase/ROCK/ROK as the model bait, we obtained about 300 interacting proteins from the rat brain cytosol fraction, which included the proteins previously reported as Rho-kinase substrates. Several novel interacting proteins, including doublecortin, were phosphorylated by Rho-kinase both in vitro and in vivo. CONCLUSIONS/SIGNIFICANCE: This method would enable identification of novel specific substrates for kinases such as Rho-kinase with high sensitivity.

  7. Atypical antipsychotics: trends in analysis and sample preparation of various biological samples.

    Science.gov (United States)

    Fragou, Domniki; Dotsika, Spyridoula; Sarafidou, Parthena; Samanidou, Victoria; Njau, Samuel; Kovatsi, Leda

    2012-05-01

    Atypical antipsychotics are increasingly popular and increasingly prescribed. In some countries, they can even be obtained over-the-counter, without a prescription, making their abuse quite easy. Although atypical antipsychotics are thought to be safer than typical antipsychotics, they still have severe side effects. Intoxications are not rare and some of them have a fatal outcome. Drug interactions involving atypical antipsychotics complicate patient management in clinical settings and the determination of the cause of death in fatalities. In view of the above, analytical strategies that can efficiently isolate atypical antipsychotics from a variety of biological samples and quantify them accurately, sensitively and reliably, are of utmost importance both for the clinical, as well as for the forensic toxicologist. In this review, we will present and discuss novel analytical strategies that have been developed from 2004 to the present day for the determination of atypical antipsychotics in various biological samples.

  8. Plant Rho-type (Rop) GTPase-dependent activation of receptor-like cytoplasmic kinases in vitro.

    Science.gov (United States)

    Dorjgotov, Dulguun; Jurca, Manuela E; Fodor-Dunai, Csilla; Szucs, Attila; Otvös, Krisztina; Klement, Eva; Bíró, Judit; Fehér, Attila

    2009-04-02

    Plants have evolved distinct mechanisms to link Rho-type (Rop) GTPases to downstream signaling pathways as compared to other eukaryotes. Here, experimental data are provided that members of the Medicago, as well as Arabidopsis, receptor-like cytoplasmic kinase family (RLCK Class VI) were strongly and specifically activated by GTP-bound Rop GTPases in vitro. Deletion analysis indicated that the residues implicated in the interaction might be distributed on various parts of the kinases. Using a chimaeric Rop GTPase protein, the importance of the Rho-insert region in kinase activation could also be verified. These data strengthen the possibility that RLCKs may serve as Rop GTPase effectors in planta.

  9. Kinases Involved in Both Autophagy and Mitosis.

    Science.gov (United States)

    Li, Zhiyuan; Zhang, Xin

    2017-08-31

    Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in almost all physiological and pathological conditions. Mitosis is a key event during the cell cycle, in which the cell divides into two daughter cells. Autophagy is a process in which the cell digests its own cellular contents. Although autophagy regulation has mainly been studied in asynchronous cells, increasing evidence indicates that autophagy is in fact tightly regulated in mitosis. Here in this review, we will discuss kinases that were originally identified to be involved in only one of either mitosis or autophagy, but were later found to participate in both processes, such as CDKs (cyclin-dependent kinases), Aurora kinases, PLK-1 (polo-like kinase 1), BUB1 (budding uninhibited by benzimidazoles 1), MAPKs (mitogen-activated protein kinases), mTORC1 (mechanistic target of rapamycin complex 1), AMPK (AMP-activated protein kinase), PI3K (phosphoinositide-3 kinase) and protein kinase B (AKT). By focusing on kinases involved in both autophagy and mitosis, we will get a more comprehensive understanding about the reciprocal regulation between the two key cellular events, which will also shed light on their related therapeutic investigations.

  10. Kinases Involved in Both Autophagy and Mitosis

    Directory of Open Access Journals (Sweden)

    Zhiyuan Li

    2017-08-01

    Full Text Available Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in almost all physiological and pathological conditions. Mitosis is a key event during the cell cycle, in which the cell divides into two daughter cells. Autophagy is a process in which the cell digests its own cellular contents. Although autophagy regulation has mainly been studied in asynchronous cells, increasing evidence indicates that autophagy is in fact tightly regulated in mitosis. Here in this review, we will discuss kinases that were originally identified to be involved in only one of either mitosis or autophagy, but were later found to participate in both processes, such as CDKs (cyclin-dependent kinases, Aurora kinases, PLK-1 (polo-like kinase 1, BUB1 (budding uninhibited by benzimidazoles 1, MAPKs (mitogen-activated protein kinases, mTORC1 (mechanistic target of rapamycin complex 1, AMPK (AMP-activated protein kinase, PI3K (phosphoinositide-3 kinase and protein kinase B (AKT. By focusing on kinases involved in both autophagy and mitosis, we will get a more comprehensive understanding about the reciprocal regulation between the two key cellular events, which will also shed light on their related therapeutic investigations.

  11. Glycogen synthase kinase 3: more than a namesake.

    Science.gov (United States)

    Rayasam, Geetha Vani; Tulasi, Vamshi Krishna; Sodhi, Reena; Davis, Joseph Alex; Ray, Abhijit

    2009-03-01

    Glycogen synthase kinase 3 (GSK3), a constitutively acting multi-functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. These diverse multiple functions attributed to GSK3 can be explained by variety of substrates like glycogen synthase, tau protein and beta catenin that are phosphorylated leading to their inactivation. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin-mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity. The primary concern is developing inhibitors of GSK3 that are anti-diabetic but do not lead to up-regulation of oncogenes. The focus of this review is the recent advances and the challenges surrounding GSK3 as an anti-diabetic therapeutic target.

  12. Potassium and ANO1/TMEM16A chloride channel profiles distinguish atypical and typical smooth muscle cells from interstitial cells in the mouse renal pelvis

    Science.gov (United States)

    Iqbal, Javed; Tonta, Mary A; Mitsui, Retsu; Li, Qun; Kett, Michelle; Li, Jinhua; Parkington, Helena C; Hashitani, Hikaru; Lang, Richard J

    2012-01-01

    BACKGROUND AND PURPOSE Although atypical smooth muscle cells (SMCs) in the proximal renal pelvis are thought to generate the pacemaker signals that drive pyeloureteric peristalsis, their location and electrical properties remain obscure. EXPERIMENTAL APPROACH Standard patch clamp, intracellular microelectrode and immunohistochemistry techniques were used. To unequivocally identify SMCs, transgenic mice with enhanced yellow fluorescent protein (eYFP) expressed in cells containing α-smooth muscle actin (α-SMA) were sometimes used. KEY RESULTS Atypical SMCs were distinguished from typical SMCs by the absence of both a transient 4-aminopyridine-sensitive K+ current (IKA) and spontaneous transient outward currents (STOCs) upon the opening of large-conductance Ca2+-activated K+ (BK) channels. Many typical SMCs displayed a slowly activating, slowly decaying Cl- current blocked by niflumic acid (NFA). Immunostaining for KV4.3 and ANO1/ TMEM16A Cl- channel subunits co-localized with α-SMA immunoreactive product predominately in the distal renal pelvis. Atypical SMCs fired spontaneous inward currents that were either selective for Cl- and blocked by NFA, or cation-selective and blocked by La3+. α-SMA- interstitial cells (ICs) were distinguished by the presence of a Xe991-sensitive KV7 current, BK channel STOCs and Cl- selective, NFA-sensitive spontaneous transient inward currents (STICs). Intense ANO1/ TMEM16A and KV7.5 immunostaining was present in Kit-α-SMA- ICs in the suburothelial and adventitial regions of the renal pelvis. CONCLUSIONS AND IMPLICATIONS We conclude that KV4.3+α-SMA+ SMCs are typical SMCs that facilitate muscle wall contraction, that ANO1/ TMEM16A and KV7.5 immunoreactivity may be selective markers of Kit- ICs and that atypical SMCs which discharge spontaneous inward currents are the pelviureteric pacemakers. PMID:22014103

  13. Phelan-McDermid syndrome in two adult brothers: atypical bipolar disorder as its psychopathological phenotype?

    Directory of Open Access Journals (Sweden)

    Verhoeven WMA

    2012-04-01

    with associated autistic-like features, whereas its psychopathological phenotype comprises an atypical bipolar disorder. The latter may have implications for the treatment regime of the syndrome-related behavioral disturbances.Keywords: 22q13.3 deletion syndrome, 22qter, Phelan-McDermid, SHANK3, autism spectrum, unstable mood disorder, cerebellar vermis

  14. Prodromal Symptoms and Atypical Affectivity as Predictors of Major Depression in Juveniles: Implications for Prevention

    Science.gov (United States)

    Kovacs, Maria; Lopez-Duran, Nestor

    2010-01-01

    Background: Given the long-term morbidity of juvenile-onset major depressive disorder (MDD), it is timely to consider whether more effort should be dedicated to its primary and secondary prevention. Methods: We reviewed studies of prodromal symptoms that may herald a first episode pediatric MDD and considered whether that literature has made an…

  15. Early adversity and learning: implications for typical and atypical behavioral development.

    Science.gov (United States)

    Hanson, Jamie L; van den Bos, Wouter; Roeber, Barbara J; Rudolph, Karen D; Davidson, Richard J; Pollak, Seth D

    2017-07-01

    Children who experience early adversity often develop emotion regulatory problems, but little is known about the mechanisms that mediate this relation. We tested whether general associative learning processes contribute to associations between adversity, in the form of child maltreatment, and negative behavioral outcomes. Eighty-one participants between 12 and 17 years of age were recruited for this study and completed a probabilistic learning Task. Forty-one of these participants had been exposed to physical abuse, a form of early adversity. Forty additional participants without any known history of maltreatment served as a comparison group. All participants (and their parents) also completed portions of the Youth Life Stress Interview to understand adolescent's behavior. We calculated measures of associative learning, and also constructed mathematical models of learning. We found that adolescents exposed to high levels of adversity early in their lives had lower levels of associative learning than comparison adolescents. In addition, we found that impaired associative learning partially explained the higher levels of behavioral problems among youth who suffered early adversity. Using mathematical models, we also found that two components of learning were specifically affected in children exposed to adversity: choice variability and biases in their beliefs about the likelihood of rewards in the environment. Participants who had been exposed to early adversity were less able than their peers to correctly learn which stimuli were likely to result in reward, even after repeated feedback. These individuals also used information about known rewards in their environments less often. In addition, individuals exposed to adversity made decisions early in the learning process as if rewards were less consistent and occurred more at random. These data suggest one mechanism through which early life experience shapes behavioral development. © 2017 Association for Child and Adolescent Mental Health.

  16. Gaze Perception Develops Atypically in Children with Autism

    Directory of Open Access Journals (Sweden)

    Simon Webster

    2011-01-01

    Full Text Available The Mindblindness model is the main model of social cognitive development in autism. This model assumes that eye direction detection and eye contact detection develop typically in autism (Baron-Cohen, 1995. The model's assumption of maturational development implies that when these skills are abnormal, they must either be absent or developmentally delayed. In contrast, the atypical modularisation hypothesis predicts that these skills can develop deviantly—successfully but atypically—in children with autism. Two computer-based tasks were used to assess eye direction detection and eye contact detection in children with autism and in typically developing children. These skills were developmentally deviant in children with autism. The findings support a model of social cognition in autism that accounts for developmental processes.

  17. A case of atypical adult-onset tic disorder.

    Science.gov (United States)

    Colosimo, Carlo

    2015-04-01

    The differential diagnosis of adult tic disorder is complex, and several common and uncommon causes have to be taken into consideration. A 30-year-old man came to our movement disorders clinic with multiple tics which had begun insidiously about 10 years earlier. No family history was reported, but his 65-year-old otherwise healthy father also had very subtle involuntary movements. A diagnosis of atypical Gilles de la Tourette syndrome was made. However, the neurological and psychiatric symptoms of the patient rapidly progressed over the following 2 years, resulting in increasingly severe involuntary movements and profound mood disorder. Further diagnostic tests were performed, and a genetic screening for Huntington disease revealed 45 repeats of the CAG nucleotide in the IT-15 gene. This case underlines the marked phenotypic variability of Huntington disease at presentation, including the presence of involuntary movements different from chorea and possibility of an apparently sporadic disorder.

  18. Atypical presentation of dopa-responsive dystonia in Taiwan.

    Science.gov (United States)

    Weng, Yi Ching; Wang, Chun Chieh; Wu, Yih Ru

    2018-02-01

    The typical clinical presentation of dopa-responsive dystonia, which is also called Segawa disease, is a young age of onset, with predominance in females, diurnal fluctuation of lower limb dystonia, and fair response to low-dose levodopa. This disease has both autosomal dominant and autosomal recessive inheritance. Autosomal dominant Segawa disease is caused by GCH1 mutation on chromosome 14q22.1-q22.2. Here, we report the case of a male patient with genetically confirmed Segawa disease and atypical presentations including no diurnal symptom fluctuation and insufficient response to levodopa. The patient's father who had the same mutation presented parkinsonism in old age. We also review the literature to address the broad clinical heterogeneity of Segawa disease and the influence of onset age on clinical presentation.

  19. Atypical antipsychotic usage among Asian Americans and Pacific Islanders.

    Science.gov (United States)

    Takeshita, Junji; Goebert, Deborah; Else, Iwalani; Carlton, Barry; Matsu, Courtenay; Guerrero, Anthony

    2014-09-01

    Previous studies have shown significant ethnic differences in prescribing patterns of two or more antipsychotics. This study examined changes in atypical and typical antipsychotic prescriptions among Asian Americans and Pacific Islanders. Five hundred consecutive charts were reviewed for antipsychotics at the time of admission and discharge from each of two inpatient psychiatric facilities in Hawai'i. Multiple antipsychotic prescription rates were 9% at intake and 6% at discharge. For the ethnic groups studied, there were no statistically significant differences by patient ethnicity regarding antipsychotics at intake (χ(2) = 29.2, df = 21, P = .110) or discharge (χ(2) = 20.5, df = 24, P = .667). There were no significant differences in prescription and polypharmacy patterns among Asian Americans and Pacific Islanders ethnic groups in this study.

  20. Atypical Exit Wound in High-Voltage Electrocution.

    Science.gov (United States)

    Parakkattil, Jamshid; Kandasamy, Shanmugam; Das, Siddhartha; Devnath, Gerard Pradeep; Chaudhari, Vinod Ashok; Shaha, Kusa Kumar

    2017-12-01

    Electrocution fatality cases are difficult to investigate. High-voltage electrocution burns resemble burns caused by other sources, especially if the person survives for few days. In that case, circumstantial evidence if correlated with the autopsy findings helps in determining the cause and manner of death. In addition, the crime scene findings also help to explain the pattern of injuries observed at autopsy. A farmer came in contact with a high-voltage transmission wire and sustained superficial to deep burns over his body. A charred and deeply scorched area was seen over the face, which was suggestive of the electric entry wound. The exit wound was present over both feet and lower leg and was atypical in the form of a burnt area of peeled blistered skin, charring, and deep scorching. The injuries were correlated with crime scene findings, and the circumstances that lead to his electrocution are discussed here.

  1. Cholesterol granuloma of the orbit: An atypical presentation

    Directory of Open Access Journals (Sweden)

    Syed A R Rizvi

    2014-01-01

    Full Text Available Cholesterol granuloma is a rare, well-defined lesion of the orbit. In the orbit, diploe of the frontal bone is involved almost exclusively. We report an atypical case of cholesterol granuloma involving superomedial quadrant of orbit. A 42-year-old male presented with progressive, painless, proptosis with infero-temporal displacement of left eye. A large mass was felt beneath the bony orbital margin in the superomedial quadrant of the left orbit. Computerized tomography (CT scan revealed an extraconal superomedial, heterogeneous enhancing mass which was isodense with brain and pushing the globe inferolaterally and anteriorly. Excision biopsy of the tumor revealed the typical features of a cholesterol granuloma without any epithelial elements. Cholesterol granuloma of the orbit is a rare entity, but it can be diagnosed and differentiated from other lesions of the superior orbit by its characteristic clinical, radiological and histopathological features. An appropriate intervention in time carries a good prognosis with almost no recurrence.

  2. [Atypical manifestations in familial type 1 Waardenburg syndrome].

    Science.gov (United States)

    Sans, B; Calvas, P; Bazex, J

    1998-01-01

    Waardenburg syndrome is an uncommon genetic disorder. Four clinical types are recognized. Three responsible genes have been identified (PAX 3: for type I syndrome, MITF and EDN3 for types II and IV respectively). We report the case of a patient with Waardenburg type I morphotype who had atypical neurological manifestations. Decisive elements for diagnosis were the presence of Waardenburg syndrome in the family and, in affected kin, a mutation causing a shift in PAX 3 gene reading. This case confirms the variability of Waardenburg signs within one family. The association of unusual neurological manifestations in the proband suggested that Vogt Koyanagi Harada disease may have been associated and may show some relationship with familial Waardenburg syndrome.

  3. Acylcarnitines profile best predicts survival in horses with atypical myopathy.

    Directory of Open Access Journals (Sweden)

    François Boemer

    Full Text Available Equine atypical myopathy (AM is caused by hypoglycin A intoxication and is characterized by a high fatality rate. Predictive estimation of survival in AM horses is necessary to prevent unnecessary suffering of animals that are unlikely to survive and to focus supportive therapy on horses with a possible favourable prognosis of survival. We hypothesized that outcome may be predicted early in the course of disease based on the assumption that the acylcarnitine profile reflects the derangement of muscle energetics. We developed a statistical model to prognosticate the risk of death of diseased animals and found that estimation of outcome may be drawn from three acylcarnitines (C2, C10:2 and C18 -carnitines with a high sensitivity and specificity. The calculation of the prognosis of survival makes it possible to distinguish the horses that will survive from those that will die despite severe signs of acute rhabdomyolysis in both groups.

  4. Acylcarnitines profile best predicts survival in horses with atypical myopathy

    Science.gov (United States)

    Detilleux, Johann; Cello, Christophe; Amory, Hélène; Marcillaud-Pitel, Christel; Richard, Eric; van Galen, Gaby; van Loon, Gunther; Lefère, Laurence; Votion, Dominique-Marie

    2017-01-01

    Equine atypical myopathy (AM) is caused by hypoglycin A intoxication and is characterized by a high fatality rate. Predictive estimation of survival in AM horses is necessary to prevent unnecessary suffering of animals that are unlikely to survive and to focus supportive therapy on horses with a possible favourable prognosis of survival. We hypothesized that outcome may be predicted early in the course of disease based on the assumption that the acylcarnitine profile reflects the derangement of muscle energetics. We developed a statistical model to prognosticate the risk of death of diseased animals and found that estimation of outcome may be drawn from three acylcarnitines (C2, C10:2 and C18 -carnitines) with a high sensitivity and specificity. The calculation of the prognosis of survival makes it possible to distinguish the horses that will survive from those that will die despite severe signs of acute rhabdomyolysis in both groups. PMID:28846683

  5. Atypical olfactory groove meningioma associated with uterine fibromatosis; case report

    Directory of Open Access Journals (Sweden)

    Toma I. Papacocea

    2016-11-01

    Full Text Available The concomitant presence of the olfactory groove meningioma with uterine fibrosis is very rare. Our report presents the case of a giant olfactory groove meningioma revealed after a uterine fibroma resection in a 44 years-old female, due to a generalized seizure 10 days after operation. Cranial CT-scan identified the tumor as an olfactory groove meningioma. The tumor was operated with a macroscopically complete resection; the endothermal coagulation of the dura attachment was performed (Simpson II with a good postoperative evolution. Laboratory results showed the presence of receptors for steroid hormones both in meningioma and uterine tumor, and the histopathological examination revealed an atypical meningioma with 17% proliferation markers. Our findings suggest that even though meningiomas are benign tumors and a complete resection usually indicates a good prognosis, the association with uterine fibromatosis and the presence of high percentage of steroid receptors creates a higher risk to relapse, imposing therefore a good monitoring.

  6. Cutaneous atypical mycobacteriosis in a clouded leopard (Neofelis nebulosa).

    Science.gov (United States)

    Cerveny, Shannon N S; Thompson, Michelle E; Corner, Sarah M; Swinford, Amy K; Coke, Rob L

    2013-09-01

    A 16-yr-old male clouded leopard (Neofelis nebulosa) was presented for lethargy and anorexia. A cutaneous abdominal mass extending from the pubis to just caudal to the xiphoid process was present. A biopsy revealed histologic lesions consistent with an atypical mycobacterial infection consisting of diffuse, severe, pyogranulomatous dermatitis and panniculitis, with clear vacuoles and 3-5 microm, intravacuolar, faintly eosinophilic, filamentous bacilli that stained positively with FiteFaraco modified acid-fast stain. The clouded leopard had biochemical findings suggestive of chronic renal failure and euthanasia was elected. Histological evaluation of tissues collected at postmortem examination revealed multicentric B-cell lymphoma involving the oral cavity, liver, spleen, and multiple lymph nodes, bilateral testicular seminomas, thyroid follicular cell adenoma, thyroid C cell adenoma, and biliary cystadenomas. Bacterial culture and molecular sequencing identified the causative agent of the cutaneous abdominal mass as belonging to the Mycobacterium fortuitum group.

  7. [From cradle to grave? Expectations from atypical antipsychotics].

    Science.gov (United States)

    Frecska, Ede

    2005-03-01

    Clinical expectations are high toward atypical, second generation antipsychotics (SGAs). Controlled clinical trials supporting the superiority of SGAs over traditional agents are scarce. Meta-analysis of existing data may come for the rescue but that kind of method has its limitations. One of the most meticulous approaches (Davis et al. 2003) reached the conclusion that some, but not all, SGAs are more efficacious than traditional ones. Within the group of distinguished drugs, clozapine and amisulpride have the highest efficacy. The present paper critically overviews the study of the Davis group. Based on in vivo D2 receptor binding data of the new SGAs and the usual post marketing changes of clinical dosing, it is expected that some of the currently and most recently marketed SGAs may show similar superiority.

  8. Atypical, unusual, and misleading imaging presentations of spondylolysis.

    Science.gov (United States)

    Viana, Sergio Lopes; Viana, Maria Angélica de Carvalho Barbosa; de Alencar, Eduardo Lopes Carreiro

    2015-09-01

    Although lumbar spondylolysis is a widely known and easily recognizable condition in its typical presentation, there are some less well-known forms that may occasionally be challenging and/or demand special attention on imaging. Examples include: acute and/or incomplete lesions; unilateral defects; lesions at unusual levels (cervical, upper lumbar, and multi-level spondylolyses); iatrogenic lesions; non-isthmic spondylolysis; and spondylolysis related to underlying diseases. In addition to their atypical, uncommon or confusing imaging presentations, these forms of spondylolysis are far rarer than the classic type and have been described, to a great extent, in the surgical literature, thus reducing the awareness of radiologists about them and raising the potential for misdiagnosis and inadequate treatment. In this review the authors address these special manifestations of spondylolysis, stressing the more important features to be considered in the differential diagnosis and the impact of a precise diagnosis of spondylolysis on the patient's care.

  9. Atypical distribution of pneumatosis intestinalis in a patient with AIDS.

    Science.gov (United States)

    Sivarajah, Vernon; Ramamurthy, Nitin Kumar; Rowe, Susan; Devalia, Kalpana

    2013-03-27

    An adult patient who had AIDS was admitted to hospital following a fall in which they sustained a T12 vertebral fracture. The patient incidentally was found to have pneumatosis intestinalis upon a thoracolumbar radiograph taken approximately 2 weeks after their admission to the hospital. At this point in time the patient reported having diarrhoea and a distended abdomen. The patient did not have any other medical history of note. Upon examination the patient appeared comfortable. The patient's abdomen was distended but soft and non-tender. Laboratory investigations revealed a chronic normocytic anaemia and neutropenia. It was likely that the pneumatosis intestinalis was AIDS related. A CT scan confirmed its presence but revealed an atypical distribution. Despite its dramatic appearance, the patient was successfully managed conservatively and remained well during admission.

  10. An atypical presentation of cystic fibrosis: a case report

    Directory of Open Access Journals (Sweden)

    Joshi Deepak

    2008-06-01

    Full Text Available Abstract Introduction The presentation of cystic fibrosis is dependant upon which organs are affected. Common presentations include chronic respiratory infections and malabsorption. Patients with atypical disease tend to present late in childhood or as adults. Eye manifestations of cystic fibrosis are less well known. Case presentation A 14-year-old Caucasian boy presented with tiredness and difficulty seeing at night, over a period of 6 months. Good vision was only described in bright conditions. There was no history of jaundice, steatorrhea or diarrhoea. Conclusion This is the first reported case of newly diagnosed cystic fibrosis-related liver disease in a teenage boy, whose presenting symptom was night blindness secondary to vitamin A deficiency.

  11. Synchronous symmetrical atypical osteoid osteoma of tibia: a case report.

    Science.gov (United States)

    Sreenivas, T; Menon, Jagdish; Nataraj, A R

    2012-11-01

    We report a case of synchronous symmetrical osteoid osteoma of tibia which was atypical in its appearance on imaging. Our patient was a 30-year-old woman presented with 2 years history of bilateral leg pain more on the right side. The pain was more during night and relieved on taking salicylates. Laboratory investigations were within normal limits. Radiographs and computed tomography revealed bilateral focal irregular cortical sclerosis with narrowing of medullary canal of mid tibia. The lesion on right side was excised enbloc followed by the lesion on left side 3 months later and histologically confirmed as osteoid osteoma. Initially, we thought it was stress fracture or subacute osteomyelitis but it was in fact histopathology which showed osteoid osteoma. Patient was completely asymptomatic postoperatively.

  12. [Differential diagnosis and atypical subsets of amyotrophic lateral sclerosis].

    Science.gov (United States)

    Pradat, P-F; Bruneteau, G

    2006-06-01

    Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of upper and lower motor neurons. In the absence of any validated biological marker, the diagnosis of ALS depends upon recognition of characteristic symptoms and signs together with supportive electrophysiological findings. The diagnosis of ALS is easy to recognize in its fully developed form but during the early stages both false positive and false negative diagnoses are common. In clinical practice, diagnostic difficulties mostly arise with patients who present either with only upper motor neuron, or with only lower motor neuron signs. It may be difficult to distinguish ALS with clinically predominant lower motor neuron involvement from alternative diagnoses including spinal atrophies of adult onset, Kennedy's disease, inclusion body myositis and motor neuropathies with conduction blocks. The diagnosis of ALS related syndromes (progressive muscular atrophy, primary lateral sclerosis and progressive bulbar palsy) requires the elimination of alternate diagnoses. This paper reviews the main characteristics of diseases mimicking ALS and the atypical subsets of ALS.

  13. [Venous thrombosis of atypical location in patients with cancer].

    Science.gov (United States)

    Campos Balea, Begoña; Sáenz de Miera Rodríguez, Andrea; Antolín Novoa, Silvia; Quindós Varela, María; Barón Duarte, Francisco; López López, Rafael

    2015-01-01

    Venous thromboembolism (VTE) is a complication that frequently occurs in patients with neoplastic diseases. Several models have therefore been developed to identify patient subgroups diagnosed with cancer who are at increased risk of developing VTE. The most common forms of thromboembolic episodes are deep vein thrombosis in the lower limbs and pulmonary thromboembolism. However, venous thrombosis is also diagnosed in atypical locations. There are few revisions of unusual cases of venous thrombosis. In most cases, VTE occurs in the upper limbs and in the presence of central venous catheters, pacemakers and defibrillators. We present the case of a patient diagnosed with breast cancer and treated with surgery, chemotherapy and radiation therapy who developed a thrombosis in the upper limbs (brachial and axillary). Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  14. Atypical teratoid/rhabdoid tumor: an unusual presentation

    International Nuclear Information System (INIS)

    Gandhi, Chirag D.; Krieger, Mark D.; McComb, J. Gordon

    2004-01-01

    Atypical teratoid/ rhabdoid tumor (AT/RT) of the central nervous system is a rare, highly aggressive malignancy of infancy. Although it is reported infrequently in the literature, it has often been histologically confused with a primitive neuroectodermal tumor (PNET)/medulloblastoma (MB) but has a much worse prognosis. We present an infant with two AT/RT tumors, one suprasellar in location and the other within the vermis without evidence of tumor elsewhere. What makes this case unusual is that there were two separate lesions in different cranial compartments, with no evidence of subarachnoid seeding. In addition, the lesions had different magnetic resonance imaging (MRI) characteristics even though they were histologically the same. (orig.)

  15. Tyr721 regulates specific binding of the CSF-1 receptor kinase insert to PI 3'-kinase SH2 domains: a model for SH2-mediated receptor-target interactions.

    Science.gov (United States)

    Reedijk, M; Liu, X; van der Geer, P; Letwin, K; Waterfield, M D; Hunter, T; Pawson, T

    1992-01-01

    Efficient binding of active phosphatidylinositol (PI) 3'-kinase to the autophosphorylated macrophage colony stimulating factor receptor (CSF-1R) requires the noncatalytic kinase insert (KI) region of the receptor. To test whether this region could function independently to bind PI 3'-kinase, the isolated CSF-1R KI was expressed in Escherichia coli, and was inducibly phosphorylated on tyrosine. The tyrosine phosphorylated form of the CSF-1R KI bound PI 3'-kinase in vitro, whereas the unphosphorylated form had no binding activity. The p85 alpha subunit of PI 3'-kinase contains two Src homology (SH)2 domains, which are implicated in the interactions of signalling proteins with activated receptors. Bacterially expressed p85 alpha SH2 domains complexed in vitro with the tyrosine phosphorylated CSF-1R KI. Binding of the CSF-1R KI to PI 3'-kinase activity, and to the p85 alpha SH2 domains, required phosphorylation of Tyr721 within the KI domain, but was independent of phosphorylation at Tyr697 and Tyr706. Tyr721 was also critical for the association of activated CSF-1R with PI 3'-kinase in mammalian cells. Complex formation between the CSF-1R and PI 3'-kinase can therefore be reconstructed in vitro in a specific interaction involving the phosphorylated receptor KI and the SH2 domains of p85 alpha. Images PMID:1314163

  16. Atypical adenocarcinoma of the colon : radiologic-pathologic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young Chan; Ko, Young Tae; Lee, Dong Ho; Yoon, Yup; Lim, Joo Won; Lee, Ju Hie [Kyunghee Univ. Hospital, Seoul (Korea, Republic of)

    1996-06-01

    To analyse unusual radiologic manifestations of colonic adenocarcinoma, and to correlate these with pathologic findings. Radiologic findings of ten patients with atypical adenocarcinoma of the colon were retrospectively evaluated. The unusual radiologic findings were defined as terminal ileal involvement of the cecal mass, long segmental involvement of oner 9cm, and exophytic tumor growth. Radiologic and sonographic findings were compared with pathologic specimens obtained from surgical resection. Involvement of the terminal ileum was noted in three cases, long segmental involvement of 11 cm in five cases, and exophytic mass in two. of three cases with thickening of the terminal ileum, two revealed the infiltration of cancer into the terminal ileum through the ileocecal valve, and the other revealed vascular congesion and edema on microscopic examination. Five cases with long segmental involvement of over 11 cm comprised on e of cancer totally infiltrated through the submucosal and proper muscle layer, one of inflammatory thickening distal to the cancer, two of inflammatory change of pericolic fat and serosal adhesion and one of a large intraluminal fungating mass. In the cases of exophytic mass, one with a larger extraluminal and a smaller intraluminal component revealed necrosis and abscess on pathologic examination, accounting for low attenuation on CT, whereas the other, with exophytic growth, disclosed abundant pools of mucin, resulting in low attenuation on CT. These two cases could not be differentiated from submucosal tumors. Atypical colon cancer may have various manifestations, such as thickening of the terminal ileum, involvement of a long segment, and an exophytically growing mass. An appreciation of the radiologic findings of this cancer may therefore help in differential diagnosis in cases simulating colitis or submucosal tumors of the colon, such as lymphoma or leiomyoma.

  17. DISRUPTION OF CONDITIONED REWARD ASSOCIATION BY TYPICAL AND ATYPICAL ANTIPSYCHOTICS

    Science.gov (United States)

    Danna, C.L.; Elmer, G.I.

    2013-01-01

    Antipsychotic drugs are broadly classified into typical and atypical compounds; they vary in their pharmacological profile however a common component is their antagonist effects at the D2 dopamine receptors (DRD2). Unfortunately, diminished DRD2 activation is generally thought to be associated with the severity of neuroleptic-induced anhedonia. The purpose of this study was to determine the effect of the atypical antipsychotic olanzapine and typical antipsychotic haloperidol in a paradigm that reflects the learned transfer of incentive motivational properties to previously neutral stimuli, namely autoshaping. In order to provide a dosing comparison to a therapeutically relevant endpoint, both drugs were tested against amphetamine-induced disruption of prepulse inhibition as well. In the autoshaping task, rats were exposed to repeated pairings of stimuli that were differentially predictive of reward delivery. Conditioned approach to the reward predictive cue (sign-tracking) and to the reward (goal-tracking) increased during repeated pairings in the vehicle treated rats. Haloperidol and olanzapine completely abolished this behavior at relatively low doses (100 μg/kg). This same dose was the threshold dose for each drug to antagonize the sensorimotor gating deficits produced by amphetamine. At lower doses (3–30 μg/kg) both drugs produced a dose-dependent decrease in conditioned approach to the reward predictive cue. There was no difference between drugs at this dose range which indicates that olanzapine disrupts autoshaping at a significantly lower proposed DRD2 receptor occupancy. Interestingly, neither drug disrupted conditioned approach to the reward at the same dose range that disrupted conditioned approach to the reward predictive cue. Thus, haloperidol and olanzapine, at doses well below what is considered therapeutically relevant, disrupts the attribution of incentive motivational value to previously neutral cues. Drug effects on this dimension of reward

  18. Figurative language processing in atypical populations: The ASD perspective

    Directory of Open Access Journals (Sweden)

    Mila eVulchanova

    2015-02-01

    Full Text Available This paper is intended to provide a critical overview of experimental and clinical research documenting problems in figurative language processing in atypical populations with a focus on the Autistic Spectrum. Research in the comprehension and processing of figurative language in autism invariably documents problems in this area. The greater paradox is that even at the higher end of the spectrum or in the cases of linguistically talented individuals with Asperger syndrome, where structural language competence is intact, problems with extended language persist. If we assume that figurative and extended uses of language essentially depend on the perception and processing of more concrete core concepts and phenomena, the commonly observed failure in atypical populations to understand figurative language remains a puzzle.Various accounts have been offered to explain this issue, ranging from linking potential failure directly to overall structural language competence (Brock et al., 2008; Norbury, 2005 to right-hemispheric involvement (Gold and Faust, 2010. We argue that the dissociation between structural language and figurative language competence in autism should be sought in more general cognitive mechanisms and traits in the autistic phenotype (e.g., in terms of weak central coherence, Vulchanova et al., 2012b, as well as failure at on-line semantic integration with increased complexity and diversity of the stimuli (Coulson and van Petten, 2002. This perspective is even more compelling in light of similar problems in a number of conditions, including both acquired (e.g., Aphasia and developmental disorders (Williams Syndrome. This dissociation argues against a simple continuity view of language interpretation.

  19. Figurative language processing in atypical populations: the ASD perspective.

    Science.gov (United States)

    Vulchanova, Mila; Saldaña, David; Chahboun, Sobh; Vulchanov, Valentin

    2015-01-01

    This paper is intended to provide a critical overview of experimental and clinical research documenting problems in figurative language processing in atypical populations with a focus on the Autistic Spectrum. Research in the comprehension and processing of figurative language in autism invariably documents problems in this area. The greater paradox is that even at the higher end of the spectrum or in the cases of linguistically talented individuals with Asperger syndrome, where structural language competence is intact, problems with extended language persist. If we assume that figurative and extended uses of language essentially depend on the perception and processing of more concrete core concepts and phenomena, the commonly observed failure in atypical populations to understand figurative language remains a puzzle. Various accounts have been offered to explain this issue, ranging from linking potential failure directly to overall structural language competence (Norbury, 2005; Brock et al., 2008) to right-hemispheric involvement (Gold and Faust, 2010). We argue that the dissociation between structural language and figurative language competence in autism should be sought in more general cognitive mechanisms and traits in the autistic phenotype (e.g., in terms of weak central coherence, Vulchanova et al., 2012b), as well as failure at on-line semantic integration with increased complexity and diversity of the stimuli (Coulson and Van Petten, 2002). This perspective is even more compelling in light of similar problems in a number of conditions, including both acquired (e.g., Aphasia) and developmental disorders (Williams Syndrome). This dissociation argues against a simple continuity view of language interpretation.

  20. Figurative language processing in atypical populations: the ASD perspective

    Science.gov (United States)

    Vulchanova, Mila; Saldaña, David; Chahboun, Sobh; Vulchanov, Valentin

    2015-01-01

    This paper is intended to provide a critical overview of experimental and clinical research documenting problems in figurative language processing in atypical populations with a focus on the Autistic Spectrum. Research in the comprehension and processing of figurative language in autism invariably documents problems in this area. The greater paradox is that even at the higher end of the spectrum or in the cases of linguistically talented individuals with Asperger syndrome, where structural language competence is intact, problems with extended language persist. If we assume that figurative and extended uses of language essentially depend on the perception and processing of more concrete core concepts and phenomena, the commonly observed failure in atypical populations to understand figurative language remains a puzzle. Various accounts have been offered to explain this issue, ranging from linking potential failure directly to overall structural language competence (Norbury, 2005; Brock et al., 2008) to right-hemispheric involvement (Gold and Faust, 2010). We argue that the dissociation between structural language and figurative language competence in autism should be sought in more general cognitive mechanisms and traits in the autistic phenotype (e.g., in terms of weak central coherence, Vulchanova et al., 2012b), as well as failure at on-line semantic integration with increased complexity and diversity of the stimuli (Coulson and Van Petten, 2002). This perspective is even more compelling in light of similar problems in a number of conditions, including both acquired (e.g., Aphasia) and developmental disorders (Williams Syndrome). This dissociation argues against a simple continuity view of language interpretation. PMID:25741261

  1. Reversible acute methotrexate leukoencephalopathy: atypical brain MR imaging features

    International Nuclear Information System (INIS)

    Ziereisen, France; Damry, Nash; Christophe, Catherine; Dan, Bernard; Azzi, Nadira; Ferster, Alina

    2006-01-01

    Unusual acute symptomatic and reversible early-delayed leukoencephalopathy has been reported to be induced by methotrexate (MTX). We aimed to identify the occurrence of such atypical MTX neurotoxicity in children and document its MR presentation. We retrospectively reviewed the clinical findings and brain MRI obtained in 90 children treated with MTX for acute lymphoblastic leukaemia or non-B malignant non-Hodgkin lymphoma. All 90 patients had normal brain imaging before treatment. In these patients, brain imaging was performed after treatment completion and/or relapse and/or occurrence of neurological symptoms. Of the 90 patients, 15 (16.7%) showed signs of MTX neurotoxicity on brain MRI, 9 (10%) were asymptomatic, and 6 (6.7%) showed signs of acute leukoencephalopathy. On the routine brain MRI performed at the end of treatment, all asymptomatic patients had classical MR findings of reversible MTX neurotoxicity, such as abnormal high-intensity areas localized in the deep periventricular white matter on T2-weighted images. In contrast, the six symptomatic patients had atypical brain MRI characterized by T2 high-intensity areas in the supratentorial cortex and subcortical white matter (n=6), cerebellar cortex and white matter (n=4), deep periventricular white matter (n=2) and thalamus (n=1). MR normalization occurred later than clinical recovery in these six patients. In addition to mostly asymptomatic classical MTX neurotoxicity, MTX may induce severe but reversible unusual leukoencephalopathy. It is important to recognize this clinicoradiological presentation in the differential diagnosis of acute neurological deterioration in children treated with MTX. (orig.)

  2. Src Family Kinases and p38 Mitogen-Activated Protein Kinases Regulate Pluripotent Cell Differentiation in Culture.

    Directory of Open Access Journals (Sweden)

    Boon Siang Nicholas Tan

    Full Text Available Multiple pluripotent cell populations, which together comprise the pluripotent cell lineage, have been identified. The mechanisms that control the progression between these populations are still poorly understood. The formation of early primitive ectoderm-like (EPL cells from mouse embryonic stem (mES cells provides a model to understand how one such transition is regulated. EPL cells form from mES cells in response to l-proline uptake through the transporter Slc38a2. Using inhibitors of cell signaling we have shown that Src family kinases, p38 MAPK, ERK1/2 and GSK3β are required for the transition between mES and EPL cells. ERK1/2, c-Src and GSK3β are likely to be enforcing a receptive, primed state in mES cells, while Src family kinases and p38 MAPK are involved in the establishment of EPL cells. Inhibition of these pathways prevented the acquisition of most, but not all, features of EPL cells, suggesting that other pathways are required. L-proline activation of differentiation is mediated through metabolism and changes to intracellular metabolite levels, specifically reactive oxygen species. The implication of multiple signaling pathways in the process suggests a model in which the context of Src family kinase activation determines the outcomes of pluripotent cell differentiation.

  3. Src Family Kinases and p38 Mitogen-Activated Protein Kinases Regulate Pluripotent Cell Differentiation in Culture

    Science.gov (United States)

    Tan, Boon Siang Nicholas; Kwek, Joly; Wong, Chong Kum Edwin; Saner, Nicholas J.; Yap, Charlotte; Felquer, Fernando; Morris, Michael B.; Gardner, David K.; Rathjen, Peter D.; Rathjen, Joy

    2016-01-01

    Multiple pluripotent cell populations, which together comprise the pluripotent cell lineage, have been identified. The mechanisms that control the progression between these populations are still poorly understood. The formation of early primitive ectoderm-like (EPL) cells from mouse embryonic stem (mES) cells provides a model to understand how one such transition is regulated. EPL cells form from mES cells in response to l-proline uptake through the transporter Slc38a2. Using inhibitors of cell signaling we have shown that Src family kinases, p38 MAPK, ERK1/2 and GSK3β are required for the transition between mES and EPL cells. ERK1/2, c-Src and GSK3β are likely to be enforcing a receptive, primed state in mES cells, while Src family kinases and p38 MAPK are involved in the establishment of EPL cells. Inhibition of these pathways prevented the acquisition of most, but not all, features of EPL cells, suggesting that other pathways are required. L-proline activation of differentiation is mediated through metabolism and changes to intracellular metabolite levels, specifically reactive oxygen species. The implication of multiple signaling pathways in the process suggests a model in which the context of Src family kinase activation determines the outcomes of pluripotent cell differentiation. PMID:27723793

  4. Receptor Tyrosine Kinases in Drosophila Development

    Science.gov (United States)

    Sopko, Richelle; Perrimon, Norbert

    2013-01-01

    Tyrosine phosphorylation plays a significant role in a wide range of cellular processes. The Drosophila genome encodes more than 20 receptor tyrosine kinases and extensive studies in the past 20 years have illustrated their diverse roles and complex signaling mechanisms. Although some receptor tyrosine kinases have highly specific functions, others strikingly are used in rather ubiquitous manners. Receptor tyrosine kinases regulate a broad expanse of processes, ranging from cell survival and proliferation to differentiation and patterning. Remarkably, different receptor tyrosine kinases share many of the same effectors and their hierarchical organization is retained in disparate biological contexts. In this comprehensive review, we summarize what is known regarding each receptor tyrosine kinase during Drosophila development. Astonishingly, very little is known for approximately half of all Drosophila receptor tyrosine kinases. PMID:23732470

  5. HIV-1 incorporates and proteolytically processes human NDR1 and NDR2 serine-threonine kinases

    International Nuclear Information System (INIS)

    Devroe, Eric; Silver, Pamela A.; Engelman, Alan

    2005-01-01

    Mammalian genomes encode two related serine-threonine kinases, nuclear Dbf2 related (NDR)1 and NDR2, which are homologous to the Saccharomyces cerevisiae Dbf2 kinase. Recently, a yeast genetic screen implicated the Dbf2 kinase in Ty1 retrotransposition. Since several virion-incorporated kinases regulate the infectivity of human immunodeficiency virus type 1 (HIV-1), we speculated that the human NDR1 and NDR2 kinases might play a role in the HIV-1 life cycle. Here we show that the NDR1 and NDR2 kinases were incorporated into HIV-1 particles. Furthermore, NDR1 and NDR2 were cleaved by the HIV-1 protease (PR), both within virions and within producer cells. Truncation at the PR cleavage site altered NDR2 subcellular localization and inhibited NDR1 and NDR2 enzymatic activity. These studies identify two new virion-associated host cell enzymes and suggest a novel mechanism by which HIV-1 alters the intracellular environment of human cells

  6. Identification of Mediator Kinase Substrates in Human Cells using Cortistatin A and Quantitative Phosphoproteomics.

    Science.gov (United States)

    Poss, Zachary C; Ebmeier, Christopher C; Odell, Aaron T; Tangpeerachaikul, Anupong; Lee, Thomas; Pelish, Henry E; Shair, Matthew D; Dowell, Robin D; Old, William M; Taatjes, Dylan J

    2016-04-12

    Cortistatin A (CA) is a highly selective inhibitor of the Mediator kinases CDK8 and CDK19. Using CA, we now report a large-scale identification of Mediator kinase substrates in human cells (HCT116). We identified over 16,000 quantified phosphosites including 78 high-confidence Mediator kinase targets within 64 proteins, including DNA-binding transcription factors and proteins associated with chromatin, DNA repair, and RNA polymerase II. Although RNA-seq data correlated with Mediator kinase targets, the effects of CA on gene expression were limited and distinct from CDK8 or CDK19 knockdown. Quantitative proteome analyses, tracking around 7,000 proteins across six time points (0-24 hr), revealed that CA selectively affected pathways implicated in inflammation, growth, and metabolic regulation. Contrary to expectations, increased turnover of Mediator kinase targets was not generally observed. Collectively, these data support Mediator kinases as regulators of chromatin and RNA polymerase II activity and suggest their roles extend beyond transcription to metabolism and DNA repair. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  7. KFC, a Ste20-like kinase with mitogenic potential and capability to activate the SAPK/JNK pathway.

    Science.gov (United States)

    Yustein, J T; Li, D; Robinson, D; Kung, H J

    2000-02-03

    The Sterile-20 (Ste20) family of serine-threonine kinases has been implicated in the activation of the stress-activated protein kinase pathways. However, the physiological role has remained ambiguous for most of the investigated mammalian Ste20's. Here we report the cloning of a novel Ste20-like kinase, from chicken embryo fibroblast (CEF) cells, which we have named KFC, for Kinase From Chicken. The 898 amino acid full-length KFC protein contains an amino-terminal kinase domain, an adjacent downstream serine-rich region, and a C-terminal tail containing a coiled-coil domain. Here we show that the coiled-coil domain of KFC negatively regulates the intrinsic kinase activity. We have also identified a splice variant of KFC in which there is a 207 nucleotide in-frame deletion. This deletion of 69 amino acids encompasses the serine-rich region. These two isoforms, called KFCL, for full-length, and KFCS for spliced (or short) form, not only differ in structure, but also in biological properties. Stable CEF cells overexpressing KFCL, but not KFCS, have a significant increase in growth rate when compared to parental cells. This mitogenic effect is the first such reported for this family of kinases. Finally, we found that KFC, when activated by truncation of the regulatory C-terminus, has a specific activation of the stress-activated protein kinase (SAPK/JNK) pathway.

  8. Novel mutations in cyclin-dependent kinase-like 5 (CDKL5) gene in Indian cases of Rett syndrome.

    Science.gov (United States)

    Das, Dhanjit Kumar; Mehta, Bhakti; Menon, Shyla R; Raha, Sarbani; Udani, Vrajesh

    2013-03-01

    Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Both the classic and atypical forms of Rett syndrome are primarily due to mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with atypical Rett syndrome, X-linked infantile spasms sharing common features of generally early-onset seizures and mental retardation. CDKL5 is known as serine/threonine protein kinase 9 (STK9) and is mapped to the Xp22 region. It has a conserved serine/threonine kinase domain within its amino terminus and a large C-terminal region. Disease-causing mutations are distributed in both the amino terminal domain and in the large C-terminal domain. We have screened the CDKL5 gene in 44 patients with atypical Rett syndrome who had tested negative for MECP2 gene mutations and have identified 6 sequence variants, out of which three were novel and three known mutations. Two of these novel mutations p.V966I and p.A1011V were missense and p.H589H a silent mutation. Other known mutations identified were p.V999M, p.Q791P and p.T734A. Sequence homology for all the mutations revealed that the two mutations (p.Q791P and p.T734A) were conserved across species. This indicated the importance of these residues in structure and function of the protein. The damaging effects of these mutations were analysed in silico using PolyPhen-2 online software. The PolyPhen-2 scores of p.Q791P and p.T734A were 0.998 and 0.48, revealing that these mutations could be deleterious and might have potential functional effect. All other mutations had a low score suggesting that they might not alter the activity of CDKL5. We have also analysed the position of the mutations in the CDKL5 protein and found that all the mutations were present in the C-terminal domain of the protein. The C-terminal domain is required for

  9. The cell wall-localized atypical β-1,3 glucanase ZERZAUST controls tissue morphogenesis in Arabidopsis thaliana.

    Science.gov (United States)

    Vaddepalli, Prasad; Fulton, Lynette; Wieland, Jennifer; Wassmer, Katrin; Schaeffer, Milena; Ranf, Stefanie; Schneitz, Kay

    2017-06-15

    Orchestration of cellular behavior in plant organogenesis requires integration of intercellular communication and cell wall dynamics. The underlying signaling mechanisms are poorly understood. Tissue morphogenesis in Arabidopsis depends on the receptor-like kinase STRUBBELIG. Mutations in ZERZAUST were previously shown to result in a strubbelig -like mutant phenotype. Here, we report on the molecular identification and functional characterization of ZERZAUST We show that ZERZAUST encodes a putative GPI-anchored β-1,3 glucanase suggested to degrade the cell wall polymer callose. However, a combination of in vitro , cell biological and genetic experiments indicate that ZERZAUST is not involved in the regulation of callose accumulation. Nonetheless, Fourier-transformed infrared-spectroscopy revealed that zerzaust mutants show defects in cell wall composition. Furthermore, the results indicate that ZERZAUST represents a mobile apoplastic protein, and that its carbohydrate-binding module family 43 domain is required for proper subcellular localization and function whereas its GPI anchor is dispensable. Our collective data reveal that the atypical β-1,3 glucanase ZERZAUST acts in a non-cell-autonomous manner and is required for cell wall organization during tissue morphogenesis. © 2017. Published by The Company of Biologists Ltd.

  10. Engineering of kinase-based protein interacting devices: active expression of tyrosine kinase domains

    KAUST Repository

    Diaz Galicia, Miriam Escarlet

    2018-01-01

    is then translated into a FRET (Fluorescence Resonance Energy Transfer) signal is here proposed. To this end, DNA constructs for interaction amplification (split kinases), positive controls (intact kinase domains), scaffolding proteins and phosphopeptide - SH2-domain

  11. PSM/SH2-B distributes selected mitogenic receptor signals to distinct components in the PI3-kinase and MAP kinase signaling pathways.

    Science.gov (United States)

    Deng, Youping; Xu, Hu; Riedel, Heimo

    2007-02-15

    The Pro-rich, PH, and SH2 domain containing mitogenic signaling adapter PSM/SH2-B has been implicated as a cellular partner of various mitogenic receptor tyrosine kinases and related signaling mechanisms. Here, we report in a direct comparison of three peptide hormones, that PSM participates in the assembly of distinct mitogenic signaling complexes in response to insulin or IGF-I when compared to PDGF in cultured normal fibroblasts. The complex formed in response to insulin or IGF-I involves the respective peptide hormone receptor and presumably the established components leading to MAP kinase activation. However, our data suggest an alternative link from the PDGF receptor via PSM directly to MEK1/2 and consequently also to p44/42 activation, possibly through a scaffold protein. At least two PSM domains participate, the SH2 domain anticipated to link PSM to the respective receptor and the Pro-rich region in an association with an unidentified downstream component resulting in direct MEK1/2 and p44/42 regulation. The PDGF receptor signaling complex formed in response to PDGF involves PI 3-kinase in addition to the same components and interactions as described for insulin or IGF-I. PSM associates with PI 3-kinase via p85 and in addition the PSM PH domain participates in the regulation of PI 3-kinase activity, presumably through membrane interaction. In contrast, the PSM Pro-rich region appears to participate only in the MAP kinase signal. Both pathways contribute to the mitogenic response as shown by cell proliferation, survival, and focus formation. PSM regulates p38 MAP kinase activity in a pathway unrelated to the mitogenic response.

  12. Measuring Kinase Activity-A Global Challenge.

    Science.gov (United States)

    Cann, Marissa L; McDonald, Ian M; East, Michael P; Johnson, Gary L; Graves, Lee M

    2017-11-01

    The kinase enzymes within a cell, known collectively as the kinome, play crucial roles in many signaling pathways, including survival, motility, differentiation, stress response, and many more. Aberrant signaling through kinase pathways is often linked to cancer, among other diseases. A major area of scientific research involves understanding the relationships between kinases, their targets, and how the kinome adapts to perturbations of the cellular system. This review will discuss many of the current and developing methods for studying kinase activity, and evaluate their applications, advantages, and disadvantages. J. Cell. Biochem. 118: 3595-3606, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. Implicative Algebras

    African Journals Online (AJOL)

    Tadesse

    In this paper we introduce the concept of implicative algebras which is an equivalent definition of lattice implication algebra of Xu (1993) and further we prove that it is a regular Autometrized. Algebra. Further we remark that the binary operation → on lattice implicative algebra can never be associative. Key words: Implicative ...

  14. Gain of chromosome arm 1q in atypical meningioma correlates with shorter progression-free survival.

    LENUS (Irish Health Repository)

    2012-02-01

    Aims: Atypical (WHO grade II) meningiomas have moderately high recurrence rates; even for completely resected tumours, approximately one-third will recur. Post-operative radiotherapy (RT) may aid local control and improve survival, but carries the risk of side effects. More accurate prediction of recurrence risk is therefore needed for patients with atypical meningioma. Previously, we used high-resolution array CGH to identify genetic variations in 47 primary atypical meningiomas and found that approximately 60% of tumors show gain of 1q at 1q25.1 and 1q25.3 to 1q32.1 and that 1q gain appeared to correlate with shorter progression-free survival. This study aimed to validate and extend these findings in an independent sample. Methods: 86 completely resected atypical meningiomas (with 25 recurrences) from two neurosurgical centres in Ireland were identified and clinical follow up was obtained. Utilizing a dual-colour interphase FISH assay, 1q gain was assessed using BAC probes directed against 1q25.1 and 1q32.1. Results: The results confirm the high prevalence of 1q gain at these loci in atypical meningiomas. We further show that gain at 1q32.1 and age each correlate with progression-free survival in patients who have undergone complete surgical resection of atypical meningiomas. Conclusions: These independent findings suggest that assessment of 1q copy number status can add clinically useful information for the management of patients with atypical meningiomas.

  15. Atypical antipsychotics for disruptive behaviour disorders in children and youths.

    Science.gov (United States)

    Loy, Jik H; Merry, Sally N; Hetrick, Sarah E; Stasiak, Karolina

    2017-08-09

    This is an update of the original Cochrane Review, last published in 2012 (Loy 2012). Children and youths with disruptive behaviour disorders may present to health services, where they may be treated with atypical antipsychotics. There is increasing usage of atypical antipsychotics in the treatment of disruptive behaviour disorders. To evaluate the effect and safety of atypical antipsychotics, compared to placebo, for treating disruptive behaviour disorders in children and youths. The aim was to evaluate each drug separately rather than the class effect, on the grounds that each atypical antipsychotic has different pharmacologic binding profile (Stahl 2013) and that this is clinically more useful. In January 2017, we searched CENTRAL, MEDLINE, Embase, five other databases and two trials registers. Randomised controlled trials of atypical antipsychotics versus placebo in children and youths aged up to and including 18 years, with a diagnosis of disruptive behaviour disorders, including comorbid ADHD. The primary outcomes were aggression, conduct problems and adverse events (i.e. weight gain/changes and metabolic parameters). The secondary outcomes were general functioning, noncompliance, other adverse events, social functioning, family functioning, parent satisfaction and school functioning. We used standard methodological procedures expected by Cochrane. Two review authors (JL and KS) independently collected, evaluated and extracted data. We used the GRADE approach to assess the quality of the evidence. We performed meta-analyses for each of our primary outcomes, except for metabolic parameters, due to inadequate outcome data. We included 10 trials (spanning 2000 to 2014), involving a total of 896 children and youths aged five to 18 years. Bar two trials, all came from an outpatient setting. Eight trials assessed risperidone, one assessed quetiapine and one assessed ziprasidone. Nine trials assessed acute efficacy (over four to 10 weeks); one of which combined

  16. Activation of protein kinase C inhibits synthesis and release of decidual prolactin

    International Nuclear Information System (INIS)

    Harman, I.; Costello, A.; Ganong, B.; Bell, R.M.; Handwerger, S.

    1986-01-01

    Activation of calcium-activated, phospholipid-dependent protein kinase C by diacylglycerol and phorbol esters has been shown to mediate release of hormones in many systems. To determine whether protein kinase C activation is also involved in the regulation of prolactin release from human decidual, the authors have examined the effects of various acylglycerols and phorbol esters on the synthesis and release of prolactin from cultured human decidual cells. sn-1,2-Dioctanolyglycerol (diC 8 ), which is known to stimulate protein kinase C in other systems, inhibited prolactin release in a dose-dependent manner with maximal inhibition of 53.1% at 100 μM. Diolein (100 μM), which also stimulates protein kinase C activity in some systems, inhibited prolactin release by 21.3%. Phorbol 12-myristate 13-acetate (PMA), phorbol 12,13-didecanoate, and 4β-phorbol 12,13-dibutyrate, which activate protein kinase C in other systems, also inhibited the release of prolactin, which the protein kinase C inactivate 4α-phorbol-12,13-didecanoate was without effect. The inhibition of prolactin release was secondary to a decrease in prolactin synthesis. Although diC 8 and PMA inhibited the synthesis and release of prolactin, these agents had no effect on the synthesis or release of trichloroacetic acid-precipitable [ 35 S]methionine-labeled decidual proteins and did not cause the release of the cytosolic enzymes lactic dehydrogenase and alkaline phosphatase. DiC 8 and PMA stimulates the specific activity of protein kinase C in decidual tissue by 14.6 and 14.0-fold, respectively. The inhibition of the synthesis and release of prolactin by diC 8 and phorbol esters strongly implicates protein kinase C in the regulation of the production and release of prolactin from the decidua

  17. Engineering of kinase-based protein interacting devices: active expression of tyrosine kinase domains

    KAUST Repository

    Diaz Galicia, Miriam Escarlet

    2018-05-01

    Protein-protein interactions modulate cellular processes in health and disease. However, tracing weak or rare associations or dissociations of proteins is not a trivial task. Kinases are often regulated through interaction partners and, at the same time, themselves regulate cellular interaction networks. The use of kinase domains for creating a synthetic sensor device that reads low concentration protein-protein interactions and amplifies them to a higher concentration interaction which is then translated into a FRET (Fluorescence Resonance Energy Transfer) signal is here proposed. To this end, DNA constructs for interaction amplification (split kinases), positive controls (intact kinase domains), scaffolding proteins and phosphopeptide - SH2-domain modules for the reading of kinase activity were assembled and expression protocols for fusion proteins containing Lyn, Src, and Fak kinase domains in bacterial and in cell-free systems were optimized. Also, two non-overlapping methods for measuring the kinase activity of these proteins were stablished and, finally, a protein-fragment complementation assay with the split-kinase constructs was tested. In conclusion, it has been demonstrated that features such as codon optimization, vector design and expression conditions have an impact on the expression yield and activity of kinase-based proteins. Furthermore, it has been found that the defined PURE cell-free system is insufficient for the active expression of catalytic kinase domains. In contrast, the bacterial co-expression with phosphatases produced active kinase fusion proteins for two out of the three tested Tyrosine kinase domains.

  18. Primary Atypical Meningioma of the Nasal Cavity: A Case Report and Review of the Literature

    Science.gov (United States)

    Neupane, Yogesh; Pradhan, Bibhu

    2018-01-01

    Background Meningioma is a central nervous system tumor that typically arises in proximity to meninges. Extracranial primary atypical meningioma of sinonasal tract is a rare one. Methods We discuss the clinical, radiological, and histological presentation of an elderly female with primary atypical meningioma of the nasal cavity, which was excised via endoscopic endonasal approach. Results There was no recurrence even up to 20 months of follow-up after endoscopic excision. Conclusion Extracranial primary atypical meningioma should be kept in mind as one of the differential diagnoses of nasal mass. Histopathological diagnosis along with immunohistochemistry should be used for definitive diagnosis. PMID:29682381

  19. Primary Atypical Meningioma of the Nasal Cavity: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Leison Maharjan

    2018-01-01

    Full Text Available Background. Meningioma is a central nervous system tumor that typically arises in proximity to meninges. Extracranial primary atypical meningioma of sinonasal tract is a rare one. Methods. We discuss the clinical, radiological, and histological presentation of an elderly female with primary atypical meningioma of the nasal cavity, which was excised via endoscopic endonasal approach. Results. There was no recurrence even up to 20 months of follow-up after endoscopic excision. Conclusion. Extracranial primary atypical meningioma should be kept in mind as one of the differential diagnoses of nasal mass. Histopathological diagnosis along with immunohistochemistry should be used for definitive diagnosis.

  20. Oncogenic Receptor Tyrosine Kinases Directly Phosphorylate Focal Adhesion Kinase (FAK) as a Resistance Mechanism to FAK-Kinase Inhibitors.

    Science.gov (United States)

    Marlowe, Timothy A; Lenzo, Felicia L; Figel, Sheila A; Grapes, Abigail T; Cance, William G

    2016-12-01

    Focal adhesion kinase (FAK) is a major drug target in cancer and current inhibitors targeted to the ATP-binding pocket of the kinase domain have entered clinical trials. However, preliminary results have shown limited single-agent efficacy in patients. Despite these unfavorable data, the molecular mechanisms that drive intrinsic and acquired resistance to FAK-kinase inhibitors are largely unknown. We have demonstrated that receptor tyrosine kinases (RTK) can directly bypass FAK-kinase inhibition in cancer cells through phosphorylation of FAK's critical tyrosine 397 (Y397). We also showed that HER2 forms a direct protein-protein interaction with the FAK-FERM-F1 lobe, promoting direct phosphorylation of Y397. In addition, FAK-kinase inhibition induced two forms of compensatory RTK reprogramming: (i) the rapid phosphorylation and activation of RTK signaling pathways in RTK High cells and (ii) the long-term acquisition of RTKs novel to the parental cell line in RTK Low cells. Finally, HER2 +: cancer cells displayed resistance to FAK-kinase inhibition in 3D growth assays using a HER2 isogenic system and HER2 + cancer cell lines. Our data indicate a novel drug resistance mechanism to FAK-kinase inhibitors whereby HER2 and other RTKs can rescue and maintain FAK activation (pY397) even in the presence of FAK-kinase inhibition. These data may have important ramifications for existing clinical trials of FAK inhibitors and suggest that individual tumor stratification by RTK expression would be important to predict patient response to FAK-kinase inhibitors. Mol Cancer Ther; 15(12); 3028-39. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. Clinical and Pathologic Findings of Spitz Nevi and Atypical Spitz Tumors with ALK Fusions

    Science.gov (United States)

    Busam, Klaus J; Kutzner, Heinz; Cerroni, Lorenzo; Wiesner, Thomas

    2016-01-01

    Spitz tumors represent a group of melanocytic neoplasms that typically affects young individuals. Microscopically the lesions are composed of cytologically distinct spindle and epithelioid melanocytes, with a range in the architectural display or the cells, their nuclear features, and secondary epidermal or stromal changes. Recently, kinase fusions have been documented in a subset of Spitz tumors, but there is limited information on the clinical and pathologic features associated with those lesions. Here, we report a series of 17 patients (9 male, 8 female) with spitzoid neoplasms showing ALK fusions (5 Spitz nevi and 12 atypical Spitz tumors). The patients’ ages ranged from 2 years to 35 years (mean = 17; median = 16). Most lesions were located on the lower extremities and presented clinically as polypoid nodules. All tumors were compound melanocytic proliferations with a predominant intradermal growth. Tumor thickness ranged from 1.1 to 6 mm (mean = 2.9 mm; median = 2.5 mm). The most characteristic histopathologic feature of the tumors (seen in all but two lesions) was a plexiform dermal growth of intersecting fascicles of fusiform melanocytes. All but two tumors were amelanotic. All tumors were strongly immunoreactive for ALK. The ALK rearrangements were confirmed in all cases by fluorescence in situ hybridization (FISH) and the fusion partner was determined by quantitative polymerase chain reaction as TPM3 (tropomyosin 3) in 11 cases and DCTN1 (dynactin 1) in 6 cases. None of the eight tumors, which were analyzed by FISH for copy number changes of 6p, 6q, 9p, or 11q met criteria for melanoma. Two patients underwent a sentinel lymph node biopsy, and in both cases melanocytes nests were found in the subcapsular sinus of the node. Array comparative genomic hybridization of these two tumors revealed no chromosomal gains or losses. In conclusion, our study revealed that Spitz nevi/tumors with ALK rearrangement show a characteristic plexiform morphology and that

  2. Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor.

    Directory of Open Access Journals (Sweden)

    Shih-Hwa Chiou

    2008-05-01

    Full Text Available Atypical teratoid/rhabdoid tumor (AT/RT is an extremely malignant neoplasm in the central nervous system (CNS which occurs in infancy and childhood. Recent studies suggested that CD133 could be considered a marker for brain cancer stem-like cells (CSCs. However, the role of CD133 in AT/RT has never been investigated. Herein we report the isolation of CD133-positive cells (CD133(+, found to have the potential to differentiate into three germ layer tissues, from tissues of nine AT/RT patients. The migration/invasion/malignancy and radioresistant capabilities of CD133(+ were significantly augmented when compared to CD133(-. The clinical data showed that the amount of CD133(+ in AT/RTs correlated positively with the degree of resistance to radiation therapy. Using cDNA microarray analysis, the genotoxic-response profiles of CD133(+ and CD133(- irradiated with 10 Gy ionizing radiation (IR were analyzed 0.5, 2, 6, 12 and 24 h post-IR. We then validated these microarray data and showed increased phosphorylation after IR of p-ATM, p-RAD17, and p-CHX2 as well as increased expression of BCL-2 protein in CD133(+ compared to CD133(-. Furthermore, we found that CD133(+ can effectively resist IR with cisplatin- and/or TRAIL-induced apoptosis. Immunohistochemical analysis confirmed the up-regulated expression of p-ATM and BCL-2 proteins in IR-treated CD133(+ xenotransgrafts in SCID mice but not in IR-treated CD133(-. Importantly, the effect of IR in CD133(+ transplanted mice can be significantly improved by a combination of BCL-2 siRNA with debromohymenialdisine, an inhibitor of checkpoint kinases. In sum, this is the first report indicating that CD133(+ AT/RT cells demonstrate the characteristics of CSCs. The IR-resistant and anti-apoptotic properties in CD133(+ may reflect the clinical refractory malignancy of AT/RTs and thus the activated p-ATM pathway and BCL-2 expression in CD133(+ could be possible targets to improve future treatment of deadly diseases

  3. Interaction of renin-angiotensin system and adenosine monophosphate-activated protein kinase signaling pathway in renal carcinogenesis of uninephrectomized rats.

    Science.gov (United States)

    Yang, Ke-Ke; Sui, Yi; Zhou, Hui-Rong; Zhao, Hai-Lu

    2017-05-01

    Renin-angiotensin system and adenosine monophosphate-activated protein kinase signaling pathway both play important roles in carcinogenesis, but the interplay of renin-angiotensin system and adenosine monophosphate-activated protein kinase in carcinogenesis is not clear. In this study, we researched the interaction of renin-angiotensin system and adenosine monophosphate-activated protein kinase in renal carcinogenesis of uninephrectomized rats. A total of 96 rats were stratified into four groups: sham, uninephrectomized, and uninephrectomized treated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Renal adenosine monophosphate-activated protein kinase and its downstream molecule acetyl coenzyme A carboxylase were detected by immunohistochemistry and western blot at 10 months after uninephrectomy. Meanwhile, we examined renal carcinogenesis by histological transformation and expressions of Ki67 and mutant p53. During the study, fasting lipid profiles were detected dynamically at 3, 6, 8, and 10 months. The results indicated that adenosine monophosphate-activated protein kinase expression in uninephrectomized rats showed 36.8% reduction by immunohistochemistry and 89.73% reduction by western blot. Inversely, acetyl coenzyme A carboxylase expression increased 83.3% and 19.07% in parallel to hyperlipidemia at 6, 8, and 10 months. The histopathology of carcinogenesis in remnant kidneys was manifested by atypical proliferation and carcinoma in situ, as well as increased expressions of Ki67 and mutant p53. Intervention with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker significantly prevented the inhibition of adenosine monophosphate-activated protein kinase signaling pathway and renal carcinogenesis in uninephrectomized rats. In conclusion, the novel findings suggest that uninephrectomy-induced disturbance in adenosine monophosphate-activated protein kinase signaling pathway resulted in hyperlipidemia and

  4. Comprehension of atypical literary text and scholastic achievement

    Directory of Open Access Journals (Sweden)

    Božin Aurel A.

    2009-01-01

    Full Text Available With the aim of gaining insight into literary text comprehension and the linkage between that comprehension and scholastic achievement during the first years of schooling, a research was conducted on the sample of 152 third and fourth grade pupils from one urban and one rural school. After having read silently a selected atypical excerpt from one literary text, interviewed pupils filled out the questionnaire constructed for the purposes of this research starting from the 11 categories of text comprehension singled out based on the theory of comprehension and interpretation of literary text and the current curriculum. In the first part of the research we applied the Children's orientation scale by Malka Margalit, and school marks were used as a measurement of scholastic achievement. Research results point out that, among other things, inferring on the basis of what has been read poses the greatest difficulty for third and fourth graders, that is, that almost three quarters of them are not capable of determining the meaning of some representative sentences from that text. In the positive sense, it was established that almost three quarters of them perceive beautiful poetic expressions and about 80% of them can at least to a certain extent recognize character descriptions, emotional situations and moods, that is, discover significant facts. Answers to the questions regarding the majority of categories of text comprehension are significantly correlated with scholastic achievement. As expected, the highest correlations between the measures on text comprehension categories are with the marks in native (Serbian language. Partial correlations between the measures on certain categories of text comprehension and measurements of scholastic achievement (excluding the influence of feeling of coherence are not significantly different from bivariate. Based on the obtained data, authors conclude that the utilized system of categories can be a useful tool for

  5. The genome of Chelonid herpesvirus 5 harbors atypical genes

    Science.gov (United States)

    Ackermann, Mathias; Koriabine, Maxim; Hartmann-Fritsch, Fabienne; de Jong, Pieter J.; Lewis, Teresa D.; Schetle, Nelli; Work, Thierry M.; Dagenais, Julie; Balazs, George H.; Leong, Jo-Ann C.

    2012-01-01

    The Chelonid fibropapilloma-associated herpesvirus (CFPHV; ChHV5) is believed to be the causative agent of fibropapillomatosis (FP), a neoplastic disease of marine turtles. While clinical signs and pathology of FP are well known, research on ChHV5 has been impeded because no cell culture system for its propagation exists. We have cloned a BAC containing ChHV5 in pTARBAC2.1 and determined its nucleotide sequence. Accordingly, ChHV5 has a type D genome and its predominant gene order is typical for the varicellovirus genus within thealphaherpesvirinae. However, at least four genes that are atypical for an alphaherpesvirus genome were also detected, i.e. two members of the C-type lectin-like domain superfamily (F-lec1, F-lec2), an orthologue to the mouse cytomegalovirus M04 (F-M04) and a viral sialyltransferase (F-sial). Four lines of evidence suggest that these atypical genes are truly part of the ChHV5 genome: (1) the pTARBAC insertion interrupted the UL52 ORF, leaving parts of the gene to either side of the insertion and suggesting that an intact molecule had been cloned. (2) Using FP-associated UL52 (F-UL52) as an anchor and the BAC-derived sequences as a means to generate primers, overlapping PCR was performed with tumor-derived DNA as template, which confirmed the presence of the same stretch of “atypical” DNA in independent FP cases. (3) Pyrosequencing of DNA from independent tumors did not reveal previously undetected viral sequences, suggesting that no apparent loss of viral sequence had happened due to the cloning strategy. (4) The simultaneous presence of previously known ChHV5 sequences and F-sial as well as F-M04 sequences was also confirmed in geographically distinct Australian cases of FP. Finally, transcripts of F-sial and F-M04 but not transcripts of lytic viral genes were detected in tumors from Hawaiian FP-cases. Therefore, we suggest that F-sial and F-M04 may play a role in FP pathogenesis

  6. A rice kinase-protein interaction map.

    Science.gov (United States)

    Ding, Xiaodong; Richter, Todd; Chen, Mei; Fujii, Hiroaki; Seo, Young Su; Xie, Mingtang; Zheng, Xianwu; Kanrar, Siddhartha; Stevenson, Rebecca A; Dardick, Christopher; Li, Ying; Jiang, Hao; Zhang, Yan; Yu, Fahong; Bartley, Laura E; Chern, Mawsheng; Bart, Rebecca; Chen, Xiuhua; Zhu, Lihuang; Farmerie, William G; Gribskov, Michael; Zhu, Jian-Kang; Fromm, Michael E; Ronald, Pamela C; Song, Wen-Yuan

    2009-03-01

    Plants uniquely contain large numbers of protein kinases, and for the vast majority of the 1,429 kinases predicted in the rice (Oryza sativa) genome, little is known of their functions. Genetic approaches often fail to produce observable phenotypes; thus, new strategies are needed to delineate kinase function. We previously developed a cost-effective high-throughput yeast two-hybrid system. Using this system, we have generated a protein interaction map of 116 representative rice kinases and 254 of their interacting proteins. Overall, the resulting interaction map supports a large number of known or predicted kinase-protein interactions from both plants and animals and reveals many new functional insights. Notably, we found a potential widespread role for E3 ubiquitin ligases in pathogen defense signaling mediated by receptor-like kinases, particularly by the kinases that may have evolved from recently expanded kinase subfamilies in rice. We anticipate that the data provided here will serve as a foundation for targeted functional studies in rice and other plants. The application of yeast two-hybrid and TAPtag analyses for large-scale plant protein interaction studies is also discussed.

  7. Discovery of inhibitors of bacterial histidine kinases

    NARCIS (Netherlands)

    Velikova, N.R.

    2014-01-01

    Discovery of Inhibitors of Bacterial Histidine Kinases Summary

    The thesis is on novel antibacterial drug discovery (http://youtu.be/NRMWOGgeysM). Using structure-based and fragment-based drug discovery approach, we have identified small-molecule histidine-kinase

  8. Acute lymphoid and gastrointestinal toxicity induced by selective p38alpha map kinase and map kinase-activated protein kinase-2 (MK2) inhibitors in the dog.

    Science.gov (United States)

    Morris, Dale L; O'Neil, Shawn P; Devraj, Rajesh V; Portanova, Joseph P; Gilles, Richard W; Gross, Cindy J; Curtiss, Sandra W; Komocsar, Wendy J; Garner, Debra S; Happa, Fernando A; Kraus, Lori J; Nikula, Kristen J; Monahan, Joseph B; Selness, Shaun R; Galluppi, Gerald R; Shevlin, Kimberly M; Kramer, Jeffrey A; Walker, John K; Messing, Dean M; Anderson, David R; Mourey, Robert J; Whiteley, Laurence O; Daniels, John S; Yang, Jerry Z; Rowlands, Philip C; Alden, Carl L; Davis, John W; Sagartz, John E

    2010-06-01

    Exposure to moderately selective p38alpha mitogen-activated protein kinase (MAPK) inhibitors in the Beagle dog results in an acute toxicity consisting of mild clinical signs (decreased activity, diarrhea, and fever), lymphoid necrosis and depletion in the gut-associated lymphoid tissue (GALT), mesenteric lymph nodes and spleen, and linear colonic and cecal mucosal hemorrhages. Lymphocyte apoptosis and necrosis in the GALT is the earliest and most prominent histopathologic change observed, followed temporally by neutrophilic infiltration and acute inflammation of the lymph nodes and spleen and multifocal mucosal epithelial necrosis and linear hemorrhages in the colon and cecum. These effects are not observed in the mouse, rat, or cynomolgus monkey. To further characterize the acute toxicity in the dog, a series of in vivo, in vitro, and immunohistochemical studies were conducted to determine the relationship between the lymphoid and gastrointestinal (GI) toxicity and p38 MAPK inhibition. Results of these studies demonstrate a direct correlation between p38alpha MAPK inhibition and the acute lymphoid and gastrointestinal toxicity in the dog. Similar effects were observed following exposure to inhibitors of MAPK-activated protein kinase-2 (MK2), further implicating the role of p38alpha MAPK signaling pathway inhibition in these effects. Based on these findings, the authors conclude that p38alpha MAPK inhibition results in acute lymphoid and GI toxicity in the dog and is unique among the species evaluated in these studies.

  9. dependent/calmodulin- stimulated protein kinase from moss

    Indian Academy of Sciences (India)

    Unknown

    stimulated protein kinase; CDPK, calmodulin domain-like protein kinase; KM14, 14 amino acid synthetic peptide; .... used were obtained from Sigma Chemical Company, USA, ..... Plant chimeric Ca2+/Calmodulin-dependent protein kinase.

  10. The Protein Kinase RSK Family - Roles in Prostate Cancer

    National Research Council Canada - National Science Library

    Lannigan, Deborah

    2006-01-01

    The Ser/Thr protein kinase p90-kDa ribosomal S6 kinase (RSK) is an important downstream effector of mitogen-activated protein kinase but its roles in prostate cancer have not been previously examined...

  11. Transcriptome and proteome analyses and the role of atypical calpain protein and autophagy in the spliced leader silencing pathway in Trypanosoma brucei.

    Science.gov (United States)

    Hope, Ronen; Egarmina, Katarina; Voloshin, Konstantin; Waldman Ben-Asher, Hiba; Carmi, Shai; Eliaz, Dror; Drori, Yaron; Michaeli, Shulamit

    2016-10-01

    Under persistent ER stress, Trypanosoma brucei parasites induce the spliced leader silencing (SLS) pathway. In SLS, transcription of the SL RNA gene, the SL donor to all mRNAs, is extinguished, arresting trans-splicing and leading to programmed cell death (PCD). In this study, we investigated the transcriptome following silencing of SEC63, a factor essential for protein translocation across the ER membrane, and whose silencing induces SLS. The proteome of SEC63-silenced cells was analyzed with an emphasis on SLS-specific alterations in protein expression, and modifications that do not directly result from perturbations in trans-splicing. One such protein identified is an atypical calpain SKCRP7.1/7.2. Co-silencing of SKCRP7.1/7.2 and SEC63 eliminated SLS induction due its role in translocating the PK3 kinase. This kinase initiates SLS by migrating to the nucleus and phosphorylating TRF4 leading to shut-off of SL RNA transcription. Thus, SKCRP7.1 is involved in SLS signaling and the accompanying PCD. The role of autophagy in SLS was also investigated; eliminating autophagy through VPS34 or ATG7 silencing demonstrated that autophagy is not essential for SLS induction, but is associated with PCD. Thus, this study identified factors that are used by the parasite to cope with ER stress and to induce SLS and PCD. © 2016 John Wiley & Sons Ltd.

  12. Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.

    Science.gov (United States)

    Filippakopoulos, Panagis; Kofler, Michael; Hantschel, Oliver; Gish, Gerald D; Grebien, Florian; Salah, Eidarus; Neudecker, Philipp; Kay, Lewis E; Turk, Benjamin E; Superti-Furga, Giulio; Pawson, Tony; Knapp, Stefan

    2008-09-05

    The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase alphaC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling.

  13. Role of the Mixed-Lineage Protein Kinase Pathway in the Metabolic Stress Response to Obesity

    Directory of Open Access Journals (Sweden)

    Shashi Kant

    2013-08-01

    Full Text Available Saturated free fatty acid (FFA is implicated in the metabolic response to obesity. In vitro studies indicate that FFA signaling may be mediated by the mixed-lineage protein kinase (MLK pathway that activates cJun NH2-terminal kinase (JNK. Here, we examined the role of the MLK pathway in vivo using a mouse model of diet-induced obesity. The ubiquitously expressed MLK2 and MLK3 protein kinases have partially redundant functions. We therefore compared wild-type and compound mutant mice that lack expression of MLK2 and MLK3. MLK deficiency protected mice against high-fat-diet-induced insulin resistance and obesity. Reduced JNK activation and increased energy expenditure contribute to the metabolic effects of MLK deficiency. These data confirm that the MLK pathway plays a critical role in the metabolic response to obesity.

  14. Glycogen Synthase Kinase-3β

    DEFF Research Database (Denmark)

    Munkholm, Klaus; Lenskjold, Toke; Jacoby, Anne Sophie

    2016-01-01

    cells were quantitated using enzyme immunometric assays. The activity of GSK-3β (serine-9-phosphorylated GSK-3β/total GSK-3β) was lower at baseline compared with follow-up. No significant mean change over time was observed in levels of total GSK-3β and serine-9-phosphorylated GSK-3β. Exploratory......Evidence indicates a role for glycogen synthase kinase-3β (GSK-3β) in the pathophysiology of mood disorders and in cognitive disturbances; however, the natural variation in GSK-3β activity over time is unknown. We aimed to investigate GSK-3β activity over time and its possible correlation...... with emotional lability, subjective mood fluctuations and cognitive function in healthy individuals. Thirty-seven healthy subjects were evaluated with neuropsychological tests and blood samples at baseline and 12-week follow-up. Total GSK-3β and serine-9-phosphorylated GSK-3β in peripheral blood mononuclear...

  15. TYROSINE KINASE INHIBITORS AND PREGNANCY

    Directory of Open Access Journals (Sweden)

    Elisabetta Abruzzese

    2014-04-01

    Full Text Available The management of patients with chronic myeloid leukemia (CML during pregnancy has became recently a matter of continuous debate.  The introduction of the Tyrosine Kinase Inhibitors (TKIs in clinical practice has dramatically changed the prognosis of CML patients.  Patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy.  This fact has come the necessity to address issues relating to fertility and pregnancy. Physicians are not infrequently being asked for advice regarding the need for, and or the appropriateness of, stopping treatment in order to conceive. In this report we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for all the approved TKIs, as well as suggest how to manage a planned and/or unplanned pregnancy.

  16. Decreased Diagnostic Accuracy of Multislice Coronary Computed Tomographic Angiography in Women with Atypical Angina Symptoms

    Directory of Open Access Journals (Sweden)

    Wen-Ying Jin

    2016-01-01

    Conclusions: Although MSCT is a reliable diagnostic modality for the exclusion of significant coronary artery stenoses in all patients, gender and atypical symptoms might have some influence on its diagnostic accuracy.

  17. Atypical mycobacterial infection mimicking carbuncle in an elderly patient: A case report

    Directory of Open Access Journals (Sweden)

    Terlinda Barros

    2015-08-01

    Full Text Available Background: Atypical mycobacterium infection occurs under certain skin conditions, namely the disruption of skin integrity and mucous membranes accompanied by the reduction of cellular immunity. However, atypical mycobacterial infection in elderly patients is rarely reported. Case: A 64 years old male patient, complained of red lumps on the upper-backfor a month, accompanied by mild fever and minimal pain. Three months before, the patient had accupuncture on the neck and upper back. Physical examination showed multiple miliar to lenticular sized papules and pustules on an erythematous-violaceus base with hard and immobile palpable nodes and infiltrate. After clinical and laboratory workup, the patient was diagnosed withcarbuncle with Candida spp colonization. The treatment consisted of systemicantibiotics and topical antifungals. There was no clinical improvement after 3 weeks. Histopathology and laboratory results suggested atypical mycobacterium infection. Discussion: Atypical mycobacterium infection should be considered in elderly patients with skin and soft tissue infections that show no clinical improvement tostandard therapy.

  18. Bilateral Persistent Sciatic Artery Aneurysm Discovered by Atypical Sciatica: A Case Report

    International Nuclear Information System (INIS)

    Mazet, Nathalie; Soulier-Guerin, Karine; Ruivard, Marc; Garcier, Jean-Marc; Boyer, Louis

    2006-01-01

    We report a case of a bilateral persistent sciatic artery aneurysm, diagnosed by atypical sciatica on computed tomography and magnetic resonance imaging. The different variants, the revealing features, and possible treatment are discussed

  19. Viral and atypical bacterial infections in the outpatient pediatric cystic fibrosis clinic

    DEFF Research Database (Denmark)

    Olesen, Hanne Vebert; Nielsen, Lars P; Schiotz, Peter Oluf

    2006-01-01

    BACKGROUND: Respiratory viral and atypical bacterial infections are associated with pulmonary exacerbations and hospitalisations in cystic fibrosis patients. We wanted to study the impact of such infections on children attending the outpatient clinic. METHODS: Seventy-five children were followed...

  20. Atypical Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6 in Denmark:

    DEFF Research Database (Denmark)

    Horsten, Hans-Henrik; Kemp, Michael; Fischer, Thea K

    2018-01-01

    , vasculitis, syphilis, dermatophytid, erythema multiforme and Stevens-Johnson syndrome. Three adults and 3 children required hospitalization due to extensive skin involvement and fever. All reported patients had laboratory confirmed enterovirus infection. This study demonstrated an upsurge in atypical HFMD...

  1. Diagnostic and therapeutic dilemma associated with atypical glandular cells on liquid-based cervical cytology.

    LENUS (Irish Health Repository)

    Chummun, K

    2012-12-01

    In 2008, the management of women in Ireland with atypical glandular cells changed to immediate referral to colposcopy. The optimal management of these women is unclear. A balance between the detection of occult disease and overtreatment is required.

  2. The use of electroconvulsive therapy in atypical psychotic presentations: a case review.

    Science.gov (United States)

    Montgomery, John H; Vasu, Devi

    2007-10-01

    Convulsive therapy and its progeny, electroconvulsive therapy (ECT), were originally used for the treatment of catatonic schizophrenia, and there is little doubt that ECT remains an effective intervention for the treatment of schizophrenia. However, current practice tends to favor the use of ECT in severe or treatment refractory affective disorders, and its use in schizophrenia and other nonaffective (atypical) psychotic disorders has become controversial.CASE REPORTS HAVE SUGGESTED A ROLE FOR ECT IN TWO SPECIFIC ATYPICAL PSYCHOTIC DISORDERS: Cotard's syndrome and cycloid psychosis. In this article, we review the atypical psychotic disorders and report a series of five case examples that signify the role of ECT in atypical psychotic presentations, particularly when the symptoms resemble those found in Cotard's syndrome and cycloid psychosis.

  3. Hemagglutinin Typing as an Aid in Identification of Biochemically Atypical Escherichia coli Strains

    OpenAIRE

    Crichton, Pamela B.; Ip, S. M.; Old, D. C.

    1981-01-01

    Tests for the presence of mannose-sensitive and mannose-resistant, eluting hemagglutinins and fimbriae were helpful in indicating whether biochemically atypical strains of the tribe Escherichieae might be escherichiae or shigellae.

  4. Hemagglutinin Typing as an Aid in Identification of Biochemically Atypical Escherichia coli Strains

    Science.gov (United States)

    Crichton, Pamela B.; Ip, S. M.; Old, D. C.

    1981-01-01

    Tests for the presence of mannose-sensitive and mannose-resistant, eluting hemagglutinins and fimbriae were helpful in indicating whether biochemically atypical strains of the tribe Escherichieae might be escherichiae or shigellae. PMID:7334072

  5. Focal Endometrial Adenocarcinoma in Atypical Polypoid Adenomyoma of Low Malignant Potential

    Directory of Open Access Journals (Sweden)

    Coskun Salman

    2009-12-01

    This report describes a perimenopausal woman with atypical polypoid adenomyoma of low malignant potential with focal adenocarcinoma on endometrial biopsy who subsequently underwent hysterectomy in which no residual malignant lesion was found.

  6. Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors

    DEFF Research Database (Denmark)

    Cao, Jianjing; Slack, Rachel D.; Bakare, Oluyomi M.

    2016-01-01

    The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacolog...

  7. Discrepant epidemiological patterns between classical and atypical scrapie in sheep flocks under French TSE control measures.

    Science.gov (United States)

    Fediaevsky, Alexandre; Gasqui, Patrick; Calavas, Didier; Ducrot, Christian

    2010-09-01

    The occurrence of secondary cases of atypical and classical scrapie was examined in 340 outbreaks of atypical and 296 of classical sheep scrapie detected in France during active surveillance programmes between 2002 and 2007. The prevalence of atypical scrapie in these flocks was 0.05% under selective culling and 0.07% under intensified monitoring i.e. not significantly different from that detected during active surveillance of the general population (P>0.5), whereas these figures were much higher for classical scrapie (3.67% and 0.25%, respectively, Pclassical scrapie but were not more efficient than active surveillance in detecting cases of atypical scrapie. Copyright 2009 Elsevier Ltd. All rights reserved.

  8. Atypical sensory profiles as core features of adult ADHD, irrespective of autistic symptoms.

    Science.gov (United States)

    Bijlenga, D; Tjon-Ka-Jie, J Y M; Schuijers, F; Kooij, J J S

    2017-06-01

    Abnormal sensory sensitivity is a feature of autism-spectrum disorder (ASD), but is also reported in attention-deficit/hyperactivity disorder (ADHD). In many cases, ADHD and ASD are comorbid. This study investigated the prevalence of sensory hyper- and hyposensitivity among adults with ADHD, controlling for autistic symptoms. One hundred and sixteen adults diagnosed with ADHD completed the Adolescent/Adult Sensory Profile-NL (AASP-NL) and the Autism-spectrum Quotient (AQ) questionnaires. Prevalences of hyper- and hyposensitivity and autism-spectrum symptoms were compared to norm values. Multivariate binary logistic regressions were used to determine the association of autistic symptoms, age, gender, ADHD subtype, self-reported severity of ADHD symptoms, comorbid disorders, and use of medication on the sensory hypo- and hypersensitivity in adults with ADHD. Adults with ADHD had more autistic symptoms, and they had both more hyper- and hyposensitivity compared to norm groups. This was especially apparent in the Activity level and Auditory sensory modalities. Sensory hypo- and hypersensitivity were both related to an increased ADHD score, even showing a dose-response relationship, but not to any autistic symptom or comorbid disorder. As much as 43% of the females with ADHD reported sensory hypo- and/or hypersensitivity, compared to 22% of the men. Sensory hypo- and hypersensitivity may be viewed as key features of adult ADHD, especially in females, regardless of any autistic symptoms. Future research should be directed at the implications of this sensory dysregulation for the understanding of the pathophysiology of (female) ADHD, and on the usefulness of assessment of atypical sensory profiles in the diagnostic procedure of ADHD in adults. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia

    Science.gov (United States)

    Piazza, Rocco; Valletta, Simona; Winkelmann, Nils; Redaelli, Sara; Spinelli, Roberta; Pirola, Alessandra; Antolini, Laura; Mologni, Luca; Donadoni, Carla; Papaemmanuil, Elli; Schnittger, Susanne; Kim, Dong-Wook; Boultwood, Jacqueline; Rossi, Fabio; Gaipa, Giuseppe; De Martini, Greta P; di Celle, Paola Francia; Jang, Hyun Gyung; Fantin, Valeria; Bignell, Graham R; Magistroni, Vera; Haferlach, Torsten; Pogliani, Enrico Maria; Campbell, Peter J; Chase, Andrew J; Tapper, William J; Cross, Nicholas C P; Gambacorti-Passerini, Carlo

    2013-01-01

    Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases. PMID:23222956

  10. Electronic brachytherapy management of atypical fibroxanthoma: report of 8 lesions

    Directory of Open Access Journals (Sweden)

    Stephen Doggett

    2017-01-01

    Full Text Available Purpose : To evaluate the suitability of treating atypical fibroxanthoma (AFX, an uncommon skin malignancy, with electronic brachytherapy. Material and methods : From Feb 2013 to Sep 2014, we were referred a total of 8 cases of AFX in 7 patients, all involving the scalp. All of them were treated with electronic brachytherapy 50 Kev radiations (Xoft Axxent®, Fremont, California. All lesions received 40 Gy in two fractions per week with 5mm margins. Results : At a median follow-up of 23.7 months, the local recurrence rate is 12.5%. The single lesion that failed was not debulked surgically prior to electronic brachytherapy. Conclusions : To our knowledge, this is the first report in the literature on the use of radiation therapy as curative primary treatment for AFX. No contraindication to the use of radiations is found in the literature, with surgery being the sole treatment for AFX noted. Our recurrence rate is 0% for debulked lesions. Risk of recurrence is mitigated with surgical debulking prior to brachytherapy. Electronic brachytherapy appears to be a safe and effective treatment for debulked AFX. Multiple excisions, skin grafting, and wound care can be avoided in elderly patients by the use of electronic brachytherapy.

  11. Atypical transistor-based chaotic oscillators: Design, realization, and diversity

    Science.gov (United States)

    Minati, Ludovico; Frasca, Mattia; OświÈ©cimka, Paweł; Faes, Luca; DroŻdŻ, Stanisław

    2017-07-01

    In this paper, we show that novel autonomous chaotic oscillators based on one or two bipolar junction transistors and a limited number of passive components can be obtained via random search with suitable heuristics. Chaos is a pervasive occurrence in these circuits, particularly after manual adjustment of a variable resistor placed in series with the supply voltage source. Following this approach, 49 unique circuits generating chaotic signals when physically realized were designed, representing the largest collection of circuits of this kind to date. These circuits are atypical as they do not trivially map onto known topologies or variations thereof. They feature diverse spectra and predominantly anti-persistent monofractal dynamics. Notably, we recurrently found a circuit comprising one resistor, one transistor, two inductors, and one capacitor, which generates a range of attractors depending on the parameter values. We also found a circuit yielding an irregular quantized spike-train resembling some aspects of neural discharge and another one generating a double-scroll attractor, which represent the smallest known transistor-based embodiments of these behaviors. Through three representative examples, we additionally show that diffusive coupling of heterogeneous oscillators of this kind may give rise to complex entrainment, such as lag synchronization with directed information transfer and generalized synchronization. The replicability and reproducibility of the experimental findings are good.

  12. Atypical hyperplasia, proliferative fibrocystic change, and exogenous hormone use.

    Science.gov (United States)

    Zera, R T; Danielson, D; Van Camp, J M; Schmidt-Steinbrunn, B; Hong, J; McCoy, M; Anderson, W R; Linzie, B M; Rodriguez, J L

    2001-10-01

    The association between breast cancer development and exogenous hormone use (EHU) is suggested by indirect clinical evidence. We undertook this study to better define the relationship that EHU has with proliferative fibrocystic change (PFC) and atypical hyperplasia (AH). Women diagnosed with AH without associated carcinoma from January 1990 to December 1999 were compared with control subjects who underwent breast biopsy procedures during the same interval and who were diagnosed with either a proliferative fibrocystic change (PFC) or a nonproliferative fibrocystic change (NPFC). EHU was defined as the use of estrogen or progesterone taken together or separately within 3 months of biopsy. EHU was significantly higher in patients with AH compared with women with NPFC (P =.01). This observation was also significant if all proliferative change (both AH and PFC) was compared with NPFC (P =.03); it was not significant when PFC alone was compared with NPFC. No significant difference in EHU was demonstrated between women with AH and those with PFC. There is strong association between AH and EHU. These results support the theory that a continuum exists between hyperplasia and carcinoma and that EHU may influence the transition from one to the other in an undefined subset of women. We encourage our patients with AH to discontinue EHU.

  13. Two Atypical Cases of Hantavirus Infections from Sri Lanka

    Directory of Open Access Journals (Sweden)

    N. D. B. Ehelepola

    2018-01-01

    Full Text Available There are two categories of hantaviruses resulting in two distinct illnesses. The Old World (Asia and Europe viruses give rise to hemorrhagic fever with renal syndrome (HFRS, and the New World (Americas viruses cause hantavirus pulmonary syndrome (HPS. Hantavirus infections have very similar clinical pictures and epidemiology to leptospirosis. Here, we present two cases of hantavirus infections from Sri Lanka (in South Asia initially misdiagnosed as leptospirosis and later further investigated and diagnosed as hantavirus infections with serological confirmation of the diagnosis. They had clinical pictures of a combination of both HFRS and HPS as well as the involvement of the central nervous system. Hantavirus infections are rarely diagnosed in South Asia. Reports on such atypical clinical pictures of hantavirus infections are extremely rare. Having arrived at the correct diagnosis late/retrospectively, both these patients recovered notwithstanding being seriously ill, indicating adequate supportive therapy can save lives in such cases. The emergence of the hantavirus, an infection seriously affecting multiple organ systems with a high case fatality rate that is spread by aerosol and other routes, could become a serious public health issue in Sri Lanka.

  14. Morphologic identification of atypical chronic lymphocytic leukemia by digital microscopy.

    Science.gov (United States)

    Marionneaux, S; Maslak, P; Keohane, E M

    2014-08-01

    Atypical chronic lymphocytic leukemia (aCLL) is a morphologic variant found in approximately 25% of patients with chronic lymphocytic leukemia (CLL). Although aCLL has a more aggressive course compared to typical CLL (tCLL), it is not usually reported. This retrospective study used digital microscopy to morphologically classify CLL patients as aCLL or tCLL, and determined the prevalence of prognostic markers in each group. CellaVision AB (Lund, Sweden) was used to evaluate lymphocyte morphology on archived blood films of 97 CLL patients, and results of their prognostic marker analysis at diagnosis were obtained. The unpaired t-test, Chi-square, or Fisher's Exact test were used for statistical analysis. 27% of CLL cases were morphologically classified as aCLL. The aCLL group had a higher prevalence of trisomy 12, unmutated IgVH, and CD38 expression (markers associated with poor prognosis), and a lower prevalence of 13q14 deletions compared to tCLL; this was statistically significant. Using digital imaging to identify aCLL is feasible, economical, and may provide clinically relevant prognostic information at diagnosis and during periodic monitoring. Further study of a larger number of patients is needed to assess the clinical utility of reporting aCLL morphology. © 2013 John Wiley & Sons Ltd.

  15. Tinea profunda of atypical location – case report

    Directory of Open Access Journals (Sweden)

    Anna Tchórzewska

    2016-02-01

    Full Text Available Introduction . Tinea profunda typically involves the scalp and beard. Infection within the mons pubis is rare. Objective . To present a case of tinea profunda in a rare location. Case report . A 19-year-old female, the owner of a hamster, noticed a nodule on her mons pubis. She had shaved this part of the skin some days before. The skin surrounding the nodule became erythematous and slightly scaly soon. She was treated with topical corticosteroids and oral antibiotics after consultation at an outpatient clinic. Despite the treatment, exacerbation of skin lesions was observed. The patient was admitted to the Department of Gynecology and, after consultation, was referred to the Department of Dermatology with the preliminary diagnosis of bacterial skin infection of the mons pubis and vulval area. Bacteriological tests were negative twice. Fungal mycelium was demonstrated on direct mycological examination and Trichophyton mentagrophytes var. granulosum was cultured. The patient was successfully treated with terbinafine, then fluconazole. Conclusions . Atypical location of fungal infection may cause a diagnostic and therapeutic dilemma.

  16. EVOLUTION OF ROTATIONAL VELOCITIES OF A-TYPE STARS

    International Nuclear Information System (INIS)

    Yang Wuming; Bi Shaolan; Tian Zhijia; Meng Xiangcun

    2013-01-01

    The equatorial velocity of A-type stars undergoes an acceleration in the first third of the main sequence (MS) stage, but the velocity decreases as if the stars were not undergoing any redistribution of angular momentum in the external layers in the last stage of the MS phase. Our calculations show that the acceleration and the decrease of the equatorial velocity can be reproduced by the evolution of the differential rotation zero-age MS model with the angular momentum transport caused by hydrodynamic instabilities during the MS stage. The acceleration results from the fact that the angular momentum stored in the interiors of the stars is transported outward. In the last stage, the core and the radiative envelope are uncoupling, and the rotation of the envelope is a quasi-solid rotation; the uncoupling and the expansion of the envelope indicate that the decrease of the equatorial velocity approximately follows the slope for the change in the equatorial velocity of the model without any redistribution of angular momentum. When the fractional age 0.3 ∼ MS ∼< 0.5, the equatorial velocity remains almost constant for stars whose central density increases with age in the early stage of the MS phase, while the velocity decreases with age for stars whose central density decreases with age in the early stage of the MS phase.

  17. Pathologic correlation to internal echogenicity of atypical breast fibroadenoma

    International Nuclear Information System (INIS)

    Cho, Nariya; Oh, Ki Keun; Kwon, Ryang; Han, Jae Ho; Jung, Woo Hee; Lee, Hy De

    1998-01-01

    To understand the cause of a typical sonographic findings by analyzing their pathologic correlation to internal echogenicity of breast fibroadenoma. Materials and Methods : Between January 1995 and April 1997, the presence of 91 fibroadenomas in 81 patients was histopathologically proven. These mass lesions were sonographically interpreted and their descriptive criteria-internal echo content (both strength and homogeneity),the presence of septum, bilateral shadowing, and posterior echo pattern-were tabulated. A pathologist reviewed each case and independently recorded the following data : cell type, the presence of septum, duct dilatation,calcification, fibrosis, hyalinization, and vascularity. We analyzed the correlation of sonographic with pathologic findings. Results : There was significant correlation between increased vascularity and increased internal echo strength and between increased fibrosis and decreased internal echo strength. There was no significant correlation between internal echo homogeneity or posterior shadowing and vascularity or stromal fibrosis, nor between hyalinization or cell type and internal echo strength, homogeneity or posterior shadowing.There was correlation between absent or thin capsule and the absence of bilateral shadowing. Conclusion :Increased vascularity or decreased stromal fibrosis might be the cause of atypical fibroadenoma

  18. Pathologic correlation to internal echogenicity of atypical breast fibroadenoma

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Nariya; Oh, Ki Keun; Kwon, Ryang; Han, Jae Ho; Jung, Woo Hee; Lee, Hy De [Yonsei Univ. College of Medicine, Seoul (Korea, Republic of)

    1998-07-01

    To understand the cause of a typical sonographic findings by analyzing their pathologic correlation to internal echogenicity of breast fibroadenoma. Materials and Methods : Between January 1995 and April 1997, the presence of 91 fibroadenomas in 81 patients was histopathologically proven. These mass lesions were sonographically interpreted and their descriptive criteria-internal echo content (both strength and homogeneity),the presence of septum, bilateral shadowing, and posterior echo pattern-were tabulated. A pathologist reviewed each case and independently recorded the following data : cell type, the presence of septum, duct dilatation,calcification, fibrosis, hyalinization, and vascularity. We analyzed the correlation of sonographic with pathologic findings. Results : There was significant correlation between increased vascularity and increased internal echo strength and between increased fibrosis and decreased internal echo strength. There was no significant correlation between internal echo homogeneity or posterior shadowing and vascularity or stromal fibrosis, nor between hyalinization or cell type and internal echo strength, homogeneity or posterior shadowing.There was correlation between absent or thin capsule and the absence of bilateral shadowing. Conclusion :Increased vascularity or decreased stromal fibrosis might be the cause of atypical fibroadenoma.

  19. Assesment, treatment and prevention of atypical hemolytic uremic syndrome

    Directory of Open Access Journals (Sweden)

    Azar Nickavar

    2013-01-01

    Full Text Available Hemolytic uremic syndrome (HUS is a heterogeneous group of hemolytic disorders. Different terminologies have been described in HUS, which are as follows: (1 D+ HUS: Presentation with a preceding diarrhea; (2 typical HUS: D+ HUS with a single and self-limited episode; (3 atypical HUS (aHUS: Indicated those with complement dysregulation; (4 recurrent HUS: Recurrent episodes of thrombocytopenia and/or microangiopathic hemolytic anemia (MAHA after improvement of hematologic abnormalities; and (5 familial HUS: Necessary to distinct synchronous outbreaks of D+ HUS in family members and asynchronous disease with an inherited risk factor. aHUS is one of the potential causes of end-stage renal disease (ESRD in children. It has a high recurrence after renal transplantation in some genetic forms. Therefore, recognition of the responsible mechanism and proper prophylactic treatment are recommended to prevent or delay the occurrence of ESRD and prolong the length of survival of the transplanted kidney. A computerized search of MEDLINE and other databases was carried out to find the latest results in pathogenesis, treatment, and prevention of aHUS.

  20. RNA-Binding Proteins in Trichomonas vaginalis: Atypical Multifunctional Proteins

    Directory of Open Access Journals (Sweden)

    Elisa E. Figueroa-Angulo

    2015-11-01

    Full Text Available Iron homeostasis is highly regulated in vertebrates through a regulatory system mediated by RNA-protein interactions between the iron regulatory proteins (IRPs that interact with an iron responsive element (IRE located in certain mRNAs, dubbed the IRE-IRP regulatory system. Trichomonas vaginalis, the causal agent of trichomoniasis, presents high iron dependency to regulate its growth, metabolism, and virulence properties. Although T. vaginalis lacks IRPs or proteins with aconitase activity, possesses gene expression mechanisms of iron regulation at the transcriptional and posttranscriptional levels. However, only one gene with iron regulation at the transcriptional level has been described. Recently, our research group described an iron posttranscriptional regulatory mechanism in the T. vaginalis tvcp4 and tvcp12 cysteine proteinase mRNAs. The tvcp4 and tvcp12 mRNAs have a stem-loop structure in the 5'-coding region or in the 3'-UTR, respectively that interacts with T. vaginalis multifunctional proteins HSP70, α-Actinin, and Actin under iron starvation condition, causing translation inhibition or mRNA stabilization similar to the previously characterized IRE-IRP system in eukaryotes. Herein, we summarize recent progress and shed some light on atypical RNA-binding proteins that may participate in the iron posttranscriptional regulation in T. vaginalis.