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Sample records for atypical kinase implicated

  1. Role of Atypical Protein Kinases in Maintenance of Long-Term Memory and Synaptic Plasticity.

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    Borodinova, A A; Zuzina, A B; Balaban, P M

    2017-03-01

    Investigation of biochemical mechanisms underlying the long-term storage of information in nervous system is one of main problems of modern neurobiology. As a molecular basis of long-term memory, long-term changes in kinase activities, increase in the level and changes in the subunit composition of receptors in synaptic membranes, local activity of prion-like proteins, and epigenetic modifications of chromatin have been proposed. Perhaps a combination of all or of some of these factors underlies the storage of long-term memory in the brain. Many recent studies have shown an exclusively important role of atypical protein kinases (PKCζ, PKMζ, and PKCι/λ) in processes of learning, consolidation and maintenance of memory. The present review is devoted to consideration of mechanisms of transcriptional and translational control of atypical protein kinases and their roles in induction and maintenance of long-term synaptic plasticity and memory in vertebrates and invertebrates.

  2. 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.

  3. BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domain

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    Devaiah, Ballachanda N.; Lewis, Brian A.; Cherman, Natasha; Hewitt, Michael C.; Albrecht, Brian K.; Robey, Pamela G.; Ozato, Keiko; Sims, Robert J.; Singer, Dinah S.

    2012-01-01

    The bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt’s lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic signature for metastatic breast cancer. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function remains unknown. We report that BRD4 is an atypical kinase that binds to the carboxyl-terminal domain (CTD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites both in vitro and in vivo under conditions where other CTD kinases are inactive. Phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin. Our finding that BRD4 is an RNA polymerase II CTD Ser2 kinase implicates it as a regulator of eukaryotic transcription. PMID:22509028

  4. Tv-RIO1 – an atypical protein kinase from the parasitic nematode Trichostrongylus vitrinus

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    Sternberg Paul W

    2008-09-01

    Full Text Available Abstract Background Protein kinases are key enzymes that regulate a wide range of cellular processes, including cell-cycle progression, transcription, DNA replication and metabolic functions. These enzymes catalyse the transfer of phosphates to serine, threonine and tyrosine residues, thus playing functional roles in reversible protein phosphorylation. There are two main groups, namely eukaryotic protein kinases (ePKs and atypical protein kinases (aPKs; RIO kinases belong to the latter group. While there is some information about RIO kinases and their roles in animals, nothing is known about them in parasites. This is the first study to characterise a RIO1 kinase from any parasite. Results A full-length cDNA (Tv-rio-1 encoding a RIO1 protein kinase (Tv-RIO1 was isolated from the economically important parasitic nematode Trichostrongylus vitrinus (Order Strongylida. The uninterrupted open reading frame (ORF of 1476 nucleotides encoded a protein of 491 amino acids, containing the characteristic RIO1 motif LVHADLSEYNTL. Tv-rio-1 was transcribed at the highest level in the third-stage larva (L3, and a higher level in adult females than in males. Comparison with homologues from other organisms showed that protein Tv-RIO1 had significant homology to related proteins from a range of metazoans and plants. Amino acid sequence identity was most pronounced in the ATP-binding motif, active site and metal binding loop. Phylogenetic analyses of selected amino acid sequence data revealed Tv-RIO1 to be most closely related to the proteins in the species of Caenorhabditis. A structural model of Tv-RIO1 was constructed and compared with the published crystal structure of RIO1 of Archaeoglobus fulgidus (Af-Rio1. Conclusion This study provides the first insights into the RIO1 protein kinases of nematodes, and a foundation for further investigations into the biochemical and functional roles of this molecule in biological processes in parasitic nematodes.

  5. Overexpression of atypical protein kinase C in HeLa cells facilitates macropinocytosis via Src activation.

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    Tisdale, Ellen J; Shisheva, Assia; Artalejo, Cristina R

    2014-06-01

    Atypical protein kinase C (aPKC) is the first recognized kinase oncogene. However, the specific contribution of aPKC to cancer progression is unclear. The pseudosubstrate domain of aPKC is different from the other PKC family members, and therefore a synthetic peptide corresponding to the aPKC pseudosubstrate (aPKC-PS) sequence, which specifically blocks aPKC kinase activity, is a valuable tool to assess the role of aPKC in various cellular processes. Here, we learned that HeLa cells incubated with membrane permeable aPKC-PS peptide displayed dilated heterogeneous vesicles labeled with peptide that were subsequently identified as macropinosomes. A quantitative membrane binding assay revealed that aPKC-PS peptide stimulated aPKC recruitment to membranes and activated Src. Similarly, aPKC overexpression in transfected HeLa cells activated Src and induced macropinosome formation. Src-aPKC interaction was essential; substitution of the proline residues in aPKC that associate with the Src-SH3 binding domain rendered the mutant kinase unable to induce macropinocytosis in transfected cells. We propose that aPKC overexpression is a contributing factor to cell transformation by interacting with and consequently promoting Src activation and constitutive macropinocytosis, which increases uptake of extracellular factors, required for altered cell growth and accelerated cell migration. Copyright © 2014. Published by Elsevier Inc.

  6. The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a Rho-Dependent Mechanism.

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    Bermingham, Daniel P; Hardaway, J Andrew; Refai, Osama; Marks, Christian R; Snider, Sam L; Sturgeon, Sarah M; Spencer, William C; Colbran, Roger J; Miller, David M; Blakely, Randy D

    2017-09-20

    The neurotransmitter dopamine (DA) regulates multiple behaviors across phylogeny, with disrupted DA signaling in humans associated with addiction, attention-deficit/ hyperactivity disorder, schizophrenia, and Parkinson's disease. The DA transporter (DAT) imposes spatial and temporal limits on DA action, and provides for presynaptic DA recycling to replenish neurotransmitter pools. Molecular mechanisms that regulate DAT expression, trafficking, and function, particularly in vivo, remain poorly understood, though recent studies have implicated rho-linked pathways in psychostimulant action. To identify genes that dictate the ability of DAT to sustain normal levels of DA clearance, we pursued a forward genetic screen in Caenorhabditis elegans based on the phenotype swimming-induced paralysis (Swip), a paralytic behavior observed in hermaphrodite worms with loss-of-function dat-1 mutations. Here, we report the identity of swip-13, which encodes a highly conserved ortholog of the human atypical MAP kinase ERK8. We present evidence that SWIP-13 acts presynaptically to insure adequate levels of surface DAT expression and DA clearance. Moreover, we provide in vitro and in vivo evidence supporting a conserved pathway involving SWIP-13/ERK8 activation of Rho GTPases that dictates DAT surface expression and function.SIGNIFICANCE STATEMENT Signaling by the neurotransmitter dopamine (DA) is tightly regulated by the DA transporter (DAT), insuring efficient DA clearance after release. Molecular networks that regulate DAT are poorly understood, particularly in vivo Using a forward genetic screen in the nematode Caenorhabditis elegans, we implicate the atypical mitogen activated protein kinase, SWIP-13, in DAT regulation. Moreover, we provide in vitro and in vivo evidence that SWIP-13, as well as its human counterpart ERK8, regulate DAT surface availability via the activation of Rho proteins. Our findings implicate a novel pathway that regulates DA synaptic availability and that may

  7. Implication of Ceramide Kinase in Adipogenesis

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    Marta Ordoñez

    2017-01-01

    Full Text Available Ceramide kinase (CerK plays a critical role in the regulation of cell growth and survival and has been implicated in proinflammatory responses. In this work, we demonstrate that CerK regulates adipocyte differentiation, a process associated with obesity, which causes chronic low-grade inflammation. CerK was upregulated during differentiation of 3T3-L1 preadipocytes into mature adipocytes. Noteworthy, knockdown of CerK using specific siRNA to silence the gene encoding this kinase resulted in substantial decrease of lipid droplet formation and potent depletion in the content of triacylglycerols in the adipocytes. Additionally, CerK knockdown caused blockade of leptin secretion, an adipokine that is crucial for regulation of energy balance in the organism and that is increased in the obese state. Moreover, CerK gene silencing decreased the expression of peroxisome proliferator-activated receptor gamma (PPARγ, which is considered the master regulator of adipogenesis. It can be concluded that CerK is a novel regulator of adipogenesis, an action that may have potential implications in the development of obesity, and that targeting this kinase may be beneficial for treatment of obesity-associated diseases.

  8. Clinical characteristics and diagnosis of atypical odontalgia: implications for dentists.

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    Ram, Saravanan; Teruel, Antonia; Kumar, Satish K S; Clark, Glenn

    2009-02-01

    Atypical odontalgia (AO) is a poorly understood and commonly misdiagnosed condition for which patients often undergo multiple unsuccessful dental or surgical procedures. The authors conducted a study to determine the prevalence and describe the characteristics of patients with AO seen at the University of Southern California Orofacial Pain and Oral Medicine Center (USC OFP-OM Center), Los Angeles. The authors conducted a retrospective record review from a database of more than 3,000 patient records from June 2003 to August 2007 to identify patients diagnosed with AO. The authors identified 64 patients (44 women and 20 men) between the ages of 26 and 93 years as having a diagnosis of AO. Of those 64 patients, 71 percent initially consulted a dentist regarding their pain, and 79 percent had undergone dental treatment that failed to resolve the pain. The pain of 64 percent of the patients had no known cause. Dentists, who often are the first health care providers to see patients with AO, must be aware of this condition and must follow the appropriate steps to determine its diagnosis. Dentists and physicians should understand the implications and importance of early diagnosis of patients with AO and of referral to pain specialists for treatment.

  9. Atypical protein kinase C regulates primary dendrite specification of cerebellar Purkinje cells by localizing Golgi apparatus.

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    Tanabe, Koji; Kani, Shuichi; Shimizu, Takashi; Bae, Young-Ki; Abe, Takaya; Hibi, Masahiko

    2010-12-15

    Neurons have highly polarized structures that determine what parts of the soma elaborate the axon and dendrites. However, little is known about the mechanisms that establish neuronal polarity in vivo. Cerebellar Purkinje cells extend a single primary dendrite from the soma that ramifies into a highly branched dendritic arbor. We used the zebrafish cerebellum to investigate the mechanisms by which Purkinje cells acquire these characteristics. To examine dendritic morphogenesis in individual Purkinje cells, we marked the cell membrane using a Purkinje cell-specific promoter to drive membrane-targeted fluorescent proteins. We found that zebrafish Purkinje cells initially extend multiple neurites from the soma and subsequently retract all but one, which becomes the primary dendrite. In addition, the Golgi apparatus specifically locates to the root of the primary dendrite, and its localization is already established in immature Purkinje cells that have multiple neurites. Inhibiting secretory trafficking through the Golgi apparatus reduces dendritic growth, suggesting that the Golgi apparatus is involved in the dendritic morphogenesis. We also demonstrated that in a mutant of an atypical protein kinase C (aPKC), Prkci, Purkinje cells retain multiple primary dendrites and show disrupted localization of the Golgi apparatus. Furthermore, a mosaic inhibition of Prkci in Purkinje cells recapitulates the aPKC mutant phenotype. These results suggest that the aPKC cell autonomously controls the Golgi localization and thereby regulates the specification of the primary dendrite of Purkinje cells.

  10. The role of atypical protein kinase C in CSF-1-dependent Erk activation and proliferation in myeloid progenitors and macrophages.

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    Angel W Lee

    Full Text Available Colony stimulating factor-1 (CSF-1 or M-CSF is the major physiological regulator of the proliferation, differentiation and survival of cells of the mononuclear phagocyte lineage. CSF-1 binds to a receptor tyrosine kinase, the CSF-1 receptor (CSF-1R. Multiple pathways are activated downstream of the CSF-1R; however, it is not clear which pathways regulate proliferation and survival. Here, we investigated the role of atypical protein kinase Cs (PKCζ in a myeloid progenitor cell line that expressed CSF-1R (32D.R and in primary murine bone marrow derived macrophages (BMMs. In 32D.R cells, CSF-1 induced the phosphorylation of PKCζ and increased its kinase activity. PKC inhibitors and transfections with mutant PKCs showed that optimal CSF-1-dependent Erk activation and proliferation depended on the activity of PKCζ. We previously reported that CSF-1 activated the Erk pathway through an A-Raf-dependent and an A-Raf independent pathway (Lee and States, Mol. Cell. Biol.18, 6779. PKC inhibitors did not affect CSF-1 induced Ras and A-Raf activity but markedly reduced MEK and Erk activity, implying that PKCζ regulated the CSF-1-Erk pathway at the level of MEK. PKCζ has been implicated in activating the NF-κB pathway. However, CSF-1 promoted proliferation in an NF-κB independent manner. We established stable 32D.R cell lines that overexpressed PKCζ. Overexpression of PKCζ increased the intensity and duration of CSF-1 induced Erk activity and rendered cells more responsive to CSF-1 mediated proliferation. In contrast to 32D.R cells, PKCζ inhibition in BMMs had only a modest effect on proliferation. Moreover, PKCζ -specific and pan-PKC inhibitors induced a paradoxical increase in MEK-Erk phosphorylation suggesting that PKCs targeted a common negative regulatory step upstream of MEK. Our results demonstrated that CSF-1 dependent Erk activation and proliferation are regulated differentially in progenitors and differentiated cells.

  11. 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.

  12. Metformin action in human hepatocytes: coactivation of atypical protein kinase C alters 5'-AMP-activated protein kinase effects on lipogenic and gluconeogenic enzyme expression.

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    Sajan, Mini P; Ivey, Robert A; Farese, Robert V

    2013-11-01

    Atypical protein kinase C (aPKC) levels and activity are elevated in hepatocytes of individuals with type 2 diabetes and cause excessive increases in the levels of lipogenic and gluconeogenic enzymes; aPKC inhibitors largely correct these aberrations. Metformin improves hepatic gluconeogenesis by activating 5'-AMP-activated protein kinase (AMPK). However, metformin also activates aPKC in certain tissues; in the liver, this activation could amplify diabetic aberrations and offset the positive effects of AMPK. In this study, we examined whether metformin activates aPKC in human hepatocytes and the metabolic consequences of any such activation. We compared protein kinase activities and alterations in lipogenic and gluconeogenic enzyme levels during activity of the AMPK activators metformin and AICAR, relative to those of an aPKC-ι inhibitor, in hepatocytes from non-diabetic and type 2 diabetic human organ donors. Metformin and 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) activated aPKC at concentrations comparable with those required for AMPK activation. Moreover, both agents increased lipogenic enzyme levels by an aPKC-dependent mechanism. Thus, whereas insulin- and diabetes-dependent increases in lipogenic enzyme levels were reversed by aPKC inhibition, such levels were increased in hepatocytes from non-diabetic donors and remained elevated in hepatocytes from diabetic donors following metformin and AICAR treatment. In addition, whereas aPKC inhibition diminished gluconeogenic enzyme levels in the absence and presence of insulin in hepatocytes from both non-diabetic and diabetic donors, metformin and AICAR increased gluconeogenic enzyme levels in hepatocytes from non-diabetic individuals, but nevertheless diminished gluconeogenic enzyme levels in insulin-treated hepatocytes from diabetic donors. Metformin and AICAR activate aPKC together with AMPK in human hepatocytes. Activation of aPKC increases lipogenic enzyme levels and alters gluconeogenic

  13. 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.

  14. Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress.

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    Numazawa, Satoshi; Ishikawa, Makie; Yoshida, Aya; Tanaka, Sachiko; Yoshida, Takemi

    2003-08-01

    Transcription factor NF-E2-related factor 2 (Nrf2) regulates the induction of antioxidative proteins, including heme oxygenase-1 (HO-1). Nrf2 is sequestered in the cytoplasm by Keap1 under unstimulated conditions but translocates into the nucleus and transactivates the antioxidant responsive element (ARE) upon exposure to oxidative insults. It has recently been demonstrated that in vitro phosphorylation of Nrf2 on Ser40 by protein kinase C (PKC) facilitates the dissociation of Nrf2 from the Keap1 complex (Huang HC, Nguyen T, and Pickett CB. J Biol Chem 277: 42769-42774, 2002). The present study was designed to examine whether PKC is involved in oxidative stress-mediated nuclear translocation of Nrf2 in vivo and, if so, which PKC isoforms are involved. Induction of HO-1 gene expression by phorone, a glutathione depletor, and 4-hydroxy-2,3-nonenal (4-HNE), an end product of lipid peroxidation, was suppressed by a specific PKC inhibitor, Ro-31-8220, at concentrations that inhibit all isoforms in WI-38 cells. The induction of HO-1 was not affected by prolonged exposure of the cells to 12-O-tetradecanoylphorbol-13 acetate (TPA), suggesting that TPA-insensitive atypical PKC (aPKC) isoforms are involved. An immunocomplex kinase assay revealed that phorone and 4-HNE increased aPKCiota activity. In COS-7 cells, 4-HNE induced nuclear translocation of the Nrf2-green fluorescent protein (GFP) fusion protein, but not the Nrf2(S40A)-GFP mutant. In the absence of oxidative insults, the Nrf2(S40E)-GFP mutant was distributed in the nucleus. The Nrf2-GFP accumulation in the nucleus was induced by coexpression of aPKCiota, but not by a kinase inactive mutant aPKCiota(K274W). The activity of an ARE-driven reporter was increased by coexpression of aPKCiota, and this effect was eliminated by Ro-31-8220 in HepG2 cells. The reporter activity induced by 4-HNE was inhibited by coexpression of aPKCiota(K274W). These results suggest that phosphorylation of Nrf2 Ser40 by aPKC(s) is involved in

  15. Procedural learning across the lifespan: A systematic review with implications for atypical development.

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    Zwart, Fenny S; Vissers, Constance Th W M; Kessels, Roy P C; Maes, Joseph H R

    2017-10-08

    This systematic review aimed to investigate procedural learning across the lifespan in typical and atypical development. Procedural learning is essential for the development of everyday skills, including language and communication skills. Although procedural learning efficiency has been extensively studied, there is no consensus yet on potential procedural learning changes during development and ageing. Currently, three conflicting models regarding this trajectory exist: (1) a model of age invariance; (2a) a model with a peak in young adulthood; and (2b) a model with a plateau in childhood followed by a decline. The aims of this study were (1) to investigate this debate on procedural learning across the lifespan by systematically reviewing evidence for each model from studies using the serial reaction time task; and (2) to review procedural learning in autism spectrum disorder (ASD) and specific language impairment (SLI), two developmental disorders characterized by deficits in communication skills, in the light of these models. Our findings on typical development strongly support a model of age-related changes (Model 2a or 2b) and show that mixed findings regarding the developmental trajectory during childhood can be explained by methodological differences across studies. Applying these conclusions to systematic reviews of studies of ASD and SLI makes it clear that there is a strong need for the inclusion of multiple age groups in these clinical studies to model procedural learning in atypical development. Clinical implications of the findings are discussed. Future research should focus on the role of declarative learning in both typical and atypical development. © 2017 The British Psychological Society.

  16. Kinase inhibitors and monoclonal antibodies in oncology: clinical implications.

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    Gharwan, Helen; Groninger, Hunter

    2016-04-01

    Molecularly targeted cancer therapies, such as small-molecule kinase inhibitors and monoclonal antibodies, constitute a rapidly growing and an important part of the oncology armamentarium. Unlike conventional (cytotoxic) chemotherapeutics, targeted therapies were designed to disrupt cancer cell pathogenesis at specific biological points essential for the development and progression of the tumour. These agents were developed to disrupt specific targets with the aim of minimizing treatment burden compared with conventional chemotherapy. Nevertheless the increasingly common use of targeted therapies has revealed some unanticipated, often clinically significant toxic effects, as well as compromising effective palliative and end-of-life management approaches. Although patients and clinicians welcome improvements in cancer prognosis, these changes can also impact patient quality-of-life. Therefore, as demand for oncology expertise increases, physicians need to apprise themselves of targeted therapies and their clinical implications, including drug-specific side effects, impact on quality of life, and cost issues, especially in relation to end-of-life care. This Review provides a useful summary and guide for professionals treating patients with malignant diseases.

  17. 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...... 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-¿ and PKC-¿ have interchangeable functions in these processes....

  18. The Structure of Lombricine Kinase: Implications for Phosphagen Conformational Changes

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    Bush, D. Jeffrey; Kirillova, Olga; Clark, Shawn A.; Davulcu, Omar; Fabiola, Felcy; Xie, Qing; Somasundaram, Thayumanasamy; Ellington, W. Ross; Chapman, Michael S. (Oregon HSU); (FSU)

    2012-05-29

    Lombricine kinase is a member of the phosphagen kinase family and a homolog of creatine and arginine kinases, enzymes responsible for buffering cellular ATP levels. Structures of lombricine kinase from the marine worm Urechis caupo were determined by x-ray crystallography. One form was crystallized as a nucleotide complex, and the other was substrate-free. The two structures are similar to each other and more similar to the substrate-free forms of homologs than to the substrate-bound forms of the other phosphagen kinases. Active site specificity loop 309-317, which is disordered in substrate-free structures of homologs and is known from the NMR of arginine kinase to be inherently dynamic, is resolved in both lombricine kinase structures, providing an improved basis for understanding the loop dynamics. Phosphagen kinases undergo a segmented closing on substrate binding, but the lombricine kinase ADP complex is in the open form more typical of substrate-free homologs. Through a comparison with prior complexes of intermediate structure, a correlation was revealed between the overall enzyme conformation and the substrate interactions of His{sup 178}. Comparative modeling provides a rationale for the more relaxed specificity of these kinases, of which the natural substrates are among the largest of the phosphagen substrates.

  19. 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.

  20. Are specific initiatives required to enhance prescribing of generic atypical antipsychotics in Scotland?: International implications.

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    Bennie, M; Bishop, I; Godman, B; Barbui, C; Raschi, E; Campbell, S; Miranda, J; Gustafsson, L L

    2013-02-01

    National and regional authorities in Scotland have introduced multiple measures to appreciably enhance prescribing efficiency for the proton pump inhibitors (PPIs), statins and renin-angiotensin inhibitor drugs. Generic oral risperidone recently became available in Scotland; however, schizophrenia is a complex disease with advice from respected authorities suggesting that treatment should be individualised. To assess (i) changes in atypical antipsychotic drug (AAP) utilisation and expenditure following the availability of oral generic risperidone in Scotland; (ii) to determine (a) current INN prescribing rates for risperidone following generic availability and (b) decrease in expenditure/DDD for generic risperidone; (iii) to suggest additional measures that could possibly be introduced in Scotland to further enhance prescribing of generic AAPs; and (iv) to provide guidance to NHS Scotland as well as other European authorities on the implications. Retrospective observational study and an interrupted time series design. No appreciable change in the utilisation patterns of risperidone pre- and postgeneric availability. Appreciable INN prescribing averaged 93-98% of total oral risperidone. Generic risperidone was 84% below prepatent loss prices by study end, reducing annual expenditure for oral risperidone in 2010 by GB£3.19mn compared with prepatent loss situation. However, overall expenditure on AAPs increased by 42% from 2005 to 2010. As expected, there was no change in utilisation patterns for risperidone, although potential to influence prescribing patterns. Continued high INN prescribing suggests no problems with generic risperidone in practice. Costs will start to decrease as more AAPs lose their patents (olanzapine and quetiapine). There is the possibility to accelerate this reduction through educational activities. There is potential to realise some savings with generic AAPs. However, this is limited by the complexity of the disease area. Any measures

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

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    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.

  2. Atypical Depression

    Science.gov (United States)

    Atypical depression Overview Any type of depression can make you feel sad and keep you from enjoying life. However, atypical depression — also called depression with atypical features — means that ...

  3. Furosemide-induced hyperglycaemia: the implication of glycolytic kinases.

    Science.gov (United States)

    Dimitriadis, G; Tegos, C; Golfinopoulou, L; Roboti, C; Raptis, S

    1993-11-01

    Hyperglycaemia is a well known adverse effect of therapy with diuretics. In adipose tissue, hydrochlorothiazide and furosemide inhibit the rate of glucose transport. In skeletal muscle, furosemide decreases the rate of glucose phosphorylation and glycolysis. However, whether furosemide has any direct effect on the activities of any of the glycolytic enzymes is not known. In the present study, the effects of furosemide on the activities of the hexokinase, phosphofructokinase and pyruvate kinase were examined. Pieces of skeletal muscle (quadriceps) and liver were obtained from 10 non-diabetic subjects during surgery. Tissues were homogenized and the activities of the enzymes were measured in the presence or absence of furosemide (0-1.5 mM). Furosemide inhibited the activity of all three key glycolytic enzymes. The concentration of furosemide required to inhibit phosphofructokinase in muscle was lower than that required to inhibit the activity of this enzyme in the liver or to inhibit the activities of hexokinase and pyruvate kinase in both muscle and liver. These direct effects of furosemide may contribute to the decrease in glucose utilisation following therapy with this and similar agents in man.

  4. The Entamoeba histolytica, Arp2/3 Complex Is Recruited to Phagocytic Cups through an Atypical Kinase EhAK1

    Science.gov (United States)

    Babuta, Mrigya; Mansuri, M Shahid; Bhattacharya, Sudha; Bhattacharya, Alok

    2015-01-01

    The parasite Entamoeba histolytica is the etiological agent of amoebiasis and phagocytosis plays a key role in virulence of this organism. Signaling pathways involved in activation of cytoskeletal dynamics required for phagocytosis remain to be elucidated. Phagocytosis is initiated with sequential recruitment of EhC2PK, EhCaBP1, EhCaBP3 and an atypical kinase EhAK1 after particle attachment. Here we show that EhARPC1, an essential subunit of the actin branching complex Arp 2/3 is recruited to the phagocytic initiation sites by EhAK1. Imaging, expression knockdown of different molecules and pull down experiments suggest that EhARPC1 interacts with EhAK1 and that it is required during initiation of phagocytosis and phagosome formation. Moreover, recruitment of EhARPC2 at the phagocytosis initiation by EhAK1 is also observed, indicating that the Arp 2/3 complex is recruited. In conclusion, these results suggests a novel mechanism of recruitment of Arp 2/3 complex during phagocytosis in E. histolytica. PMID:26646565

  5. 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.

  6. Atypical pneumonia

    Science.gov (United States)

    Walking pneumonia; Community-acquired pneumonia - atypical ... Bacteria that cause atypical pneumonia include: Mycoplasma pneumonia is caused by the bacteria Mycoplasma pneumoniae . It often affects people younger than age 40. Pneumonia due ...

  7. Atypical Depression

    Directory of Open Access Journals (Sweden)

    Erhan Ertekin

    2013-09-01

    Full Text Available Atypical depression is defined as a specifier of major depressive disorder. Columbia criteria for atypical depression are commonly used to make a diagnosis. Female sex, onset at early age, chronic course, and higher rate of comorbidity (especially anxiety disorder and bipolar disorder is noteworthy in atypical depression. Although, the atypical depression seems to support the familial genetic transition, there is not any specific study supporting these data. In the treatment of atypical depression, monoamine oxidase inhibitors are reported to be more effective than tricyclic antidepressants. In recent studies, selective serotonin reuptake inhibitors have also proven to be efficient.

  8. Cellular and Developmental Biology of TRPM7 Channel-Kinase: Implicated Roles in Cancer

    Directory of Open Access Journals (Sweden)

    Nelson S. Yee

    2014-07-01

    Full Text Available The transient receptor potential melastatin-subfamily member 7 (TRPM7 is a ubiquitously expressed cation-permeable ion channel with intrinsic kinase activity that plays important roles in various physiological functions. Biochemical and electrophysiological studies, in combination with molecular analyses of TRPM7, have generated insights into its functions as a cellular sensor and transducer of physicochemical stimuli. Accumulating evidence indicates that TRPM7 channel-kinase is essential for cellular processes, such as proliferation, survival, differentiation, growth, and migration. Experimental studies in model organisms, such as zebrafish, mouse, and frog, have begun to elucidate the pleiotropic roles of TRPM7 during embryonic development from gastrulation to organogenesis. Aberrant expression and/or activity of the TRPM7 channel-kinase have been implicated in human diseases including a variety of cancer. Studying the functional roles of TRPM7 and the underlying mechanisms in normal cells and developmental processes is expected to help understand how TRPM7 channel-kinase contributes to pathogenesis, such as malignant neoplasia. On the other hand, studies of TRPM7 in diseases, particularly cancer, will help shed new light in the normal functions of TRPM7 under physiological conditions. In this article, we will provide an updated review of the structural features and biological functions of TRPM7, present a summary of current knowledge of its roles in development and cancer, and discuss the potential of TRPM7 as a clinical biomarker and therapeutic target in malignant diseases.

  9. 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

  10. 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

    2015-03-01

    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: (1) behavioral and brain data from adults and children, showing that prosody and other aspects of timing of sentences influence online morpho-syntactic processing; (2) comorbidity of impaired rhythm with grammatical deficits in children with language impairment; and (3) 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 6-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. © 2015 New York Academy of Sciences.

  11. Sex-Typical and Sex-Atypical Interests of Kuder Occupational Interest Survey Criterion Groups: Implications for Counseling.

    Science.gov (United States)

    Diamond, Esther E.

    1981-01-01

    The degree of overlap between scores on male-normed and female-normed scales for Kuder Occupational Interest Survey criterion groups was studied. Results provide clues to sex-typical and sex-atypical interests of these groups. (Author)

  12. Strongly lateralized activation in language fMRI of atypical dominant patients-implications for presurgical work-up.

    Science.gov (United States)

    Wellmer, Jörg; Weber, Bernd; Weis, Susanne; Klaver, Peter; Urbach, Horst; Reul, Jürgen; Fernandez, Guillen; Elger, Christian E

    2008-07-01

    Functional magnetic resonance imaging (fMRI) is being used increasingly for language dominance assessment in the presurgical work-up of patients with pharmacoresistant epilepsy. However, the interpretation of bilateral fMRI-activation patterns is difficult. Various studies propose fMRI-lateralization index (LI) thresholds between +/-0.1 and +/-0.5 for discrimination of atypical from typical dominant patients. This study examines if these thresholds allow identifying atypical dominant patients with sufficient safety for presurgical settings. 65 patients had a tight comparison, fully controlled semantic decision fMRI-task and a Wada-test for language lateralization. According to Wada-test, 22 were atypical language dominant. In the remaining, Wada-test results were compatible with unilateral left dominance. We determined fMRI-LI for two frontal and one temporo-parietal functionally defined, protocol-specific volume of interest (VOI), and for the least lateralized of these VOIs ("low-VOI") in each patient. We find large intra-individual LI differences between functionally defined VOIs irrespective of underlying type of language dominance (mean LI difference 0.33+/-0.35, range 0-1.6; 15% of patients have inter-VOI-LI differences >1.0). Across atypical dominant patients fMRI-LI in the Broca's and temporo-parietal VOI range from -1 to +1, in the "remaining frontal" VOI from -0.93 to 1. The highest low-VOI-LI detected in atypical dominant patients is 0.84. Large intra-individual inter-VOI-LI differences and strongly lateralized fMRI-activation in patients with Wada-test proven atypical dominance question the value of the proposed fMRI-thresholds for presurgical language lateralization. Future studies have to develop strategies allowing the reliable identification of atypical dominance with fMRI. The low-VOI approach may be useful.

  13. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care.

    Science.gov (United States)

    Epstein, Jonathan I; Herawi, Mehsati

    2006-03-01

    We identified information critical for patient treatment on prostate needle biopsies diagnosed with prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma. A search was performed using the MEDLINE database and referenced lists of relevant studies to obtain articles addressing the significance of finding PIN or atypical foci suspicious for carcinoma on needle biopsy. There were certain results concerning PIN. 1) Low grade PIN should not be documented in pathology reports due to poor interobserver reproducibility and a relatively low risk of cancer following re-biopsy. 2) The expected incidence of HGPIN on needle biopsy is between 5% and 8%. 3) Although the diagnosis of HGPIN is subjective, interobserver reproducibility for its diagnosis is fairly high among urological pathologists, and yet only moderate among pathologists without special expertise in prostate pathology. 4) The median risk recorded in the literature for cancer following the diagnosis of HGPIN on needle biopsy is 24.1%, which is not much higher than the risk reported in the literature for repeat biopsy following a benign diagnosis. 5) The majority of publications that compared the risk of cancer in the same study following a needle biopsy diagnosis of HGPIN to the risk of cancer following a benign diagnosis on needle biopsy show no differences between the 2 groups. 6) Clinical and pathological parameters do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. 7) A major factor contributing to the decreased incidence of cancer following a diagnosis of HGPIN on needle biopsy in the contemporary era is related to increased needle biopsy core sampling, which detects many associated cancers on initial biopsy, such that re-biopsy, even with good sampling, does not detect many additional cancers. 8) It is recommended that men do not need routine repeat needle biopsy within the first year following the diagnosis of HGPIN, while further studies are needed

  14. Atypical Antidepressants

    Science.gov (United States)

    ... which is also used to treat insomnia Vortioxetine (Trintellix) Side effects may occur with antidepressants, including atypical ... traz_imtb_ins.pdf. Accessed May 23, 2016. Trintellix (prescribing information). Deerfield, Ill.: Takeda Pharmaceuticals; 2016. http:// ...

  15. The two kinases, AbrC1 and AbrC2, of the atypical two-component system AbrC are needed to regulate antibiotic production and differentiation in Streptomyces coelicolor.

    Directory of Open Access Journals (Sweden)

    Héctor eRodríguez

    2015-05-01

    Full Text Available Two-component systems (TCSs are the most important sensing mechanisms in bacteria. In Streptomyces, Two-component systems (TCSs are the most important sensing mechanisms in bacteria. In Streptomyces, TCSs-mediated responses to environmental stimuli are involved in the regulation of antibiotic production. This study examines the individual role of two histidine kinases (HKs, AbrC1 and AbrC2, which form part of an atypical TCS in Streptomyces coelicolor. qRT-PCR analysis of the expression of both kinases demonstrated that both are expressed at similar levels in NB and NMMP media. Single deletion of abrC1 elicited a significant increase in antibiotic production, while deletion of abrC2 did not have any clear effect. The origin of this phenotype, probably related to the differential phosphorylation ability of the two kinases, was also explored indirectly, analyzing the toxic phenotypes associated with high levels of phosphorylated RR. The higher the AbrC3 regulator phosphorylation rate, the greater the cell toxicity. For the first time, the present work shows in Streptomyces the combined involvement of two different HKs in the response of a regulator to environmental signals. Regarding the possible applications of this research, the fact that an abrC1 deletion mutant overproduces three of the S. coelicolor antibiotics makes this strain an excellent candidate as a host for the heterologous production of secondary metabolites.

  16. [Implication of MAP kinases in obesity-induced inflammation and insulin resistance].

    Science.gov (United States)

    Ceppo, Franck; Jager, Jennifer; Berthou, Flavien; Giorgetti-Peraldi, Sophie; Cormont, Mireille; Bost, Fréderic; Tanti, Jean-François

    2014-01-01

    Insulin resistance is often associated with obesity and is a major risk factor for development of type 2 diabetes as well as cardiovascular and hepatic diseases. Insulin resistance may also increase the incidence or the aggressiveness of some cancers. Insulin resistance occurs owing to defects in insulin signaling in target tissues of this hormone. During the last ten years, it became evident that the chronic low-grade inflammatory state that develops during obesity plays an important role in insulin resistance development. Indeed, inflammatory cytokines activate several signaling pathways that impinge on the insulin signaling pathway. Among them, this review will focus on the implication of the MAP kinases JNK and ERK1/2 signaling in the development of insulin signaling alterations and will discuss the possibility to target these pathways in order to fight insulin resistance. © Société de Biologie, 2014.

  17. 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.

  18. Atypical Cities

    Science.gov (United States)

    DiJulio, Betsy

    2011-01-01

    In this creative challenge, Surrealism and one-point perspective combine to produce images that not only go "beyond the real" but also beyond the ubiquitous "imaginary city" assignment often used to teach one-point perspective. Perhaps the difference is that in the "atypical cities challenge," an understanding of one-point perspective is a means…

  19. Atypical Depression

    Science.gov (United States)

    ... coping Other mental health disorders such as anxiety Suicide from feelings of depression Prevention There's no sure way to prevent depression. ... the association between oversleeping and overeating in atypical depression. Journal of Psychosomatic Research. 2015;78:52. Koyuncu A, et al. Relationship ...

  20. Petrogenesis of two Triassic A-type intrusions in the interior of South China and their implications for tectonic transition

    Science.gov (United States)

    Sun, Li-Qiang; Ling, Hong-Fei; Shen, Wei-Zhou; Wang, Kai-Xing; Huang, Guo-Long

    2017-07-01

    The evolution of the tectonic regime that was responsible for the Indosinian granitoids in the South China Block (SCB) is still controversial. Investigations on A-type granites can provide important information regarding this tectonic evolution. A detailed study that utilizes whole-rock elemental, Sr-Nd isotopic, in situ zircon U-Pb and Lu-Hf isotopic geochemistry is conducted on the Miantuwo biotite granite in northern Guangdong Province and the Pingtian biotite monzogranite in southern Jiangxi Province, South China. The new data indicate that both the Miantuwo and Pingtian granites were emplaced at 233 ± 2 Ma and show metaluminous to slightly peraluminous A-type granite affinity. The two granites are characterized by high amounts of rare earth elements (total REEs = 247 ppm-557 ppm and 251 ppm-342 ppm) and high field strength elements (Zr + Nb + Ce + Y = 325 ppm-605 ppm and 343 ppm-496 ppm) and high Ga/Al ratios (10,000 × Ga/Al = 2.50-2.98 and 2.62-2.70). Calculations from a zircon saturation thermometer and apatite saturation thermometer indicate that the magmatic temperatures were 800 °C-980 °C for both granites. Both the Miantuwo and Pingtian granites show relatively high initial 87Sr/86Sr ratios (0.7151-0.7185 and 0.7170-0.7189), low εNd(t) values (- 9.8 to - 8.6 and - 9.7 to - 9.1) and low to moderate zircon εHf(t) values (- 10.4 to - 6.6 and - 9.5 to - 4.6). Based on these data, we suggest that these two A-type granites were derived from the partial melting of existing mafic to intermediate rocks in the lower crust in response to the underplating and/or intraplating of mantle-derived magma. Our study on the Miantuwo and Pingtian granites, alongside previous studies on other Triassic A-type granites in South China, indicates an extensional tectonic environment during the Late Triassic in the interior of the Cathaysia Block. Alongside existing geological observations and the tectonic evolution in the SCB, we suggest that the interior of the SCB was

  1. 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.

  2. 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.

  3. [Atypical odontalgia].

    Science.gov (United States)

    Türp, Jens Christoph

    2005-01-01

    In spite of its first description by the English surgeon JOHN HUNTER more than 200 years ago, atypical odontalgia (AO), or phantom tooth pain, is not universally known among dentists. AO is a persistent neuropathic pain which may be initiated after deafferentiation of trigeminal nerve fibers following root canal treatment, apicectomy, or tooth extraction. In the absence of pathological clinical or radiological findings, the diagnosis is made by exclusion. After a thorough patient education about the condition, pharmacological and psychological pain management is required. Invasive and irreversible treatment attempts are contraindicated.

  4. The Atypical Guanylate Kinase MoGuk2 Plays Important Roles in Asexual/Sexual Development, Conidial Septation, and Pathogenicity in the Rice Blast Fungus

    Directory of Open Access Journals (Sweden)

    Xingjia Cai

    2017-12-01

    Full Text Available Guanylate kinases (GKs, which convert guanosine monophosphate into guanosine diphosphate (GDP, are important for growth and mannose outer chain elongation of cell wall N-linked glycoproteins in yeast. Here, we identified the ortholog of Saccharomyces cerevisiae GK Guk1, named MoGuk1 and a novel family of fungal GKs MoGuk2 in the rice blast fungus Magnaporthe oryzae. MoGuk1 contains 242 aa with an C-terminal GuKc domain that very similar to yeast Guk1. MoGuk2 contains 810 amino acids with a C-terminal GuKc domain and an additional N-terminal efThoc1 domain. Expression of either MoGuk1 or MoGuk2 in heterozygote yeast guk1 mutant could increase its GDP level. To investigate the biological role of MoGuk1 and MoGuk2 in M. oryzae, the gene replacement vectors were constructed. We obtained the ΔMoguk2 but not ΔMoguk1 mutant by screening over 1,000 transformants, indicating MoGuk1 might be essential for M. oryzae. The ΔMoguk2 mutant showed weak reductions in vegetative growth, conidial germination, appressorial formation, and appressorial turgor, and showed significant reductions in sporulation and pathogenicity. Moreover, the ΔMoguk2 mutant failed to produce perithecia and was sensitive to neomycin and a mixture of neomycin-tunicamycin. Exogenous GDP and ATP partially rescued the defects in conidial germination, appressorial formation, and infectious growth of the mutant. Further analysis revealed that intracellular GDP and GTP level was decreased, and GMP level was increased in the mutant, suggesting that MoGuk2 exhibits enzymatic activity. Structural analysis proved that the efThoc1, GuKc, and P-loop domains are essential for the full function of MoGuk2. Taken together, our data suggest that the guanylate kinase MoGuk2 is involved in the de novo GTP biosynthesis pathway and is important for infection-related morphogenesis in the rice blast fungus.

  5. Substrate-Specific Reorganization of the Conformational Ensemble of CSK Implicates Novel Modes of Kinase Function

    Science.gov (United States)

    Jamros, Michael A.; Oliveira, Leandro C.; Whitford, Paul C.; Onuchic, José N.; Adams, Joseph A.; Jennings, Patricia A.

    2012-01-01

    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. PMID:23028292

  6. 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.

  7. A novel predicted calcium-regulated kinase family implicated in neurological disorders.

    Directory of Open Access Journals (Sweden)

    Małgorzata Dudkiewicz

    Full Text Available The catalogues of protein kinases, the essential effectors of cellular signaling, have been charted in Metazoan genomes for a decade now. Yet, surprisingly, using bioinformatics tools, we predicted protein kinase structure for proteins coded by five related human genes and their Metazoan homologues, the FAM69 family. Analysis of three-dimensional structure models and conservation of the classic catalytic motifs of protein kinases present in four out of five human FAM69 proteins suggests they might have retained catalytic phosphotransferase activity. An EF-hand Ca(2+-binding domain in FAM69A and FAM69B proteins, inserted within the structure of the kinase domain, suggests they may function as Ca(2+-dependent kinases. The FAM69 genes, FAM69A, FAM69B, FAM69C, C3ORF58 (DIA1 and CXORF36 (DIA1R, are by large uncharacterised molecularly, yet linked to several neurological disorders in genetics studies. The C3ORF58 gene is found deleted in autism, and resides in the Golgi. Unusually high cysteine content and presence of signal peptides in some of the family members suggest that FAM69 proteins may be involved in phosphorylation of proteins in the secretory pathway and/or of extracellular proteins.

  8. The alpha-kinase family: an exceptional branch on the protein kinase tree.

    NARCIS (Netherlands)

    Middelbeek, J.A.J.; Clark, K.; Venselaar, H.; Huynen, M.A.; Leeuwen, F.N. van

    2010-01-01

    The alpha-kinase family represents a class of atypical protein kinases that display little sequence similarity to conventional protein kinases. Early studies on myosin heavy chain kinases in Dictyostelium discoideum revealed their unusual propensity to phosphorylate serine and threonine residues in

  9. Protein kinase C activation in mixed micelles. Mechanistic implications of phospholipid, diacylglycerol, and calcium interdependencies.

    Science.gov (United States)

    Hannun, Y A; Loomis, C R; Bell, R M

    1986-06-05

    The phospholipid, sn-1,2-diacylglycerol, and calcium dependencies of rat brain protein kinase C were investigated with a mixed micellar assay (Hannun, Y., Loomis, C., and Bell, R.M. (1985) J. Biol. Chem. 260, 10039-10043). Protein kinase C activity was independent of the number of Triton X-100, phosphatidylserine (PS), and sn-1,2-dioleoylglycerol (diC18:1) mixed micelles. Activation was strongly dependent on the mole per cent of PS and diC18:1. Activity of protein kinase C was dependent on PS, diC18:1, and calcium in mixed micelles prepared from detergents other than Triton X-100. This is consistent with the micelle providing an inert surface into which the lipid cofactors partition. Molecular sieve chromatography provided direct evidence for the homogeneity of Triton X-100, PS, and diC18:1 mixed micelles. Mixing studies and surface dilution studies indicated that PS and diC18:1 rapidly equilibrate among the mixed micelles. At saturating calcium, the diC18:1 dependence was strongly dependent on the mole per cent PS present. At 10 mol % PS, 0.25 mol % diC18:1 gave maximal activity whereas 6 mol % PS and 6 mol % diC18:1 did not give maximal activity. diC18:1 dependencies were hyperbolic at all PS levels tested. The data support the conclusion that a single molecule of diC18:1/micelle is sufficient to activate monomeric protein kinase C. The mole per cent PS required for maximal activation was reduced markedly as the mole per cent diC18:1 increased. Under all conditions tested, the PS dependence of protein kinase C activation lagged until greater than 3 mol % PS was present. Then activation occurred in a cooperative manner with Hill numbers near 4. These data indicate that 4 or more molecules of PS are required to activate monomeric protein kinase C. PS was the most effective of all the phospholipids tested in the mixed micelle assay. diC18:1 was found to modulate the amount of calcium required for maximal activity. As the level of Ca2+ increased, the mole per cent PS

  10. Oxidized, magnetite-series, rapakivi-type granites of Carajás, Brazil: Implications for classification and petrogenesis of A-type granites

    Science.gov (United States)

    Dall'Agnol, Roberto; de Oliveira, Davis Carvalho

    2007-02-01

    The varying geochemical and petrogenetic nature of A-type granites is a controversial issue. The oxidized, magnetite-series A-type granites, defined by Anderson and Bender [Anderson, J.L., Bender, E.E., 1989. Nature and origin of Proterozoic A-type granitic magmatism in the southwestern United States of America. Lithos 23, 19-52.], are the most problematic as they do not strictly follow the original definition of A-type granites, and approach calc-alkaline and I-type granites in some aspects. The oxidized Jamon suite A-type granites of the Carajás province of the Amazonian craton are compared with the magnetite-series granites of Laurentia, and other representative A-type granites, including Finnish rapakivi and Lachlan Fold Belt A-type granites, as well as with calc-alkaline, I-type orogenic granites. The geochemistry and petrogenesis of different groups of A-types granites are discussed with an emphasis on oxidized A-type granites in order to define their geochemical signatures and to clarify the processes involved in their petrogenesis. Oxidized A-type granites are clearly distinguished from calc-alkaline Cordilleran granites not only regarding trace element composition, as previously demonstrated, but also in their major element geochemistry. Oxidized A-type granites have high whole-rock FeO t/(FeO t + MgO), TiO 2/MgO, and K 2O/Na 2O and low Al 2O 3 and CaO compared to calc-alkaline granites. The contrast of Al 2O 3 contents in these two granite groups is remarkable. The CaO/(FeO t + MgO + TiO 2) vs. CaO + Al 2O 3 and CaO/(FeO t + MgO + TiO 2) vs. Al 2O 3 diagrams are proposed to distinguish A-type and calc-alkaline granites. Whole-rock FeO t/(FeO t + MgO) and the FeO t/(FeO t + MgO) vs. Al 2O 3 and FeO t/(FeO t + MgO) vs. Al 2O 3/(K 2O/Na 2O) diagrams are suggested for discrimination of oxidized and reduced A-type granites. Experimental data indicate that, besides pressure, the nature of A-type granites is dependent of ƒO 2 conditions and the water content

  11. Distribution of creatine kinase in the general population: Implications for statin therapy

    NARCIS (Netherlands)

    Brewster, Lizzy M.; Mairuhu, Gideon; Sturk, August; van Montfrans, Gert A.

    2007-01-01

    Background Eligible subjects with mildly elevated serum creatine kinase (CK) activity are often excluded before randomization in statin trials, but patients may potentially be misclassified as having hyperCKemia when inappropriate reference limits are used. Little information is usually given

  12. 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.

  13. Atypical panmixia in a European dolphin species (Delphinus delphis): implications for the evolution of diversity across oceanic boundaries.

    Science.gov (United States)

    Moura, A E; Natoli, A; Rogan, E; Hoelzel, A R

    2013-01-01

    Despite the scarcity of geographical barriers in the ocean environment, delphinid cetaceans often exhibit marked patterns of population structure on a regional scale. The European coastline is a prime example, with species exhibiting population structure across well-defined environmental boundaries. Here we undertake a comprehensive population genetic study on the European common dolphin (Delphinus delphis, based on 492 samples and 15 loci) and establish that this species shows exceptional panmixia across most of the study range. We found differentiation only between the eastern and western Mediterranean, consistent with earlier studies, and here use approximate Bayesian computations to explore different scenarios to explain the observed pattern. Our results suggest that a recent population bottleneck likely contributed significantly to the differentiation of the Eastern Mediterranean population (in Greek waters). This interpretation is consistent with independent census data that suggest a sharp population decline in the recent past. The implication is that an unperturbed population may currently show panmixia across the full study range. This exception to the more typical pattern of population structure seen for other regional dolphin species (and for common dolphin populations elsewhere in the world) suggests particular ecological or life-history traits distinct to this species in European waters. © 2012 The Authors. Journal of Evolutionary Biology © 2012 European Society For Evolutionary Biology.

  14. M-Type Pyruvate Kinase Isoforms and Lactate Dehydrogenase A in the Mammalian Retina: Metabolic Implications.

    Science.gov (United States)

    Casson, Robert J; Wood, John P M; Han, Guoge; Kittipassorn, Thaksaon; Peet, Daniel J; Chidlow, Glyn

    2016-01-01

    Like cancer cells, photoreceptor cells produce lactate aerobically, requiring lactate dehydrogenase A (LDH-A). Cancer cells also use glycolytic intermediates for biosynthesis. The molecular switch controlling glycolytic flow is thought to be an isoenzyme of pyruvate kinase (PKM2). Here, we determined the expression and localization of PKM2 and LDH-A in mammalian retina and make comparisons with the brain. Single- and double-labeling immunohistochemistry for PKM2, pyruvate kinase M1 (PKM1), and LDH-A were performed using retinal sections from C57BL/6 mice, Sprague-Dawley rats, rabbits, marmosets, and humans. Pyruvate kinase M1 and PKM2 mRNA and protein expression levels were quantified in rodent retina and brain by using qPCR and immunoblotting. The quaternary forms of PKM2 in rat retina were also determined. Pyruvate kinase M2 was present in some glial cells and rod and cone photoreceptors in the retina of all species but was exclusively localized to glia in the brain. Pyruvate kinase M1 was confined to neurons in the retina and brain. Lactate dehydrogenase A was principally found in photoreceptors and inner portion of the avascular rabbit retina. Western blotting and qPCR confirmed high levels of PKM2 and LDH-A in the retina. There was a 6- to 9-fold greater expression of PKM2 mRNA in the rodent retina than in the brain. Both the dimeric (inactive, biosynthesis-driving form) and the active tetrameric (glycolytic-driving) forms of PKM2 were present in retina but not in brain. Mammalian photoreceptors contain dimeric and tetrameric PKM2 and LDH-A. This is consistent with the ability to switch between energy production and biosynthesis like a proliferating tissue, possibly due to demands of opsin synthesis.

  15. Differential role of human choline kinase alpha and beta enzymes in lipid metabolism: implications in cancer onset and treatment.

    Directory of Open Access Journals (Sweden)

    David Gallego-Ortega

    Full Text Available BACKGROUND: The Kennedy pathway generates phosphocoline and phosphoethanolamine through its two branches. Choline Kinase (ChoK is the first enzyme of the Kennedy branch of synthesis of phosphocholine, the major component of the plasma membrane. ChoK family of proteins is composed by ChoKalpha and ChoKbeta isoforms, the first one with two different variants of splicing. Recently ChoKalpha has been implicated in the carcinogenic process, since it is over-expressed in a variety of human cancers. However, no evidence for a role of ChoKbeta in carcinogenesis has been reported. METHODOLOGY/PRINCIPAL FINDINGS: Here we compare the in vitro and in vivo properties of ChoKalpha1 and ChoKbeta in lipid metabolism, and their potential role in carcinogenesis. Both ChoKalpha1 and ChoKbeta showed choline and ethanolamine kinase activities when assayed in cell extracts, though with different affinity for their substrates. However, they behave differentially when overexpressed in whole cells. Whereas ChoKbeta display an ethanolamine kinase role, ChoKalpha1 present a dual choline/ethanolamine kinase role, suggesting the involvement of each ChoK isoform in distinct biochemical pathways under in vivo conditions. In addition, while overexpression of ChoKalpha1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKbeta overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKalpha1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKbeta mRNA levels were observed. Finally, MN58b, a previously described potent inhibitor of ChoK with in vivo antitumoral activity, shows more than 20-fold higher efficiency towards ChoKalpha1 than ChoKbeta. CONCLUSION/SIGNIFICANCE: This study represents the first evidence of the distinct metabolic role of ChoKalpha and ChoKbeta isoforms, suggesting different physiological roles and implications in human

  16. Colorectal laterally spreading tumors show characteristic expression of cell polarity factors, including atypical protein kinase C λ/ι, E-cadherin, β-catenin and basement membrane component.

    Science.gov (United States)

    Ichikawa, Yasushi; Nagashima, Yoji; Morioka, Kaori; Akimoto, Kazunori; Kojima, Yasuyuki; Ishikawa, Takashi; Goto, Ayumu; Kobayashi, Noritoshi; Watanabe, Kazuteru; Ota, Mitsuyoshi; Fujii, Shoichi; Kawamata, Mayumi; Takagawa, Ryo; Kunizaki, Chikara; Takahashi, Hirokazu; Nakajima, Atsushi; Maeda, Shin; Shimada, Hiroshi; Inayama, Yoshiaki; Ohno, Shigeo; Endo, Itaru

    2014-09-01

    Colorectal flat-type tumors include laterally spreading tumors (LSTs) and flat depressed-type tumors. The former of which shows a predominant lateral spreading growth rather than an invasive growth. The present study examined the morphological characteristics of LSTs, in comparison with polypoid- or flat depressed-type tumors, along with the expression of atypical protein kinase C (aPKC) λ/ι, a pivotal cell polarity regulator, and the hallmarks of cell polarity, as well as with type IV collagen, β-catenin and E-cadherin. In total, 37 flat-type (24 LSTs and 13 flat depressed-type tumors) and 20 polypoid-type colorectal tumors were examined. The LSTs were classified as 15 LST adenoma (LST-A) and nine LST cancer in adenoma (LST-CA). An immunohistochemical examination was performed on aPKC λ/ι, type IV collagen, β-catenin and E-cadherin. The LST-A and -CA showed a superficial replacing growth pattern, with expression of β-catenin and E-cadherin in the basolateral membrane and type IV collagen along the basement membrane. In addition, 86.6% of LST-A and 55.6% of LST-CA showed aPKC λ/ι expression of 1+ (weak to normal intensity staining in the cytoplasm compared with the normal epithelium). Furthermore, ~45% of the polypoid-type adenomas showed 2+ (moderate intensity staining in the cytoplasm and/or nucleus) and 66.7% of the polypoid-type cancer in adenoma were 3+ (strong intensity staining in the cytoplasm and nucleus). A statistically significant positive correlation was observed between the expression of aPKC λ/ι and β-catenin (r=0.842; P<0.001), or type IV collagen (r=0.823; P<0.001). The LSTs showed a unique growth pattern, different from the expanding growth pattern presented by a polypoid tumor and invasive cancer. The growth characteristics of LST appear to be caused by adequate coexpression of β-catenin, type IV collagen and aPKC λ/ι.

  17. 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.

  18. Relationship Between Buprenorphine Dosing and Triglyceride Lowering and Creatinine Kinase Elevation in Felines: Possible Human Implications.

    Science.gov (United States)

    Srinivas, Nuggehally R

    2016-01-01

    Recently published feline data suggest that high doses of buprenorphine can elevate creatinine kinase (CK) and profoundly influence triglyceride levels in an inverted dose versus effect relationship. This intriguing observation in felines, hitherto not documented for buprenorphine, should be considered in human situations for any trends of translatability. The report evaluates the observed effects in domestic cats and what is known about buprenorphine in human subjects. Based on the objective assessment, the following are deduced: (a) although elevated CK levels is a nonissue in humans, one needs to pay attention especially when buprenorphine is used at the high end of therapeutic dose range in the presence of drugs that can impair the hepatic metabolism of buprenorphine; and (b) the potential for triglyceride lowering can be easily confirmed in human trials, and since it may occur at the relevant therapeutic doses of buprenorphine, it may be beneficial in such patients who may have added cardiovascular risk factors.

  19. Synaptic roles of cyclin-dependent kinase 5 & its implications in epilepsy

    Directory of Open Access Journals (Sweden)

    Aparna Banerjee Dixit

    2017-01-01

    Full Text Available There is an urgent need to understand the molecular mechanisms underlying epilepsy to find novel prognostic/diagnostic biomarkers to prevent epilepsy patients at risk. Cyclin-dependent kinase 5 (CDK5 is involved in multiple neuronal functions and plays a crucial role in maintaining homeostatic synaptic plasticity by regulating intracellular signalling cascades at synapses. CDK5 deregulation is shown to be associated with various neurodegenerative diseases such as Alzheimer's disease. The association between chronic loss of CDK5 and seizures has been reported in animal models of epilepsy. Genetic expression of CDK5 at transcriptome level has been shown to be abnormal in intractable epilepsy. In this review various possible mechanisms by which deregulated CDK5 may alter synaptic transmission and possibly lead to epileptogenesis have been discussed. Further, CDK5 has been proposed as a potential biomarker as well as a pharmacological target for developing treatments for epilepsy.

  20. The Plasticity of Oncogene Addiction: Implications for Targeted Therapies Directed to Receptor Tyrosine Kinases

    Directory of Open Access Journals (Sweden)

    Vinochani Pillay

    2009-05-01

    Full Text Available A common mutation of the epidermal growth factor receptor (EGFR in glioblastoma multiforme (GBM is an extracellular truncation known as the de2-7 EGFR (or EGFRvIII. Hepatocyte growth factor (HGF is the ligand for the receptor tyrosine kinase (RTK c-Met, and this signaling axis is often active in GBM. The expression of the HGF/c-Met axis or de2-7 EGFR independently enhances GBMgrowth and invasiveness, particularly through the phosphatidylinositol-3 kinase/pAkt pathway. Using RTK arrays, we show that expression of de2-7 EGFR in U87MG GBM cells leads to the coactivation of several RTKs, including platelet-derived growth factor receptor β and c-Met. A neutralizing antibody to HGF (AMG102 did not inhibit de2-7 EGFR-mediated activation of c-Met, demonstrating that it is ligand-independent. Therapy for parental U87MG xenografts with AMG 102 resulted in significant inhibition of tumor growth, whereas U87MG.Δ2-7 xenografts were profoundly resistant. Treatment of U87MG.Δ2-7 xenografts with panitumumab, an anti-EGFR antibody, only partially inhibited tumor growth as xenografts rapidly reverted to the HGF/c-Met signaling pathway. Cotreatment with panitumumab and AMG 102 prevented this escape leading to significant tumor inhibition through an apoptotic mechanism, consistent with the induction of oncogenic shock. This observation provides a rationale for using panitumumab and AMG 102 in combination for the treatment of GBM patients. These results illustrate that GBM cells can rapidly change the RTK driving their oncogene addiction if the alternate RTK signals through the same downstream pathway. Consequently, inhibition of a dominant oncogene by targeted therapy can alter the hierarchy of RTKs resulting in rapid therapeutic resistance.

  1. Horizontal transfer of bacterial polyphosphate kinases to eukaryotes: implications for the ice age and land colonisation.

    Science.gov (United States)

    Whitehead, Michael P; Hooley, Paul; W Brown, Michael R

    2013-06-05

    Studies of online database(s) showed that convincing examples of eukaryote PPKs derived from bacteria type PPK1 and PPK2 enzymes are rare and currently confined to a few simple eukaryotes. These enzymes probably represent several separate horizontal transfer events. Retention of such sequences may be an advantage for tolerance to stresses such as desiccation or nutrient depletion for simple eukaryotes that lack more sophisticated adaptations available to multicellular organisms. We propose that the acquisition of encoding sequences for these enzymes by horizontal transfer enhanced the ability of early plants to colonise the land. The improved ability to sequester and release inorganic phosphate for carbon fixation by photosynthetic algae in the ocean may have accelerated or even triggered global glaciation events. There is some evidence for DNA sequences encoding PPKs in a wider range of eukaryotes, notably some invertebrates, though it is unclear that these represent functional genes.Polyphosphate (poly P) is found in all cells, carrying out a wide range of essential roles. Studied mainly in prokaryotes, the enzymes responsible for synthesis of poly P in eukaryotes (polyphosphate kinases PPKs) are not well understood. The best characterised enzyme from bacteria known to catalyse the formation of high molecular weight polyphosphate from ATP is PPK1 which shows some structural similarity to phospholipase D. A second bacterial PPK (PPK2) resembles thymidylate kinase. Recent reports have suggested a widespread distribution of these bacteria type enzymes in eukaryotes. On - line databases show evidence for the presence of genes encoding PPK1 in only a limited number of eukaryotes. These include the photosynthetic eukaryotes Ostreococcus tauri, O. lucimarinus, Porphyra yezoensis, Cyanidioschyzon merolae and the moss Physcomitrella patens, as well as the amoeboid symbiont Capsaspora owczarzaki and the non-photosynthetic eukaryotes Dictyostelium (3 species

  2. Focal adhesion kinase (FAK) perspectives in mechanobiology: implications for cell behaviour.

    Science.gov (United States)

    Tomakidi, Pascal; Schulz, Simon; Proksch, Susanne; Weber, Wilfried; Steinberg, Thorsten

    2014-09-01

    Mechanobiology is a scientific interface discipline emerging from engineering and biology. With regard to tissue-regenerative cell-based strategies, mechanobiological concepts, including biomechanics as a target for cell and human mesenchymal stem cell behaviour, are on the march. Based on the periodontium as a paradigm, this mini-review discusses the key role of focal-adhesion kinase (FAK) in mechanobiology, since it is involved in mediating the transformation of environmental biomechanical signals into cell behavioural responses via mechanotransducing signalling cascades. These processes enable cells to adjust quickly to environmental cues, whereas adjustment itself relies on the specific intramolecular phosphorylation of FAK tyrosine residues and the multiple interactions of FAK with distinct partners. Furthermore, interaction-triggered mechanotransducing pathways govern the dynamics of focal adhesion sites and cell behaviour. Facets of behaviour not only include cell spreading and motility, but also proliferation, differentiation and apoptosis. In translational terms, identified and characterized biomechanical parameters can be incorporated into innovative concepts of cell- and tissue-tailored clinically applied biomaterials controlling cell behaviour as desired.

  3. The Late Cretaceous I- and A-type granite association of southeast China: Implications for the origin and evolution of post-collisional extensional magmatism

    Science.gov (United States)

    Zhao, Jiao-Long; Qiu, Jian-Sheng; Liu, Liang; Wang, Rui-Qiang

    2016-01-01

    We present new geochronological, mineralogical, and geochemical data for granitic plutons that crop out within the Zhoushan archipelago, northeastern coastal Zhejiang Province, in order to constrain their origin, and the genetic relationship between the I- and A-type granites. These granites can be divided into two groups: (1) the northern I-type Putuoshan (PTS) and Dadong'ao (DDA) plutons; and (2) the southern A-type Daqingshan (DQS), Taohuadao (THD), and Xiazhidao (XZD) plutons. Zircon LA-ICP-MS U-Pb dating yielded ages of 98-96 Ma for the northern I-type plutons and 89-86 Ma for the southern A-type plutons. All of these granites are highly siliceous, K-rich, and have similar total alkali and total rare earth element (REE) abundances. However, there are also geochemical differences between the I-type and the A-type granites. The northern I-type alkali-feldspar granites are high-K calc-alkaline, metaluminous to mildly peraluminous, contain low concentrations of the high field strength elements (HFSE; e.g., Nb, Ta, Zr, and Hf), and have low Ga/Al ratios (2.04-2.44). In contrast, the southern A-type granites are peralkaline and F-rich, and have lower CaO and Al2O3 concentrations, and higher Fe2O3T and HFSE concentrations and Ga/Al ratios (3.25-3.86). Meanwhile, they have slightly higher heavy REE (HREE) concentrations, and are more depleted in Ba, Sr, P, Ti, and Eu than the northern I-type granites. Both the I- and A-type granites have homogeneous whole-rock Nd and highly variable zircon Hf isotopic compositions. Of note, the southern peralkaline A-type granites appear to have more radiogenic Nd and Hf isotope compositions than the northern I-type granites. The present data, together with the results of a previous study on mafic enclaves within the PTS pluton, suggest that the northern I-type alkali-feldspar granites were generated by mixing of mantle-derived material with crustal-derived magmas that formed by dehydration melting of mica-bearing basaltic rocks

  4. 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.

  5. CPD: Atypical pathogens and challenges in community-acquired ...

    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 ...

  6. 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 situ...... activation of the receptor kinase in skeletal muscle was reduced about 70%. Selection of only those receptors that bound to anti-phosphotyrosine antibody showed that these receptors had normal kinase activity and that the reduction in overall kinase activity was due to the inability of about 70......% of the receptors to become insulin-dependently activated. The mother carries a point mutation at the last base pair in exon 17 which, due to abnormal alternative splicing, could lead to normally transcribed receptor or truncated receptor lacking the kinase region. Kinase activation was normal in the mother...

  7. Anaplastic lymphoma kinase gene copy number gain in inflammatory breast cancer (IBC: prevalence, clinicopathologic features and prognostic implication.

    Directory of Open Access Journals (Sweden)

    Min Hwan Kim

    Full Text Available Inflammatory breast cancer (IBC is the most aggressive form of breast cancer, and its molecular pathogenesis still remains to be elucidated. This study aimed to evaluate the prevalence and implication of anaplastic lymphoma kinase (ALK copy number change in IBC patients.We retrospectively collected formalin-fixed, paraffin-embedded tumor tissues and medical records of IBC patients from several institutes in Korea. ALK gene copy number change and rearrangement were assessed by fluorescence in situ hybridization (FISH assay, and ALK expression status was evaluated by immunohistochemical (IHC staining.Thirty-six IBC patients including those with HER2 (+ breast cancer (16/36, 44.4% and triple-negative breast cancer (13/36, 36.1% were enrolled in this study. ALK copy number gain (CNG was observed in 47.2% (17/36 of patients, including one patient who harbored ALK gene amplification. ALK CNG (+ patients showed significantly worse overall survival compared to ALK CNG (- patients in univariate analysis (24.9 months vs. 38.1 months, p = 0.033. Recurrence free survival (RFS after curative mastectomy was also significantly shorter in ALK CNG (+ patients than in ALK CNG (- patients (n = 22, 12.7 months vs. 43.3 months, p = 0.016. Multivariate Cox regression analysis with adjustment for HER2 and ER statuses showed significantly poorer RFS for ALK CNG (+ patients (HR 5.63, 95% CI 1.11-28.44, p = 0.037.This study shows a significant presence of ALK CNG in IBC patients, and ALK CNG was associated with significantly poorer RFS.

  8. 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.

  9. Structure-function study of deinococcal serine/threonine protein kinase implicates its kinase activity and DNA repair protein phosphorylation roles in radioresistance of Deinococcus radiodurans.

    Science.gov (United States)

    Rajpurohit, Yogendra S; Misra, Hari S

    2013-11-01

    The DR2518 (RqkA) a eukaryotic type serine/threonine protein kinase in Deinococcus radiodurans was characterized for its role in bacterial response to oxidative stress and DNA damage. The K42A, S162A, T169A and S171A mutation in RqkA differentially affected its kinase activity and functional complementation for γ radiation resistance in Δdr2518 mutant. For example, K42A mutant was completely inactive and showed no complementation while S171A, T169A and T169A/S171A mutants were less active and complemented proportionally to different levels as compared to wild type. Amongst, different DNA binding proteins that purified RqkA could phosphorylate, PprA a DNA repair protein, phosphorylation had improved its affinity to DNA by 4 fold and could enhance its supportive role in intermolecular ligation by T4 DNA ligase. RqkA phosphorylates PprA at threonine 72 (T72), serine 112 (S112) and threonine 144 (T144) in vitro with the majority of it goes to T72 site. Unlike wild type PprA and single mutants of T72, S112 and T144 residues, the T72AS112A double and T72AS112AT144A triple mutant derivatives of PprA did not phosphorylate in vivo and also failed to complement PprA loss in D. radiodurans. Deletion of rqkA in pprA::cat background enhanced radiosensitivity of pprA mutant, which became nearly similar to ΔrqkA resistance to γ radiation. These results suggested that K42 of RqkA is essential for catalytic functions and the kinase activity of RqkA as well as phosphorylation of PprA have roles in γ radiation resistance of D. radiodurans. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Two Late Cretaceous A-type granites related to the Yingwuling W-Sn polymetallic mineralization in Guangdong province, South China: Implications for petrogenesis, geodynamic setting, and mineralization

    Science.gov (United States)

    Zheng, Wei; Mao, Jingwen; Zhao, Haijie; Zhao, Caisheng; Yu, Xiaofei

    2017-03-01

    Major and trace elements, whole rock Sr-Nd-Pb isotopes, LA-ICP-MS U-Pb zircon dating, zircon trace elements and Hf isotope data are reported for a suite of A-type granites from Yingwuling pluton in western Guangdong province, South China. Zircon U-Pb ages obtained by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) show that biotite granite and alkali feldspar granite were emplaced in 81.3 ± 0.6 Ma and 80.6 ± 0.5 Ma, respectively. Both of the two suites have the petrographic and geochemical characteristics of A-type granite. These granitic rocks are metaluminous to weakly peraluminous and have pronounced contents of total alkalis (Na2O + K2O = 7.80-8.84%), Fe2O3T/MgO and Ga/Al ratios. They exhibit low MgO, CaO and TiO2 contents, enrichment in some LILEs and HFSEs (except for Zr, Eu and Y), depletion in Ba, Sr, P and Ti. They show A2 subtype affinity and were probably formed a temperature of 800 °C. The Yingwuling biotite granite has relatively high (87Sr/86Sr)i ratios of 0.70655 to 0.70928, low εNd(t) values of - 5.8 to - 4.2 and zircon εHf(t) values (- 5.70-1.37). Whole-rock Nd isotopic and zircon Hf isotopic two-stages model ages mostly vary from 1057 to 1506 Ma. The alkali feldspar granite display bulk rock εNd(t) values and (87Sr/86Sr)i ratios in the range of - 6.6 to - 6.1 and 0.70640 to 0.71077, respectively, and zircon εHf(t) values from - 5.44 to 0.54, with Mesoproterozoic T2DM for both Nd and Hf isotopes. Geochemical and isotopic data indicate the Yingwuling A-type granitic magmas were drived from mantle-crust interaction. Zircon grains of Yingwuling granites have relatively low Eu/Eu* and Ce4 +/Ce3 + ratios, indicating low oxygen fugacity. The visible tetrad effect in the Yingwuling granites indicates that it experienced strong fractionation and is close relationship to the W-Sn mineralization. Our new data together with previous published data indicate that Late Mesozoic A-type granitiods or alkaline intrusive rocks in South

  11. Late Carboniferous bimodal volcanic rocks and coeval A-type granite in the Suman Khad area, Southwest Mongolia: Implications for the tectonic evolution

    Science.gov (United States)

    Zhu, Mingshuai; Zhang, Fochin; Fan, Jingjing; Miao, Laicheng; Baatar, Munkhtsengel; Anaad, Chimedtseren; Yang, Shunhu; Li, Xingbo; Ganbat, Ariuntsetseg

    2017-08-01

    The volcanic rocks in the Suman Khad area in Southwest Mongolia form a bimodal suite consisting mainly of peralkaline rhyolites with subordinate basalts. The rhyolite sample collected from the bimodal suite yielded a SHRIMP zircon U-Pb age of 314 ± 5 Ma (MSWD = 1.41, n = 12), which was interpreted to represent formation time of the bimodal volcanic suite. The basalts were characterized by enrichment in LILE and LREE, and depletion in HFSE, indicating their formation was related to subduction processes. These features, together with their positive εNd (t) values (6.3-6.7), suggest that the basalts were likely derived from a depleted mantle source metasomatized by subduction-related fluids. In various tectonic discrimination diagrams, the basalts exhibited a transition from true arc basalts to intraplate basalts and thus were suggested to from in a back-arc tectonic setting. The rhyolites show a close affinity to A-type granites with enrichment in LILE and LREE, depletion in Nb, Ta and Ti and positive εNd (t) values (6.0-6.4). Considering the observed distinct compositional gap between the endmembers of the bimodal suite, the rhyolites are proposed to originate from partial melting of juvenile basaltic crustal rocks rather than fractional crystallization of basaltic melt. The granite associated with the bimodal volcanic rocks yielded a SHRIMP zircon U-Pb ages of 312 ± 5 Ma (MSWD = 0.75, n = 13), indicating that the granite is contemporaneous with the bimodal volcanic suite. The granite samples showed typical A-type granitic geochemical affinities and are considered to have been formed by partial melting of crustal rocks in a within-plate tectonic setting. Based on a combination of the available data, we suggest that the Late Carboniferous bimodal volcanic suite together with the coeval A-type granites in the Suman Khad region probably document a back-arc basin extensional environment, which probably related to the roll-back of the Paleo-Asian oceanic plate during

  12. Atypical charles bonnet syndrome

    OpenAIRE

    Priti Arun; Rajan Jain; Vaibhav Tripathi

    2013-01-01

    Charles Bonnet syndrome (CBS) is not uncommon disorder. It may not present with all typical symptoms and intact insight. Here, a case of atypical CBS is reported where antipsychotics were not effective. Patient improved completely after restoration of vision.

  13. Petrology of the anorogenic, oxidised Jamon and Musa granites, Amazonian Craton: implications for the genesis of Proterozoic A-type granites

    Science.gov (United States)

    Dall'Agnol, Roberto; Rämö, O. Tapani; de Magalhães, Marilia Sacramento; Macambira, Moacir José Buenano

    1999-03-01

    The 1.88 Ga Jamon and Musa granites are magnetite-bearing anorogenic, A-type granites of Paleoproterozoic age. They intrude the Archaean rocks of the Rio Maria Granite-Greenstone Terrain in the eastern part of the Amazonian Craton in northern Brazil. A suite of biotite±amphibole monzogranite to syenogranite, with associated dacite porphyry (DP) and granite porphyry (GP) dykes, dominates in these subalkaline granites that vary from metaluminous to peraluminous and show high FeO/(FeO+MgO) and K 2O/Na 2O. In spite of their broad geochemical similarities, the Jamon and Musa granites show some significant differences in their REE patterns and in the behaviour of Y. The Jamon granites are related by fractional crystallisation of plagioclase, potassium feldspar, quartz, biotite, magnetite±amphibole±apatite±ilmenite. Geochemical modelling and Nd isotopic data indicate that the Archaean granodiorites, trondhjemites and tonalites of the Rio Maria region are not the source of the Jamon Granite and associated dyke magmas. Archaean quartz diorites, differentiated from the mantle at least 1000 m.y. before the emplacement of the granites, have a composition adequate to generate DP and the hornblende-biotite monzogranite magmas by different degrees of partial melting. A larger extent of amphibole fractionation during the evolution of the Musa pluton can explain some of the observed differences between it and the Jamon pluton. The studied granites crystallised at relatively high fO 2 and are anorogenic magnetite-series granites. In this aspect, as well as concerning geochemical characteristics, they display many affinities with the Proterozoic A-type granites of south-western United States. The Jamon and Musa granites differ from the anorthosite-mangerite-charnockite-rapakivi granite suites of north-eastern Canada and from the reduced rapakivi granites of the Fennoscandian Shield in several aspects, probably because of different magmatic sources.

  14. Atypical odontalgia: a review of the literature.

    Science.gov (United States)

    Melis, Marcello; Lobo, Silvia Lobo; Ceneviz, Caroline; Zawawi, Khalid; Al-Badawi, Emad; Maloney, George; Mehta, Noshir

    2003-01-01

    To review previous reports of cases of atypical odontalgia to examine its epidemiological and clinical characteristics and to explore the etiology and pathophysiology of the disease. Atypical odontalgia is one of many painful conditions that affect the oral cavity and is often overlooked in the differential diagnosis. A search of the literature was performed for all cases of atypical odontalgia reported from 1966 to the present. The typical clinical presentation of atypical odontalgia that has been reported involves pain in a tooth in the absence of any sign of pathology; the pain may spread to areas of the face, neck, and shoulder. The existing literature suggests that this condition occurs in 3% to 6% of the patients who undergo endodontic treatment, with high female preponderance and a concentration of cases in the fourth decade of life. Deafferentation seems to be the most likely mechanism to initiate the pain, but psychological factors, alteration of neural mechanisms, and even an idiopathic mechanism have been implicated. Not all reported cases were preceded by trauma to the teeth or gums. The treatment of choice is a tricyclic antidepressant, alone or in combination with a phenothiazine. The outcome is usually fair, with many patients obtaining complete relief from pain. Especially in the absence of overt pathology, particular attention should be paid to avoiding any unnecessary and potentially dangerous dental intervention on the teeth. Atypical odontalgia is surprisingly common, of uncertain origin, and potentially treatable.

  15. Structure, function, and evolution of plant NIMA-related kinases: implication for phosphorylation-dependent microtubule regulation.

    Science.gov (United States)

    Takatani, Shogo; Otani, Kento; Kanazawa, Mai; Takahashi, Taku; Motose, Hiroyasu

    2015-11-01

    Microtubules are highly dynamic structures that control the spatiotemporal pattern of cell growth and division. Microtubule dynamics are regulated by reversible protein phosphorylation involving both protein kinases and phosphatases. Never in mitosis A (NIMA)-related kinases (NEKs) are a family of serine/threonine kinases that regulate microtubule-related mitotic events in fungi and animal cells (e.g. centrosome separation and spindle formation). Although plants contain multiple members of the NEK family, their functions remain elusive. Recent studies revealed that NEK6 of Arabidopsis thaliana regulates cell expansion and morphogenesis through β-tubulin phosphorylation and microtubule destabilization. In addition, plant NEK members participate in organ development and stress responses. The present phylogenetic analysis indicates that plant NEK genes are diverged from a single NEK6-like gene, which may share a common ancestor with other kinases involved in the control of microtubule organization. On the contrary, another mitotic kinase, polo-like kinase, might have been lost during the evolution of land plants. We propose that plant NEK members have acquired novel functions to regulate cell growth, microtubule organization, and stress responses.

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

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    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

  17. ERG transcriptional networks in primary acute leukemia cells implicate a role for ERG in deregulated kinase signaling.

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    Juliane Bock

    Full Text Available High expression of the E26 transforming sequence related gene (ERG is associated with poor prognosis in a subgroup of leukemia patients with acute myeloid (AML and acute T-lymphoblastic leukemia (T-ALL. In a previous study we proposed that ERG overexpression may deregulate several signaling cascades in acute leukemia. Herein, we further expand those studies by identifying a consensus of biological targets in primary blasts of newly diagnosed acute leukemia patients. Our findings of chromatin immunoprecipitation-on-chip of primary samples revealed 48 significantly enriched single genes including DAAM1 and NUMB. Significantly enriched signaling pathways included WNT/β-catenin, p53, and PI3K/AKT with ERG overexpression inducing dephosphorylation of AKT(Ser473 relative to non ERG expressing K562 cells. Cell based ERG overexpression studies also revealed drug resistance to multi-kinase inhibitor, BAY 43-9006 (Sorafenib and to the tyrosine kinase inhibitor TKI258. Thus in primary leukemic cells, ERG may contribute to the dysregulation of kinase signaling, which results in resistance to kinase inhibitors.

  18. Magnetic anisotropy of the Redenção granite, eastern Amazonian craton (Brazil): Implications for the emplacement of A-type plutons

    Science.gov (United States)

    de Oliveira, Davis Carvalho; Neves, Sérgio Pacheco; Trindade, Ricardo I. F.; Dall'Agnol, Roberto; Mariano, Gorki; Correia, Paulo Barros

    2010-10-01

    A magnetic fabric study was performed on the Redenção pluton in an attempt to understand its emplacement history. The Redenção pluton is part of the 1.88 Ga, anorogenic, A-type Jamon suite that intruded 2.97-2.86 Ga-old Archean granitoids of the Rio Maria Granite-Greenstone Terrane in the eastern Amazonian craton (northern Brazil). Previous gravity survey indicates that the pluton is a 6 km-thick, tabular intrusion. It is characterized by a concentric distribution of facies, with rings of seriated and porphyritic granite that cut across the main facies of even-grained monzogranites. The whole set is intruded by leucogranites that occupy the center of the pluton. Petrographic examination, magnetic susceptibilities, coercivity-spectra and thermomagnetic curves indicate that the magnetic fabric is primarily carried by coarse-grained multidomain magnetite. This is reinforced by the coincidence of magnetic susceptibility and remanence anisotropy principal axes. The absence of solid-state deformation features and the low anisotropy degrees indicate that the magnetic fabric is magmatic in origin. The magnetic fabric displays a systematic pattern, with all facies, including the rings of porphyritic granite, being characterized by concentric, gently dipping foliations associated with gently plunging lineations. Only the central leucogranitic facies shows a slightly discordant pattern with steeply dipping fabrics at its northeastern sector. An emplacement model by vertical stacking of successive magma batches is proposed for the construction of the Redenção pluton, which reconciles the tabular shape of the intrusion, the petrographic and geochemical zoning, and the magnetic fabric pattern. Initially, two magma batches were emplaced as sills. First the even-grained monzogranite, then the seriated and porphyritic granites, which formed by mingling of a leucogranitic melt with the host biotite-monzogranitic magma as attested by geochemical data and field evidence. The

  19. Atypical swallowing: a review.

    Science.gov (United States)

    Maspero, C; Prevedello, C; Giannini, L; Galbiati, G; Farronato, G

    2014-06-01

    Atypical swallowing is a myofunctional problem consisting of an altered tongue position during the act of swallowing. High incidence in population, multifactorial etiology and the recurring connection with the presence of malocclusions made it a topic of strong interest and discussion in science. The purpose of this review is to illustrate the current orientation on the topic of atypical swallowing, trying in particular to answer two questions: 1) what kind of connection is there between atypical swallowing and malocclusion; 2) what kind of therapy should be used to solve it. This review was conducted on the Medline database [www.ncbi.nim.nih.gov/pubmed] searching for the keywords "atypical swallowing" and "tongue thrust". We examined all the documents from the year 1990 onwards, excluding the ones about syndromic cases of the central motor system. The causal relation between the two problems seems to be biunique: some authors affirm that this oral habit starts as a compensation mechanism for a preexisting malocclusion (especially in case of open-bite); other texts show that it has a tendency to exacerbate cases of malocclusion; it is also proven that a non-physiological tongue thrust can negatively influence the progress of an ongoing orthodontic therapy. Thereby, the best therapeutic approach seems to be a multidisciplinary one: beside orthodontics, which is necessary to correct the malocclusion, it is essential to set up a myofunctional rehabilitation procedure to correct the oral habit, therefore granting long time permanent results. There is also proof of a substantial difference between the results obtained from early (deciduous or primary mixed dentition) or later treatments. The biunique causal relation between atypical swallowing and malocclusion suggests a multidisciplinary therapeutic approach, orthodontic and myofunctional, to temporarily solve both problems. An early diagnosis and a prompt intervention have a significantly positive influence on the

  20. Atypical Neurological Manifestations Of Hypokalemia

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    pal P K

    2004-01-01

    Full Text Available A part from the well-established syndrome of motor paralysis, hypokalemia may present with atypical neurological manifestations, which are not well documented in literature. Methods: We treated 30 patients of hypokalemia whose neurological manifestations improved after corrections of hypokalemia. A retrospective chart review of the clinical profile was done with emphasis on the evolution of symptoms and occurrence of unusual manifestations. Results: Twenty-eight patients had subacute quadriparesis with duration of symptoms varying from 10hrs to 7 days and two had slowly progressive quadriparesis. Fifty percent of patients had more than one attack of paralysis. Early asymmetric weakness (11, stiffness and abnormal posture of hands (7, predominant bibrachial weakness (4, distal paresthesias (4, hemiparesthesia (1, hyperreflexia(4, early severe weakness of neck muscles (3, chorea (1, trismus (1,and, retention of urine (1 were the unusual features observed. The means level of serum potassium on admission was 2.1+0.6mEq/L.and the serum creatine kinase was elevated in 14 out of 17 patients. All patients except two had complete recovery.

  1. Opposing effects of cortisol and dehydroepiandrosterone on the expression of the receptor for Activated C Kinase 1: implications in immunosenescence.

    Science.gov (United States)

    Buoso, Erica; Lanni, Cristina; Molteni, Elisabetta; Rousset, Françoise; Corsini, Emanuela; Racchi, Marco

    2011-11-01

    Aging is associated to a decline in immune functions that are in part related to a defective protein kinase C dependent signal transduction machinery. RACK-1 (Receptor for Activated C Kinase 1) is a scaffold protein for different kinases and membrane receptors. We have previously demonstrated, in the elderly, a defective PCKβII (Protein Kinase C βII) translocation related to a decrease in RACK-1 protein expression, which is correlated to the age-associated decline in DHEA (dehydroepiandrosterone) levels. As a consequence of this signal transduction impairment, a significant decrease in immune cells functionality was observed. Furthermore, we could demonstrate that in vivo and in vitro DHEA administration restored RACK-1 level and immune functions, indicating that this hormone behaved as a positive RACK-1 regulator. We have most recently characterized the human GNB2L1 promoter region, coding for RACK-1 protein. Although no direct DHEA responsive elements were found, a glucocorticoid responsive element (GRE) was identified. The purpose of this work was to investigate, in the human pro-myelocytic cell line THP-1, whether physiological cortisol concentrations were able to modulate GNB2L1 promoter activity, RACK-1 transcription as well as cytokine production. As DHEA is endowed of anti-glucocorticoid properties in several cellular systems, and as cortisol:DHEA ratio imbalance is relevant in aging, we also investigated their possible interaction at the RACK-1 expression level. We could demonstrate that cortisol acted in a dose-related manner as a GNB2L1 promoter repressor, reducing RACK-1 mRNA expression and protein level. Probably by interfering with glucocorticoid receptor binding to GRE sequence, prolonged DHEA exposure counteracted cortisol effects, restoring RACK-1 levels and cytokine production, as assessed by LPS-induced TNF-α release. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. Atypical femoral fractures

    OpenAIRE

    Giannini, Sandro; Chiarello, Eugenio; Tedesco, Giuseppe; Cadossi, Matteo; Luciani, Deianira; Mazzotti, Antonio; Donati, Davide Maria

    2013-01-01

    Bisphosphonates (BPs) represent the most widely used therapy for osteoporosis. Recently, a relationship between long-term treatment with BPs and a subset of atypical femoral fractures (AFFs) from below the lesser trochanter to the sovracondilar line has been described. Many etiopathogenetic theories have been invoked to explain AFFs: reduced bone turnover and increased osteoblast bone apposition with accumulation of microdamage and decreased bone toughness with subsequent increased risk of mi...

  3. Structural Evolution of the Protein Kinase-Like Superfamily.

    Directory of Open Access Journals (Sweden)

    2005-10-01

    Full Text Available The protein kinase family is large and important, but it is only one family in a larger superfamily of homologous kinases that phosphorylate a variety of substrates and play important roles in all three superkingdoms of life. We used a carefully constructed structural alignment of selected kinases as the basis for a study of the structural evolution of the protein kinase-like superfamily. The comparison of structures revealed a "universal core" domain consisting only of regions required for ATP binding and the phosphotransfer reaction. Remarkably, even within the universal core some kinase structures display notable changes, while still retaining essential activity. Hence, the protein kinase-like superfamily has undergone substantial structural and sequence revision over long evolutionary timescales. We constructed a phylogenetic tree for the superfamily using a novel approach that allowed for the combination of sequence and structure information into a unified quantitative analysis. When considered against the backdrop of species distribution and other metrics, our tree provides a compelling scenario for the development of the various kinase families from a shared common ancestor. We propose that most of the so-called "atypical kinases" are not intermittently derived from protein kinases, but rather diverged early in evolution to form a distinct phyletic group. Within the atypical kinases, the aminoglycoside and choline kinase families appear to share the closest relationship. These two families in turn appear to be the most closely related to the protein kinase family. In addition, our analysis suggests that the actin-fragmin kinase, an atypical protein kinase, is more closely related to the phosphoinositide-3 kinase family than to the protein kinase family. The two most divergent families, alpha-kinases and phosphatidylinositol phosphate kinases (PIPKs, appear to have distinct evolutionary histories. While the PIPKs probably have an

  4. Atypical odontalgia--an update.

    Science.gov (United States)

    Patel, Seena B; Boros, Audrey L; Kumar, Satish K S

    2012-09-01

    Atypical odontalgia is a commonly misdiagnosed condition that frequently leads to unnecessary dental treatments such as extraction and endodontic therapy. These treatments often worsen the pain. Despite greater recognition and understanding of this condition, proper diagnosis and treatment remains a challenge. It is believed that atypical odontalgia is a neuropathic condition. This article updates the current understanding of the etiology and pathophysiology of atypical odontalgia, and provides appropriate diagnostic and management approaches for this condition.

  5. Assembly of the transmembrane domain of E. coli PhoQ histidine kinase: implications for signal transduction from molecular simulations.

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    Thomas Lemmin

    Full Text Available The PhoQP two-component system is a signaling complex essential for bacterial virulence and cationic antimicrobial peptide resistance. PhoQ is the histidine kinase chemoreceptor of this tandem machine and assembles in a homodimer conformation spanning the bacterial inner membrane. Currently, a full understanding of the PhoQ signal transduction is hindered by the lack of a complete atomistic structure. In this study, an atomistic model of the key transmembrane (TM domain is assembled by using molecular simulations, guided by experimental cross-linking data. The formation of a polar pocket involving Asn202 in the lumen of the tetrameric TM bundle is crucial for the assembly and solvation of the domain. Moreover, a concerted displacement of the TM helices at the periplasmic side is found to modulate a rotation at the cytoplasmic end, supporting the transduction of the chemical signal through a combination of scissoring and rotational movement of the TM helices.

  6. Differential inhibitor sensitivity between human kinases VRK1 and VRK2.

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    Marta Vázquez-Cedeira

    Full Text Available Human vaccinia-related kinases (VRK1 and VRK2 are atypical active Ser-Thr kinases implicated in control of cell cycle entry, apoptosis and autophagy, and affect signalling by mitogen activated protein kinases (MAPK. The specific structural differences in VRK catalytic sites make them suitable candidates for development of specific inhibitors. In this work we have determined the sensitivity of VRK1 and VRK2 to kinase inhibitors, currently used in biological assays or in preclinical studies, in order to discriminate between the two proteins as well as with respect to the vaccinia virus B1R kinase. Both VRK proteins and vaccinia B1R are poorly inhibited by inhibitors of different types targeting Src, MEK1, B-Raf, JNK, p38, CK1, ATM, CHK1/2 and DNA-PK, and most of them have no effect even at 100 µM. Despite their low sensitivity, some of these inhibitors in the low micromolar range are able to discriminate between VRK1, VRK2 and B1R. VRK1 is more sensitive to staurosporine, RO-31-8220 and TDZD8. VRK2 is more sensitive to roscovitine, RO 31-8220, Cdk1 inhibitor, AZD7762, and IC261. Vaccinia virus B1R is more sensitive to staurosporine, KU55933, and RO 31-8220, but not to IC261. Thus, the three kinases present a different pattern of sensitivity to kinase inhibitors. This differential response to known inhibitors can provide a structural framework for VRK1 or VRK2 specific inhibitors with low or no cross-inhibition. The development of highly specific VRK1 inhibitors might be of potential clinical use in those cancers where these kinases identify a clinical subtype with a poorer prognosis, as is the case of VRK1 in breast cancer.

  7. 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.

  8. Functional Coexpression of HSV-1 Thymidine Kinase and Green Fluorescent Protein: Implications for Noninvasive Imaging of Transgene Expression

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    Andreas Jacobs

    1999-06-01

    Full Text Available Current gene therapy technology is limited by the paucity of methodology for determining the location and magnitude of therapeutic transgene expression in vivo. We describe and validate a paradigm for monitoring therapeutic transgene expression by noninvasive imaging of the herpes simplex virus type 1 thymidine kinase (HSV-1-tk marker gene expression. To test proportional coexpression of therapeutic and marker genes, a model fusion gene comprising green fluorescent protein (gfp and HSV-1-tk genes was generated (tkgfp gene and assessed for the functional coexpression of the gene product, TKGFP fusion protein, in rat 9L gliosarcoma, RG2 glioma, and W256 carcinoma cells. Analysis of the TKGFP protein demonstrated that it can serve as a therapeutic gene by rendering tkgfp transduced cells sensitive to ganciclovir or as a screening marker useful for identifying transduced cells by fluorescence microscopy or fluorescence-activated cell sorting (FACS. TK and GFP activities in the TKGFP fusion protein were similar to corresponding wild-type proteins and accumulation of the HSV-1-tk-specific radiolabeled substrate, 2′-fluoro-2′-deoxy-1β-D-arabino-furanosyl-5-iodo-uracil (FIAU, in stability transduced clones correlated with gfp-fluorescence intensity over a wide range of expression levels. The tkgfp fusion gene itself may be useful in developing novel cancer gene therapy approaches. Valuable information about the efficiency of gene transfer and expression could be obtained by non-invasive imaging of tkgfp expression with FIAU and clinical imaging devices (gamma camera, positron-emission tomography [PET], single photon emission computed tomography [SPECT], and/or direct visualization of gfp expression in situ by fluorescence microscopy or endoscopy.

  9. 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.

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

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    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

  11. Atypical Presentation of Neurosyphilis

    Directory of Open Access Journals (Sweden)

    L C Anand

    1980-01-01

    Full Text Available Five cases of neurospyhilis with atypical manifestation have been reported. Of these four cases presented as acute neurological illness and showed variable recovery after antisyp′iiilitic therapy. One of these cases had parinaud sip which was unaffected by treatment One case presented as dementia and gave poor response to therapy. In only one of these five cases was reagin in CSF demonstrated. Lange′s colloidal gold test was negative in all. As such failure to demonstrate reagin in CSF does not rule out the diagnosis of neurosyphilis. In an antibiotic era patients may inadvertently receive some antibiotics prior to presentation to a clinician and therefore are unlikely to present with typical neurological and laboratory findings.

  12. [Atypical bipolar disorders].

    Science.gov (United States)

    Gay, Christian

    2009-04-20

    Some epidemiologic data reveal how difficult detecting atypic bipolar disorders is: 9 years of progression before the diagnosis is properly established and a specific treatment is initiated, and intervention of 4 to 5 different specialists. Incomplete symptomatology, impulsive actions, periodic alcohol abuse, compulsive buying behaviors, acute delusional episodes, medicolegal actions and comorbidities can hide or modify bipolar symptomatology. Bipolarity should be systematically screened for in case of substance abuse (40 to 60 percent of bipolar disorders), anxiety disorders (panic disorder, generalized anxiety, obsessive-compulsive disorders etc.) and feeding disorders. In these various situations, history taking and clinical examination will help to detect signs of bipolarity: reaction to antidepressants, inefficiency, paradoxical worsening, development of behavior disorders and mood changes. Besides screening for thymic disorders, the examination will be completed by history taking of thymic disorders, suicide, toxic abuse, anxiety disorders, personal history of attention deficit hyperactivity disorder in childhood, depression or postpartum psychosis in women, as well as premenstrual depressive manifestations.

  13. Atypical odontalgia: a review.

    Science.gov (United States)

    Koratkar, Harish; Pedersen, Jerome

    2008-01-01

    Since persistent and chronic pain is more common in the head and neck region than in any other part of the body, dentists are more likely to encounter these rather complex cases in their practices. This article is a review and update on atypical odontalgia (AO). AO is a persistent neuropathic pain which may be initiated after deafferentiation of trigeminal nerve fibers following root canal treatment, apicectomy, or tooth extraction, or it may be of idiopathic origin. Details concerning its characteristics, pathophysiology, diagnostic criteria, differential diagnosis, and treatment are made. The aim of this article is to help the clinician with the diagnosis and management of AO. The prognosis for AO is most often only fair, and the administration of tricyclic antidepressants often resolves symptoms. Invasive and irreversible treatment attempts are not recommended.

  14. ATYPICAL KAWASAKI DISEASE.

    Science.gov (United States)

    Ristovski, Ljiljana; Milankov, Olgica; Vislavski, Melanija; Savić, Radojica; Bjelica, Milena

    2016-01-01

    Kawasaki disease is an acute vasculitis which occurs primarily in children under the age of 5. The etiology of the disease is still unknown. Diagnostic criteria for Kawasaki disease are fever and at least four of the five additional clinical signs. Incomplete Kawasaki disease should be taken into consideration in case of all children with unexplained fever for more than 5 days, associated with 2 or 3 of the main clinical findings of Kawasaki disease. The diagnosis of incomplete Kawasaki disease is based on echocardiographic findings indicating the involvement of the coronary arteries. Cardiac complications, mostly coronary artery aneurysm, can occur in 20% to 25% of untreated patients and in 4% of treated patients. CASE REPORT. In this report we present a case of atypical Kawasaki disease in a 3.5-month-old infant. As soon as the diagnosis was made, the patient received high doses of intravenous immunoglobulin, with the initial introduction of ibuprofen, then aspirin with a good clinical response. Due to the presence of aneurysm of coronary arteries, further therapy involved aspirin and clopidogrel over the following 3 months, and then only aspirin for 2 years. There was a gradual regression of the changes in the coronary blood vessels to the normalization of the echocardiographic findings after 2 years. Kawasaki disease is the second most common vasculitis of childhood, so it should be included in the differential diagnosis for any child with a prolonged unexplained fever. Atypical Kawasaki disease should be taken into consideration in cases when not all clinical criteria are present but coronary abnormalities are documented.

  15. Atypical depression: current perspectives

    Directory of Open Access Journals (Sweden)

    Łojko D

    2017-09-01

    Full Text Available Dorota Łojko,1 Janusz K Rybakowski1,2 1Department of Adult Psychiatry, 2Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, Poznan, Poland Abstract: The history and present status of the definition, prevalence, neurobiology, and treatment of atypical depression (AD is presented. The concept of AD has evolved through the years, and currently, in Diagnostic and Statistical Manual of Mental Disorders (DSM, Fifth Edition, the specifier of depressive episode with atypical feature is present for both diagnostic groups, that is, depressive disorders and bipolar and related disorders. This specifier includes mood reactivity, hyperphagia, hypersomnia, leaden paralysis, and interpersonal rejection sensitivity. Prevalence rates of AD are variable, depending on the criteria, methodology, and settings. The results of epidemiological studies using DSM criteria suggest that 15%–29% of depressed patients have AD, and the results of clinical studies point to a prevalence of 18%–36%. A relationship of AD with bipolar depression, seasonal depression, and obesity has also been postulated. Pathogenic research has been mostly focused on distinguishing AD from melancholic depression. The differences have been found in biochemical studies in the areas of hypothalamic–pituitary–adrenal axis, inflammatory markers, and the leptin system, although the results obtained are frequently controversial. A number of findings concerning such differences have also been obtained using neuroimaging and neurophysiological and neuropsychological methods. An initial concept of AD as a preferentially monoamine oxidase inhibitor-responsive depression, although confirmed in some further studies, is of limited use nowadays. Currently, despite numerous drug trials, there are no comprehensive treatment guidelines for AD. We finalize the article by describing the future research perspectives for the definition, neurobiology, and treatment. A better

  16. Atypical depression: current perspectives

    Science.gov (United States)

    Łojko, Dorota; Rybakowski, Janusz K

    2017-01-01

    The history and present status of the definition, prevalence, neurobiology, and treatment of atypical depression (AD) is presented. The concept of AD has evolved through the years, and currently, in Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition, the specifier of depressive episode with atypical feature is present for both diagnostic groups, that is, depressive disorders and bipolar and related disorders. This specifier includes mood reactivity, hyperphagia, hypersomnia, leaden paralysis, and interpersonal rejection sensitivity. Prevalence rates of AD are variable, depending on the criteria, methodology, and settings. The results of epidemiological studies using DSM criteria suggest that 15%–29% of depressed patients have AD, and the results of clinical studies point to a prevalence of 18%–36%. A relationship of AD with bipolar depression, seasonal depression, and obesity has also been postulated. Pathogenic research has been mostly focused on distinguishing AD from melancholic depression. The differences have been found in biochemical studies in the areas of hypothalamic–pituitary–adrenal axis, inflammatory markers, and the leptin system, although the results obtained are frequently controversial. A number of findings concerning such differences have also been obtained using neuroimaging and neurophysiological and neuropsychological methods. An initial concept of AD as a preferentially monoamine oxidase inhibitor-responsive depression, although confirmed in some further studies, is of limited use nowadays. Currently, despite numerous drug trials, there are no comprehensive treatment guidelines for AD. We finalize the article by describing the future research perspectives for the definition, neurobiology, and treatment. A better specification of diagnostic criteria and description of clinical picture, a genome-wide association study of AD, and establishing updated treatment recommendations for this clinical phenomenon should be

  17. Atypical manifestations of leptospirosis.

    Science.gov (United States)

    Rajapakse, Senaka; Rodrigo, Chaturaka; Balaji, Krishan; Fernando, Sumadhya Deepika

    2015-05-01

    Leptospirosis is an illness with a wide spectrum of clinical manifestations and severe illness affects nearly all organ systems. Serious and potentially life-threatening clinical manifestations of acute leptospirosis are caused by both direct tissue invasion by spirochaetes and by the host immune responses. In its severe form, leptospirosis can cause multi-organ dysfunction and death in a matter of days. Therefore it is critical to suspect and recognize the disease early, in order to initiate timely treatment. While the classical presentation of the disease is easily recognized by experienced clinicians practising in endemic regions, rarer manifestations can be easily missed. In this systematic review, we summarize the atypical manifestations reported in literature in patients with confirmed leptospirosis. Awareness of these unusual manifestations would hopefully guide clinicians towards early diagnosis. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. 'INDOTEST' in atypical hemicrania continua.

    Science.gov (United States)

    Baldacci, F; Nuti, A; Cafforio, G; Lucetti, C; Logi, C; Cipriani, G; Orlandi, G; Bonuccelli, U

    2008-03-01

    Hemicrania continua (HC) is an indomethacin-responsive headache characterized by a chronic, strictly unilateral, side-locked without side-shifting, persistent headache. We report three cases of HC with atypical features in which an acute administration of indomethacin 50 mg IM (INDOTEST) was performed. In all three cases INDOTEST predicted chronic responsiveness to indomethacin. Thus, in cases of HC with atypical features, INDOTEST could help for a correct diagnosis and therapy.

  19. Profile of the GSK Published Protein Kinase Inhibitor Set Across ATP-Dependent and-Independent Luciferases: Implications for Reporter-Gene Assays

    Science.gov (United States)

    Dranchak, Patricia; MacArthur, Ryan; Guha, Rajarshi; Zuercher, William J.; Drewry, David H.; Auld, Douglas S.; Inglese, James

    2013-01-01

    A library of 367 protein kinase inhibitors, the GSK Published Kinase Inhibitor Set (PKIS), which has been annotated for protein kinase family activity and is available for public screening efforts, was assayed against the commonly used luciferase reporter enzymes from the firefly, Photinus pyralis (FLuc) and marine sea pansy, Renilla reniformis (RLuc). A total of 22 compounds (∼6% of the library) were found to inhibit FLuc with 10 compounds showing potencies ≤1 µM. Only two compounds were found to inhibit RLuc, and these showed relatively weak potency values (∼10 µM). An inhibitor series of the VEGFR2/TIE2 protein kinase family containing either an aryl oxazole or benzimidazole-urea core illustrate the different structure activity relationship profiles FLuc inhibitors can display for kinase inhibitor chemotypes. Several FLuc inhibitors were broadly active toward the tyrosine kinase and CDK families. These data should aid in interpreting the results derived from screens employing the GSK PKIS in cell-based assays using the FLuc reporter. The study also underscores the general need for strategies such as the use of orthogonal reporters to identify kinase or non-kinase mediated cellular responses. PMID:23505445

  20. Profile of the GSK published protein kinase inhibitor set across ATP-dependent and-independent luciferases: implications for reporter-gene assays.

    Directory of Open Access Journals (Sweden)

    Patricia Dranchak

    Full Text Available A library of 367 protein kinase inhibitors, the GSK Published Kinase Inhibitor Set (PKIS, which has been annotated for protein kinase family activity and is available for public screening efforts, was assayed against the commonly used luciferase reporter enzymes from the firefly, Photinus pyralis (FLuc and marine sea pansy, Renilla reniformis (RLuc. A total of 22 compounds (∼6% of the library were found to inhibit FLuc with 10 compounds showing potencies ≤1 µM. Only two compounds were found to inhibit RLuc, and these showed relatively weak potency values (∼10 µM. An inhibitor series of the VEGFR2/TIE2 protein kinase family containing either an aryl oxazole or benzimidazole-urea core illustrate the different structure activity relationship profiles FLuc inhibitors can display for kinase inhibitor chemotypes. Several FLuc inhibitors were broadly active toward the tyrosine kinase and CDK families. These data should aid in interpreting the results derived from screens employing the GSK PKIS in cell-based assays using the FLuc reporter. The study also underscores the general need for strategies such as the use of orthogonal reporters to identify kinase or non-kinase mediated cellular responses.

  1. National atypical mycobacteria survey, 2000.

    Science.gov (United States)

    Haverkort, Frank

    2003-01-01

    Infections with atypical mycobacteria in Australia during 2000 occurred at a rate of 1.8 cases per 100,000 population. The main sites of disease were the respiratory tract, soft tissue, and the lymphatics. The Mycobacterium avium complex was the most common group of mycobacteria isolated from respiratory, lymphatic sites, and blood. The rapidly growing mycobacteria, predominantly the M. fortuitum-M. abscessus-M. chelonae group were the most common soft tissue infections. Atypical mycobacteria were isolated from significant numbers of sputum 'smear positive' patients, requiring further tests to exclude M. tuberculosis. Geographical differences were observed for some Mycobacterium species, notably the isolation of M. haemophilum from Western Australia, and M. ulcerans from Victoria and Queensland. Newer molecular techniques, while improving precision and accuracy of identification, raise additional questions about the ecology of the atypical mycobacteria and their role in disease.

  2. [Modulation by some fatty acids of protein kinase C-dependent NADPH oxidase in human adherent monocyte: mechanism of action, possible implication in atherogenesis].

    Science.gov (United States)

    Léger, C L; Kadri-Hassani, N

    1995-01-01

    It is largely admitted nowadays that the early stage of the atherosclerotic lesion involves formation of oxidized (and minimally oxidized) low-density lipoprotein. Their properties are briefly reviewed. It is recalled that a lipolytic process also takes place both at the lumenal surface and in the subendothelial space of the vessels implying lipoprotein lipase (LpL) activity. Recent studies emphasize the role of LpL in accumulating LDL in the vascular tissue (Rutledge & Golberg, J. Lipid Res., 1994, 35, 1152-1160), but the role of LpL-generated unesterified fatty acids (UEFA) in these two locations and their possible implication in atherogenesis are largely neglected. Physiological and pathophysiological significance of UEFA in the human adherent monocyte modulation of the superoxide anion (O2.-) production has been examined by our group, leading to a possible mechanism of modulation of LDL oxidative modification. The O2.- production-modulating effect of a 30-min UEFA preincubation has been studied in intact human adherent monocytes (HAM) after stimulation by a direct effector of protein kinase C (PKC). It has been established that UEFA alone (in the absence of PKC effectors) were not able to modulate the O2.- production of HAM whereas they had such a capacity in the presence of PKC effectors, phorbol myristate acetate (PMA) or diacylglycerol (DAG). In this case inhibitors of PKC such as GF 109203 X suppressed the modulating effect. UEFA have also been shown to possess a bimodal action in the presence of PKC effectors: they depressed or enhanced O2.- production at micromolar or nanomolar concentrations, respectively. All these results contrasted with others obtained in neutrophils or nonadherent monocytes, suggesting an absolute requirement of PKC for the phagocyte-NADPH oxydase (PHOX) activation especially in the case of HAM. In HAM, the maximal enhancing effects were obtained with monomethyl ramified saturated (MMRS) and linear unsaturated (LU) FAs such as

  3. In-situ zircon U-Pb age and Hf-O isotopic constraints on the origin of the Hasan-Robat A-type granite from Sanandaj-Sirjan zone, Iran: implications for reworking of Cadomian arc igneous rocks

    Science.gov (United States)

    Honarmand, Maryam; Li, Xian-Hua; Nabatian, Ghasem; Neubauer, Franz

    2017-10-01

    The Lower Permian Hasan-Robat syenogranite occurs as a single pluton and intruded the Upper Carboniferous-Lower Permian sandstones and dolomitic limestones in the central part of the Sanandaj-Sirjan zone. This syenogranitic intrusion shows A-type granitic affinity and is a good representative of Early Permian igneous activity in Iran. SIMS U-Pb zircon analyses indicate a crystallization age of 294.2 ± 2.5 Ma for the Hasan-Robat A-type granite. In-situ Lu-Hf and oxygen isotope analyses of magmatic zircons were carried out to infer the magma sources and evolution of the Hasan-Robat A-type syenogranite. The Hf-O zircon isotopic compositions are relatively homogeneous, with nearly chondritic ɛHf(t) values of -0.8 to +2.4 corresponding to two-stage zircon Hf model ages of 1.15-1.36 Ga. The δ18O values of zircon range from +7.6 to +8.6‰. The Hf model ages of the Hasan-Robat zircons is within the range of those reported from the Cadomian granitoids in Iran. The isotopic features of the Hasan-Robat syenogranite are in good agreement with Hf isotopic values and Hf and Nd model ages reported from the Cadomian arc magmatic suites in Iran. Thus, partial melting of these Cadomian igneous rocks would be the favorite source for the Hasan-Robat syenogranitic magma during the opening of the Neotethys Ocean and separation of Iranian terranes from the northern margin of Gondwana.

  4. Atypical moles: diagnosis and management.

    Science.gov (United States)

    Perkins, Allen; Duffy, R Lamar

    2015-06-01

    Atypical moles are benign pigmented lesions. Although they are benign, they exhibit some of the clinical and histologic features of malignant melanoma. They are more common in fair-skinned individuals and in those with high sun exposure. Atypical moles are characterized by size of 6 mm or more at the greatest dimension, color variegation, border irregularity, and pebbled texture. They are associated with an increased risk of melanoma, warranting enhanced surveillance, especially in patients with more than 50 moles and a family history of melanoma. Because an individual lesion is unlikely to display malignant transformation, biopsy of all atypical moles is neither clinically beneficial nor cost-effective. The ABCDE (asymmetry, border irregularity, color unevenness, diameter of 6 mm or more, evolution) mnemonic is a valuable tool for clinicians and patients to identify lesions that could be melanoma. Also, according to the "ugly duckling" concept, benign moles tend to have a similar appearance, whereas an outlier with a different appearance is more likely to be undergoing malignant change. Atypical moles with changes suggestive of malignant melanoma should be biopsied, using an excisional method, if possible.

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

    African Journals Online (AJOL)

    Infection by the human immunodeficiency virus (HIV) has since the mid-1980's been known to distinguish atypical, aggressive Kaposi's sarcoma (AAKS) from the endemic type in Africa (1). In our series at the University of Maiduguri Teaching Hospital, we recorded 44 patients with AAKS, 35 of them male and 9 female, giving ...

  6. Atypical odontalgia: phantom tooth pain.

    Science.gov (United States)

    Bates, R E; Stewart, C M

    1991-10-01

    The findings in 30 cases diagnosed as atypical odontalgia are presented. The clinical characteristics of these cases are compared with other cases reported in the literature. Three cases are described in detail. Patient understanding and treatment with tricyclic antidepressants are discussed together with medication side effects and interactions. The importance of deferring invasive procedures is emphasized.

  7. 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...

  8. Geochronology and geochemistry of the Triassic bimodal volcanic rocks and coeval A-type granites of the Olzit area, Middle Mongolia: Implications for the tectonic evolution of Mongol-Okhotsk Ocean

    Science.gov (United States)

    Zhu, Mingshuai; Zhang, Fochin; Miao, Laicheng; Baatar, Munkhtsengel; Anaad, Chimedtseren; Yang, Shunhu; Li, Xingbo

    2016-05-01

    The Olzit volcanism in Middle Mongolia comprises a bimodal suite of basalts and peralkaline rhyolites adjacent to the Main Mongolia Lineament. The basalts are characterized by enrichment in LILE and LREE, and depletion in HFSE with typical Sr-Nd isotopic signatures (εNd(t) = -2.50 to -0.38 and (87Sr/86Sr)i = 0.7058-0.7063), indicating they were likely derived from partial melting of an enriched lithospheric mantle, modified by subducted slab-derived fluids. The rhyolites show a close affinity to A-type granites with enrichment in LILE and LREE, and depletion in Nb, Ta and Ti. They also show a significant negative Eu anomaly, and have εNd(t) values ranging from 0.50 to 1.38 and initial 87Sr/86Sr ratios ranging from 0.7022 to 0.7200, suggesting the rhyolites stem from partial melting of crustal rocks rather than fractional crystallization of the basaltic melt. The rhyolite porphyry yields a SHRIMP zircon U-Pb age of 207 ± 2 Ma (MSWD = 1.42), indicating the bimodal volcanic suite formed in the Late Triassic. The miarolitic per-alkaline granite and biotite-bearing granite, which are associated with the bimodal volcanic rocks, show typical A-type granitic geochemical affinity with εNd(t) = 0.89-0.91 and (87Sr/86Sr)i = 0.7021-0.7043, indicating they are likely generated by partial melting of crustal rocks similar to the rhyolitic end-member of bimodal suite. The miarolitic per-alkaline granite and biotite-bearing granite yielded SHRIMP zircon U-Pb ages of 209 ± 2 Ma (MSWD = 0.91) and 213 ± 3 Ma (MSWD = 1.65) respectively, which are nearly coeval with the age of the bimodal volcanic suites. In view of the new geochemical and chronological data in this study, we suggest the Olzit Late Triassic bimodal volcanic rocks together with the coeval A-type granites represent a back-arc basin extensional environment, which probably related to the roll-back of Mongol-Okhotsk oceanic plate during the southward subduction under the Central Mongolia microcontinent.

  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...... and magnetic resonance imaging data and obtained follow-up (FU) information on 77 of these patients over a mean duration of 4 years. The AIIDLs presented as a single lesion in 72 (80 %) patients and exhibited an infiltrative (n = 35), megacystic (n = 16), Baló (n = 10) or ring-like (n = 16) lesion appearance...... in 77 (86 %) patients. Additional multiple sclerosis (MS)-typical lesions existed in 48 (53 %) patients. During FU, a further clinical attack occurred rarely (23-35 % of patients) except for patients with ring-like AIIDLs (62 %). Further attacks were also significantly more often in patients...

  10. 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.

  11. Ca2+ is required for phosphorylation of clam p82/CPEB in vitro: implications for dual and independent roles of MAP and Cdc2 kinases.

    Science.gov (United States)

    Katsu, Y; Minshall, N; Nagahama, Y; Standart, N

    1999-05-01

    During early development gene expression is controlled principally at the translational level. Oocytes of the surf clam Spisula solidissima contain large stockpiles of maternal mRNAs which are translationally dormant or masked until meiotic maturation. Fertilisation of the oocyte leads to rapid polysomal recruitment of the abundant cyclin and ribonucleotide reductase mRNAs at about the time they undergo cytoplasmic polyadenylation. Clam p82, a 3' UTR RNA-binding protein, and a member of the CPEB (cytoplasmic polyadenylation element binding protein) family, functions as a translational masking factor in oocytes and as a polyadenylation factor in fertilised eggs. In meiotically maturing clam oocytes, p82/CPEB is rapidly phosphorylated on multiple residues to a 92-kDa apparent size, prior to its degradation during the first cell cleavage. Here we examine the protein kinase(s) that phosphorylates clam p82/CPEB using a clam oocyte activation cell-free system that responds to elevated pH, mirroring the pH rise that accompanies fertilisation. We show that p82/CPEB phosphorylation requires Ca2+ (model of clam p82/CPEB phosphorylation in which MAP kinase initially phosphorylates clam p82/CPEB, at a minor subset of sites that does not alter its migration, and cdc2 kinase is necessary for the second wave of phosphorylation that results in the large mobility size shift of clam p82/CPEB. The possible roles of phosphorylation for the function and regulation of p82/CPEB are discussed. Copyright 1999 Academic Press.

  12. Biopsychosocial Aspects of Atypical Odontalgia

    OpenAIRE

    Ciaramella, A.; Paroli, M.; Lonia, L.; Bosco, M.; Poli, P.

    2013-01-01

    Background. A few studies have found somatosensory abnormalities in atypical odontalgia (AO) patients. The aim of the study is to explore the presence of specific abnormalities in facial pain patients that can be considered as psychophysical factors predisposing to AO. Materials and Methods. The AO subjects (n = 18) have been compared to pain-free (n = 14), trigeminal neuralgia (n = 16), migraine (n = 17), and temporomandibular disorder (n = 14). The neurometer current perception threshold (C...

  13. Atypical odontalgia: a case report.

    Science.gov (United States)

    Koratkar, Harish; Koratkar, Sonal

    2008-01-01

    Diagnosis and treatment of orofacial pain is not uncommon; however, reaching a definitive diagnosis in these cases can be a complex challenge. Dentists are most likely to face this situation, because persistent and chronic pain is more common in the head and neck region than in any other part of the body. However, the complexities and diagnostic challenges mean that misdiagnosing neuropathic pain is common. This article presents a case of atypical odontalgia and illustrates the complexities involved when diagnosing the condition.

  14. 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.

  15. Interaction of the interferon-induced PKR protein kinase with inhibitory proteins P58IPK and vaccinia virus K3L is mediated by unique domains: implications for kinase regulation.

    Science.gov (United States)

    Gale, M; Tan, S L; Wambach, M; Katze, M G

    1996-08-01

    Expression of the double-stranded RNA-activated protein kinase (PKR) is induced by interferons, with PKR activity playing a pivotal role in establishing the interferon-induced antiviral and antiproliferative states. PKR is directly regulated by physical association with the specific inhibitor, P58IPK, a cellular protein of the tetratricopeptide repeat (TPR) family, and K3L, the product of the corresponding vaccinia virus gene. P58IPK and K3L repress PKR activation and activity. To investigate the mechanism of P58IPK- and K3L-mediated PKR inhibition, we have used a combination of in vitro and in vivo binding assays to identify the interactive regions of these proteins. The P58IPK-interacting site of PKR was mapped to a 52-amino-acid aa segment (aa 244 to 296) spanning the ATP-binding region of the protein kinase catalytic domain. The interaction with PKR did not require the C-terminal DNA-J homology region of P58IPK but was dependent on the presence of the eukaryotic initiation factor 2-alpha homology region, mapping to the 34 aa within the sixth P58IPK TPR motif. Consistent with other TPR proteins, P58IPK formed multimers in vivo: the N-terminal 166 aa were both necessary and sufficient for complex formation. A parallel in vivo analysis to map the K3L-binding region of PKR revealed that like P58IPK , K3L interacted exclusively with the PKR protein kinase catalytic domain. In contrast, however, the K3L-binding region of PKR was localized to within aa 367 to 551, demonstrating that each inhibitor bound PKR in unique, nonoverlapping domains. These data, taken together, suggest that P58IPK and K3L may mediate PKR inhibition by distinct mechanisms. Finally, we will propose a model of PKR inhibition in which P58IPK or a P58IPK complex binds PKR and interferes with nucleotide binding and autoregulation, while formation of a PKR-K3L complex interferes with active-site function and/or substrate association.

  16. Impaired inflammatory pain and thermal hyperalgesia in mice expressing neuron-specific dominant negative mitogen activated protein kinase kinase (MEK

    Directory of Open Access Journals (Sweden)

    Kaplan David

    2006-01-01

    Full Text Available Abstract Background Numerous studies have implicated spinal extracellular signal-regulated kinases (ERKs as mediators of nociceptive plasticity. These studies have utilized pharmacological inhibition of MEK to demonstrate a role for ERK signaling in pain, but this approach cannot distinguish between effects of ERK in neuronal and non-neuronal cells. The present studies were undertaken to test the specific role of neuronal ERK in formalin-induced inflammatory pain. Dominant negative MEK (DN MEK mutant mice in which MEK function is suppressed exclusively in neurons were tested in the formalin model of inflammatory pain. Results Formalin-induced second phase spontaneous pain behaviors as well as thermal hyperalgesia measured 1 – 3 hours post-formalin were significantly reduced in the DN MEK mice when compared to their wild type littermate controls. In addition, spinal ERK phosphorylation following formalin injection was significantly reduced in the DN MEK mice. This was not due to a reduction of the number of unmyelinated fibers in the periphery, since these were almost double the number observed in wild type controls. Further examination of the effects of suppression of MEK function on a downstream target of ERK phosphorylation, the A-type potassium channel, showed that the ERK-dependent modulation of the A-type currents is significantly reduced in neurons from DN MEK mice compared to littermate wild type controls. Conclusion Our results demonstrate that the neuronal MEK-ERK pathway is indeed an important intracellular cascade that is associated with formalin-induced inflammatory pain and thermal hyperalgesia.

  17. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas

    Science.gov (United States)

    Wiesner, Thomas; He, Jie; Yelensky, Roman; 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 tumours with distinctive histopathological features. They include benign tumours (Spitz naevi), malignant tumours (spitzoid melanomas) and tumours with borderline histopathological features and uncertain clinical outcome (atypical Spitz tumours). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbour 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 signalling pathways, are tumourigenic and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz naevi, 56% of atypical Spitz tumours and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signalling 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.

  18. Mitogen-actived protein kinase activation is an early event in melanoma progression.

    Science.gov (United States)

    Cohen, Cynthia; Zavala-Pompa, Angel; Sequeira, Judy H; Shoji, Mamoru; Sexton, Deborah G; Cotsonis, George; Cerimele, Francesca; Govindarajan, Baskaran; Macaron, Nada; Arbiser, Jack L

    2002-12-01

    Melanoma is the most common cause of death from cutaneous malignancy, and is the cancer that is most rapidly rising in incidence. Because current therapeutic methods for metastatic melanoma are poorly efficacious, enhanced understanding of signal transduction in melanoma progression is warranted. Prior experimental studies in murine models and human tissues have shown a correlation among activation of mitogen activated protein kinase (MAPK) signaling, angiogenesis, and tumorigenesis. Because of these findings, we wanted to assess the role of MAPK signaling in melanoma progression and angiogenesis. We studied expression of phosphorylated (active) MAPK and two target genes known to be induced by MAPK signaling, tissue factor and vascular endothelial growth factor, in 131 melanocytic lesions, ranging from atypical nevi to metastatic melanoma. We observed little staining for activated (phosphorylated) MAPK and low amounts of angiogenesis in atypical nevi, but angiogenesis and MAPK activation were activated in radial growth melanoma and in later stage lesions. Our findings implicate MAPK activation as an early event in melanoma progression, and MAPK may be a potential target for pharmacologic intervention.

  19. 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.

  20. Treatment options for atypical optic neuritis

    Directory of Open Access Journals (Sweden)

    Amina Malik

    2014-01-01

    Full Text Available Context: Optic neuritis (ON is defined as inflammation of the optic nerve and can have various etiologies. The most common presentation in the US is demyelinating, or "typical" ON, usually associated with multiple sclerosis. This is in contrast to "atypical" causes of ON, which differ in their clinical presentation, management, and prognosis. These atypical cases are characterized by lack of eye pain, exudates, and hemorrhages on exam, very severe, bilateral or progressive visual loss, or with failure to recover vision. Aims: The aim was to describe the clinical presentations of atypical ON and their treatments. Settings and Design: Review article. Materials and Methods: Literature review. Results: Types of atypical ON identified include neuromyelitis optica, autoimmune optic neuropathy, chronic relapsing inflammatory optic neuropathy, idiopathic recurrent neuroretinitis, and optic neuropathy associated with systemic diseases. Atypical ON usually requires corticosteroid treatment and often will require aggressive immunosuppression. Conclusions: Unlike demyelinating ON, atypical ON requires treatment to preserve vision.

  1. A Nd- and O-isotope study of the REE-rich peralkaline Strange Lake granite: implications for Mesoproterozoic A-type magmatism in the Core Zone (NE-Canada)

    Science.gov (United States)

    Siegel, Karin; Williams-Jones, Anthony E.; Stevenson, Ross

    2017-07-01

    It is well established that A-type granites enriched in high field strength elements, such as Zr, Nb and the REE, form in anorogenic tectonic settings. The sources of these elements and the processes controlling their unusual enrichment, however, are still debated. They are addressed here using neodymium and oxygen isotope analyses of samples from the 1.24 Ga Strange Lake pluton in the Paleoproterozoic Core Zone of Québec-Labrador, an A-type granitic body characterized by hyper-enrichment in the REE, Zr, and Nb. Age-corrected ɛNd values for bulk rock samples and sodic amphiboles (mainly arfvedsonite) from the pluton range from -0.6 to -5.7, and -0.3 to -5.3, respectively. The ɛNd values for the Napeu Kainiut quartz monzonite, which hosts the pluton, range from -4.8 to -8.1. The 147Sm/144Nd ratios of the suite and the host quartz monzonite range from 0.0967 to 0.1659, large variations that can be explained by in situ fractionation of early LREE-minerals (Strange Lake), and late hydrothermal HREE remobilization. Oxygen isotope analyses of quartz of both Strange Lake and the host yielded δ18O values between +8.2 and +9.1, which are considerably higher than the mantle value of 5.7 ± 0.2‰. Bulk rock oxygen isotope analyses of biotite-gneisses in the vicinity of the Strange Lake pluton yielded δ18O values of 6.3, 8.6 and 9.6‰. The negative ɛNd values and positive δ18O values of the Strange Lake and Napeu Kainiut samples indicate that both magmas experienced considerable crustal contamination. The extent of this contamination was estimated, assuming that the contaminants were sedimentary-derived rocks from the underlying Archean Mistinibi (para-) gneiss complex, which is characterized by low ɛNd and high δ18O values. Mixing of 5-15% of a gneiss, having an ɛNd value of -15 and a δ18O value of +11, with a moderately enriched mantle source (ɛNd = +0.9, δ18O = +6.3) would produce values similar to those obtained for the Strange Lake granites. Based on

  2. Gravimetric, radiometric, and magnetic susceptibility study of the Paleoproterozoic Redenção and Bannach plutons, eastern Amazonian Craton, Brazil: Implications for architecture and zoning of A-type granites

    Science.gov (United States)

    de Oliveira, Davis Carvalho; Dall'Agnol, Roberto; Corrêa da Silva, João Batista; Costa de Almeida, José Arimatéia

    2008-02-01

    The 1.88 Ga, anorogenic, A-type Redenção and Bannach granites, representative of the Jamon suite and associated dikes, are intrusive in Archean granitoids of the Rio Maria Granite-Greenstone Terrane in the eastern Amazonian Craton in northern Brazil. Petrographic and geochemical aspects associated with magnetic susceptibility and gamma-ray spectrometry data show that the Redenção and the northern part of Bannach plutons are normally zoned. They were formed by two magmatic pulses: (1) a first magma pulse was fractionated in situ after emplacement at shallow crustal level, generating a series of coarse, even-grained monzogranites with variable modal proportions of biotite and hornblende; and (2) a second, slightly younger magma pulse, located to the center of the plutons, was composed of a more evolved liquid from which even-grained leucogranites derived. Gravity modeling indicates that the Redenção and Bannach plutons are sheeted-like composite intrusions, approximately 6 and 2 km thick, respectively. These plutons follow the general power law for laccolith dimension and are similar in this respect to classical rapakivi granite plutons. Gravity data suggest that the growth of the northern part of the Bannach pluton resulted from the amalgamation of smaller sheeted-like plutons that intruded in sequence from northwest to southeast. The Jamon suite plutons were emplaced in an extensional tectonic setting, and the stress was oriented approximately NNE-SSW to ENE-WSW, as indicated by the occurrence of diabase and granite porphyry dyke swarms, orientated WNW-ESE to NNW-SSE and coeval with the Jamon suite. The 1.88 Ga A-type granite plutons and stocks of Carajás are disposed along a belt that follows the general trend defined by the dikes. The inferred tabular geometry of the studied plutons and the high contrast of viscosity between the granites and their Archean country rocks can be explained by magma transport via dikes.

  3. ATP-binding site of adenylate kinase: mechanistic implications of its homology with ras-encoded p21, F1-ATPase, and other nucleotide-binding proteins.

    Science.gov (United States)

    Fry, D C; Kuby, S A; Mildvan, A S

    1986-02-01

    The MgATP binding site of adenylate kinase, located by a combination of NMR and x-ray diffraction, is near three protein segments, five to seven amino acids in length, that are homologous in sequence to segments found in other nucleotide-binding phosphotransferases, such as myosin and F1-ATPase, ras p21 and transducin GTPases, and cAMP-dependent and src protein kinases, suggesting equivalent mechanistic roles of these segments in all of these proteins. Segment 1 is a glycine-rich flexible loop that, on adenylate kinase, may control access to the ATP-binding site by changing its conformation. Segment 2 is an alpha-helix containing two hydrophobic residues that interact with the adenine-ribose moiety of ATP, and a lysine that may bind to the beta- and gamma-phosphates of ATP. Segment 3 is a hydrophobic strand of parallel beta-pleated sheet, terminated by a carboxylate, that flanks the triphosphate binding site. The various reported mutations of ras p21 that convert it to a transforming agent all appear to involve segment 1, and such substitutions may alter the properties of p21 by hindering a conformational change at this segment. In F1-ATPase, the flexible loop may, by its position, control both the accessibility and the ATP/ADP equilibrium constant on the enzyme.

  4. Integrin-linked kinase is a functional Mn2+-dependent protein kinase that regulates glycogen synthase kinase-3β (GSK-3beta phosphorylation.

    Directory of Open Access Journals (Sweden)

    Mykola Maydan

    2010-08-01

    Full Text Available Integrin-linked kinase (ILK is a highly evolutionarily conserved, multi-domain signaling protein that localizes to focal adhesions, myofilaments and centrosomes where it forms distinct multi-protein complexes to regulate cell adhesion, cell contraction, actin cytoskeletal organization and mitotic spindle assembly. Numerous studies have demonstrated that ILK can regulate the phosphorylation of various protein and peptide substrates in vitro, as well as the phosphorylation of potential substrates and various signaling pathways in cultured cell systems. Nevertheless, the ability of ILK to function as a protein kinase has been questioned because of its atypical kinase domain.Here, we have expressed full-length recombinant ILK, purified it to >94% homogeneity, and characterized its kinase activity. Recombinant ILK readily phosphorylates glycogen synthase kinase-3 (GSK-3 peptide and the 20-kDa regulatory light chains of myosin (LC(20. Phosphorylation kinetics are similar to those of other active kinases, and mutation of the ATP-binding lysine (K220 within subdomain 2 causes marked reduction in enzymatic activity. We show that ILK is a Mn-dependent kinase (the K(m for MnATP is approximately 150-fold less than that for MgATP.Taken together, our data demonstrate that ILK is a bona fide protein kinase with enzyme kinetic properties similar to other active protein kinases.

  5. Atypical temporomandibular joint pain: a case report.

    Science.gov (United States)

    Widmer, Charles G; Wold, Courtney C; Stoll, Ethan M; Dolwick, M Franklin

    2014-12-01

    Atypical temporomandibular joint (TMJ) pain can consist of an unusual intensity, location or set of pain descriptors that do not match what is traditionally observed for TMJ capsular pain, disc displacements or arthritic conditions. Presented in this case report is an atypical pain report regarding a unilateral TMJ pain as the chief complaint. An overview of typical vs atypical TMJ pain is also reviewed to highlight unusual signs and symptoms so that the clinician can identify these atypical presentations and pursue further diagnostic approaches. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. 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 at...... 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.......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...

  7. Is atypical odontalgia a psychological problem?

    Science.gov (United States)

    Graff-Radford, S B; Solberg, W K

    1993-05-01

    Several authors have asserted that psychological factors are the underlying cause of atypical odontalgia. However, objective evidence is lacking to support this claim. In this study, the Minnesota Multiphasic Personality Inventory was used to assess psychological functioning of an atypical odontalgia population. Means of the standard scores for each Minnesota Multiphasic Personality Inventory scale were within normal ranges. Standard scores for atypical odontalgia profiles compared with standard scores for a chronic headache group (matched for age, sex, and chronicity) were similar and scales for both groups were within normal ranges. These findings fail to support psychological dysfunction as a primary condition associated with patients suffering from atypical odontalgia.

  8. [Atypical courses of rheumatoid arthritis].

    Science.gov (United States)

    Keitel, W

    1979-04-01

    For the investigation of the question of atypical forms of course selected findings of a multicentric electronic data processing investigation carried out on 1,000 patients with manifest rheumatoid arthritis were attracted. In these cases differences of the clinical symptomatology in the sexes were the result, at a different moment of the beginning and concerning serological findings. The latter was concerned clearly by the titres of rheumatoid factors, only suggestively cases with antinuclear factors. These differences, however, were not regarded as special forms in the sense of separated disease units. They rather represent only statistically provable deviations, the borderlines of which are by far transgressed by individual characteristics.

  9. 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.

  10. 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

  11. 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

  12. Geochemistry of the Late Neoproterozoic Hadb adh Dayheen ring complex, Central Arabian Shield: Implications for the origin of rare-metal-bearing post-orogenic A-type granites

    Science.gov (United States)

    Moghazi, A. M.; Harbi, H. M.; Ali, K. A.

    2011-11-01

    The Hadb adh Dayheen ring complex (HDRC), Central Arabian Shield, is an alkaline to peralkaline A-type granite complex. It consists of an inner core of monzogranite followed outward by porphyritic alkali feldspar granite (hornblende biotite granite and aegirine riebeckite granite). Field and textural observations indicate that the different granite types were separated from magma reservoir, at different stages, and emplaced at higher levels along pre-existing fractures. The geochemical characteristics indicate that their magma was most plausibly originated by partial melting of juvenile lower crust following collision between East and West Gondwana at the final stage of the Arabian Shield evolution. The alkali feldspar granites have high abundances of albite and fluorite and wide variation of HFSE and REE that indicate interaction with hydrothermal F-rich fluids. Although there are many geochemical, mineralogical and textural evidence of secondary metasomatic alteration superimposed on the granitic rocks, they show textural features such as the arrangement of albite inclusions along growth planes in quartz (snowball texture) and aegirine that indicate early magmatic crystallization of albite. Also, the strong linear positive correlation of Ta vs. Nb and Zr vs. Hf emphasize that the behavior and enrichment of Ta and Nb are largely controlled by magmatic processes. The events that can explain the evolution of these rocks are: (1) during magmatic evolution, F dissolved in the magma and lowered the crystallization temperature causing REE and HFSE to form complexes and thus behave as incompatible elements, (2) prolonged crystallization of the major mineral phases (quartz and feldspar) formed a late-stage magmatic fluid enriched in volatiles (H 2O, F) and trace elements, (3) accessory minerals crystallized from such a phase in the interstices between the major mineral phases, and (4) post-magmatic re-equilibration and formation of secondary albite (Na-metasomatism) has

  13. Atypical Presentation of Atypical Teratoid Rhabdoid Tumor in a Child

    Directory of Open Access Journals (Sweden)

    Y. T. Udaka

    2013-01-01

    Full Text Available Atypical Teratoid Rhabdoid Tumor (ATRT is a rare malignant intracranial neoplasm more commonly diagnosed in young children. The authors report the case of an 11-year-old boy with a long standing history of slowly progressive weight loss, fatigue, and weakness over 1.5 years whose magnetic resonance imaging revealed a large heterogeneous enhancing dorsally exophytic lower brainstem mass. Examination revealed extreme cachexia, gaze-evoked nystagmus, dysphagia, dysarthria, bilateral dysmetria, and global weakness without ambulation. The protracted history and neuroimaging features were most suggestive of a low grade glioma. However, pathology revealed a hypercellular tumor with large hyperchromatic nucleoli and loss of INI-1 staining on immunohistochemistry consistent with a diagnosis of an ATRT. The child died shortly after surgery due to complications from his brainstem infiltrative disease. This case illustrates the diverse presentation of ATRT in childhood that can clinically and radiographically mimic that of low grade glioma.

  14. Constrictive Pericarditis Associated with Atypical Antipsychotics

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    Kuan-chin Jean Chen

    2012-01-01

    Full Text Available We report the successful surgical intervention in a case of constrictive pericarditis after long-term use of atypical antipsychotics. Pericarditis developed in our patient with a longstanding history of schizophrenia treated with atypical antipsychotics. Pericardiectomy was undertaken, and the patient's presenting symptom of shortness of breath resolved subsequently with an uneventful postoperative course.

  15. Deletion of Protein Kinase C λ in POMC Neurons Predisposes to Diet-Induced Obesity.

    Science.gov (United States)

    Dorfman, Mauricio D; Krull, Jordan E; Scarlett, Jarrad M; Guyenet, Stephan J; Sajan, Mini P; Damian, Vincent; Nguyen, Hong T; Leitges, Michael; Morton, Gregory J; Farese, Robert V; Schwartz, Michael W; Thaler, Joshua P

    2017-04-01

    Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that central nervous system (CNS) action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacological inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high-fat diet (HFD) feeding. Similarly, selective deletion of the aPKC isoform Pkc-λ in proopiomelanocortin (POMC) neurons disrupts leptin action, reduces melanocortin content in the paraventricular nucleus, and markedly increases susceptibility to obesity, glucose intolerance, and insulin resistance specifically in HFD-fed male mice. These data implicate aPKC as a novel regulator of energy and glucose homeostasis downstream of the leptin-PI3K pathway in POMC neurons. © 2017 by the American Diabetes Association.

  16. Petrogenesis, zircon U-Pb age, and geochemistry of the A-type Mogou syenite, western Henan Province: Implications for Mesozoic tectono-magmatic evolution of the Qinling Orogen

    Science.gov (United States)

    He, Xinyu; Wang, Jionghui; Wang, Changming; Carranza, Emmanuel John M.; Chen, Liang; Wu, Bin

    2016-04-01

    The Mogou syenite intruded into the Mesoproterozoic Xiong'er Group is the main lithostratigraphic unit, along the southern margin of the North China Craton (NCC). This paper reports zircon LA-ICP-MS data, whole-rock major and trace element compositions of late Triassic magmatic rocks in the Mogou syenite, in order to constrain the formation age of the Mogou syenite, research the origin and evolution of the magma and analyse the geodynamic setting of the Qinling Orogen (QO) in Late Triassic. These rocks consist of medium- to coarse-grained syenite and fine-grained quartz syenite. Zircon U-Pb dating yields a crystallization age of 226.5±2.7 Ma. The syenites are characterized by high SiO2 (63.49-72.17%), alkali (K2O+Na2O of 11.18-15.38%) and potassium (K2O/Na2O of 2.88-28.11), are peralkaline or metaluminous (molar A/CNK of 0.87-1.02) and belong to shoshonite series. The syenites have ΣREE of 33.01-191.30 ppm, LREE/HREE of 14-20, (La/Yb)N of 11-24, with LREE-rich distribution pattern and obvious differentiation between HREE and LREE. Eu anomalies are positive for the medium- to coarse-grained syenite and weakly negative for the fine-grained quartz syenite. In addition, the syenites are enriched in large-ion lithophile elements (Ba, K, Sr, and Pb) but depleted in high strength field elements (Ti, Ta, Nb, Zr, and Hf), and have high differentiation indices of 91.69-97.06. These geochemical features indicate that the primary magma of the Mogou syenite most likely originated from a mantle source with minor crustal component, and underwent a fractional crystallization process during its emplacement. The late Triassic A-type Moguo syenite along the southern margin of the NCC was generated in the late stage of the syn-collision event of QO, recording a transition period from compression to extension at around 227 Ma.

  17. Atypical manifestations of tinea faciei

    Directory of Open Access Journals (Sweden)

    Mittal R

    1996-01-01

    Full Text Available A study of 58 paitents of tinea faciei was conducted. Twenty five (43.1% patients had history of photosensitivity. Twenty eight (48.2% patients were applying topical steroids, 2 (3.4% patients were on 10 mg of prednisolone daily. Associated tinea of other sites were observed in 14 (24.13%. 23 (39.6% patients had typical circinate, arcuate, annular plaques with raised margin showing vesiculo-pustules. Atypical manifestations were in the form of arcuate plaques on the pinna in 4 patients, erythematous plaques full of vesiculo-pustules without central clearing in 3. Thirty two (55.17% patients had plaques with broad edges and indistinct central clearing. In 2 patients lesions resembled discoid lupus erythematosus. Skin scrapings for fungus was positive in 36 (62.06% cases. All patients responded to systemic griseofulvin 10mg/kg with 1% clotrimazole topicaly in 4-8 weeks.

  18. 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.

  19. Cutting Edge: Molecular Structure of the IL-1R-Associated Kinase-4 Death Domain and Its Implications for TLR Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Lasker, Michael V.; Gajjar, Mark M.; Nair, Satish K. (UIUC)

    2010-07-19

    IL-1R-associated kinase (IRAK) 4 is an essential component of innate immunity. IRAK-4 deficiency in mice and humans results in severe impairment of IL-1 and TLR signaling. We have solved the crystal structure for the death domain of Mus musculus IRAK-4 to 1.7 {angstrom} resolution. This is the first glimpse of the structural details of a mammalian IRAK family member. The crystal structure reveals a six-helical bundle with a prominent loop, which among IRAKs and Pelle, a Drosophila homologue, is unique to IRAK-4. This highly structured loop contained between helices two and three, comprises an 11-aa stretch. Although innate immune domain recognition is thought to be very similar between Drosophila and mammals, this structural component points to a drastic difference. This structure can be used as a framework for future mutation and deletion studies and potential drug design.

  20. Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer.

    Science.gov (United States)

    Pontier, S M; Huck, L; White, D E; Rayment, J; Sanguin-Gendreau, V; Hennessy, B; Zuo, D; St-Arnaud, R; Mills, G B; Dedhar, S; Marshall, C J; Muller, W J

    2010-06-10

    Elevated expression of the integrin-linked kinase (ILK) has been observed in a variety of cancers and has been further correlated with poor clinical outcome. Here, we show that mammary epithelial disruption of ILK results in a profound block in mammary tumor induction. Consistent with these observations, inhibition of ILK function in ErbB2-expressing cells with small molecule inhibitor or RNA interference resulted in profound block in their in vitro invasive properties due to the induction of apoptotic cell death. The rare ILK-deficient tumors that eventually arose overcame this block in tumor induction by an upregulation of ErB3 phosphorylation. These observations provide direct evidence that ILK has a critical role in the initiation phase of ErbB2 tumor induction.

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

    Science.gov (United States)

    Langmesser, Sonja; Franken, Paul; Feil, Susanne; Emmenegger, Yann; Albrecht, Urs; Feil, Robert

    2009-01-01

    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.

  2. Apoptosis signal-regulating kinase 1 inhibition attenuates cardiac hypertrophy and cardiorenal fibrosis induced by uremic toxins: Implications for cardiorenal syndrome.

    Science.gov (United States)

    Savira, Feby; Cao, Longxing; Wang, Ian; Yang, Wendi; Huang, Kevin; Hua, Yue; Jucker, Beat M; Willette, Robert N; Huang, Li; Krum, Henry; Li, Zhiliang; Fu, Qiang; Wang, Bing Hui

    2017-01-01

    Intracellular accumulation of protein-bound uremic toxins in the setting of cardiorenal syndrome leads to adverse effects on cardiorenal cellular functions, where cardiac hypertrophy and cardiorenal fibrosis are the hallmarks. In this study, we sought to determine if Apoptosis Signal-Regulated Kinase 1 (ASK1), an upstream regulator of cellular stress response, mediates cardiac hypertrophy and cardiorenal fibrosis induced by indoxyl sulfate (IS) and p-cresol sulfate (PCS) in vitro, and whether ASK1 inhibition is beneficial to ameliorate these cellular effects. PCS augmented cardiac myocyte hypertrophy and fibroblast collagen synthesis (as determined by 3H-leucine and 3H-proline incorporation, respectively), similar to our previous finding with IS. IS and PCS also increased collagen synthesis of proximal tubular cells and renal mesangial cells. Pro-hypertrophic (α-skeletal muscle actin and β-MHC) and pro-fibrotic genes (TGF-β1 and ctgf) were induced by both IS and PCS. Western blot analyses revealed the activation of ASK1 and downstream mitogen activated protein kinases (MAPKs) (p38MAPK and ERK1/2) as well as nuclear factor-kappa B (NF-κB) by IS and PCS. ASK1, OAT1/3, ERK1/2 and p38MAPK inhibitors suppressed all these effects. In summary, IS and PCS exhibit pro-hypertrophic and pro-fibrotic properties, at least in part, via the activation of ASK1 and its downstream pathways. ASK1 inhibitor is an effective therapeutic agent to alleviate protein-bound uremic toxin-induced cardiac hypertrophy and cardiorenal fibrosis in vitro, and may be translated further for cardiorenal syndrome therapy.

  3. 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.

  4. 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.

  5. Pseudoarthrosis in atypical femoral fracture: case report.

    Science.gov (United States)

    Giannotti, S; Bottai, V; Dell'Osso, G; De Paola, G; Ghilardi, M; Guido, G

    2013-11-01

    Atypical femoral fractures can be subsequent to a long-term biphosphonates treatment; they have a high frequency of delayed healing. The authors describe a femoral pseudoarthrosis of an atypical fracture treated with intramedullary nailing in a female after prolonged alendronate therapy. Atypical femoral fractures can be subsequent to a long-term biphosphonates treatment even if, in the literature, there is no clarity on the exact pathogenetic mechanism. The Task Force of the American Society for Bone and Mineral Research described the major and minor features to define atypical fractures and recommends that all the five major features must be present while minor features are not necessary. Another controversial aspect regarding the atypical femoral fractures is the higher frequency of the delayed healing that can be probably related to a suppressed bone turnover caused by a prolonged period of bisphosphonates treatment. This concept could be corroborated by the Spet Tc exam. In the case of a pseudoarthrosis, there is not a standardization of the treatment. In this report, the authors describe a femoral pseudoarthrosis of an atypical fracture treated with intramedullary nailing in a female after prolonged alendronate therapy; the patient was studied with clinical, bioumoral end SPECT-Tc exam of both femurs. Many studies show the relationship between bisphosphonates and the presence of atypical fractures. These fractures should be monitored more closely due to the risk of nonunion and they require considering an initial treatment with pharmacological augmentation to reduce the complications for the patient and the health care costs.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Ca(2+)/calmodulin-dependent protein kinase IIα (αCaMKII) controls the activity of the dopamine transporter: implications for Angelman syndrome.

    Science.gov (United States)

    Steinkellner, Thomas; Yang, Jae-Won; Montgomery, Therese R; Chen, Wei-Qiang; Winkler, Marie-Therese; Sucic, Sonja; Lubec, Gert; Freissmuth, Michael; Elgersma, Ype; Sitte, Harald H; Kudlacek, Oliver

    2012-08-24

    The dopamine transporter (DAT) is a crucial regulator of dopaminergic neurotransmission, controlling the length and brevity of dopaminergic signaling. DAT is also the primary target of psychostimulant drugs such as cocaine and amphetamines. Conversely, methylphenidate and amphetamine are both used clinically in the treatment of attention-deficit hyperactivity disorder and narcolepsy. The action of amphetamines, which induce transport reversal, relies primarily on the ionic composition of the intra- and extracellular milieus. Recent findings suggest that DAT interacting proteins may also play a significant role in the modulation of reverse dopamine transport. The pharmacological inhibition of the serine/threonine kinase αCaMKII attenuates amphetamine-triggered DAT-mediated 1-methyl-4-phenylpyridinium (MPP(+)) efflux. More importantly, αCaMKII has also been shown to bind DAT in vitro and is therefore believed to be an important player within the DAT interactome. Herein, we show that αCaMKII co-immunoprecipitates with DAT in mouse striatal synaptosomes. Mice, which lack αCaMKII or which express a permanently self-inhibited αCaMKII (αCaMKII(T305D)), exhibit significantly reduced amphetamine-triggered DAT-mediated MPP(+) efflux. Additionally, we investigated mice that mimic a neurogenetic disease known as Angelman syndrome. These mice possess reduced αCaMKII activity. Angelman syndrome mice demonstrated an impaired DAT efflux function, which was comparable with that of the αCaMKII mutant mice, indicating that DAT-mediated dopaminergic signaling is affected in Angelman syndrome.

  8. The P21-activated kinase PAK4 is implicated in fatty-acid potentiation of insulin secretion downstream of free fatty acid receptor 1.

    Science.gov (United States)

    Bergeron, Valérie; Ghislain, Julien; Poitout, Vincent

    2016-11-01

    Free fatty acid receptor 1 (FFA1/GPR40) plays a key role in the potentiation of glucose-stimulated insulin secretion by fatty acids in pancreatic β cells. We previously demonstrated that GPR40 signaling leads to cortical actin remodeling and potentiates the second phase of insulin secretion. In this study, we examined the role of p21 activated kinase 4 (PAK4), a known regulator of cytoskeletal dynamics, in GPR40-dependent potentiation of insulin secretion. The fatty acid oleate induced PAK4 phosphorylation in human islets, in isolated mouse islets and in the insulin secreting cell line INS832/13. However, oleate-induced PAK4 phosphorylation was not observed in GPR40-null mouse islets. siRNA-mediated knockdown of PAK4 in INS832/13 cells abrogated the potentiation of insulin secretion by oleate, whereas PAK7 knockdown had no effect. Our results indicate that PAK4 plays an important role in the potentiation of insulin secretion by fatty acids downstream of GPR40.

  9. [Neurological manifestations in atypical Kawasaki disease].

    Science.gov (United States)

    Martínez-Guzmán, Edgar; Gámez-González, Luisa Berenise; Rivas-Larrauri, Francisco; Sorcia-Ramírez, Giovanni; Yamazaki-Nakashimada, Marco

    2017-01-01

    Kawasaki disease (KD) is a type of systemic vasculitis of unknown etiology. Atypical Kawasaki disease is defined as that where there are signs and symptoms not corresponding to the classical criteria for this nosological entity. Children with atypical Kawasaki disease may present with acute abdominal symptoms, meningeal irritation, pneumonia or renal failure. We describe 4 children with ages ranging from 2 to 12 years who had atypical Kawasaki disease, with neurological and gastrointestinal symptoms as part of the systemic presentation of the disease. Treatment consisted of immunoglobulin and corticosteroids with good evolution. KD is a systemic vasculitis that can involve many territories. Atypical manifestations can mislead the clinician and delay diagnosis. Pediatricians and sub-specialists should be aware of these neurological manifestations in order to provide adequate and opportune treatment.

  10. Atypical CT findings in bacterial meningoencephalitis

    Energy Technology Data Exchange (ETDEWEB)

    Fink, I.J.; Dillon, W.P.; Brant-Zawadzki, M.; Danziger, A.; Rechthand, E.

    1984-01-01

    Computed tomography has become a valuable imaging modality in the evaluation and management of most intracerebral infections. We report two cases of intracranial infections with atypical CT findings, and attempt to correlate these findings with the pathophysiology.

  11. 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.

  12. Atypical odontalgia. Its aetiology and prognosis.

    Science.gov (United States)

    Brooke, R I; Schnurr, R F

    1993-12-01

    Atypical odontalgia is a chronic pain disorder in which persistent pain develops in clinically normal teeth. Its possible aetiology and long-term prognosis are discussed. Suggested management regimes are reviewed.

  13. Novel Library of Selenocompounds as Kinase Modulators

    Directory of Open Access Journals (Sweden)

    Carmen Sanmartín

    2011-07-01

    Full Text Available Although the causes of cancer lie in mutations or epigenic changes at the genetic level, their molecular manifestation is the dysfunction of biochemical pathways at the protein level. The 518 protein kinases encoded by the human genome play a central role in various diseases, a fact that has encouraged extensive investigations on their biological function and three dimensional structures. Selenium (Se is an important nutritional trace element involved in different physiological functions with antioxidative, antitumoral and chemopreventive properties. The mechanisms of action for selenocompounds as anticancer agents are not fully understood, but kinase modulation seems to be a possible pathway. Various organosulfur compounds have shown antitumoral and kinase inhibition effects but, in many cases, the replacement of sulfur by selenium improves the antitumoral effect of compounds. Although Se atom possesses a larger atomic volume and nucleophilic character than sulfur, Se can also formed interactions with aminoacids of the catalytic centers of proteins. So, we propose a novel chemical library that includes organoselenium compounds as kinase modulators. In this study thirteen selenocompounds have been evaluated at a concentration of 3 or 10 µM in a 24 kinase panel using a Caliper LabChip 3000 Drug Discover Platform. Several receptor (EGFR, IGFR1, FGFR1… and non-receptor (Abl kinases have been selected, as well as serine/threonine/lipid kinases (AurA, Akt, CDKs, MAPKs… implicated in main cancer pathways: cell cycle regulation, signal transduction, angiogenesis regulation among them. The obtained results showed that two compounds presented inhibition values higher than 50% in at least four kinases and seven derivatives selectively inhibited one or two kinases. Furthermore, three compounds selectively activated IGF-1R kinase with values ranging from −98% to −211%. In conclusion, we propose that the replacement of sulfur by selenium seems to be

  14. Atypical presentations of neuromyelitis optica

    Directory of Open Access Journals (Sweden)

    Douglas Sato

    2011-10-01

    Full Text Available Neuromyelitis optica (NMO is an inflammatory disease of central nervous system classically characterized by acute, severe episodes of optic neuritis and longitudinally extensive transverse myelitis, usually with a relapsing course. The identification of an autoantibody exclusively detected in NMO patients against aquaporin-4 (AQP-4 has allowed identification of cases beyond the classical phenotype. Brain lesions, once thought as infrequent, can be observed in NMO patients, but lesions have different characteristics from the ones seen in multiple sclerosis. Additionally, some AQP-4 antibody positive patients may present with a variety of symptoms not being restricted to optic neuritis and acute myelitis during the first attack or in a relapse. Examples are not limited to, but may include patients only with brain and/or brainstem lesions, narcolepsy with hypothalamic lesions or patients with intractable hiccups, nausea and vomiting. The prompt identification of NMO patients with atypical presentations may benefit these patients with institution of early treatment to reduce disability and prevent further attacks.

  15. Biopsychosocial aspects of atypical odontalgia.

    Science.gov (United States)

    Ciaramella, A; Paroli, M; Lonia, L; Bosco, M; Poli, P

    2013-01-01

    Background. A few studies have found somatosensory abnormalities in atypical odontalgia (AO) patients. The aim of the study is to explore the presence of specific abnormalities in facial pain patients that can be considered as psychophysical factors predisposing to AO. Materials and Methods. The AO subjects (n = 18) have been compared to pain-free (n = 14), trigeminal neuralgia (n = 16), migraine (n = 17), and temporomandibular disorder (n = 14). The neurometer current perception threshold (CPT) was used to investigate somatosensory perception. Structured clinical interviews based on the DSM-IV axis I and DSM III-R axis II criteria for psychiatric disorders and self-assessment questionnaires were used to evaluate psychopathology and aggressive behavior among subjects. Results. Subjects with AO showed a lower A β , A δ , and C trigeminal fiber pain perception threshold when compared to a pain-free control group. Resentment was determined to be inversely related to A β (rho: 0.62, P < 0.05), A δ (rho: 0.53, P < 0.05) and C fibers (rho: 0.54, P < 0.05), and depression was inversely related with C fiber (rho: 0.52, P < 0.05) perception threshold only in AO subjects. Conclusion. High levels of depression and resentment can be considered predictive psychophysical factors for the development of AO after dental extraction.

  16. Low-Grade Esthesioneuroblastoma Presenting as SIADH: A Review of Atypical Manifestations

    Directory of Open Access Journals (Sweden)

    Andrew Senchak

    2012-01-01

    Full Text Available Esthesioneuroblastoma (ENB is a neuroendocrine tumor that typically manifests as advanced stage malignancy in the superior nasal cavity. The hallmark symptoms include nasal obstruction and epistaxis, which result from local tissue invasion. Atypical clinical features can also arise and must be considered when diagnosing and treating ENB. These can include origin in an ectopic location, unusual presenting symptoms, and associated paraneoplastic syndromes. The case described here reports a nasal cavity ENB with atypical clinical features that occurred in a young female. Her tumor was low grade, appeared to arise primarily from the middle nasal cavity, and presented as syndrome of inappropriate antidiuretic hormone (SIADH. She also became pregnant shortly after diagnosis, which had implications on her surgical management. We review the atypical features that uncommonly occur with ENB and the clinical considerations that arise from these unusual characteristics.

  17. An Atypical Rett Syndrome Phenotype Due to a Novel Missense Mutation in CACNA1A.

    Science.gov (United States)

    Epperson, Madison V; Haws, Michael E; Standridge, Shannon M; Gilbert, Donald L

    2018-03-01

    Some typical and atypical Rett syndrome patients lack known genetic mutations. Mutations in the P/Q type calcium channel CACNA1A have been implicated in epileptic encephalopathy, familial hemiplegic migraine, episodic ataxia 2, and spinocerebellar ataxia 6, but not Rett syndrome. Patient Description: The authors describe a female patient with developmental regression and a de novo, likely pathogenic mutation in CACNA1A who meets 3 of 4 main criteria (stereotypic hand movements, loss of purposeful hand movements, gait disturbance), and 6 of 11 supportive criteria (impaired sleep, abnormal tone, vasomotor disturbance, scoliosis, growth retardation, and screaming spells) for atypical Rett syndrome. Furthermore, she resembles the early seizure variant of Rett syndrome. Previously, 3 children with similar CACNA1A mutations have been reported, but a Rett syndrome phenotype has not been described. CACNA1A mutations should be considered in children presenting with an atypical Rett syndrome phenotype, specifically, the early seizure variant.

  18. [Clinical features of atypical refractory anemia (RA)].

    Science.gov (United States)

    Matsuda, A; Jinnai, I; Kusumoto, S; Shiramatsu, F; Bessho, M; Saito, M; Hirashima, K

    1991-08-01

    Twenty-three patients with bicytopenia or pancytopenia were retrospectively studied. The patients with underlying disorders, blast count of more than 5% on bone marrow (BM) aspirate, blast count of more than 1% on peripheral blood or ringed sideroblast count of more than 15% on BM aspirate were excluded. According to Yoshida's criteria, 23 patients were classified into 6 subtypes [AA (aplastic anemia)1: typical AA, AA2: atypical AA, MDS (myelodysplastic syndrome)3: typical RA (refractory anemia, MDS4-6: atypical RA], and AA1 7 cases; AA2 2 cases; MDS3 5 cases; MDS4 1 case; MDS5 2 cases; MDS6 6 cases. To clarify the clinical features of atypical RA group (MDS4-6), we investigated ferrokinetics, RBC life span, karyotype, serum Epo (erythropoietin) concentration, response to therapy and prognosis. Results were as follows: 1) all three RA patients who were younger than 30 years old were included in atypical RA group, 2) in ferrokinetics study PID (plasma iron disappearance time) values of MDS4 and MDS6 patients ranged between those of AA1 and those of MDS3 patients (5 of 7 patients), 3) two cases who developed leukemia belonged to typical RA group, 4) patients with atypical RA showed response to therapy and their prognosis were better than those with typical RA. These observations suggest that atypical RA have different clinical features from typical RA.

  19. 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

  20. The Ca2+/CaMKK2 axis mediates the telbivudine induced upregulation of creatine kinase: Implications for mechanism of antiviral nucleoside analogs' side effect.

    Science.gov (United States)

    Jianfei, Long; Min, Wang; Chunlai, Ma; Bicui, Chen; Jiming, Zhang; Bin, Wang

    2017-12-15

    Telbivudine (LdT), a widely prescribed anti-hepatitis B virus (HBV) drug for the treatment of chronic Hepatitis B (CHB), causes adverse reactions ranging from creatine kinase (CK) elevation to myopathy. The purpose of this study was to explore the mechanism(s) of LdT induced CK elevation. The effects of LdT on mitochondrial morphology and proteins (TK2 and β-actin), oxidative stress, intracellular Ca2+ levels, Ca2+-related signaling pathway (CaMKK2/AMPK), and Ca2+-related biomarkers such as superoxide dismutase (SOD) and malondialdehyde (MDA) were assessed in human skeletal muscle cells (HSKMCs). The results showed that LdT induced a dose-dependent increase in CK activity in HSKMCs, without affecting mitochondrial morphology, and TK2 and β-actin protein levels, following 72 h of treatment. In addition, LdT increased Ca2+ production, ROS generation, MDA and lipid peroxide (LPO) levels, and activated the CaMKK2/AMPK signaling pathway. Moreover, these effects were attenuated by the BAPIA-AM (the calcium chelator). We also confirmed the presence of relevant markers (MDA, LPO, and SOD) in serum from CHB patients after LdT treatment, and found that CK was positively correlated with MDA and LPO, and negatively associated with SOD. These findings indicate that LdT induces CK elevation and oxidative stress associated with imbalance of intracellular Ca2+ in HSKMCs, suggesting that Ca2+/CaMKK2 axis imbalance may underlie human LdT-induced CK elevation. The present findings provide a solid basis for assessing the mechanism of drug-induced CK elevation, which can help develop new tools for the prevention and treatment of diseases associated with drug-induced CK elevation. Copyright © 2017. Published by Elsevier Inc.

  1. The clinical and biological implications of the focal adhesion kinase pathway in ShenLingLan mediated suppression of cellular migration of ovarian cancer cells

    Directory of Open Access Journals (Sweden)

    Owen S

    2017-06-01

    Full Text Available The incidence of ovarian cancer in the UK has increased by almost twenty percent since the 1970’s and the majority of cases are not diagnosed until the late stages, when metastasis is more likely to have occurred. Focal Adhesion Kinase (FAK is one of the key protein complexes which is integral to cell migration and has been linked to a variety of solid tumours. ShenLingLan (SLDM is a traditional herbal medicine which has been formulated for the treatment of solid tumours. This study aimed to establish the impact of SLDM on FAK in ovarian cancer cells in vitro and transcript levels of FAK in an ovarian cancer cohort. FAK and paxillin phosphorylation events stimulated by SLDM treatment were identified using a Kinexus™ antibody based protein array. The impact of SLDM on cell attachment and migration was evaluated using Electric cell-substrate impedance sensing (ECIS, whilst the changes in focal adhesion complex localisation were assessed using immunofluorescence. In an ovarian cancer cohort, differences in FAK and paxillin transcript levels were assessed against key clinical parameters such as differentiation, stage and survival outcome. SLDM treatment of ovarian cancer cells in vitro resulted in the suppression of FAK and paxillin phosphorylation at several sites, which appeared to manifest as decreased cellular attachment and migration in a range of immortalised ovarian cancer cells. Increased FAK and paxillin transcript copies were observed in high grade and poorly differentiated ovarian tumours as well as in tumours from patients with ovarian cancer related incidence. SLDM has a profound effect on the migratory and adhesive properties of ovarian cancer cells, potentially via inhibitory effects on the activation of the FAK pathway, which is aberrant in clinical ovarian cancers.

  2. [Cytoplasmic kinase inhibitors].

    Science.gov (United States)

    Mano, Hiroyuki

    2010-10-01

    Protein kinases play essential roles in the regulation of cell proliferation. Point mutations or/and fusions of protein kinases are frequently identified in human cancers, and targeting such activated kinases provides us with a chance to eradicate tumor cells. This was first proved by imatinib mesylate that inhibits ABL tyrosine kinase and, thereby, efficiently kills malignant cells in chronic myeloid leukemia. In addition, other clinical trials are ongoing for kinase inhibitors against EML4--ALK in lung cancer, JAK2 in myeloproliferative disorders and BRAF in malignant melanoma. Early reports indeed reveal that such targeting compounds are promising drugs for human cancers with activated kinases.

  3. Allosteric regulation of protein kinase PKCζ by the N-terminal C1 domain and small compounds to the PIF-pocket

    DEFF Research Database (Denmark)

    Lopez-Garcia, Laura A; Schulze, Jörg O; Fröhner, Wolfgang

    2011-01-01

    Protein kinases are key mediators of cellular signaling, and therefore, their activities are tightly controlled. AGC kinases are regulated by phosphorylation and by N- and C-terminal regions. Here, we studied the molecular mechanism of inhibition of atypical PKCζ and found that the inhibition by ...

  4. MAP kinase meets mitosis: A role for Raf Kinase Inhibitory Protein in spindle checkpoint regulation

    Directory of Open Access Journals (Sweden)

    Rosner Marsha

    2007-01-01

    Full Text Available Abstract Raf Kinase Inhibitory Protein (RKIP is an evolutionarily conserved protein that functions as a modulator of signaling by the MAP kinase cascade. Implicated as a metastasis suppressor, Raf Kinase Inhibitory Protein depletion correlates with poor prognosis for breast, prostate and melanoma tumors but the mechanism is unknown. Recent evidence indicates that Raf Kinase Inhibitory Protein regulates the mitotic spindle assembly checkpoint by controlling Aurora B Kinase activity, and the mechanism involves Raf/MEK/ERK signaling. In contrast to elevated MAP kinase signaling during the G1, S or G2 phases of the cell cycle that activates checkpoints and induces arrest or senescence, loss of RKIP during M phase leads to bypass of the spindle assembly checkpoint and the generation of chromosomal abnormalities. These results reveal a role for Raf Kinase Inhibitory Protein and the MAP kinase cascade in ensuring the fidelity of chromosome segregation prior to cell division. Furthermore, these data highlight the need for precise titration of the MAP kinase signal to ensure the integrity of the spindle assembly process and provide a mechanism for generating genomic instability in tumors. Finally, these results raise the possibility that RKIP status in tumors could influence the efficacy of treatments such as poisons that stimulate the Aurora B-dependent spindle assembly checkpoint.

  5. Kinase Inhibitor Profiling Reveals Unexpected Opportunities to Inhibit Disease-Associated Mutant Kinases

    Directory of Open Access Journals (Sweden)

    Krisna C. Duong-Ly

    2016-02-01

    Full Text Available Small-molecule kinase inhibitors have typically been designed to inhibit wild-type kinases rather than the mutant forms that frequently arise in diseases such as cancer. Mutations can have serious clinical implications by increasing kinase catalytic activity or conferring therapeutic resistance. To identify opportunities to repurpose inhibitors against disease-associated mutant kinases, we conducted a large-scale functional screen of 183 known kinase inhibitors against 76 recombinant mutant kinases. The results revealed lead compounds with activity against clinically important mutant kinases, including ALK, LRRK2, RET, and EGFR, as well as unexpected opportunities for repurposing FDA-approved kinase inhibitors as leads for additional indications. Furthermore, using T674I PDGFRα as an example, we show how single-dose screening data can provide predictive structure-activity data to guide subsequent inhibitor optimization. This study provides a resource for the development of inhibitors against numerous disease-associated mutant kinases and illustrates the potential of unbiased profiling as an approach to compound-centric inhibitor development.

  6. Neuregulin-1 regulates cell adhesion via an ErbB2/phosphoinositide-3 kinase/Akt-dependent pathway: potential implications for schizophrenia and cancer.

    Directory of Open Access Journals (Sweden)

    Christopher G Kanakry

    2007-12-01

    Full Text Available Neuregulin-1 (NRG1 is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis. Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1alpha-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT, a second gene implicated both in schizophrenia susceptibility and in cancer.Here, we examine cell adhesion, an essential component process of cell motility, using an integrin-mediated cell adhesion assay based on an interaction between ICAM-1 and the CD11a/CD18 integrin heterodimer expressed on lymphoblasts. In our assay, NRG1alpha induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. The maximum range of variation in adhesion over sixty minutes correlates strongly with NRG1alpha-induced migration (r(2 = 0.61. NRG1alpha-induced adhesion variation is blocked by erbB2, PI3K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/PI3K/Akt1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 patients with schizophrenia and 20 normal controls, cells from patients show a significant deficiency in the range of NRG1alpha-induced adhesion (p = 0.0002. In contrast, the response of patient-derived cells to phorbol myristate acetate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1alpha-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p = 0.063.Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion.

  7. NF- κB Essential Modulator Deficiency Leading to Disseminated Cutaneous Atypical Mycobacteria

    Directory of Open Access Journals (Sweden)

    Jonathan Braue

    2014-12-01

    Full Text Available NF- κB essential modulator (NEMO is a kinase integral to the macrophage TNF-α pathway, which leads to the intracellular destruction of Mycobacteria species. Defects in the NEMO pathway lead to a spectrum of diseases, including but not limited to ectodermal dysplasia, Mendelian susceptibility to mycobacterial diseases, and incontinentia pigmenti. In addition, paucity of NEMO can lead to the inability to mount a proper immune response against opportunistic pyogenic and mycobacterial infections, leading to dissemination to various organ systems. This manuscript will discuss the numerous clinical manifestations of NEMO deficiency, the differential diagnosis for atypical mycobacterial infections in immunocompetent adults, and feature a case report of rare isolated susceptibility to disseminated atypical mycobacteria due to a mutation in the first exon of the NEMO gene.

  8. Conservation, variability and the modeling of active protein kinases.

    Directory of Open Access Journals (Sweden)

    James D R Knight

    2007-10-01

    Full Text Available The human proteome is rich with protein kinases, and this richness has made the kinase of crucial importance in initiating and maintaining cell behavior. Elucidating cell signaling networks and manipulating their components to understand and alter behavior require well designed inhibitors. These inhibitors are needed in culture to cause and study network perturbations, and the same compounds can be used as drugs to treat disease. Understanding the structural biology of protein kinases in detail, including their commonalities, differences and modes of substrate interaction, is necessary for designing high quality inhibitors that will be of true use for cell biology and disease therapy. To this end, we here report on a structural analysis of all available active-conformation protein kinases, discussing residue conservation, the novel features of such conservation, unique properties of atypical kinases and variability in the context of substrate binding. We also demonstrate how this information can be used for structure prediction. Our findings will be of use not only in understanding protein kinase function and evolution, but they highlight the flaws inherent in kinase drug design as commonly practiced and dictate an appropriate strategy for the sophisticated design of specific inhibitors for use in the laboratory and disease therapy.

  9. Enhanced expression of a calcium-dependent protein kinase from ...

    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. Mitotic regulation by NIMA-related kinases

    Directory of Open Access Journals (Sweden)

    Blot Joelle

    2007-08-01

    Full Text Available Abstract The NIMA-related kinases represent a family of serine/threonine kinases implicated in cell cycle control. The founding member of this family, the NIMA kinase of Aspergillus nidulans, as well as the fission yeast homologue Fin1, contribute to multiple aspects of mitotic progression including the timing of mitotic entry, chromatin condensation, spindle organization and cytokinesis. Mammals contain a large family of eleven NIMA-related kinases, named Nek1 to Nek11. Of these, there is now substantial evidence that Nek2, Nek6, Nek7 and Nek9 also regulate mitotic events. At least three of these kinases, as well as NIMA and Fin1, have been localized to the microtubule organizing centre of their respective species, namely the centrosome or spindle pole body. Here, they have important functions in microtubule organization and mitotic spindle assembly. Other Nek kinases have been proposed to play microtubule-dependent roles in non-dividing cells, most notably in regulating the axonemal microtubules of cilia and flagella. In this review, we discuss the evidence that NIMA-related kinases make a significant contribution to the orchestration of mitotic progression and thereby protect cells from chromosome instability. Furthermore, we highlight their potential as novel chemotherapeutic targets.

  11. Mitotic regulation by NIMA-related kinases.

    Science.gov (United States)

    O'regan, Laura; Blot, Joelle; Fry, Andrew M

    2007-08-29

    The NIMA-related kinases represent a family of serine/threonine kinases implicated in cell cycle control. The founding member of this family, the NIMA kinase of Aspergillus nidulans, as well as the fission yeast homologue Fin1, contribute to multiple aspects of mitotic progression including the timing of mitotic entry, chromatin condensation, spindle organization and cytokinesis. Mammals contain a large family of eleven NIMA-related kinases, named Nek1 to Nek11. Of these, there is now substantial evidence that Nek2, Nek6, Nek7 and Nek9 also regulate mitotic events. At least three of these kinases, as well as NIMA and Fin1, have been localized to the microtubule organizing centre of their respective species, namely the centrosome or spindle pole body. Here, they have important functions in microtubule organization and mitotic spindle assembly. Other Nek kinases have been proposed to play microtubule-dependent roles in non-dividing cells, most notably in regulating the axonemal microtubules of cilia and flagella. In this review, we discuss the evidence that NIMA-related kinases make a significant contribution to the orchestration of mitotic progression and thereby protect cells from chromosome instability. Furthermore, we highlight their potential as novel chemotherapeutic targets.

  12. ATYPICAL ANTIPSYCHOTICS USE IN CHILDREN AND ADOLESCENTS

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    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.

  13. [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.

  14. 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

    2016-12-24

    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. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Evolution of acetylcholinesterase and butyrylcholinesterase in the vertebrates: an atypical butyrylcholinesterase from the Medaka Oryzias latipes.

    Directory of Open Access Journals (Sweden)

    Leo Pezzementi

    2011-02-01

    Full Text Available Acetylcholinesterase (AChE and butyrylcholinesterase (BChE are thought to be the result of a gene duplication event early in vertebrate evolution. To learn more about the evolution of these enzymes, we expressed in vitro, characterized, and modeled a recombinant cholinesterase (ChE from a teleost, the medaka Oryzias latipes. In addition to AChE, O. latipes has a ChE that is different from either vertebrate AChE or BChE, which we are classifying as an atypical BChE, and which may resemble a transitional form between the two. Of the fourteen aromatic amino acids in the catalytic gorge of vertebrate AChE, ten are conserved in the atypical BChE of O. latipes; by contrast, only eight are conserved in vertebrate BChE. Notably, the atypical BChE has one phenylalanine in its acyl pocket, while AChE has two and BChE none. These substitutions could account for the intermediate nature of this atypical BChE. Molecular modeling supports this proposal. The atypical BChE hydrolyzes acetylthiocholine (ATCh and propionylthiocholine (PTCh preferentially but butyrylthiocholine (BTCh to a considerable extent, which is different from the substrate specificity of AChE or BChE. The enzyme shows substrate inhibition with the two smaller substrates but not with the larger substrate BTCh. In comparison, AChE exhibits substrate inhibition, while BChE does not, but may instead show substrate activation. The atypical BChE from O. latipes also shows a mixed pattern of inhibition. It is effectively inhibited by physostigmine, typical of all ChEs. However, although the atypical BChE is efficiently inhibited by the BChE-specific inhibitor ethopropazine, it is not by another BChE inhibitor, iso-OMPA, nor by the AChE-specific inhibitor BW284c51. The atypical BChE is found as a glycophosphatidylinositol-anchored (GPI-anchored amphiphilic dimer (G(2 (a, which is unusual for any BChE. We classify the enzyme as an atypical BChE and discuss its implications for the evolution of ACh

  16. Weight change after an atypical antipsychotic switch.

    Science.gov (United States)

    Ried, L Douglas; Renner, Bernard T; Bengtson, Michael A; Wilcox, Brian M; Acholonu, Wilfred W

    2003-10-01

    Atypical antipsychotics successfully treat schizophrenia and other conditions, with a lower incidence of extrapyramidal side effects than other agents used in treatment of these disorders. However, some atypical antipsychotics are associated with weight gain. To quantify the impact on weight and identify atypical antipsychotics causing the least amount of weight gain among patients switched from risperidone to olanzapine and olanzapine to risperidone. Patients included in the study (n = 86) were > or =18 years and had received > or =2 prescriptions for risperidone or olanzapine for > or =60 days, switched to the other atypical antipsychotic, and were dispensed > or =2 prescriptions for at least 60 days after the index date. Age, weight, and body mass index (BMI) were retrospectively abstracted from automated databases containing patient-specific prescription and vital sign information. At the time of their switch, the average patient age was 53.2 years (range 25-83). The average weight change in patients switched to olanzapine (n = 47) was +2.3 kg (p = 0.01) and the BMI change was +0.8 kg/m(2) (p = 0.02). The average percent body weight change was +2.8% and the BMI change was +3.0%. The average weight change after patients switched to risperidone (n = 39) was -0.45 kg (p = 0.69) and BMI change was -0.2 kg/m2 (p = 0.64). The average percentage weight change was -0.4% and BMI change was -0.5%. Practitioners' concern regarding weight changes after switching atypical antipsychotics seems warranted and patients should be provided consistent, ongoing weight monitoring. Further investigations should examine whether weight changes associated with atypical antipsychotic treatment further jeopardize this already at-risk population for severe comorbid conditions such as hypertension, coronary artery disease, and type 2 diabetes.

  17. Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment.

    Science.gov (United States)

    Klein, Christian L; Rovelli, Giorgio; Springer, Wolfdieter; Schall, Christoph; Gasser, Thomas; Kahle, Philipp J

    2009-11-01

    Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal-dominant familial and late-onset sporadic Parkinson's disease (PD). LRRK2 is a large multi-domain protein featuring a GTP-binding C-terminal of Ras of complex proteins (ROC) (ROCO) domain combination unique for the ROCO protein family, directly followed by a kinase domain. Dimerization is a well-established phenomenon among protein kinases. Here, we confirm LRRK2 self-interaction, and provide evidence for general homo- and heterodimerization potential among the ROCO kinase family (LRRK2, LRRK1, and death-associated protein kinase 1). The ROCO domain was critically, though not exclusively involved in dimerization, as a LRRK2 deletion mutant lacking the ROCO domain retained dimeric properties. GTP binding did not appear to influence ROCO(LRRK2) self-interaction. Interestingly, ROCO(LRRK2) fragments exerted an inhibitory effect on both wild-type and the elevated G2019S LRRK2 autophosphorylation activity. Insertion of PD mutations into ROCO(LRRK2) reduced self-interaction and led to a reduction of LRRK2 kinase inhibition. Collectively, these results suggest a functional link between ROCO interactions and kinase activity of wild-type and mutant LRRK2. Importantly, our finding of ROCO(LRRK2) fragment-mediated LRRK2 kinase inhibition offers a novel lead for drug design and thus might have important implications for new therapeutic avenues in PD.

  18. Atypical radiological findings in cerebral hydatid disease.

    Science.gov (United States)

    Benzagmout, Mohammed; Maaroufi, Mustapha; Chakour, Khalid; Chaoui, Mohammed E

    2011-07-01

    Cerebral hydatid disease is very rare, representing only 2% of all cerebral space occupying lesions. The diagnosis is usually based on a pathognomonic CT pattern. Exceptionally, the image is atypical raising suspicion of many differential diagnoses such as intracerebral infectious, vascular lesions, or tumors. We report 2 atypical cases of cerebral hydatid cysts diagnosed in a 21, and a 24-year-old woman. The CT scan results suggest oligodendroglioma in the first case and brain abscess in the second. An MRI was helpful in the diagnosis of the 2 cases. Both patients underwent successful surgery with a good outcome. The hydatid nature of the cyst was confirmed by histology in both cases.

  19. Pediatric Melanoma and Atypical Melanocytic Neoplasms.

    Science.gov (United States)

    Sreeraman Kumar, Radhika; Messina, Jane L; Reed, Damon; Navid, Fariba; Sondak, Vernon K

    2016-01-01

    Melanoma is uncommon in the pediatric age range, but is increasing in frequency and often presents with atypical features compared to the classic ABCDE criteria common to adult melanoma cases. Moreover, many melanocytic neoplasms in childhood pose diagnostic challenges to the pathologist, and sometimes cannot be unequivocally classified as benign nevi or melanoma. This chapter addresses the evaluation and management of pediatric patients with melanoma and atypical melanocytic neoplasms, including the roles of and unresolved questions surrounding sentinel lymph node biopsy, completion lymphadenectomy, adjuvant therapy, and treatment of advanced disease.

  20. Primary lateral sclerosis mimicking atypical parkinsonism

    DEFF Research Database (Denmark)

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

    2007-01-01

    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...... 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...

  1. 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...

  2. A misdiagnosed myasthenia gravis with anti-muscle-specific tyrosine kinase antibodies with possible childhood onset

    Directory of Open Access Journals (Sweden)

    Nikolić Ana V.

    2015-01-01

    Full Text Available Introduction. Childhood onset myasthenia gravis associated with anti-muscle-specific tyrosine kinase antibodies is very rare and atypical in presentation. Case report. As a baby, the pre-sented patient was choking and sleeping with open eyes. She had weak cry and breathing difficulties. In childhood, there were frequent falls and fluctuating swallowing difficulties. At the age of 19 she was misdiagnosed with Miller Fisher syndrome due to the presence of diplopia, ataxia and hyporeflexia with spontaneous recovery. Repetitive nerve stimulation test was normal. Four years later, after several relapses, there was significant decrement on facial muscles. Neostigmine test was negative, provoking muscle fasciculations. Serum anti-muscle-specific tyrosine kinase antibodies were positive. With cyclosporine therapy she achieved the minimal manifestations status. Conclusion. The presented case confirms that childhood onset myasthenia gravis associated with anti-muscle-specific tyrosine kinase antibodies is often with atypical presentation and spontaneous remissions, so it could be easily misdiagnosed.

  3. Nima- and Aurora-related kinases of malaria parasites.

    Science.gov (United States)

    Carvalho, Teresa Gil; Doerig, Christian; Reininger, Luc

    2013-07-01

    Completion of the life cycle of malaria parasite requires a succession of developmental stages which vary greatly with respect to proliferation status, implying a tightly regulated control of the parasite's cell cycle, which remains to be understood at the molecular level. Progression of the eukaryotic cell cycle is controlled by members of mitotic kinase of the families CDK (cyclin-dependent kinases), Aurora, Polo and NIMA. Plasmodium parasites possess cyclin-dependent protein kinases and cyclins, which strongly suggests that some of the principles underlying cell cycle control in higher eukaryotes also operate in this organism. However, atypical features of Plasmodium cell cycle organization and important divergences in the composition of the cell cycle machinery suggest the existence of regulatory mechanisms that are at variance with those of higher eukaryotes. This review focuses on several recently described Plasmodium protein kinases related to the NIMA and Aurora kinase families and discusses their functional involvement in parasite's biology. Given their demonstrated essential roles in the erythrocytic asexual cycle and/or sexual stages, these enzymes represent novel potential drug targets for antimalarial intervention aiming at inhibiting parasite replication and/or blocking transmission of the disease. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012). Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Disentangling the Emerging Evidence around Atypical Fractures

    DEFF Research Database (Denmark)

    Abrahamsen, Bo; Clark, Emma M

    2012-01-01

    Atypical femur fractures are rare but a growing concern, as they are more common in patients who use bisphosphonates. The best radiology-based studies have had access to only short-term exposure data, while the studies using prescription databases with substantial long-term data did not have access...

  5. Atypical Alpha Asymmetry in Adults with ADHD

    Science.gov (United States)

    Hale, T. Sigi; Smalley, Susan L.; Hanada, Grant; Macion, James; McCracken, James T.; McGough, James J.; Loo, Sandra K.

    2009-01-01

    Introduction: A growing body of literature suggests atypical cerebral asymmetry and interhemispheric interaction in ADHD. A common means of assessing lateralized brain function in clinical populations has been to examine the relative proportion of EEG alpha activity (8-12 Hz) in each hemisphere (i.e., alpha asymmetry). Increased rightward alpha…

  6. 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.

  7. Atypical Neural Self-Representation in Autism

    Science.gov (United States)

    Lombardo, Michael V.; Chakrabarti, Bhismadev; Bullmore, Edward T.; Sadek, Susan A.; Pasco, Greg; Wheelwright, Sally J.; Suckling, John; Baron-Cohen, Simon

    2010-01-01

    The "self" is a complex multidimensional construct deeply embedded and in many ways defined by our relations with the social world. Individuals with autism are impaired in both self-referential and other-referential social cognitive processing. Atypical neural representation of the self may be a key to understanding the nature of such impairments.…

  8. 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.

  9. 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.

  10. Atypical visuomotor performance in children with PDD

    NARCIS (Netherlands)

    Schlooz, W.A.J.M.; Hulstijn, W.

    2012-01-01

    Children with autism spectrum disorders (ASD) frequently encounter difficulties in visuomotor tasks, which are possibly caused by atypical visuoperceptual processing. This was tested in children (aged 9–12 years) with pervasive developmental disorder (PDD; including PDD-NOS and Asperger syndrome),

  11. Lymph node dissection in atypical endometrial hyperplasia.

    Science.gov (United States)

    Taşkın, Salih; Kan, Özgür; Dai, Ömer; Taşkın, Elif A; Koyuncu, Kazibe; Alkılıç, Ayşegül; Güngör, Mete; Ortaç, Fırat

    2017-09-01

    The rate of concomitant endometrial carcinoma in patients with atypical endometrial hyperplasia is high. We aimed to investigate the role of lymphadenectomy in deciding adjuvant treatment in patients with concomitant atypical endometrial hyperplasia and endometrial carcinoma. Women with atypical endometrial hyperplasia were enrolled in this retrospective study. Lymph node dissection was performed in only some patients who gave informed consent if their surgeon elected to do so, or if the intraoperative findings necessitated. The final histopathologic evaluations of surgical specimens were compared with endometrial biopsy results. Eighty eligible patients were evaluated. Seventy-two (90%) patients had complex hyperplasia with atypia, and 8 (10%) patients had simple hyperplasia with atypia. Hysterectomy and bilateral salpingo-oophorectomy were performed to all patients; 37 also underwent lymph node dissection. Lymph node dissection was extended to the paraaortic region in 9 of 37 patients. The concomitant endometrial carcinoma rate was 50%. Two patients had lymph node metastasis. Among 40 cases of carcinoma, 17 had deep myometrial invasion and/or cervical or ovarian involvement or grade 2 tumors with superficial myometrial invasion on hysterectomy specimens; 27.5% of all carcinomas were stage Ib or higher. The concomitant endometrial carcinoma rate was high in patients with atypical endometrial hyperplasia. Nearly half of these patients had risk factors for extrauterine spread. Lymph node dissection might be helpful to decide adjuvant treatment.

  12. 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.

  13. Th,e Diagnosis of Atypical Varicella*

    African Journals Online (AJOL)

    tion from generalized herpes simplex or variola virus infections. Atypical varicella may show widespread bullous or haemorrhagic cutaneous lesions and visceral involvement may occur with lesions in practically every tissue of the body. A feature of varicella is the affinity for epithelial tissues and the early involvement of the ...

  14. Infant Perception of Atypical Speech Signals

    Science.gov (United States)

    Vouloumanos, Athena; Gelfand, Hanna M.

    2013-01-01

    The ability to decode atypical and degraded speech signals as intelligible is a hallmark of speech perception. Human adults can perceive sounds as speech even when they are generated by a variety of nonhuman sources including computers and parrots. We examined how infants perceive the speech-like vocalizations of a parrot. Further, we examined how…

  15. latrogenic Pulpal Injury Masquerading as Atypical Odontalgia

    OpenAIRE

    Praveena Tantradi

    2011-01-01

    Several pain conditions may mimic atypical odontalgia (AO). Diagnosis of AO is made by ruling out other pain conditions. It is said that the most difficult diagnoses to rule out are pulpal pain condition. This report presents a case of iatrogenic pulpal injury mimicking AO.

  16. latrogenic Pulpal Injury Masquerading as Atypical Odontalgia

    Directory of Open Access Journals (Sweden)

    Praveena Tantradi

    2011-01-01

    Full Text Available Several pain conditions may mimic atypical odontalgia (AO. Diagnosis of AO is made by ruling out other pain conditions. It is said that the most difficult diagnoses to rule out are pulpal pain condition. This report presents a case of iatrogenic pulpal injury mimicking AO.

  17. 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

  18. 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

  19. Prevalence and correlates of atypical patterns of drug use progression

    African Journals Online (AJOL)

    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 ...

  20. A kinome wide screen identifies novel kinases involved in regulation of monoamine transporter function

    DEFF Research Database (Denmark)

    Vuorenpää, Anne Elina; Ammendrup-Johnsen, Ina; Jorgensen, Trine N.

    2016-01-01

    in regulation of monoamine transporter function and surface expression. A primary screen in HEK 293 cells stably expressing DAT or SERT with siRNAs against 573 human kinases revealed 93 kinases putatively regulating transporter function. All 93 hits, which also included kinases previously implicated...... in monoamine transporter regulation, such as Protein kinase B (Akt) and mitogen-activated protein kinases (MAPK), were validated with a new set of siRNAs in a secondary screen. In this screen we assessed both changes in uptake and surface expression leading to selection of 11 kinases for further evaluation...

  1. 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.

  2. Atypical face gaze in autism.

    Science.gov (United States)

    Trepagnier, Cheryl; Sebrechts, Marc M; Peterson, Rebecca

    2002-06-01

    An eye-tracking study of face and object recognition was conducted to clarify the character of face gaze in autistic spectrum disorders. Experimental participants were a group of individuals diagnosed with Asperger's disorder or high-functioning autistic disorder according to their medical records and confirmed by the Autism Diagnostic Interview-Revised (ADI-R). Controls were selected on the basis of age, gender, and educational level to be comparable to the experimental group. In order to maintain attentional focus, stereoscopic images were presented in a virtual reality (VR) headset in which the eye-tracking system was installed. Preliminary analyses show impairment in face recognition, in contrast with equivalent and even superior performance in object recognition among participants with autism-related diagnoses, relative to controls. Experimental participants displayed less fixation on the central face than did control-group participants. The findings, within the limitations of the small number of subjects and technical difficulties encountered in utilizing the helmet-mounted display, suggest an impairment in face processing on the part of the individuals in the experimental group. This is consistent with the hypothesis of disruption in the first months of life, a period that may be critical to typical social and cognitive development, and has important implications for selection of appropriate targets of intervention.

  3. Relationship between atypical depression and social anxiety disorder.

    Science.gov (United States)

    Koyuncu, Ahmet; Ertekin, Erhan; Ertekin, Banu Aslantaş; Binbay, Zerrin; Yüksel, Cağrı; Deveci, Erdem; Tükel, Raşit

    2015-01-30

    In this study, we aimed to investigate the effects of atypical and non-atypical depression comorbidity on the clinical characteristics and course of social anxiety disorder (SAD). A total of 247 patients with SAD were enrolled: 145 patients with a current depressive episode (unipolar or bipolar) with atypical features, 43 patients with a current depressive episode with non-atypical features and 25 patients without a lifetime history of depressive episodes were compared regarding sociodemographic and clinical features, comorbidity rates, and severity of SAD, depression and functional impairment. Thirty four patients with a past but not current history of major depressive episodes were excluded from the comparisons. 77.1% of current depressive episodes were associated with atypical features. Age at onset of SAD and age at initial major depressive episode were lower in the group with atypical depression than in the group with non-atypical depression. History of suicide attempts and bipolar disorder comorbidity was more common in the atypical depression group as well. Atypical depression group has higher SAD and depression severity and lower functionality than group with non-atypical depression. Our results indicate that the presence of atypical depression is associated with more severe symptoms and more impairment in functioning in patients with SAD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. 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)....

  5. 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.)

  6. Typical and Atypical Manifestations of Intrathoracic Sarcoidosis

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hyun Jin; Jung, Jung Im; Chung, Myung Hee; Song, Sun Wha; Kim, Hyo Lim; Baik, Jun Hyun; Han, Dae Hee [St. Vincent' s Hospital, The Catholic University of Korea, Suwon (Korea, Republic of); Kim, Ki Jun [Incheon St. Mary' s Hospital, The Catholic University of Korea, Incheon (Korea, Republic of); Lee, Kyo Young [Seoul St. Mary' s Hospital, The Catholic University of Korea, Seoul (Korea, Republic of)

    2009-12-15

    Sarcoidosis is a systemic disorder of unknown cause that is characterized by the presence of noncaseating granulomas. The radiological findings associated with sarcoidosis have been well described. The findings include symmetric, bilateral hilar and paratracheal lymphadenopathy, with or without concomitant parenchymal abnormalities (multiple small nodules in a peribronchovascular distribution along with irregular thickening of the interstitium). However, in 25% to 30% of cases, the radiological findings are atypical and unfamiliar to most radiologists, which cause difficulty for making a correct diagnosis. Many atypical forms of intrathoracic sarcoidosis have been described sporadically. We have collected cases with unusual radiological findings associated with pulmonary sarcoidosis (unilateral or asymmetric lymphadenopathy, necrosis or cavitation, large opacity, ground glass opacity, an airway abnormality and pleural involvement) and describe the typical forms of the disorder as well. The understanding of a wide range of the radiological manifestations of sarcoidosis will be very helpful for making a proper diagnosis.

  7. 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.

  8. 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.)

  9. Congenital left atrial appendage aneurysm: Atypical presentation

    Directory of Open Access Journals (Sweden)

    Mehdi Bamous

    2017-01-01

    Full Text Available Congenital left atrial appendage aneurysm is a rare condition caused by dysplasia of the atrial muscles. We report a case of a 14-year-old boy, with a 5-month history of cough and in sinus rhythm. Transthoracic echocardiography and computerized tomographic angiography confirmed the aneurysm of the left atrial appendage which was resected through median sternotomy on cardiopulmonary bypass. This case is presented not only for its rarity but also for its atypical clinical presentation.

  10. Recurrent atypical fibroxanthoma of the cheek.

    Science.gov (United States)

    Skoulas, I G; Price, M; Andrew, J E; Kountakis, S E

    2001-01-01

    We report a case of recurrent atypical fibroxanthoma (AFX) of the preauricular area that recurred after Mohs micrographic surgery. AFX is a benign cutaneous fibrohistiocytic tumor that is most commonly found in elderly patients. Although these tumors are benign, they may mimic spindle cell carcinoma, squamous cell carcinoma, and melanoma on histologic examination. AFX tumors rarely recur or metastasize. Wide excision is recommended for the achievement of the best results.

  11. 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.

  12. An atypical case of segmental spinal dysgenesis

    Energy Technology Data Exchange (ETDEWEB)

    Zana, Elodie; Chalard, Francois; Sebag, Guy [Hopital Robert Debre, Department of Paediatric Imaging, Paris (France); Mazda, Keyvan [Hopital Robert Debre, Department of Paediatric Orthopaedic Surgery, Paris (France)

    2005-09-01

    Spinal segmental dysgenesis is a complex closed dysraphism. The diagnostic criteria are: lumbar or thoracolumbar vertebral dysgenesis causing kyphosis, focal spinal cord narrowing without exiting roots, deformity of the lower limbs and paraplegia or paraparesis. We present a newborn who showed atypical features of bifocal spinal cord narrowing, without any vertebral abnormality at the proximal level. This seems to be a variant of this rare entity, whose early diagnosis is important, as surgical stabilisation of the spine is required. (orig.)

  13. Atypical human infections by animal trypanosomes.

    Directory of Open Access Journals (Sweden)

    Philippe Truc

    Full Text Available The two classical forms of human trypanosomoses are sleeping sickness due to Trypanosoma brucei gambiense or T. brucei rhodesiense, and Chagas disease due to T. cruzi. However, a number of atypical human infections caused by other T. species (or sub-species have been reported, namely due to T. brucei brucei, T. vivax, T. congolense, T. evansi, T. lewisi, and T. lewisi-like. These cases are reviewed here. Some infections were transient in nature, while others required treatments that were successful in most cases, although two cases were fatal. A recent case of infection due to T. evansi was related to a lack of apolipoprotein L-I, but T. lewisi infections were not related to immunosuppression or specific human genetic profiles. Out of 19 patients, eight were confirmed between 1974 and 2010, thanks to improved molecular techniques. However, the number of cases of atypical human trypanosomoses might be underestimated. Thus, improvement, evaluation of new diagnostic tests, and field investigations are required for detection and confirmation of these atypical cases.

  14. Atypical pharmacologies at β-adrenoceptors

    Science.gov (United States)

    Summers, R J

    2008-01-01

    β-Adrenoceptors are one of the most widely studied groups of G-protein-coupled receptors but continue to provide surprises and insights that have general relevance to pharmacology. Atypical pharmacologies have been described for ligands formerly (and still) described as antagonists acting at β1-, β2- and β3-adrenoceptors that involve ligand-directed signalling and possibly allosteric interactions at the receptors. In the article by Ngala et al., in this issue of the Br J Pharmacol, another example of atypical interactions with β-adrenoceptors is described, this time for agonists. Some of the responses to BRL37344 and clenbuterol can be explained in terms of actions at β2-adrenoceptors, whereas others such as the increased glucose uptake and palmitate oxidation observed with pM concentrations of BRL37344 may involve interactions with other (possibly allosteric) sites. Atypical pharmacologies of ligands acting at β-adrenoceptors have already indicated new ways in which ligands can interact with G-protein-coupled receptors and these mechanisms are likely to have important consequences for future drug development. PMID:18641673

  15. Atypical caudate anatomy in children who stutter.

    Science.gov (United States)

    Foundas, Anne L; Mock, Jeffrey R; Cindass, Renford; Corey, Dave M

    2013-04-01

    A temporal motor defect in speech preparation and/or planning may contribute to the development of stuttering. This defect may be linked to a dysfunctional cortical-subcortical network at the level of the striatum. To determine whether structural differences exist and whether group differences are associated with stuttering severity or manual laterality, the caudate was measured in 14 children who stutter (CWS) and in a control group of right-handed boys, ages 8-13 years. There was a statistically significant hemisphere by group effect for caudate volume. CWS had reduced right caudate volume and atypical leftward asymmetry compared to controls. Nine of the 13 CWS with atypical caudate asymmetry had atypical manual laterality. These anomalies may represent a vulnerability that perturbs speech planning/preparation and contributes to inefficiencies in action-perception coupling that may be an indicator of stuttering susceptibility. These results suggest that right-handed boys who stutter may have a defect in the feedforward cortico-striato-thalamo-cortical networks.

  16. Transpupillary thermotherapy for atypical central serous chorioretinopathy

    Directory of Open Access Journals (Sweden)

    Kawamura R

    2012-01-01

    Full Text Available Ryosuke Kawamura1,2, Hidenao Ideta1, Hideyuki Hori1, Kenya Yuki2, Tsuyoshi Uno1, Tatsurou Tanabe1, Kazuo Tsubota2, Tsutomu Kawasaki11Ideta Eye Hospital, Kumamoto, Japan; 2Keio University, School of Medicine, Department of Ophthalmology, Tokyo, JapanBackground: Central serous chorioretinopathy (CSC has been traditionally treated with laser photocoagulation. We thought that transpupillary thermotherapy (TTT utilizing a lower temperature than that of conventional laser photocoagulation might minimize permanent retinal and choroidal damage. Studies suggest that undesirable effects on vision due to TTT are minimal even if it is applied to foveal and/or parafoveal lesions when TTT requires a larger irradiation spot. The aim of this study was to evaluate the efficacy of TTT in the management of atypical CSC.Methods: We defined atypical CSC as bullous retinal detachment with diffuse or several leakages, severe leakage with fibrin formation under serous retinal detachment, or leakage within a pigment epithelium detachment. Eight consecutive patients with atypical CSC underwent visual acuity testing, ophthalmic examination, color photography, fluorescein angiography, and optical coherence tomography to evaluate the results of transpupillary thermotherapy. Retreatment of atypical CSC was based on ophthalmic examination, optical coherence tomography, and fluorescein angiography. TTT was performed on the leaking spots shown in fluorescein angiography, with a power of 50–250 mW, spot size of 500–1200 µm, and exposure time of 13–60 seconds to minimize retinal damage.Results: In five of eight affected eyes, serous detachments completely resolved within 1 month after the initial TTT. One eye had persistent subretinal fluid and required a second TTT treatment. Two eyes showed no resolution of CSC and were treated by conventional photocoagulation. Initial best-corrected visual acuity (BCVA ranged from 20/600 to 20/20 (mean, 20/40; median, 20/30. Final BCVA

  17. Oncogenic mutations of ALK kinase in neuroblastoma.

    Science.gov (United States)

    Chen, Yuyan; Takita, Junko; Choi, Young Lim; Kato, Motohiro; Ohira, Miki; Sanada, Masashi; Wang, Lili; Soda, Manabu; Kikuchi, Akira; Igarashi, Takashi; Nakagawara, Akira; Hayashi, Yasuhide; Mano, Hiroyuki; Ogawa, Seishi

    2008-10-16

    Neuroblastoma in advanced stages is one of the most intractable paediatric cancers, even with recent therapeutic advances. Neuroblastoma harbours a variety of genetic changes, including a high frequency of MYCN amplification, loss of heterozygosity at 1p36 and 11q, and gain of genetic material from 17q, all of which have been implicated in the pathogenesis of neuroblastoma. However, the scarcity of reliable molecular targets has hampered the development of effective therapeutic agents targeting neuroblastoma. Here we show that the anaplastic lymphoma kinase (ALK), originally identified as a fusion kinase in a subtype of non-Hodgkin's lymphoma (NPM-ALK) and more recently in adenocarcinoma of lung (EML4-ALK), is also a frequent target of genetic alteration in advanced neuroblastoma. According to our genome-wide scans of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, the ALK locus, centromeric to the MYCN locus, was identified as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed eight novel missense mutations in 13 out of 215 (6.1%) fresh tumours and 8 out of 24 (33%) neuroblastoma-derived cell lines. All but one mutation in the primary samples (12 out of 13) were found in stages 3-4 of the disease and were harboured in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wild-type kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumours in nude mice. Furthermore, we demonstrate that downregulation of ALK through RNA interference suppresses proliferation of neuroblastoma cells harbouring mutated ALK. We anticipate that our findings will provide new insights into the pathogenesis of advanced neuroblastoma and that ALK-specific kinase inhibitors might improve its clinical outcome.

  18. SRC kinase regulation in progressively invasive cancer.

    Directory of Open Access Journals (Sweden)

    Weichen Xu

    Full Text Available Metastatic progression is a multistep process that involves tumor growth and survival, motility and invasion, and subsequent proliferation in an inappropriate environment. The Src protein tyrosine kinase has been implicated in many of the biochemical pathways that drive these behaviors. Although Src itself is only rarely mutated in human tumors, its aberrant activity has been noted in various cancers and suggested to serve as a barometer of metastatic potential. With these features in mind, we examined Src kinase regulation at the structural, enzymatic, and expression levels as a function of progressively invasive prostate cancer cell lines. Surprisingly, both total Src content and kinase activity decrease with increasing cell line aggressiveness, an observation that appears to be inconsistent with the well-documented role of Src in the signaling pathways that drive growth and invasion. However, we do observe a direct correlation between Src kinase specific activity (total Src kinase activity/total Src content and metastatic aggressiveness, possibly suggesting that in highly aggressive cell lines, key signaling enzymes are globally recruited to drive the cancerous phenotype. In addition, although the expected enhanced phosphorylation of Src at Tyr-416 (activation site is present in the most aggressive prostate cancer cell lines, unexpectedly high phosphorylation levels at the Tyr-527 inhibitory site are observed as well. The latter, rather than representative of inhibited enzyme, is more indicative of primed Src responsive to local phosphorylated binding partners.

  19. Therapeutic Innovations: Tyrosine Kinase Inhibitors in Cancer

    Directory of Open Access Journals (Sweden)

    Nikolaos Dervisis

    2016-01-01

    Full Text Available Conventional cytotoxic chemotherapy involving DNA-interacting agents and indiscriminate cell death is no longer the future of cancer management. While chemotherapy is not likely to completely disappear from the armamentarium; the use of targeted therapies in combination with conventional treatment is becoming the standard of care in human medicine. Tyrosine kinases are pivotal points of functional cellular pathways and have been implicated in malignancy, inflammatory, and immune-mediated diseases. Pharmaceutical interventions targeting aberrant tyrosine kinase signaling has exploded and is the second most important area of drug development. The “Valley of Death” between drug discovery and approval threatens to blunt the enormous strides in cancer management seen thus far. Kinase inhibitors, as targeted small molecules, hold promise in the treatment and diagnosis of cancer. However, there are still many unanswered questions regarding the use of kinase inhibitors in the interpretation and management of cancer. Comparative oncology has the potential to address restrictions and limitations in the advancement in kinase inhibitor therapy.

  20. Atypical depression and non-atypical depression: Is HPA axis function a biomarker? A systematic review.

    Science.gov (United States)

    Juruena, Mario F; Bocharova, Mariia; Agustini, Bruno; Young, Allan H

    2017-10-06

    The link between the abnormalities of the Hypothalamic-pituitary-adrenal (HPA) axis and depression has been one of the most consistently reported findings in psychiatry. At the same time, multiple studies have demonstrated a stronger association between the increased activation of HPA-axis and melancholic, or endogenous depression subtype. This association has not been confirmed for the atypical subtype, and some researchers have suggested that as an antinomic depressive subtype, it may be associated with the opposite type, i.e. hypo-function, of the HPA-axis, similarly to PTSD. The purpose of this systematic review is to summarise existing studies addressing the abnormalities of the HPA-axis in melancholic and/or atypical depression. We conducted a systematic review in the literature by searching MEDLINE, PsycINFO, OvidSP and Embase databases until June 2017. The following search items were used: "hypothalamic-pituitary-adrenal" OR "HPA" OR "cortisol" OR "corticotropin releasing hormone" OR "corticotropin releasing factor" OR "glucocorticoid*" OR "adrenocorticotropic hormone" OR "ACTH" AND "atypical depression" OR "non-atypical depression" OR "melancholic depression" OR "non-melancholic depression" OR "endogenous depression" OR "endogenomorphic depression" OR "non-endogenous depression". Search limits were set to include papers in English or German language published in peer-reviewed journals at any period. All studies were scrutinized to determine the main methodological characteristics, and particularly possible sources of bias influencing the results reported. We selected 48 relevant studies. Detailed analysis of the methodologies used in the studies revealed significant variability especially regarding the samples' definition comparing the HPA axis activity of melancholic patients to atypical depression, including healthy controls. The results were subdivided into 4 sections: (1) 27 studies which compared melancholic OR endogenous depression vs. non

  1. 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1

    DEFF Research Database (Denmark)

    Jensen, Claus Antonio Juel; Buch, M B; Krag, T O

    1999-01-01

    90-kDa ribosomal S6 kinase-2 (RSK2) belongs to a family of growth factor-activated serine/threonine kinases composed of two kinase domains connected by a regulatory linker region. The N-terminal kinase of RSK2 is involved in substrate phosphorylation. Its activation requires phosphorylation of th...... of Ser(227), Ser(369), and Ser(386). Our study extend recent findings which implicate PDK1 in the activation of protein kinases B and C and p70(S6K), suggesting that PDK1 controls several major growth factor-activated signal transduction pathways.......90-kDa ribosomal S6 kinase-2 (RSK2) belongs to a family of growth factor-activated serine/threonine kinases composed of two kinase domains connected by a regulatory linker region. The N-terminal kinase of RSK2 is involved in substrate phosphorylation. Its activation requires phosphorylation...... involvement of ERK, leading to partial activation of RSK2. Similarly, two other members of the RSK family, RSK1 and RSK3, were partially activated by PDK1 in COS7 cells. Finally, our data indicate that full activation of RSK2 by growth factor requires the cooperation of ERK and PDK1 through phosphorylation...

  2. Studying Kinetochore Kinases

    NARCIS (Netherlands)

    Saurin, Adrian T; Kops, Geert J P L

    2016-01-01

    Mitotic kinetochores are signaling network hubs that regulate chromosome movements, attachment error-correction, and the spindle assembly checkpoint. Key switches in these networks are kinases and phosphatases that enable rapid responses to changing conditions. Describing the mechanisms and dynamics

  3. 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 ...

  4. Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance.

    Science.gov (United States)

    Nandipati, Kalyana C; Subramanian, Saravanan; Agrawal, Devendra K

    2017-02-01

    Obesity-induced low-grade inflammation (metaflammation) impairs insulin receptor signaling. This has been implicated in the development of insulin resistance. Insulin signaling in the target tissues is mediated by stress kinases such as p38 mitogen-activated protein kinase, c-Jun NH2-terminal kinase, inhibitor of NF-kB kinase complex β (IKKβ), AMP-activated protein kinase, protein kinase C, Rho-associated coiled-coil containing protein kinase, and RNA-activated protein kinase. Most of these kinases phosphorylate several key regulators in glucose homeostasis. The phosphorylation of serine residues in the insulin receptor and IRS-1 molecule results in diminished enzymatic activity in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. This has been one of the key mechanisms observed in the tissues that are implicated in insulin resistance especially in type 2 diabetes mellitus (T2-DM). Identifying the specific protein kinases involved in obesity-induced chronic inflammation may help in developing the targeted drug therapies to minimize the insulin resistance. This review is focused on the protein kinases involved in the inflammatory cascade and molecular mechanisms and their downstream targets with special reference to obesity-induced T2-DM.

  5. Intracranial Tuberculoma Presenting as Atypical Eclampsia: A Case Report

    OpenAIRE

    Arumugam, Sendhil Coumary; Murugesan, Sharmila; Pradeep, Sunitha; John, Lopamudra; Kolluru, Vasavi

    2016-01-01

    Occurrence of eclampsia before 20 weeks of pregnancy and after 48 hours of delivery in the absence of typical signs of hypertension and or proteinuria is termed as atypical eclampsia. Atypical or non-classic eclampsia will have some symptoms of eclampsia but without the usual proteinuria or hypertension. All patients with atypical onset should undergo neurological evaluation to rule out neurologic causes of seizures. Cerebral tuberculosis is a rare and serious form of disease secondary to hae...

  6. Atypical meningioma and extensive calvarium defects in neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Simsek, Enver [Department of Paediatrics, Duzce Medical Faculty, Abant Izzet Baysal University, Konuralp-Duzce (Turkey); Yavuz, Cevdet [Department of Neurosurgery, Duzce Medical Faculty, Abant Izzet Baysal University, Konuralp-Duzce (Turkey); Ustundag, Nil [Department of Pathology, Abant Izzet Baysal University School of Medicine, Konuralp-Duzce (Turkey)

    2003-08-01

    A 9-year-old girl with neurofibromatosis type 1 (NF1) presented with a massive atypical meningioma and calvarial defect. Skull radiographs and cranial CT showed an extensive lytic bone lesion at the vertex. MRI demonstrated a large mass invading the calvarium and sagittal sinus. The histopathological and immunohistochemical diagnosis of the resected mass was atypical meningioma. To our knowledge, this is the first case of NF1 associated with atypical meningioma and massive calvarial defect in a child. (orig.)

  7. Cost-effectiveness of an atypical conventional antipsychotic in South ...

    African Journals Online (AJOL)

    Cost-effectiveness of an atypical conventional antipsychotic in South Africa: An economic evaluation of quetiapine versus haloperidol in the treatment of patients partially responsive to previous antipsychotics.

  8. Atypical teratoid rhabdoid tumor: current therapy and future directions

    Directory of Open Access Journals (Sweden)

    Kevin F. Ginn

    2012-09-01

    Full Text Available 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 three 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 three 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 anectdotal 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.

  9. Viral pneumonias: Typical and atypical findings

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-10-01

    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.

  10. Gorlin’s syndrome: Atypical case report

    Directory of Open Access Journals (Sweden)

    Sanjay N. Agrawal

    2014-10-01

    Full Text Available Gorlin syndrome or basal cell nevus syndrome (BCNS is a rare autosomal dominant disorder. The condition appears to have complete penetrance and variable expressivity, which makes clinilcal presentation among families variable. All known BCNS carry mutations in PATCHED gene. A 65 years old male patient presented with complaints of characteristic skin lesions on his face, back, palms since early adulthood. The lesions were pigmented nodules with characteristic border. The histopathology showed characteristic features suggestive of Basal Cell Carcinoma (BCC. This case was atypical due to appearance of lesions quite later in life.

  11. 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.

  12. Bisphosphonates and Atypical Fractures of Femur

    Directory of Open Access Journals (Sweden)

    Tero Yli-Kyyny

    2011-01-01

    Full Text Available Bisphosphonates are the most widely prescribed medicines for the treatment of osteoporosis and have generally been regarded as well-tolerated and safe drugs. Since 2005, there have been numerous case reports about atypical fractures of the femur linked to long-term treatment of osteoporosis with bisphosphonates. Some attempts to characterize pathophysiology and epidemiology of these fractures have been published as well. However, as the American Society for Bone and Mineral Research (ASBMR concluded in their task force report, the subject warrants further studies.

  13. Atypical calcific tendinitis with cortical erosions

    Energy Technology Data Exchange (ETDEWEB)

    Kraemer, E.J. [College of Medicine, Univ. of Iowa, Iowa City, IA (United States); El-Khoury, G.Y. [Dept. of Radiology and Orthopaedics, Univ. of Iowa, Iowa City, IA (United States)

    2000-12-01

    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.)

  14. Atypical odontalgia--a diagnostic dilemma.

    Science.gov (United States)

    Thorburn, D N; Polonowita, A D

    2012-06-01

    Atypical odontalgia (AO) is a chronic orofacial pain condition of unclear pathophysiology, often presenting as toothache or pain at an extraction site. Idiopathic, psychogenic, vascular, and neuropathic causes have been proposed. In view of demonstrable somatosensory changes, and responses to management proposed for other forms of neuropathic pain, the best current evidence supports a neuropathic hypothesis. It is proposed that certain individuals with as-yet-undefined genetic vulnerability can develop AO when exposed to certain risk factors, including invasive dental treatment. The diagnosis and treatment of AO can be challenging, but can be aided by a multidisciplinary approach. Two cases of differing complexity are presented in this paper.

  15. [Persistent idiopathic facial pain and atypical odontalgia].

    Science.gov (United States)

    Gaul, Charly; Ettlin, Dominik; Pfau, Doreen B

    2013-01-01

    The terms 'persistent idiopathic facial pain' (PIFP) and 'atypical odontalgia' (AO) are currently used as exclusion diagnoses for chronic toothache and chronic facial pain. Knowledge about these pain conditions in medical and dental practices is of crucial importance for the prevention of iatrogenic tissue damage by not-indicated invasive interventions, such as endodontic treatment and tooth extraction. In the present paper, etiology and pathogenesis, differential diagnostic criteria, and diagnostic approaches will be explained and relevant therapeutic principles will be outlined. Copyright © 2013. Published by Elsevier GmbH.

  16. Treatment of atypically-localized cavernous hemangioma in abdomen with atypical pain

    Directory of Open Access Journals (Sweden)

    Mehmet Ilhan

    2016-01-01

    Conclusion: Cavernous hemangiomas of the liver rarely require treatment. Surgery is one of the options in selected cases and abdominal pain is one of the indications. In patients complaining from persistent abdominal pain, if intraabdominal atypical-localized mass was seen in examinations, hemangioma should be remembered in differential diagnosis.

  17. 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.

  18. Arabidopsis mitogen-activated protein kinase kinases MKK1 and MKK2 have overlapping functions in defense signaling mediated by MEKK1, MPK4, and MKS1

    DEFF Research Database (Denmark)

    Qiu, Jin-Long; Zhou, Lu; Yun, Byung-Wook

    2008-01-01

    by biochemical and molecular analyses implicating the kinases in jasmonate- and salicylate-dependent defense responses, mediated in part via the MPK4 substrate MKS1. In addition, transcriptome analyses delineate overlapping and specific effects of the kinases on global gene expression patterns demonstrating both...

  19. Pontine Infarct Presenting with Atypical Dental Pain: A Case Report.

    Science.gov (United States)

    Goel, Rajat; Kumar, Sanjeev; Panwar, Ajay; Singh, Abhishek B

    2015-01-01

    Orofacial pain' most commonly occurs due to dental causes like caries, gingivitis or periodontitis. Other common causes of 'orofacial pain' are sinusitis, temporomandibular joint(TMJ) dysfunction, otitis externa, tension headache and migraine. In some patients, the etiology of 'orofacial pain' remains undetected despite optimal evaluation. A few patients in the practice of clinical dentistry presents with dental pain without any identifiable dental etiology. Such patients are classified under the category of 'atypical odontalgia'. 'Atypical odontalgia' is reported to be prevalent in 2.1% of the individuals. 'Atypical orofacial pain' and 'atypical odontalgia' can result from the neurological diseases like multiple sclerosis, trigeminal neuralgia and herpes infection. Trigeminal neuralgia has been frequently documented as a cause of 'atypical orofacial pain' and 'atypical odontalgia'. There are a few isolated case reports of acute pontine stroke resulting in 'atypical orofacial pain' and 'atypical odontalgia'. However, pontine stroke as a cause of atypical odontalgia is limited to only a few cases, hence prevalence is not established. This case is one, where a patient presented with acute onset atypical dental pain with no identifiable dental etiology, further diagnosed as an acute pontine infarct on neuroimaging. A 40 years old male presented with acute onset, diffuse teeth pain on right side. Dental examination was normal. Magnetic resonance imaging(MRI) of the brain had an acute infarct in right pons near the trigeminal root entry zone(REZ). Pontine infarct presenting with dental pain as a manifestation of trigeminal neuropathy, has rarely been reported previously. This stresses on the importance of neuroradiology in evaluation of atypical cases of dental pain.

  20. 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.

  1. Neuromyelitis optica: atypical clinical and neuroradiological presentation.

    Science.gov (United States)

    Splendiani, Alessandra; Mariani, Silvia; Anselmi, Monica; Catalucci, Alessia; Di Cesare, Ernesto; Gallucci, Massimo

    2015-02-01

    The extreme variability of clinical and MRI findings in the suspicion of Devic's disease always requires the detection of specific antibodies (AQP4). MRI scans were performed with a high-field MRI scanner (1.5T General Electric Signa Horizon): the MRI protocol of the brain employed axial DP, T2, T1, FLAIR and DWI weighted images (wi) and coronal T2-wi. After intravenous administration of contrast medium axial and sagittal T1-weighted images of the brain were repeated. The spine protocol employed after contrast medium included sagittal T2-wi, T2-wi with fat suppression and T1-wi. In May 2004, a 64-year-old healthy Caucasian woman began to suffer loss of motor and thermal sensitivity in the left lower limb. MRI showed non-specific areas of abnormal signal intensity on the deep left frontal and right frontoparietal white matter with no pathological enhancement after contrast medium and a small intramedullary area of altered signal at metameric level C2-C4 with a diagnosis of post-viral transverse myelitis. The patient had two similar episodes years later so the neurologist decided to search for circulating IgG AQP4 with the definitive diagnosis of neuromyelitis optica. In this case, compared to a clinical presentation of atypical deficit neurological involvement, the neuroradiological results of a progressive diffuse involvement of the white matter were atypical. © The Author(s) 2015 Reprints and permissions:sagepub.co.uk/journalsPermissions.nav.

  2. [Treatment with bisphosphonates and atypical fractures].

    Science.gov (United States)

    Spivacow, Francisco R; Sarli, Marcelo; Buttazzoni, Mirena

    2009-01-01

    In the last twenty five years aminobisphosphonates have became the drugs of choice for the treatment of osteoporosis. They strongly inhibit osteoclastic bone resorption and reduce the incidence of new fractures in patients with established osteoporosis, but their long half-life and their chronic effects on bone physiology are a matter of concern. Theoretically a harmful consequence of a prolonged inhibition of bone remodeling could be the microdamage accumulation, and paradoxically the occurrence of new and atypical fractures. Until now, few cases of these unusual fractures have been reported in the international literature. All these patients shared some common characteristics, apart from the chronic use of bisphosphonates for the treatment of osteoporosis. The more frequent is the atypical location of the fractures. Since the majority happened in one or both femoral shafts, others bones such as sacrum, ischium, ribs and pubic rami could be affected. The fractures were atraumatic or caused by minimal trauma and, in some cases, it was preceded by a prodromal pain in the affected area. All cases had biochemical or histomorphometric evidence of low bone turnover. The aim of this paper is to report three new cases of patients that fulfill with the diagnostic criteria of this new entity, two of them with femoral shaft fractures and the remainder with a pelvis one.

  3. [Atypical odontalgia - a little known phantom pain].

    Science.gov (United States)

    Türp, J C

    2001-02-01

    Atypical odontalgia (AO) was described in the dental literature more than 200 years ago, and it is included in most taxonomies and textbooks of pain. Nonetheless, it remains one of the most frequently misdiagnosed intraoral pain conditions. Due to similarities with phantom pain, AO is also referred to as "phantom tooth pain". AO is characterized by persistent throbbing pain in or around a former or present permanent tooth (preferably molars and premolars). Clinical and radiographic examination, however, does not reveal any organic cause of the pain. The complaints associated with AO usually begin after deafferentiation of primary afferent trigeminal nerve fibers, e. g., after pulp extirpation, apicectomy, or extraction of a tooth. AO is a diagnosis by exclusion. Patients and dentists must be aware of the fact that the therapeutic options are limited. AO is primarily managed with topically or systemically administered pharmacological agents. Unnecessary and harmful procedures around teeth and jaws must be avoided by all means. A concept was recently proposed which aims to unify a group of four types of orofacial pain under the term "idiopathic orofacial pain" (Woda & Pionchon 1999, 2000). These pain conditions - AO, atypical facial pain, burning mouth syndrome ("stomatodynia"), and subgroups of temporomandibular disorders ("idiopathic facial arthromyalgia") - are characterized by unknown etiology, but common clinical characteristics. It is to be hoped that the suggested classification will stimulate reflection on these enigmatic orofacial pain disorders.

  4. Application of Kinase Inhibitors for Anti-aging Intervention.

    Science.gov (United States)

    Cano, Mercedes; Ayala, Antonio; Marotta, Francesco; Arguelles, Sandro

    2017-11-16

    Protein phosphorylation, mediated by protein kinases, has important physiological and pathological implications in our lives. Targeting kinase is one of the most interesting of the emerging topics in the pharmaceutical industry, especially since there is a focus on cancer therapy. Given that kinases may be involved in the aging process the focus will be on using the kinase inhibitor for anti-aging intervention to enhance healthspan and increase longevity. In this review, we will summarize: (i) the impact of the phosphoproteomic approach to elucidate molecular mechanisms of diseases; (ii) importance of the drug discovery approach for targeting kinases; (iii) the dysregulation of Janus kinase (JAK) / signal-transducing adapter molecules (STAT) and p70 ribosomal protein S6 kinase (S6Ks) pathway in aging and the age-related process; (iv) the epidemiological studies available in order to see whether a correlation between JAK/STAT and S6Ks mRNA expression levels exist in cancer and in patient outcome; (v) finally, we will show selected inhibitors of these kinases approved by the US Food and Drug Administration (FDA). Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Atypically rightward cerebral asymmetry in male adults with autism stratifies individuals with and without language delay

    Science.gov (United States)

    Lai, Meng‐Chuan; Auer, Tibor; Lombardo, Michael V.; Ecker, Christine; Chakrabarti, Bhismadev; Wheelwright, Sally J.; Bullmore, Edward T.; Murphy, Declan G.M.; Baron‐Cohen, Simon; Suckling, John

    2015-01-01

    Abstract In humans, both language and fine motor skills are associated with left‐hemisphere specialization, whereas visuospatial skills are associated with right‐hemisphere specialization. Individuals with autism spectrum conditions (ASC) show a profile of deficits and strengths that involves these lateralized cognitive functions. Here we test the hypothesis that regions implicated in these functions are atypically rightward lateralized in individuals with ASC and, that such atypicality is associated with functional performance. Participants included 67 male, right‐handed adults with ASC and 69 age‐ and IQ‐matched neurotypical males. We assessed group differences in structural asymmetries in cortical regions of interest with voxel‐based analysis of grey matter volumes, followed by correlational analyses with measures of language, motor and visuospatial skills. We found stronger rightward lateralization within the inferior parietal lobule and reduced leftward lateralization extending along the auditory cortex comprising the planum temporale, Heschl's gyrus, posterior supramarginal gyrus, and parietal operculum, which was more pronounced in ASC individuals with delayed language onset compared to those without. Planned correlational analyses showed that for individuals with ASC, reduced leftward asymmetry in the auditory region was associated with more childhood social reciprocity difficulties. We conclude that atypical cerebral structural asymmetry is a potential candidate neurophenotype of ASC. Hum Brain Mapp 37:230–253, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:26493275

  6. [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.).

  7. Morphological and syntactic skills in language samples of pre school aged children with autism: atypical development?

    Science.gov (United States)

    Park, Carlie J; Yelland, Gregory W; Taffe, John R; Gray, Kylie M

    2012-04-01

    This study investigated whether children with autism have atypical development of morphological and syntactic skills, including whether they use rote learning to compensate for impaired morphological processing and acquire grammatical morphemes in an atypical order. Participants were children aged from 3-6 years who had autism (n = 17), developmental delay without autism (n = 7), and typically-developing children (n = 19). Language samples were taken from participants during the administration of the Autism Diagnostic Observation Schedule, and transcripts were coded using the Index of Productive Syntax, and for usage of Brown's grammatical morphemes. Participants were also administered an elicitation task requiring the application of inflections to non-words; the Wugs Task. The main finding of this study was that children with autism have unevenly developed morphological and syntactic sub-skills; they have skills which are a combination of intact, delayed, and atypical. It was also found that children with autism and children with developmental delays can acquire and use morphological rules. The implications of these findings are that, in order to maximize language acquisition for these children, clinicians need to utilize comprehensive language assessment tools and design interventions that are tailored to the child's strengths and weaknesses.

  8. Atypically rightward cerebral asymmetry in male adults with autism stratifies individuals with and without language delay.

    Science.gov (United States)

    Floris, Dorothea L; Lai, Meng-Chuan; Auer, Tibor; Lombardo, Michael V; Ecker, Christine; Chakrabarti, Bhismadev; Wheelwright, Sally J; Bullmore, Edward T; Murphy, Declan G M; Baron-Cohen, Simon; Suckling, John

    2016-01-01

    In humans, both language and fine motor skills are associated with left-hemisphere specialization, whereas visuospatial skills are associated with right-hemisphere specialization. Individuals with autism spectrum conditions (ASC) show a profile of deficits and strengths that involves these lateralized cognitive functions. Here we test the hypothesis that regions implicated in these functions are atypically rightward lateralized in individuals with ASC and, that such atypicality is associated with functional performance. Participants included 67 male, right-handed adults with ASC and 69 age- and IQ-matched neurotypical males. We assessed group differences in structural asymmetries in cortical regions of interest with voxel-based analysis of grey matter volumes, followed by correlational analyses with measures of language, motor and visuospatial skills. We found stronger rightward lateralization within the inferior parietal lobule and reduced leftward lateralization extending along the auditory cortex comprising the planum temporale, Heschl's gyrus, posterior supramarginal gyrus, and parietal operculum, which was more pronounced in ASC individuals with delayed language onset compared to those without. Planned correlational analyses showed that for individuals with ASC, reduced leftward asymmetry in the auditory region was associated with more childhood social reciprocity difficulties. We conclude that atypical cerebral structural asymmetry is a potential candidate neurophenotype of ASC. © 2015 Wiley Periodicals, Inc.

  9. CASE REPORT CASE Atypical tuberculosis of the knee joint CASE ...

    African Journals Online (AJOL)

    This case report demonstrates the MRI findings of atypical tuberculosis. (TB) of the knee joint, caused by Mycobacterium kansasii. Osteoarticular. TB caused by atypical mycobacteria is rare; instead, it is predomi- nantly a synovial disease affecting the tendon sheaths rather than bone. Predisposing factors are ...

  10. '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 ...

  11. Comparing the side effect profile of the Atypical Antipsychotics | Alao ...

    African Journals Online (AJOL)

    Post clozapine, the Food and Drug Administration (FDA) has approved the use of four newer atypical antipsychotics; risperidone, olanzapine, quetiapine and ziprasidone for the treatment of schizophrenia. Because of their dual serotonin and dopamine receptor blocking abilities, atypical antipsychotics have greater efficacy ...

  12. An atypical presentation of myositis ossificans | Bultheel | South ...

    African Journals Online (AJOL)

    An atypical presentation of myositis ossificans. M Bultheel, JH Kirby, JT Viljoen, PL Viviers. Abstract. In the following case study an atypical presentation of myositis ossificans (MO) in the superior anterolateral thigh of a young soccer player is discussed. This case demonstrates that MO can present without obvious history of ...

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

    African Journals Online (AJOL)

    The two most common organisms were C. pneumoniae (20,7%) and L. pneumophila (8,7%). There. were no differences in the clinical and radiographic features of patients with and without 'atypical' bacteria. Clinicians prescribed erythromycin or tetracyclines with equal frequency in the two groups. Conclusions. 'Atypical' ...

  14. 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

  15. 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.

  16. The effects of tricyclic and 'atypical' antidepressants on spontaneous locomotor activity in rodents.

    Science.gov (United States)

    Tucker, J C; File, S E

    1986-01-01

    With the exception of amineptin, buproprion and nomifensine all tricyclic and 'atypical' antidepressants have been reported to reduce spontaneous motor activity in rodents, after both acute and chronic administration. However, with the diversity of chemical actions of these drugs it is unlikely that a single neurochemical mechanism is underlying this one behavioral effect. These widespread sedative effects have implications for interpreting behavioral changes in other test situations, since sedation generally occurs at doses that fall within the dose-range effective in other tests. We also review the effects on spontaneous motor activity of withdrawal from chronic antidepressant treatment.

  17. [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.

  18. 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...

  19. Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells.

    Science.gov (United States)

    Ashour, Ahmed A; Abdel-Aziz, Abdel-Aziz H; Mansour, Ahmed M; Alpay, S Neslihan; Huo, Longfei; Ozpolat, Bulent

    2014-01-01

    Pancreatic cancer (PaCa) is one of the most aggressive, apoptosis-resistant and currently incurable cancers with a poor survival rate. Eukaryotic elongation factor-2 kinase (eEF-2K) is an atypical kinase, whose role in PaCa survival is not yet known. Here, we show that eEF-2K is overexpressed in PaCa cells and its down-regulation induces apoptotic cell death. Rottlerin (ROT), a polyphenolic compound initially identified as a PKC-δ inhibitor, induces apoptosis and autophagy in a variety of cancer cells including PaCa cells. We demonstrated that ROT induces intrinsic apoptosis, with dissipation of mitochondrial membrane potential (ΔΨm), and stimulates extrinsic apoptosis with concomitant induction of TNF-related apoptosis inducing ligand (TRAIL) receptors, DR4 and DR5, with caspase-8 activation, in PANC-1 and MIAPaCa-2 cells. Notably, while none of these effects were dependent on PKC-δ inhibition, ROT down-regulates eEF-2K at mRNA level, and induce eEF-2K protein degradation through ubiquitin-proteasome pathway. Down-regulation of eEF-2K recapitulates the events observed after ROT treatment, while its over-expression suppressed the ROT-induced apoptosis. Furthermore, eEF-2K regulates the expression of tissue transglutaminase (TG2), an enzyme previously implicated in proliferation, drug resistance and survival of cancer cells. Inhibition of eEF-2K/TG2 axis leads to caspase-independent apoptosis which is associated with induction of apoptosis-inducing factor (AIF). Collectively, these results indicate, for the first time, that the down-regulation of eEF-2K leads to induction of intrinsic, extrinsic as well as AIF-dependent apoptosis in PaCa cells, suggesting that eEF-2K may represent an attractive therapeutic target for the future anticancer agents in PaCa.

  20. G protein-coupled receptor kinases: more than just kinases and not only for GPCRs

    Science.gov (United States)

    Gurevich, Eugenia V.; Tesmer, John J. G.; Mushegian, Arcady; Gurevich, Vsevolod V.

    2011-01-01

    G protein-coupled receptor (GPCR) kinases (GRKs) are best known for their role in homologous desensitization of GPCRs. GRKs phosphorylate activated receptors and promote high affinity binding of arrestins, which precludes G protein coupling. GRKs have a multidomain structure, with the kinase domain inserted into a loop of a regulator of G protein signaling homology domain. Unlike many other kinases, GRKs do not need to be phosphorylated in their activation loop to achieve an activated state. Instead, they are directly activated by docking with active GPCRs. In this manner they are able to selectively phosphorylate Ser/Thr residues on only the activated form of the receptor, unlike related kinases such as protein kinase A. GRKs also phosphorylate a variety of non-GPCR substrates and regulate several signaling pathways via direct interactions with other proteins in a phosphorylation-independent manner. Multiple GRK subtypes are present in virtually every animal cell, with the highest expression levels found in neurons, with their extensive and complex signal regulation. Insufficient or excessive GRK activity was implicated in a variety of human disorders, ranging from heart failure to depression to Parkinson’s disease. As key regulators of GPCR-dependent and -independent signaling pathways, GRKs are emerging drug targets and promising molecular tools for therapy. Targeted modulation of expression and/or of activity of several GRK isoforms for therapeutic purposes was recently validated in cardiac disorders and Parkinson’s disease. PMID:21903131

  1. Imaging the neurobiological substrate of atypical depression by SPECT

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    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.)

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

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    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.

  3. Function of the A-type cyclins during gametogenesis and early embryogenesis.

    Science.gov (United States)

    Wolgemuth, Debra J

    2011-01-01

    The cyclins and their cyclin-dependent kinase partners, the Cdks, are the basic components of the machinery that regulates the passage of cells through the cell cycle. Among the cyclins, those known as the A-type cyclins are unique in that in somatic cells, they appear to function at two stages of the cell cycle, at the G1-S transition and again as the cells prepare to enter M-phase. Higher vertebrate organisms have two A-type cyclins, cyclin A1 and cyclin A2, both of which are expressed in the germ line and/or early embryo, following highly specialized patterns that suggest functions in both mitosis and meiosis. Insight into their in vivo functions has been obtained from gene targeting experiments in the mouse model. Loss of cyclin A1 results in disruption of spermatogenesis and male sterility due to cell arrest in the late diplotene stage of the meiotic cell cycle. In contrast, cyclin A2-deficiency is marked by early embryonic lethality; thus, understanding the function of cyclin A2 in the adult germ line awaits conditional mutagenesis or other approaches to knock down its expression.

  4. 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.

  5. Brugada Syndrome with atypical characteristics: Case report

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    Hatem Ari

    2013-09-01

    Full Text Available The Brugada Syndrome (BrS is a heterogeneous genetic disease characterized by persistent or transient ST-segment elevation in the right precordial electrocardiography (ECG leads and a high incidence of sudden death and life-threatening ventricular tachyarrhythmias in patients with structurally normal hearts. The syndrome generally manifests in men during adulthood. The ECG manifestations can be overt or concealed. We report a case of BrS whose type 1 ECG pattern during febrile state converted to type 2 ECG after alleviation of fever with atypical characteristics (78-year-old woman with monomorphic ventricular tachycardia on holter monitoring, a history of the sudden infant death of her child, and without inducible ventricular arrhythmia by programed ventricular stimulation [PVS].

  6. Atypical Bacteria and Macrolides in Asthma

    Directory of Open Access Journals (Sweden)

    Xepapadaki Paraskevi

    2008-09-01

    Full Text Available Chlamydophila pneumoniae and Mycoplasma pneumoniae are common pathogens causing acute illness in both the upper and lower airways. Several observations are supportive of a possible causative role of these pathogens in asthma; however, more evidence is required before this becomes meaningful in clinical practice. Atypical bacteria can enhance airway hyperresponsiveness and inflammation, both of which have been associated with exacerbations in patients with preexisting asthma. It is less clear whether the above mechanisms might also be responsible for the development of asthma. Difficulties in accurately diagnosing these infections contribute to such uncertainty. In the present report, evidence of the involvement of Chlamydophila and Mycoplasma infection in the development and the progression of asthma are reviewed.

  7. Atypical Radiological Manifestation of Pulmonary Metastatic Calcification

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    Kang, Eun Hae; Kim, Eun Sun; Kim, Chul Hwan; Ham, Soo Youn; Oh, Yu Whan [Korea University College of Medicine, Seoul (Korea, Republic of)

    2008-04-15

    Metastatic pulmonary calcification is a condition of calcium deposition in the normal pulmonary parenchyma, and this is secondary to abnormal calcium metabolism without any prior soft tissue damage. The predisposing factors for this condition include chronic renal failure, hypercalcemia and increased tissue alkalinity. The most common radiologic manifestation consists of poorly defined nodular opacities in the upper lung zone. These opacities reflect the deposition of calcium salts in the pulmonary interstitium. We present here a case of metastatic pulmonary calcification in a patient who recovered from pneumonia with sepsis and whose high-resolution CT (HRCT) images demonstrated localized parenchymal airspace calcification that was limited to the bilateral lower lobes. These lower lobes had been involved with pneumonic consolidation without calcification, as seen on the previous CT scan. In summary, we report here on an atypical presentation of metastatic pulmonary calcification that showed dense airspace consolidation localized to the bilateral lower lobes in a patient with primary hyperparathyroidism and pneumonia.

  8. 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.

  9. MANAGEMENT OF ATYPICAL CLUBFOOT BY PONSETI METHOD

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    V. F. Blandinsky

    2010-01-01

    Full Text Available From May 2006 to August 2009 analyzed 28 clinical observations (34 feet for children aged from 7 days to 1.5 years with severe atypical congenital clubfoot (Pirani 5,6 points, treated by the method of I. Ponseti. The average number of gypsum one foot to the full correction was - 6.3. It was written 38 achillotomy. Dates from the beginning of gypsum to achillotomy averaged - 34 days. All of the children undergoing treatment with us after the removal of plaster, dressed brace, fixing the foot fixed in position 45° abduction and 15° of flexion of the back and encouraged them to carry up to 3-4 years. All the children in this group achieved a complete correction of foot deformities without performing tenoligamentocapsulotomy. Results of treatment were evaluated according to the classification C. Pirani. Average score was 1.1 points. Follow-up was an average of 1 year 35 days.

  10. Atypical Celiac Disease Resistant to Thyroxine Replacement

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    Oguzhan Aksu

    2014-08-01

    Full Text Available Celiac disease, an immune-mediated enteropathy that develops in susceptible individuals upon ingestion of gluten containing diet, is closely associated with other autoimmune endocrine disorders, particularly autoimmune thyroid disease. Celiac disease and hypothyroidism ( especially due to Hashimoto disease cooccurence is frequently mentioned in the literature. The relationship between celiac disease and autoimmune thyroid disease was first described three decades ago. Patients usually have the classical presentation of diarrhoea and steatorrhoea but hypothyroidism with weight loss and increased dose requirement of L Thyroxine are two well recognised presentations of celiac disease in hypothyroidism. It is known that these cases are resistant to thyroxine replacement. Herein we presented a 35 year old female patient with atypical celiac disease and needed an extremely high dose of thyroxine such as 1600 mcg/day for treatment.

  11. Atypical odontalgia - pathophysiology and clinical management.

    Science.gov (United States)

    Baad-Hansen, L

    2008-01-01

    Atypical odontalgia (AO) is a chronic form of dental pain without signs of pathology. Several hypotheses have been put forward regarding the pathophysiology. AO has been proposed to be psychogenic, vascular, neuropathic or idiopathic. The scientific evidence supporting or rejecting these hypotheses are reviewed in this paper. At this time, the best supported hypothesis is that AO is a neuropathic pain condition. Relevant differential diagnoses, such as odontogenic pain, sinusitis, trigeminal neuralgia among others, are presented and the evidence regarding possible management strategies is reviewed. A treatment algorithm for AO is proposed based on the rather scarce scientific evidence available and inspired by a similar treatment algorithm for peripheral neuropathic pain. The proposed strategy involves an interdisciplinary approach including patient education, psychological counselling, topical and systemic medication and, importantly, avoidance of invasive treatments like surgery and endodontics. Two illustrative cases are presented.

  12. Slipped Capital Femoral Epiphysis in Atypical Patients.

    Science.gov (United States)

    Whyte, Noelle; Sullivan, Christopher

    2016-04-01

    When patients who are thin present with knee pain, it can be easy to overlook the possibility of slipped capital femoral epiphysis (SCFE). Although 80% of patients with a "slip" are obese, thin children are not immune to this problem. Endocrinopathies, especially hypothyroidism, can be associated with SCFE. This article describes guidelines for evaluating patients for a slip and highlights some important considerations for the atypical SCFE. Patients with open growth plates with thigh or knee pain should routinely have a hip examination as part of the evaluation. Plain radiographs, with an emphasis on obtaining a frog lateral image, are usually sufficient to make the diagnosis of SCFE. Patients diagnosed with SCFE should be immediately referred to an orthopedic surgeon because treatment for this condition is always surgical. Copyright 2016, SLACK Incorporated.

  13. 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.

  14. 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

  15. [Atypical scurvy associated with anorexia nervosa].

    Science.gov (United States)

    André, R; Gabrielli, A; Laffitte, E; Kherad, O

    2017-02-01

    Scurvy, or "Barlow's disease", is a widely described disease involving cutaneous and mucosal lesions resulting from vitamin C deficiency. Herein, we report a case of scurvy in a 48-year-old woman that was unusual in its atypical cutaneous-mucosal presentation as well as its association with anorexia nervosa. A 48-year-old woman treated for depression for several years was admitted to hospital for her impaired general state of health. Over the last year, she had presented palmoplantar rash and episodes of perimalleolar oedema. The clinical examination showed the patient to have wasting syndrome, with a BMI of 11.9kg/m2, lower-limb oedema, palmoplantar fissures, geographic tongue, telogen effluvium and purpuric petechiae on her right knee. However, no gingival bleeding was noted and there was no loss of tooth enamel. The remainder of the clinical examination was normal. Blood tests revealed extremely low vitamin C levels without any other associated deficiencies, as well as laboratory signs of cytolysis and anicteric cholestasis without inflammatory syndrome. The diagnosis of anorexia nervosa was made by psychiatrists, despite the unusual age of onset. Favorable clinical outcome was rapidly achieved via a one-month course of vitamin C supplements at a daily dose of 1g. The absence of classical buccal-dental symptoms and the presence of keratotic dermatosis with fissures and ulcers on the hands and feet are atypical in scurvy; however, this diagnosis was confirmed by the existence of purpura evoking capillary fragility, the patient's drastically low vitamin C level and the rapid subsidence of symptoms following treatment with oral vitamin C alone. Anorexia nervosa was doubtless the cause of deficiency. This situation is rare and a systematic review of the literature in Medline via PubMed showed that only three reports of scurvy associated with mental anorexia have been published since 1975. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. 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.

  17. 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.

  18. Structural and evolutionary divergence of eukaryotic protein kinases in Apicomplexa

    Directory of Open Access Journals (Sweden)

    Talevich Eric

    2011-11-01

    evolutionary implications of these lineage-specific variations and propose specific hypotheses for experimental investigation. The apicomplexan-specific kinase features reported in this study can be used in the design of selective kinase inhibitors.

  19. Acetylation of cyclin-dependent kinase 5 is mediated by GCN5

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Juhyung; Yun, Nuri; Kim, Chiho [Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749 (Korea, Republic of); Song, Min-Young; Park, Kang-Sik [Department of Physiology and Biomedical Science Institute, Kyung Hee University School of Medicine, Seoul 130-701 (Korea, Republic of); Oh, Young J., E-mail: yjoh@yonsei.ac.kr [Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749 (Korea, Republic of)

    2014-04-25

    Highlights: • Cyclin-dependent kinase 5 (CDK5) is present as an acetylated form. • CDK5 is acetylated by GCN5. • CDK5’s acetylation site is mapped at Lys33. • Its acetylation may affect CDK5’s kinase activity. - Abstract: Cyclin-dependent kinase 5 (CDK5), a member of atypical serine/threonine cyclin-dependent kinase family, plays a crucial role in pathophysiology of neurodegenerative disorders. Its kinase activity and substrate specificity are regulated by several independent pathways including binding with its activator, phosphorylation and S-nitrosylation. In the present study, we report that acetylation of CDK5 comprises an additional posttranslational modification within the cells. Among many candidates, we confirmed that its acetylation is enhanced by GCN5, a member of the GCN5-related N-acetyl-transferase family of histone acetyltransferase. Co-immunoprecipitation assay and fluorescent localization study indicated that GCN5 physically interacts with CDK5 and they are co-localized at the specific nuclear foci. Furthermore, liquid chromatography in conjunction with a mass spectrometry indicated that CDK5 is acetylated at Lys33 residue of ATP binding domain. Considering this lysine site is conserved among a wide range of species and other related cyclin-dependent kinases, therefore, we speculate that acetylation may alter the kinase activity of CDK5 via affecting efficacy of ATP coordination.

  20. Getting in and out of mitosis with Polo-like kinase-1

    NARCIS (Netherlands)

    Vugt, M.A.T.M. van; Medema, R.H.

    2005-01-01

    Research in different species has shown that Polo-like kinases are essential for successful cell division. In human cells, Polo-like kinase-1 (Plk1) has been implicated in the regulation of different processes, including mitotic entry, spindle formation and cytokinesis. Recently, a range of new

  1. 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.

  2. Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues

    Science.gov (United States)

    Andréoletti, Olivier; Orge, Leonor; Benestad, Sylvie L.; Beringue, Vincent; Litaise, Claire; Simon, Stéphanie; Le Dur, Annick; Laude, Hubert; Simmons, Hugh; Lugan, Séverine; Corbière, Fabien; Costes, Pierrette; Morel, Nathalie; Schelcher, François; Lacroux, Caroline

    2011-01-01

    Atypical/Nor98 scrapie was first identified in 1998 in Norway. It is now considered as a worldwide disease of small ruminants and currently represents a significant part of the detected transmissible spongiform encephalopathies (TSE) cases in Europe. Atypical/Nor98 scrapie cases were reported in ARR/ARR sheep, which are highly resistant to BSE and other small ruminants TSE agents. The biology and pathogenesis of the Atypical/Nor98 scrapie agent in its natural host is still poorly understood. However, based on the absence of detectable abnormal PrP in peripheral tissues of affected individuals, human and animal exposure risk to this specific TSE agent has been considered low. In this study we demonstrate that infectivity can accumulate, even if no abnormal PrP is detectable, in lymphoid tissues, nerves, and muscles from natural and/or experimental Atypical/Nor98 scrapie cases. Evidence is provided that, in comparison to other TSE agents, samples containing Atypical/Nor98 scrapie infectivity could remain PrPSc negative. This feature will impact detection of Atypical/Nor98 scrapie cases in the field, and highlights the need to review current evaluations of the disease prevalence and potential transmissibility. Finally, an estimate is made of the infectivity loads accumulating in peripheral tissues in both Atypical/Nor98 and classical scrapie cases that currently enter the food chain. The results obtained indicate that dietary exposure risk to small ruminants TSE agents may be higher than commonly believed. PMID:21347349

  3. Association between paroxysmal trigeminal neuralgia and atypical facial pain.

    Science.gov (United States)

    Juniper, R P; Glynn, C J

    1999-12-01

    Paroxysmal trigeminal neuralgia and atypical facial pain are both fairly common conditions that produce pain in the face of different character. Trigeminal neuralgia is sharp and shooting, brought on by facial movement, change of temperature and by touching the face at a specific point (the trigger point). Atypical facial pain is dull and unrelenting and its site is ill-defined. Trigeminal neuralgia is generally more common in older people, and affects women slightly more than men, and atypical facial pain generally affects younger people, with women predominating. The pains should never be confused. We have noticed that many patients with trigeminal neuralgia have additional symptoms of atypical facial pain and so we reviewed the records of the Pain Relief Unit retrospectively. Of the 83 patients identified with trigeminal neuralgia where records were adequate, 35 (42%) also had atypical facial pain. Five of these had developed it before the onset of trigeminal neuralgia and could be examples of pretrigeminal neuralgia. There were eight patients in the series with multiple sclerosis, of whom two also had atypical facial pain. There seemed to be no relationship between the development of atypical facial pain and the interventions used to treat trigeminal neuralgia. It is important that both conditions are identified and treated individually.

  4. 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.

  5. Emerging roles of protein kinases in microglia-mediated neuroinflammation.

    Science.gov (United States)

    Lee, Sun-Hwa; Suk, Kyoungho

    2017-12-15

    Neuroinflammation is mediated by resident central nervous system glia, neurons, peripherally derived immune cells, blood-brain barrier, and inflammatory mediators secreted from these cells. Neuroinflammation has been implicated in stroke and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Protein kinases have been one of the most exploited therapeutic targets in the current pharmacological research, especially in studies on cancer and inflammation. To date, 32 small-molecule protein kinase inhibitors have been approved by the United States Food and Drug Administration for the treatment of cancer and inflammation. However, there is no drug effectively targeting neuroinflammation and/or neurodegenerative diseases. Recent studies have advanced several protein kinases as important drug targets in neuroinflammation and/or neurodegenerative diseases. Here, we review emerging protein kinases potentially involved in neuroinflammation and subsequent neurodegenerative diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Identification and characterization of CKLiK, a novel granulocyteCa^(++)/calmodulin-dependent kinase

    NARCIS (Netherlands)

    Verploegen, Sandra; Lammers, J.W.J.; Koenderman, L.; Coffer, P.J.

    2000-01-01

    Human granulocytes are characterized by a variety of specific effector functions involved in host defense. Several widely expressed protein kinases have been implicated in the regulation of these effector functions. A polymerase chain reaction- based strategy was used to identify

  7. Mitochondrial Kinases in Parkinson's Disease: Converging Insights from Neurotoxin and Genetic Models

    Science.gov (United States)

    Dagda, Ruben K.; Zhu, Jianhui; Chu, Charleen T.

    2009-01-01

    Alterations in mitochondrial biology have long been implicated in neurotoxin, and more recently, genetic models of parkinsonian neurodegeneration. In particular, kinase regulation of mitochondrial dynamics and turnover are emerging as central mechanisms at the convergence of neurotoxin, environmental and genetic approaches to studying Parkinson's disease (PD). Kinases that localize to mitochondria during neuronal injury include mitogen activated protein kinases (MAPK) such as extracellular signal regulated protein kinases (ERK) and c-Jun N-terminal kinases (JNK), protein kinase B/Akt, and PTEN-induced kinase 1 (PINK1). Although site(s) of action within mitochondria and specific kinase targets are still unclear, these signaling pathways regulate mitochondrial respiration, transport, fission-fusion, calcium buffering, reactive oxygen species (ROS) production, mitochondrial autophagy and apoptotic cell death. In this review, we summarize accelerating experimental evidence gathered over the last decade that implicate a central role for kinase signaling at the mitochondrion in Parkinson's and related neurodegenerative disorders. Interactions involving α-synuclein, leucine rich repeat kinase 2 (LRRK2), DJ-1 and parkin are discussed. Converging mechanisms from different model systems support the concept of common pathways in parkinsonian neurodegeneration that may be amenable to future therapeutic interventions. PMID:19563915

  8. Nasal potential difference measurements in patients with atypical cystic fibrosis.

    Science.gov (United States)

    Wilschanski, M; Famini, H; Strauss-Liviatan, N; Rivlin, J; Blau, H; Bibi, H; Bentur, L; Yahav, Y; Springer, H; Kramer, M R; Klar, A; Ilani, A; Kerem, B; Kerem, E

    2001-06-01

    The diagnosis of cystic fibrosis (CF) is based on characteristic clinical and laboratory findings. However, a subgroup of patients present with an atypical phenotype that comprises partial CF phenotype, borderline sweat tests and one or even no common cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The aim of this study was to evaluate the role of nasal potential difference (PD) measurements in the diagnosis of CF patients with an atypical presentation and in a population of patients suspected to have CF. Nasal PD was measured in 162 patients from four different groups: patients with classical CF (n = 31), atypical phenotype (n = 11), controls (n = 50), and patients with questionable CF (n = 70). The parameter, or combination of nasal PD parameters was calculated in order to best discriminate all CF patients (including atypical CF) from the non-CF group. The patients with atypical CF disease had intermediate values of PD measurements between the CF and non-CF groups. The best discriminate model that assigned all atypical CF patients as CF used: e(response to chloride-free and isoproterenol/response to amiloride) with a cut-off >0.70 to predict a CF diagnosis. When this model was applied to the group of 70 patients with questionable CF, 24 patients had abnormal PD similar to the atypical CF group. These patients had higher levels of sweat chloride concentration and increased rate of CFTR mutations. Nasal potential difference is useful in diagnosis of patients with atypical cystic fibrosis. Taking into account both the sodium and chloride transport elements of the potential difference allows for better differentiation between atypical cystic fibrosis and noncystic fibrosis patients. This calculation may assist in the diagnostic work-up of patients whose diagnosis is questionable.

  9. Structure and inhibitor specificity of the PCTAIRE-family kinase CDK16

    Science.gov (United States)

    Dixon-Clarke, Sarah E.; Shehata, Saifeldin N.; Krojer, Tobias; Sharpe, Timothy D.; vonDelft, Frank; Sakamoto, Kei

    2017-01-01

    CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that has emerged as a key regulator of neurite outgrowth, vesicle trafficking and cancer cell proliferation. CDK16 is activated through binding to cyclin Y via a phosphorylation-dependent 14-3-3 interaction and has a unique consensus substrate phosphorylation motif compared with conventional CDKs. To elucidate the structure and inhibitor-binding properties of this atypical CDK, we screened the CDK16 kinase domain against different inhibitor libraries and determined the co-structures of identified hits. We discovered that the ATP-binding pocket of CDK16 can accommodate both type I and type II kinase inhibitors. The most potent CDK16 inhibitors revealed by cell-free and cell-based assays were the multitargeted cancer drugs dabrafenib and rebastinib. An inactive DFG-out binding conformation was confirmed by the first crystal structures of CDK16 in separate complexes with the inhibitors indirubin E804 and rebastinib, respectively. The structures revealed considerable conformational plasticity, suggesting that the isolated CDK16 kinase domain was relatively unstable in the absence of a cyclin partner. The unusual structural features and chemical scaffolds identified here hold promise for the development of more selective CDK16 inhibitors and provide opportunity to better characterise the role of CDK16 and its related CDK family members in various physiological and pathological contexts. PMID:28057719

  10. Results of surgical treatment of atypical endometrial hyperplasia

    Directory of Open Access Journals (Sweden)

    O. A. Gornykh

    2014-01-01

    Full Text Available The results of surgical treatment in 132 patients with atypical endometrial hyperplasia have been studied. Post-operative diagnosis was: en- dometrial cancer – in 19 %, atypical hyperplasia – in 35 %, simple and complex hyperplasia – in 33 %, only atrophic endometrial changes – in 13 % of patients. The tumor was within the endometrium in 5 patients, the superficial invasion of the myometrium (1–2 mm were in 8 patients, invasion to half of the myometrium – in 9 patients, invasion of more than half of the myometrium – in 3 patients. The questions of tactics of treatment of atypical endometrial hyperplasia is under discussion.

  11. Intracranial Tuberculoma Presenting as Atypical Eclampsia: A Case Report.

    Science.gov (United States)

    Arumugam, Sendhil Coumary; Murugesan, Sharmila; Pradeep, Sunitha; John, Lopamudra; Kolluru, Vasavi

    2016-06-01

    Occurrence of eclampsia before 20 weeks of pregnancy and after 48 hours of delivery in the absence of typical signs of hypertension and or proteinuria is termed as atypical eclampsia. Atypical or non-classic eclampsia will have some symptoms of eclampsia but without the usual proteinuria or hypertension. All patients with atypical onset should undergo neurological evaluation to rule out neurologic causes of seizures. Cerebral tuberculosis is a rare and serious form of disease secondary to haematogenous spread of Mycobacterium tuberculosis. Here we present a case of cerebral tuberculoma with seizures in late pregnancy mimicking eclampsia.

  12. 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.

  13. 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

    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......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...... to be an allosteric mechanism. Furthermore, we demonstrate that anisomycin- and tumor necrosis factor-alpha-induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase and CK2 activities....

  14. Isoform Specificity of Protein Kinase Cs in Synaptic Plasticity

    Science.gov (United States)

    Sossin, Wayne S.

    2007-01-01

    Protein kinase Cs (PKCs) are implicated in many forms of synaptic plasticity. However, the specific isoform(s) of PKC that underlie(s) these events are often not known. We have used "Aplysia" as a model system in order to investigate the isoform specificity of PKC actions due to the presence of fewer isoforms and a large number of documented…

  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.

    Science.gov (United States)

    Iqbal, Zafar; Aleem, Aamer; Iqbal, Mudassar; Naqvi, Mubashar Iqbal; Gill, Ammara; Taj, Abid Sohail; Qayyum, Abdul; ur-Rehman, Najeeb; Khalid, Ahmad Mukhtar; Shah, Ijaz Hussain; Khalid, Muhammad; Haq, Riazul; Khan, Mahwish; Baig, Shahid Mahmood; Jamil, Abid; Abbas, Muhammad Naeem; Absar, Muhammad; Mahmood, Amer; Rasool, Mahmood; Akhtar, Tanveer

    2013-01-01

    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. 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. 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. 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 leukemia along with imatinib, all of which vary in their

  16. 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

    Science.gov (United States)

    Iqbal, Mudassar; Naqvi, Mubashar Iqbal; Gill, Ammara; Taj, Abid Sohail; Qayyum, Abdul; ur-Rehman, Najeeb; Khalid, Ahmad Mukhtar; Shah, Ijaz Hussain; Khalid, Muhammad; Haq, Riazul; Khan, Mahwish; Baig, Shahid Mahmood; Jamil, Abid; Abbas, Muhammad Naeem; Absar, Muhammad; Mahmood, Amer; Rasool, Mahmood; Akhtar, Tanveer

    2013-01-01

    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 leukemia along with

  17. 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

  18. Direct observation of inclined a-type threading dislocation with a-type screw dislocation in GaN

    Science.gov (United States)

    Matsubara, Tohoru; Sugimoto, Kohei; Goubara, Shin; Inomoto, Ryo; Okada, Narihito; Tadatomo, Kazuyuki

    2017-05-01

    We investigated both the atomic arrangements in the core structure of threading dislocations (TDs) and their behaviors in unintentionally doped c-plane-GaN layers grown by metalorganic vapor phase epitaxy and hydride vapor phase epitaxy using high angle annular dark-field scanning transmission electron microscopy (HAADF-STEM). The extra image contrast near the core was attributed to an extra displacement in a-type TDs in addition to the core structures revealed in previous reports; we used the notation "with displacement" to describe the new core structure. We found that TDs incline towards both the m- and a-directions from the c-direction. The transition of a-type TDs from the conventional core structure to the structure with displacement was deduced from its relationship to the TD inclination. We also found similarities between a-type screw dislocations and a-type TDs with displacement in the atomic-scale HAADF-STEM images. We concluded that a-type TDs could incline towards the a-direction via a-type screw dislocations, and that these inclined a-type TDs are observed as the core structure with displacement.

  19. JAK protein kinase inhibitors.

    Science.gov (United States)

    Thompson, James E

    2005-06-01

    In humans, the Janus protein tyrosine kinase family (JAKs) contains four members: JAK1, JAK2, JAK3 and TYK2. JAKs phosphorylate signal transducers and activators of transcription (STATs) simultaneously with other phosphorylations required for activation, and there are several cellular mechanisms in place to inhibit JAK/STAT signaling. That one might be able to modulate selected JAK/STAT-mediated cellular signals by inhibiting JAK kinase activity to effect a positive therapeutic outcome is a tantalizing prospect, as yet incompletely realized. While current data suggest no therapeutic use for JAK1 and TYK2 inhibition, JAK2 inhibition seems a promising but not definitively tested mechanism for treatment of leukemia. More promising, however, are data indicating a possible therapeutic use of JAK3 inhibition. The restriction of the JAK3-deficient phenotype to the hematopoietic system and the resulting profound immune suppression suggest that JAK3 could be a target for immunosuppressive therapies used to prevent organ transplant rejection.

  20. 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.

  1. 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......Protein kinase CK2 is a ubiquitous pleiotropic serine/threonine protein kinase whose holoenzyme is comprised of two catalytic (alpha and/or alpha') and two non-catalytic, beta-subunits. The beta-subunit possesses antagonist functions that can be physically dissected by generating synthetic...... fragments encompassing its N-terminal and C-terminal domains. Here we show that by mutating basic residues in the 74-77 and in the 191-198 regions of the alpha-subunit, the negative regulation by the beta-subunit and by its N-terminal synthetic fragment CK2beta-(1-77), which is observable using calmodulin...

  2. Profile of hepatitis A infection with atypical manifestations in children.

    Science.gov (United States)

    Samanta, Tryambak; Das, Anjan Kumar; Ganguly, Sutapa

    2010-01-01

    We assessed the clinical course and biochemical profile of symptomatic children with viral hepatitis A who had atypical manifestations. Of 229 children with hepatitis A, atypical manifestations were found in 32 (14%) subjects. Prolonged cholestasis (n = 14), acute liver failure (9), relapse (9), ascites (8), and hematological problems (8) were the common presentations. Liver histology was suggestive of chronic liver disease in six children with protracted jaundice. Patients with atypical presentations were older (7.7 [1.6] years vs. 6.5 [2.6] years; p=0.012) and had higher total serum bilirubin (13.7 [8.1] mg/dL vs. 7.2 [4.0] mg/dL; p=children with acute hepatitis A infection have atypical presentation which is associated with increase in morbidity.

  3. Neural Correlates of Reward Processing in Typical and Atypical Development

    Directory of Open Access Journals (Sweden)

    Emma G. Duerden PhD

    2016-09-01

    Full Text Available Atypically developing children including those born preterm or who have autism spectrum disorder can display difficulties with evaluating rewarding stimuli, which may result from impaired maturation of reward and cognitive control brain regions. During functional magnetic resonance imaging, 58 typically and atypically developing children (6-12 years participated in a set-shifting task that included the presentation of monetary reward stimuli. In typically developing children, reward stimuli were associated with age-related increases in activation in cognitive control centers, with weaker changes in reward regions. In atypically developing children, no age-related changes were evident. Maturational disturbances in the frontostriatal regions during atypical development may underlie task-based differences in activation.

  4. 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

  5. Atypical brain torque in boys with developmental stuttering.

    Science.gov (United States)

    Mock, Jeffrey Ryan; Zadina, Janet N; Corey, David M; Cohen, Jeremy D; Lemen, Lisa C; Foundas, Anne L

    2012-01-01

    The counterclockwise brain torque, defined as a larger right prefrontal and left parietal-occipital lobe, is a consistent brain asymmetry. Reduced or reversed lobar asymmetries are markers of atypical cerebral laterality and have been found in adults who stutter. It was hypothesized that atypical brain torque would be more common in children who stutter. Magnetic resonance imaging-based morphology measures were completed in boys who stutter (n = 14) and controls (n = 14), ages 8-13. The controls had the expected brain torque configurations whereas the boys who stutter were atypical. These results support the hypothesis that developmental stuttering is associated with atypical prefrontal and parietal-occipital lobe asymmetries.

  6. Macroporous hydrogel micropillars for quantifying Met kinase activity in cancer cell lysates

    Science.gov (United States)

    Powers, Alicia D.; Liu, Bi; Lee, Andrew G.; Palecek, Sean P.

    2012-01-01

    Overactive and overexpressed kinases have been implicated in the cause and progression of many cancers. Kinase inhibitors offer a targeted approach for treating cancers associated with increased or deregulated kinase activity. Often, however, cancer cells exhibit initial resistance to these inhibitors or evolve to develop resistance during treatment. Additionally, cancers of any one tissue type are typically heterogeneous in their oncogenesis mechanisms, and thus diagnosis of a particular type of cancer does not necessarily provide insight into what kinase therapies may be effective. For example, while some lung cancer cells that overexpress the epidermal growth factor receptor (EFGR) respond to treatment with EGFR kinase inhibitors, overexpression or hyperactivity of Met kinase correlates with resistance to EGFR kinase inhibitors. Here we describe a microfluidic-based assay for quantifying Met kinase activity in cancer cell lysates with the eventual goals of predicting cancer cell responsiveness to kinase inhibitors and monitoring development of resistance to these inhibitors. In this assay, we immobilized a phosphorylation substrate for Met kinase into macroporous hydrogel micropillars. We then exposed the micropillars to a cancer cell lysate and detected substrate phosphorylation using a fluorescently-conjugated antibody. This assay is able to quantify Met kinase activity in whole cell lysate from as few as 150 cancer cells. It can also detect cells expressing overactive Met kinase in a background of up to 75% non-cancerous cells. Additionally, the assay can quantify kinase inhibition by the Met-specific kinase inhibitors SU11274 and PHA665752, suggesting predictive capability for cellular response to kinase inhibitors. PMID:22814332

  7. [Prevalence and determinants of atypical presentation of acute coronary syndrome].

    Science.gov (United States)

    Pinto, David; Lunet, Nuno; Azevedo, Ana

    2011-12-01

    Knowledge of the characteristics of patients with atypical presentation of acute coronary syndromes may contribute to increased sensitivity in diagnosis in a given population. The purpose of this study is to quantify the prevalence of atypical presentation, to identify its determinants, and to describe the presenting symptoms in cases of acute coronary syndrome at the emergency department of Hospital São João, Porto. Systematic sample of 288 emergency admissions with a confirmed diagnosis of acute coronary syndrome in 2007. Atypical presentation was defined as absence of chest pain and/or syncope. The prevalence of atypical presentation was 20.5% [95% confidence interval (CI): 16.0 to 25.5], with no important variation by gender. It increased with age and was more frequent in cases of ST-segment elevation myocardial infarction. In multivariate analysis, atypical presentation was associated with age [>70 versus ≤ 50 years, odds ratio (OR)=3.45; 95%CI: 1.03-11.61] and it was about four times less likely in the presence of history of ischemic heart disease, hypertension, dyslipidemia and smoking. A history of heart failure was independently associated with a higher likelihood of acute coronary syndrome with atypical presentation (OR = 4.15, 95%CI 1.50-11.46). Among the 223 cases who had chest pain or discomfort, a growing, oppressive, prolonged (longer than 30 minutes), recurrent and episodic pain prevailed. Among other symptoms, dyspnea was the most frequently reported, either as the main symptom in cases of atypical presentation or concurrently with typical symptoms. Factors associated with atypical presentation are consistent with those described in other populations. Using routine clinical data allowed access to a large data base on a representative sample of patients admitted to the emergency department of a third-level hospital that serves a large part of the local urban population. In medical records, data are unstandardized and heterogeneous in validity

  8. Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality

    DEFF Research Database (Denmark)

    Buchou, Thierry; Vernet, Muriel; Blond, Olivier

    2003-01-01

    Protein kinase CK2 is a ubiquitous protein kinase implicated in proliferation and cell survival. Its regulatory beta subunit, CK2beta, which is encoded by a single gene in mammals, has been suspected of regulating other protein kinases. In this work, we show that knockout of the CK2beta gene in m...

  9. 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....... Moreover, MK2 activity was required for damage response, accumulation of ssDNA, and decreased survival when cells were treated with the nucleoside analogue gemcitabine or when the checkpoint kinase Chk1 was antagonized. By using DNA fiber assays, we found that MK2 inhibition or knockdown rescued DNA...

  10. 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.

  11. [Sturge-Weber syndrome with atypical calcifications].

    Science.gov (United States)

    Prieto, M L; de Juan, J; Antón, M; Roiz, C; Crespo, M

    1997-09-01

    The syndrome, or disease, or Sturge Weber (SSW) is a neuro-ectodermic disorder of unknown incidence, sporadic presentation and specific sex incidence. It is characterized by the presence of a flat, facial angioma which affects at least the first branch of the trigeminal nerve, association with ipsilateral leptomeningeal vascular anomalies, one or more symptoms (epilepsy, hemiparesia, hemiplegia or mental retardation) and ipsilateral vascular lesions of the choroid which lead to glaucoma. As a consequence of lepto-meningeal involvement, homolateral cerebral hemi-atrophy develops together with cortico-subcortical calcifications with a characteristic "railway line" appearance. We present the case of a six month old girl with a flat port wine angioma on the left half of her face, including three branches of the trigeminal nerve and the left half of her body. She had partial motor crises of the right leg. On the cranial CT there were left periventricular calcifications and calcifications of the choroid plexus. Gadolinium-MR showed signs of left cerebral hemi-atrophy, which was confirmed on the cerebral SPECT (left temporal hypoperfusion). This case is interesting on account of the presence of atypical calcifications, both with regard to the sites and age of presentation. We emphasize the need for cranial CT to rule out the presence of calcifications, (as in this case) not seen on Xray of the skull or on MR. We favour the use of cerebral SPECT as a complementary diagnostic technique.

  12. 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.

  13. 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.

  14. Atypical proliferating mucinous tumors of gigantic dimensions

    Directory of Open Access Journals (Sweden)

    Likić-Lađević Ivana

    2008-01-01

    Full Text Available Background. Ovarian tumors of low malignant potential (LMP are also known as atypically proliferating tumors. Ovarian tumors of LPM account for approximately 15% of all epithelial ovarian cancers. Mean age of occurrence is 40 years and they are 15-20 cm in diameter. Case report. A 32-year-old female patient was hospitalized as an urgent case with a large tumor mass that filled the entire abdomen. Cyst was 100 × 70 cm dimensions belonging to the right ovary and filled with 18 liters of content. Right adnexectomy, resection of the second ovary, as well as biopsy of the omentum were performed. Lymphadenectomy of the right iliac and obturator area was also performed. After receiving definitive histopathological results it was decided to perform a radical reoperation. On the 10th postoperative day relaparotomy, total hysterectomy and left adnexectomy were performed. The patient was released on the 6th postoperative day. She used to come to regular examinations up to date. Conclusion. This case is a proof that LMP tumors have low malignant potential, they grow slowly and can reach great proportions.

  15. Blink reflexes in patients with atypical odontalgia.

    Science.gov (United States)

    Baad-Hansen, Lene; List, Thomas; Jensen, Troels Staehelin; Leijon, Göran; Svensson, Peter

    2005-01-01

    To use the human blink reflex (BR) to explore possible neuropathic pain mechanisms in patients with atypical odontalgia (AO). In 13 AO patients, the BR was elicited using a concentric electrode and recorded bilaterally with surface electromyographic (EMG) electrodes on both orbicularis oculi muscles. Electrical stimuli were applied to the skin above branches of the V1, V2, and V3 nerves and to the V branch contralateral to the painful branch. Sensory and pain thresholds were determined. The BR examination of the painful V branch was repeated during a capsaicin pain-provocation test. The data were analyzed with nonparametric statistics. The BR responses (R2 and R3) evoked by stimulation of V3 were significantly smaller than the BR responses evoked by stimulation of V1 and V2 (P .569), and the BR (R2 and R3) was not significantly modulated by experimental pain (P > .080). The sensory thresholds were significantly lower on the painful side compared to the nonpainful side (P = .014). The pain thresholds were not different between sides (P > .910). No major differences between the V nociceptive pathways on the right and left sides were found in a relatively small group of AO patients. Future studies that compare BRs in AO patients and healthy volunteers are needed to provide further knowledge on the pain mechanisms in AO.

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

    OpenAIRE

    Goldknopf, Emily J.

    2013-01-01

    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 dra...

  17. Importance of the swallowing atypical in them malocclusions

    OpenAIRE

    Jiménez Jiménez, Jonatan; Universidad Nacional Mayor de San Marcos, Facultad de Odontología.

    2017-01-01

    This review aims to determine the atypical swallowing malocclusions. When there are inadequate move-ments of the tongue and / or other structures during oral and pharyngolaryngeal phase of swallowing, talking about atypical swallowing, as a non-physiological habit. Its objectives may be multiple, simul-taneously acting alone or cumulatively. The size of a large tongue has been found as an impediment to correct such alternations, though this is a cause of causing malocclusion. the importance o...

  18. 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.

  19. 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.

  20. 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.

  1. MR findings of atypical meningioma: comparison with benign meningioma

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Ji Hoon; Lee, Ho Kyu; Kim, Jung Hoon; Shin, Byung Suck; Lim, Soo Mee; Kim, Dae Hong; Choi, Choong Gon; Suh, Dae Chul [Ulsan Univ. College of Medicine, Seoul (Korea, Republic of)

    1998-10-01

    Atypical meningioma is an intermediate type, between benign and malignant meningiomas, and has a higher recurrence rate and poorer prognosis than the benign type. The purpose of this study was to evaluate the differential imaging findings between atypical and benign meningiomas. Over a five-year period, 11 acses of atypical meningioma (in ten patients) were pathologically proven, and 30 benign meningiomas were collected consecutively over 6 months. In retrospective analysis, the MR findings of atypical and benign meningiomas were compared with respect to tumor margin, lobulation, intra-/peritumoral hemorrhage, cystic change, heterogeneity, peritumoral edema, enhacement of adjacent meninges, invasion of adjacent venous sinus and adjacent bony change. Signigicant differential MR findings between the two groups were ill-defined tumor margin(atypical-27%;benign-0%), lobulation(82%;43%), heterogeneity(73%;30%), and peritumoral edema(100%;47%). With regard to moderate edema, there was no significant difference between the two groups (36%;23%), and with regard to intra-/peritumoral hemorrhage, cystic change, enhancement of adjacent meninges, invasion of adjacent venous sinus, and adjacent bony change, MR findings between the two groups were not significantly different. The MR findings of atypical meningioma are significantly different in several ways from those of benign meningioma, and these differences may help differentiate the two types.=20.

  2. Neurological manifestations of atypical celiac disease in childhood.

    Science.gov (United States)

    Sel, Çiğdem Genç; Aksoy, Erhan; Aksoy, Ayşe; Yüksel, Deniz; Özbay, Ferda

    2017-09-01

    Various typical and atypical neurological manifestations can be seen as the initial symptoms of celiac disease (CD). We suggest that gluten toxicity is the most suspicious triggering risk factor for probable pathophysiological pathways of neurological involvement in atypical CD. The medical charts of 117 patients diagnosed with atypical CD were retrieved from a tertiary center in Ankara, Turkey. Eight patients reported as having neurologic manifestations as initiating symptoms were evaluated in detail. The initial neurological manifestations of CD in our study included atypical absence, which was reported first in this study, generalized tonic-clonic seizures, complex partial seizures, severe axial hypotonia and down phenotype, multifocal leukoencephalopathy, mild optic neuritis, attention deficit hyperactivity disorder, and short duration headaches. Seizures mostly emphasizing atypical absence could be the initial presentation manifestation of CD, first described in this literature. Gluten toxicity could be one of the most powerful triggering factors for developing epilepsy in CD. Learning disorders such as attention deficit hyperactivity disorder, short duration headaches, mild optic neuritis, encephalopathy, and DS could also be the initial neurological manifestations of atypical CD. A gluten-restricted diet may improve neurological complaints, epileptic discharges, and neuropsychiatric symptoms. All we found may be a small part of the full range of neurological disorders of unknown origin related to CD. Clinical suspicion should be the rule for accurate diagnosis of the disease.

  3. 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.

  4. Vaccinia-Related Kinase 2 Modulates the Stress Response to Hypoxia Mediated by TAK1▿

    Science.gov (United States)

    Blanco, Sandra; Santos, Claudio; Lazo, Pedro A.

    2007-01-01

    Hypoxia represents a major stress that requires an immediate cellular response in which different signaling pathways participate. Hypoxia induces an increase in the activity of TAK1, an atypical mitogen-activated protein kinase kinase kinase (MAPKKK), which responds to oxidative stress by triggering cascades leading to the activation of c-Jun N-terminal kinase (JNK). JNK activation by hypoxia requires assembly with the JIP1 scaffold protein, which might also interact with other intracellular proteins that are less well known but that might modulate MAPK signaling. We report that TAK1 is able to form a stable complex with JIP1 and thus regulate the activation of JNK, which in turn determines the cellular stress response to hypoxia. This activation of TAK1-JIP1-JNK is suppressed by vaccinia-related kinase 2 (VRK2). VRK2A is able to interact with TAK1 by its C-terminal region, forming stable complexes. The kinase activity of VRK2 is not necessary for this interaction or the downregulation of AP1-dependent transcription. Furthermore, reduction of the endogenous VRK2 level with short hairpin RNA can increase the response induced by hypoxia, suggesting that the intracellular levels of VRK2 can determine the magnitude of this stress response. PMID:17709393

  5. Bacterial Protein-Tyrosine Kinases

    DEFF Research Database (Denmark)

    Shi, Lei; Kobir, Ahasanul; Jers, Carsten

    2010-01-01

    enzymes that are unique in exploiting the ATP/GTP-binding Walker motif to catalyze phosphorylation of protein tyrosine residues. Characterized for the first time only a decade ago, BY-kinases have now come to the fore. Important regulatory roles have been linked with these enzymes, via their involvement......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...... 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...

  6. Eculizumab in secondary atypical haemolytic uraemic syndrome

    Science.gov (United States)

    Cavero, Teresa; Rabasco, Cristina; López, Antía; Román, Elena; Ávila, Ana; Sevillano, Ángel; Huerta, Ana; Rojas-Rivera, Jorge; Fuentes, Carolina; Blasco, Miquel; Jarque, Ana; García, Alba; Mendizabal, Santiago; Gavela, Eva; Macía, Manuel; Quintana, Luis F.; María Romera, Ana; Borrego, Josefa; Arjona, Emi; Espinosa, Mario; Portolés, José; Gracia-Iguacel, Carolina; González-Parra, Emilio; Aljama, Pedro; Morales, Enrique; Cao, Mercedes; Rodríguez de Córdoba, Santiago

    2017-01-01

    Abstract Background. Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. Methods. We identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 109/L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration. Results. Twenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Conclusion. Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing condition. PMID:28339660

  7. Eculizumab in secondary atypical haemolytic uraemic syndrome.

    Science.gov (United States)

    Cavero, Teresa; Rabasco, Cristina; López, Antía; Román, Elena; Ávila, Ana; Sevillano, Ángel; Huerta, Ana; Rojas-Rivera, Jorge; Fuentes, Carolina; Blasco, Miquel; Jarque, Ana; García, Alba; Mendizabal, Santiago; Gavela, Eva; Macía, Manuel; Quintana, Luis F; María Romera, Ana; Borrego, Josefa; Arjona, Emi; Espinosa, Mario; Portolés, José; Gracia-Iguacel, Carolina; González-Parra, Emilio; Aljama, Pedro; Morales, Enrique; Cao, Mercedes; Rodríguez de Córdoba, Santiago; Praga, Manuel

    2017-03-01

    Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. We identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 10 9 /L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration. Twenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing condition.

  8. Psychiatric comorbidities in patients with Atypical Odontalgia.

    Science.gov (United States)

    Miura, Anna; Tu, Trang T H; Shinohara, Yukiko; Mikuzuki, Lou; Kawasaki, Kaoru; Sugawara, Shiori; Suga, Takayuki; Watanabe, Takeshi; Watanabe, Motoko; Umezaki, Yojiro; Yoshikawa, Tatsuya; Motomura, Haruhiko; Takenoshita, Miho; Maeda, Hidefumi; Toyofuku, Akira

    2018-01-01

    Atypical Odontalgia (AO) is a condition characterized by tooth pain with no apparent cause. Although psychiatric comorbidity seems to be very common, it has rarely been studied. To clarify the influence of psychiatric comorbidity on the clinical features in patients with AO, we retrospectively evaluated their examination records. Clinical features and psychiatric diagnoses of 383 patients with AO were investigated by reviewing patients' medical records and referral letters. Psychiatric diagnoses were categorized according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We also analyzed visual analogue scale (VAS), self-rating depression scale (SDS), and the short-form McGill pain questionnaire (SF-MPQ) scores. Of the 383 patients with AO, 177 (46.2%) had comorbid psychiatric disorders. The most common were depressive disorders (15.4%) and anxiety disorders (10.1%). Serious psychotic disorders such as bipolar disorder (3.0%) and schizophrenia (1.8%) were rare. Dental trigger of AO was reported in 217 (56.7%) patients. There were no significant correlations between psychiatric comorbidities and most of the demographic features. Higher VAS and SDS scores, higher frequency of sleep disturbance, and higher ratings of "Fearful" and "Punishing-cruel" descriptors of the SF-MPQ were found in patients with psychiatric comorbidity. About half of AO patients had comorbid psychiatric disorders. Dental procedures are not necessarily causative factors of AO. In AO patients with comorbid psychiatric disorders, pain might have a larger emotional component than a sensory one. VAS, SDS, and SF-MPQ scores might aid in the noticing of underlying comorbid psychiatric disorders in AO patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Clozapine versus other atypical antipsychotics for schizophrenia

    Science.gov (United States)

    Asenjo Lobos, Claudia; Komossa, Katja; Rummel-Kluge, Christine; Hunger, Heike; Schmid, Franziska; Schwarz, Sandra; Leucht, Stefan

    2014-01-01

    Background Clozapine is an atypical antipsychotic demonstrated to be superior in the treatment of refractory schizophrenia which causes fewer movement disorders. Clozapine, however, entails a significant risk of serious blood disorders such as agranulocytosis which could be potentially fatal. Currently there are a number of newer antipsychotics which have been developed with the purpose to find both a better tolerability profile and a superior effectiveness. Objectives To compare the clinical effects of clozapine with other atypical antipsychotics (such as amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine) in the treatment of schizophrenia and schizophrenia-like psychoses. Search methods We searched the Cochrane Schizophrenia Groups Register (June 2007) and reference lists of all included randomised controlled trials. We also manually searched appropriate journals and conference proceedings relating to clozapine combination strategies and contacted relevant pharmaceutical companies. Selection criteria All relevant randomised, at least single-blind trials, comparing clozapine with other atypical antipsychotics, any dose and oral formulations, for people with schizophrenia or related disorders. Data collection and analysis We selected trials and extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) 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 27 blinded randomised controlled trials, which involved 3099 participants. Twelve randomised control trials compared clozapine with olanzapine, five with quetiapine, nine with risperidone, one with ziprasidone and two with zotepine. Attrition from these studies was high (overall 30.1%), leaving the interpretation

  10. Focal adhesion kinase signaling in cardiac hypertrophy and failure

    Directory of Open Access Journals (Sweden)

    K.G. Franchini

    2009-01-01

    Full Text Available Focal adhesion kinase (FAK is a broadly expressed tyrosine kinase implicated in cellular functions such as migration, growth and survival. Emerging data support a role for FAK in cardiac development, reactive hypertrophy and failure. Data reviewed here indicate that FAK plays a critical role at the cellular level in the responses of cardiomyocytes and cardiac fibroblasts to biomechanical stress and to hypertrophic agonists such as angiotensin II and endothelin. The signaling mechanisms regulated by FAK are discussed to provide insight into its role in the pathophysiology of cardiac hypertrophy and failure.

  11. Childhood Learning Disabilities and Atypical Dementia: A Retrospective Chart Review.

    Directory of Open Access Journals (Sweden)

    Alon Seifan

    Full Text Available To further our understanding of the association between self-reported childhood learning disabilities (LDs and atypical dementia phenotypes (Atypical Dementia, including logopenic primary progressive aphasia (L-PPA, Posterior Cortical Atrophy (PCA, and Dysexecutive-type Alzheimer's Disease (AD.This retrospective case series analysis of 678 comprehensive neuropsychological assessments compared rates of self-reported LD between dementia patients diagnosed with Typical AD and those diagnosed with Atypical Dementia. 105 cases with neuroimaging or CSF data available and at least one neurology follow-up were identified as having been diagnosed by the neuropsychologist with any form of neurodegenerative dementia. These cases were subject to a consensus diagnostic process among three dementia experts using validated clinical criteria for AD and PPA. LD was considered Probable if two or more statements consistent with prior LD were documented within the Social & Developmental History of the initial neuropsychological evaluation.85 subjects (Typical AD n=68, Atypical AD n=17 were included in the final analysis. In logistic regression models adjusted for age, gender, handedness, education and symptom duration, patients with Probable LD, compared to patients without Probable LD, were significantly more likely to be diagnosed with Atypical Dementia vs. Typical AD (OR 13.1, 95% CI 1.3-128.4. All three of the L-PPA cases reporting a childhood LD endorsed childhood difficulty with language. By contrast, both PCA cases reporting Probable childhood LD endorsed difficulty with attention and/or math.In people who develop dementia, childhood LD may predispose to atypical phenotypes. Future studies are required to confirm whether atypical neurodevelopment predisposes to regional-specific neuropathology in AD and other dementias.

  12. fMRI and MEG in the study of typical and atypical cognitive development.

    Science.gov (United States)

    Taylor, M J; Donner, E J; Pang, E W

    2012-01-01

    The tremendous changes in brain structure over childhood are critical to the development of cognitive functions. Neuroimaging provides a means of linking these brain-behaviour relations, as task protocols can be adapted for use with young children to assess the development of cognitive functions in both typical and atypical populations. This paper reviews some of our research using magnetoencephalography (MEG) and functional MRI (fMRI) in the study of cognitive development, with a focus on frontal lobe functions. Working memory for complex abstract patterns showed clear development in terms of the recruitment of frontal regions, seen with fMRI, with indications of strategy differences across the age range, from 6 to 35 years of age. Right hippocampal involvement was also evident in these n-back tasks, demonstrating its involvement in recognition in simple working memory protocols. Children born very preterm (7 to 9 years of age) showed reduced fMRI activation particularly in the precuneus and right hippocampal regions relative to control children. In a large normative n-back study (n=90) with upright and inverted faces, MEG data also showed right hippocampal activation that was present across the age range; frontal sources were evident only from 10 years of age. Other studies have investigated the development of set shifting, an executive function that is often deficit in atypical populations. fMRI showed recruitment of frontal areas, including the insula, that have significantly different patterns in children (7 to 14 years of age) with autism spectrum disorder compared to typically developing children, indicating that successful performance implicated differing strategies in these two groups of children. These types of studies will help our understanding of both normal brain-behaviour development and cognitive dysfunction in atypically developing populations. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  13. 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.

  14. Identification of a fungi-specific lineage of protein kinases closely related to tyrosine kinases.

    Directory of Open Access Journals (Sweden)

    Zhongtao Zhao

    Full Text Available Tyrosine kinases (TKs specifically catalyze the phosphorylation of tyrosine residues in proteins and play essential roles in many cellular processes. Although TKs mainly exist in animals, recent studies revealed that some organisms outside the Opisthokont clade also contain TKs. The fungi, as the sister group to animals, are thought to lack TKs. To better understand the origin and evolution of TKs, it is important to investigate if fungi have TK or TK-related genes. We therefore systematically identified possible TKs across the fungal kingdom by using the profile hidden Markov Models searches and phylogenetic analyses. Our results confirmed that fungi lack the orthologs of animal TKs. We identified a fungi-specific lineage of protein kinases (FslK that appears to be a sister group closely related to TKs. Sequence analysis revealed that members of the FslK clade contain all the conserved protein kinase sub-domains and thus are likely enzymatically active. However, they lack key amino acid residues that determine TK-specific activities, indicating that they are not true TKs. Phylogenetic analysis indicated that the last common ancestor of fungi may have possessed numerous members of FslK. The ancestral FslK genes were lost in Ascomycota and Ustilaginomycotina and Pucciniomycotina of Basidiomycota during evolution. Most of these ancestral genes, however, were retained and expanded in Agaricomycetes. The discovery of the fungi-specific lineage of protein kinases closely related to TKs helps shed light on the origin and evolution of TKs and also has potential implications for the importance of these kinases in mushroom fungi.

  15. Ichthyosiform mycosis fungoides with alopecia and atypical membranous nephropathy

    Directory of Open Access Journals (Sweden)

    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.

  16. 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.

  17. 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

  18. The Gene YALI0E20207g from Yarrowia lipolytica Encodes an N-Acetylglucosamine Kinase Implicated in the Regulated Expression of the Genes from the N-Acetylglucosamine Assimilatory Pathway

    Science.gov (United States)

    Flores, Carmen-Lisset; Gancedo, Carlos

    2015-01-01

    The non-conventional yeast Yarrowia lipolytica possesses an ORF, YALI0E20207g, which encodes a protein with an amino acid sequence similar to hexokinases from different organisms. We have cloned that gene and determined several enzymatic properties of its encoded protein showing that it is an N-acetylglucosamine (NAGA) kinase. This conclusion was supported by the lack of growth in NAGA of a strain carrying a YALI0E20207g deletion. We named this gene YlNAG5. Expression of YlNAG5 as well as that of the genes encoding the enzymes of the NAGA catabolic pathway—identified by a BLAST search—was induced by this sugar. Deletion of YlNAG5 rendered that expression independent of the presence of NAGA in the medium and reintroduction of the gene restored the inducibility, indicating that YlNag5 participates in the transcriptional regulation of the NAGA assimilatory pathway genes. Expression of YlNAG5 was increased during sporulation and homozygous Ylnag5/Ylnag5 diploid strains sporulated very poorly as compared with a wild type isogenic control strain pointing to a participation of the protein in the process. Overexpression of YlNAG5 allowed growth in glucose of an Ylhxk1glk1 double mutant and produced, in a wild type background, aberrant morphologies in different media. Expression of the gene in a Saccharomyces cerevisiae hxk1 hxk2 glk1 triple mutant restored ability to grow in glucose. PMID:25816199

  19. The gene YALI0E20207g from Yarrowia lipolytica encodes an N-acetylglucosamine kinase implicated in the regulated expression of the genes from the N-acetylglucosamine assimilatory pathway.

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    Carmen-Lisset Flores

    Full Text Available The non-conventional yeast Yarrowia lipolytica possesses an ORF, YALI0E20207g, which encodes a protein with an amino acid sequence similar to hexokinases from different organisms. We have cloned that gene and determined several enzymatic properties of its encoded protein showing that it is an N-acetylglucosamine (NAGA kinase. This conclusion was supported by the lack of growth in NAGA of a strain carrying a YALI0E20207g deletion. We named this gene YlNAG5. Expression of YlNAG5 as well as that of the genes encoding the enzymes of the NAGA catabolic pathway-identified by a BLAST search-was induced by this sugar. Deletion of YlNAG5 rendered that expression independent of the presence of NAGA in the medium and reintroduction of the gene restored the inducibility, indicating that YlNag5 participates in the transcriptional regulation of the NAGA assimilatory pathway genes. Expression of YlNAG5 was increased during sporulation and homozygous Ylnag5/Ylnag5 diploid strains sporulated very poorly as compared with a wild type isogenic control strain pointing to a participation of the protein in the process. Overexpression of YlNAG5 allowed growth in glucose of an Ylhxk1glk1 double mutant and produced, in a wild type background, aberrant morphologies in different media. Expression of the gene in a Saccharomyces cerevisiae hxk1 hxk2 glk1 triple mutant restored ability to grow in glucose.

  20. Early alterations of bile canaliculi dynamics and the rho kinase/myosin light chain kinase pathway are characteristics of drug-induced intrahepatic cholestasis

    OpenAIRE

    Burbank, M.G.; Burban, Audrey; Sharanek, Ahmad; Weaver, R J; Guguen-Guillouzo, Christiane; Guillouzo, André

    2016-01-01

    International audience; Intrahepatic cholestasis represents 20%-40%of drug-induced injuries from which a large proportion remains unpredictable. We aimed to investigate mechanisms underlying drug-induced cholestasis and improve its early detection using human HepaRG cells and a set of 12 cholestatic drugs and six noncholestatic drugs. In this study, we analyzed bile canaliculi dynamics, Rho kinase (ROCK)/myosin light chain kinase (MLCK) pathway implication, efflux inhibition of taurocholate [...

  1. Children's responses to social atypicality among group members - advantages of a contextualized social developmental account.

    Science.gov (United States)

    Abrams, Dominic; Rutland, Adam; Palmer, Sally B; Purewal, Kiran

    2014-09-01

    Abrams, Rutland, Palmer, Ferrell, and Pelletier (2014) showed that better second-order mental state understanding facilitates 6-7-year-olds' ability to link a partially disloyal child's atypicality to inclusive or exclusive reactions by in-group or outgroup members. This finding is interpreted in terms of predictions from the developmental subjective group dynamics model. We respond to thoughtful commentaries by Rhodes and Chalik, Patterson, and Rakoczy. Children face a significant developmental challenge in becoming able to recognize and interpret social atypicality in intergroup contexts. Researching that ability to contextualize judgements raises new questions about the nature of peer inclusion and exclusion, about children's social cognition, and about the way that social cognitive development and social experience combine. Rather than individual-focused cognition taking priority over category-based cognition, we argue the two become more systematically integrated during development. We note that loyalty is but one example of typicality, and we also consider the role of more advanced perspective taking among older children, and the role of multiple classification skill among younger children, as well as potential implications for intervention to reduce peer victimization and prejudice. © 2014 The British Psychological Society.

  2. Olanzapine versus other atypical antipsychotics for schizophrenia

    Science.gov (United States)

    Komossa, Katja; Rummel-Kluge, Christine; Hunger, Heike; Schmid, Franziska; Schwarz, Sandra; Duggan, Lorna; 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. In this review we examined how the efficacy and tolerability of olanzapine differs from that of other second generation antipsychotics. Objectives To evaluate the effects of olanzapine compared to 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 reference 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 trials that used at least single-blind (rater-blind) design, comparing oral olanzapine with oral forms of amisulpride, aripiprazole, clozapine, quetiapine, risperidone, 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 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 (WMD) again based on a random effects model. Main results The review currently includes 50 studies and 9476 participants which provided data for six comparisons (olanzapine compared to amisulpride, aripiprazole

  3. 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

  4. Structure prediction and validation of the ERK8 kinase domain.

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    Angela Strambi

    Full Text Available Extracellular signal-regulated kinase 8 (ERK8 has been already implicated in cell transformation and in the protection of genomic integrity and, therefore, proposed as a novel potential therapeutic target for cancer. In the absence of a crystal structure, we developed a three-dimensional model for its kinase domain. To validate our model we applied a structure-based virtual screening protocol consisting of pharmacophore screening and molecular docking. Experimental characterization of the hit compounds confirmed that a high percentage of the identified scaffolds was able to inhibit ERK8. We also confirmed an ATP competitive mechanism of action for the two best-performing molecules. Ultimately, we identified an ERK8 drug-resistant "gatekeeper" mutant that corroborated the predicted molecular binding mode, confirming the reliability of the generated structure. We expect that our model will be a valuable tool for the development of specific ERK8 kinase inhibitors.

  5. Presence of Phlebotomus perniciosus Atypical Form in Algeria.

    Science.gov (United States)

    Benallal, Kamel Eddine; Benikhlef, Razika; Garni, Rafik; Gassen, Brahim; Dedet, Jean-Pierre; Harrat, Zoubir

    2017-03-01

    Phlebotomus perniciosus and Phlebotomus longicuspis are two phlebotomine sand fly species morphologically similar and differing in males only by the shape of the copulatory valves which are bifurcated in P. perniciosus, tip long and tapered in P. longicuspis. A count of the median coxite setae was carried out on 208 specimens from the collections of Dedet and of Parrot, identified previously as P. longicuspis and on 38 P. perniciosus male sand flies captured during the year 2012-2013, in order to seek the presence of atypical P. perniciosus form. The analysis revealed the presence of 33/246 (13%) atypical P. perniciosus previously confused with P. longicuspis species and whose distribution is mainly located in the semi-arid and arid bioclimatic regions. This study proved for the first time the presence of atypical form of P. perniciosus in Algeria.

  6. Atypical Craniosynostosis with Torticollis and Neurological Symptoms: A Rhombencephalosynapsis Sequence

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    Virve Koljonen

    2009-01-01

    Full Text Available Purpose. We describe a case of 3-year-old girl with rhombencephalosynapsis, a rare cerebellar anomaly. Patient. A 3-year-old girl was admitted to our hospital due to congenital torticollis and asymmetry of face, skull and trunk. Craniosynostosis was suspected due to abnormal head shape. 3D-CT revealed closure of the sagittal suture without scaphocephalic skull. Due to atypical craniosynostosis with neurological symptoms, brain-MRI was performed revealing rhombencephalosynapsis. Results. Our patient presented with atypical craniosynostosis and balance problems, not typical for scaphocephaly. Operative treatment for craniosynotosis was not carried out because the cause of the problems was the cerebellum instead of the brain. Conclusions. Therefore, we conclude that patients with atypical craniosynostosis should be examined with brain-MRI to exclude the intracranial malformations, which 3D-CT does not reveal. Without brain-MRI, decision (not to perform surgery could have been different.

  7. 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.

  8. 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.

  9. 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.

  10. Presence of Phlebotomus perniciosus Atypical Form in Algeria

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    Kamel Eddine Benallal

    2017-04-01

    Full Text Available Background: Phlebotomus perniciosus and Phlebotomus longicuspis are two phlebotomine sand fly species morphologically similar and differing in males only by the shape of the copulatory valves which are bifurcated in P. perniciosus, tip long and tapered in P. longicuspis.Methods: A count of the median coxite setae was carried out on 208 specimens from the collections of Dedet and of Parrot, identified previously as P. longicuspis and on 38 P. perniciosus male sand flies captured during the year 2012–2013, in order to seek the presence of atypical P. perniciosus form.Results: The analysis revealed the presence of 33/246 (13% atypical P. perniciosus previously confused with P. longicuspis species and whose distribution is mainly located in the semi-arid and arid bioclimatic regions.Conclusion: This study proved for the first time the presence of atypical form of P. perniciosus in Algeria.

  11. Presence of Phlebotomus perniciosus Atypical Form in Algeria

    Science.gov (United States)

    Benallal, Kamel Eddine; Benikhlef, Razika; Garni, Rafik; Gassen, Brahim; Dedet, Jean-Pierre; Harrat, Zoubir

    2017-01-01

    Background: Phlebotomus perniciosus and Phlebotomus longicuspis are two phlebotomine sand fly species morphologically similar and differing in males only by the shape of the copulatory valves which are bifurcated in P. perniciosus, tip long and tapered in P. longicuspis. Methods: A count of the median coxite setae was carried out on 208 specimens from the collections of Dedet and of Parrot, identified previously as P. longicuspis and on 38 P. perniciosus male sand flies captured during the year 2012–2013, in order to seek the presence of atypical P. perniciosus form. Results: The analysis revealed the presence of 33/246 (13%) atypical P. perniciosus previously confused with P. longicuspis species and whose distribution is mainly located in the semi-arid and arid bioclimatic regions. Conclusion: This study proved for the first time the presence of atypical form of P. perniciosus in Algeria. PMID:29026861

  12. A role for mitogen-activated protein kinase in the spindle assembly checkpoint in XTC cells.

    Science.gov (United States)

    Wang, X M; Zhai, Y; Ferrell, J E

    1997-04-21

    The spindle assembly checkpoint prevents cells whose spindles are defective or chromosomes are misaligned from initiating anaphase and leaving mitosis. Studies of Xenopus egg extracts have implicated the Erk2 mitogen-activated protein kinase (MAP kinase) in this checkpoint. Other studies have suggested that MAP kinases might be important for normal mitotic progression. Here we have investigated whether MAP kinase function is required for mitotic progression or the spindle assembly checkpoint in vivo in Xenopus tadpole cells (XTC). We determined that Erk1 and/or Erk2 are present in the mitotic spindle during prometaphase and metaphase, consistent with the idea that MAP kinase might regulate or monitor the status of the spindle. Next, we microinjected purified recombinant XCL100, a Xenopus MAP kinase phosphatase, into XTC cells in various stages of mitosis to interfere with MAP kinase activation. We found that mitotic progression was unaffected by the phosphatase. However, XCL100 rendered the cells unable to remain arrested in mitosis after treatment with nocodazole. Cells injected with phosphatase at prometaphase or metaphase exited mitosis in the presence of nocodazole-the chromosomes decondensed and the nuclear envelope re-formed-whereas cells injected with buffer or a catalytically inactive XCL100 mutant protein remained arrested in mitosis. Coinjection of constitutively active MAP kinase kinase-1, which opposes XCL100's effects on MAP kinase, antagonized the effects of XCL100. Since the only known targets of MAP kinase kinase-1 are Erk1 and Erk2, these findings argue that MAP kinase function is required for the spindle assembly checkpoint in XTC cells.

  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. 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.

  15. SUCCESSFUL TREATMENT FOR ATYPICAL HEMOLYTIC UREMIC SYNDROME IN A PUERPERA

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    O. N. Ulitkina

    2015-01-01

    Full Text Available Objective: to show the problems of differential diagnosis and treatment of atypical hemolytic-uremic syndrome in a 23-year-old patient.Results. Eculizumab (Soliris, (Alexon Pharmaceuticals Inc., USA that is a glycosylated humanized monoclonal antibody to immunoglobulins (IgG2/4k is shown to be effective in treating this disease.Conclusion. Atypical hemolytical-uremic syndrome in pregnancy is a disease, whose treatment difficulties are largely associated with the problem of differential diagnosis with thrombotic thrombocytopenic purpura and man-ifestations of multiple organ dysfunction. The treatment for this disease gives a key role to Eculizumab.

  16. Atypical Wernicke's encephalopathy showing involvement of substantia nigra.

    Science.gov (United States)

    Kalidass, Bhagheerathi; Sunnathkal, Rajani; Rangashamanna, Dr Vital; Paraswani, Rajesh

    2012-04-01

    Wernicke's encephalopathy is a metabolic disorder caused by deficiency of thiamine (vitamin B1) seen in alcoholics and even in nonalcoholic patients, classically presenting with a triad of ataxia, ophthalmoplegia, and altered mental status. Typical findings in magnetic resonance imaging are represented by symmetric signal alterations in medial thalami, mamillary bodies, tectal plate, and periaqueductal area and atypical findings involve lesions in cerebellum, midline vermis, red nuclei, dentate, caudate, cranial nerve nuclei, splenium and cerebral cortex. We report here a case of nonalcoholic starvation induced atypical WE showing symmetrical lesions in substantia nigra in addition to the classical neuroradiological findings. Copyright © 2010 by the American Society of Neuroimaging.

  17. 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.

  18. Atypical presentations of acute disseminated encephalomyelitis (ADEM) in HIV infection.

    Science.gov (United States)

    Naidoo, Ansuya; Paruk, Hoosain; Bhagwan, Bhupendra; Moodley, Anand

    2017-02-01

    Acute disseminated encephalomyelitis is a monophasic demyelinating disorder of the central nervous system associated with various viral infections including HIV infection. We present the findings of seven HIV-infected patients with mild to moderate immunosuppression presenting with atypical features. Four patients had a multiphasic course; three patients had tumefactive lesions, and two patients had corpus callosum lesions. Two patients with the multiphasic course also had tumefactive lesions. Their clinical and radiological findings are presented. Despite the few cases, we propose that the dysimmune process lying between marked immunosuppression (CD4  500 cells/μL) might be responsible for these atypical presentations.

  19. Atypical psychotic symptoms and Dandy-Walker variant.

    Science.gov (United States)

    Williams, Aislinn J; Wang, Zhenni; Taylor, Stephan F

    2016-10-01

    New-onset psychotic symptoms often respond well to antipsychotic treatment; however, symptoms may be difficult to treat when an underlying brain malformation is present. Here, we present a case of atypical psychotic symptoms in the context of a congenital cerebellar malformation (Dandy-Walker variant). The patient ultimately improved with paliperidone palmitate after multiple antipsychotic medication trials (both oral and one long-acting injectable) were ineffective. Neuroimaging may provide valuable diagnostic and prognostic information in cases of new-onset psychosis with atypical features and treatment resistance, even in the absence of neurologic signs and symptoms.

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

    Science.gov (United States)

    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 uncommon, delay in recognition of PD peritonitis caused by atypical organisms can lead to poor patient outcomes if there is a delay in diagnosis and implementation of appropriate treatment. There is also a large difference in prevalence of antibiotic-resistant infections across the world with variable impact on reported patient-level outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Genetics Home Reference: phosphoglycerate kinase deficiency

    Science.gov (United States)

    ... Genetic Testing Registry: Phosphoglycerate kinase 1 deficiency Other Diagnosis and Management Resources (1 link) Children Living with Inherited Metabolic Diseases (CLIMB) (UK): Phosphoglycerate Kinase Deficiency (PDF) General Information ...

  2. Atypical energy eigenstates in the Hubbard chain and quantum disentangled liquids.

    Science.gov (United States)

    Veness, Thomas; Essler, Fabian H L; Fisher, Matthew P A

    2017-12-13

    We investigate the implications of integrability for the existence of quantum disentangled liquid (QDL) states in the half-filled one-dimensional Hubbard model. We argue that there exist finite energy-density eigenstates that exhibit QDL behaviour in the sense of Grover & Fisher (2014 J. Stat. Mech.2014, P10010. (doi:10.1088/1742-5468/2014/10/P10010)). These states are atypical in the sense that their entropy density is smaller than that of thermal states at the same energy density. Furthermore, we show that thermal states in a particular temperature window exhibit a weaker form of the QDL property, in agreement with recent results obtained by strong-coupling expansion methods in Veness et al. (2016 (http://arxiv.org/abs/1611.02075)).This article is part of the themed issue 'Breakdown of ergodicity in quantum systems: from solids to synthetic matter'. © 2017 The Author(s).

  3. Teaching Fluid Mechanics for Undergraduate Students in Applied Industrial Biology: from Theory to Atypical Experiments

    CERN Document Server

    Absi, Rafik; Dufour, Florence; Huet, Denis; Bennacer, Rachid; Absi, Tahar

    2011-01-01

    EBI is a further education establishment which provides education in applied industrial biology at level of MSc engineering degree. Fluid mechanics at EBI was considered by students as difficult who seemed somewhat unmotivated. In order to motivate them, we applied a new play-based pedagogy. Students were asked to draw inspiration from everyday life situations to find applications of fluid mechanics and to do experiments to verify and validate some theoretical results obtained in course. In this paper, we present an innovative teaching/learning pedagogy which includes the concept of learning through play and its implications in fluid mechanics for engineering. Examples of atypical experiments in fluid mechanics made by students are presented. Based on teaching evaluation by students, it is possible to know how students feel the course. The effectiveness of this approach to motivate students is presented through an analysis of students' teaching assessment. Learning through play proved a great success in fluid...

  4. Acute generalized exanthematous pustulosis induced by hydroxychloroquine: a case with atypical clinical presentation.

    Science.gov (United States)

    Duman, Hatice; Topal, Ilteris Oguz; Kocaturk, Emek; Cure, Kubra; Mansuroglu, Ilknur

    2017-01-01

    Acute generalized exanthematous pustulosis is a rare drug-induced eruption that is characterized by acute, nonfollicular sterile pustules on an erythematous and edematous base. The most frequently implicated drugs are beta-lactam antibiotics. Hydroxychloroquine has been widely used to treat dermatologic and rheumatologic diseases and has been reported as a rare cause of acute generalized exanthematous pustulosis. A 42-year-old female presented with pustular lesions on the skin surface with erythema, facial edema, and occasional atypical target-like lesions after 21 days of treatment with 200mg/day hydroxychloroquine for rheumatoid arthritis, diagnosed one month previously. We report a case with acute generalized exanthematous pustulosis induced by hydroxychloroquine and treated with dapsone and systemic corticosteroid.

  5. Role of Protein Kinase C (PKC in Podocytes and Development of Glomerular Damage in Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Beina eTeng

    2014-11-01

    Full Text Available The early glomerular changes in diabetes include a podocyte phenotype with loss of slit diaphragm proteins, changes in the actin cytoskeleton and foot process architecture. This review focusses on the role of the Protein Kinase C family in podocytes and points out the differential roles of classical, novel and atypical PKCs in podocytes. Some PKC-isoforms are indispensable for proper glomerular development and slit diaphragm maintenance whereas others might be harmful when activated in the diabetic milieu. Therefore some might be interesting treatment targets in the early phase of diabetes.

  6. Recent Outbreaks of Atypical Contact Lens-Related Keratitis: What Have We Learned?

    Science.gov (United States)

    Tu, Elmer Y.; Joslin, Charlotte E

    2010-01-01

    Purpose To examine the public health implications of two recent outbreaks of atypical contact lens-related infectious keratitis. Design A perspective based on the literature and authors’ experience. Results The contact lens-related fusarium and acanthamoeba keratitis outbreaks were both detected by dramatic rises seen in tertiary care centers in Singapore and the US, respectively. Case control studies in both outbreaks each were able to identify a strong association with the use of different contact lens disinfection solutions. Their respective recalls resulted in a steep decline of fusarium keratitis, but not of acanthamoeba keratitis. Early investigations into each solution association implicate components not directly related to their primary disinfectant, but the true pathogenesis remains unknown. However, the number of Acanthamoeba cases individually attributed to each of almost all available disinfection systems exceeds previously understood total US incidence, suggesting other risk factors. Current standards do not require demonstration of anti-acanthamoebal activity. Yet, despite the inclusion of fusarium in mandatory testing for solutions, current pre-market testing was not predictive of the outbreak. Conclusions The two recent outbreaks of atypical contact-lens related keratitis have reinforced the value of tertiary care eye care centers in detecting early rises in rare infections and the power of adaptable, well-designed epidemiologic investigations. While fusarium keratitis has significantly declined with the recall of Renu with Moistureloc, the persistence of Acanthamoeba keratitis begs fundamental changes in contact lens hygiene practices, inclusion of acanthamoeba as a test organism and contact lens disinfectant test regimens for all contact lens–related pathogens which are verifiably reflective of end user contact lens wear complications. PMID:21036209

  7. 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 syndrome...

  8. 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.

  9. 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.

  10. Can Neurotypical Individuals Read Autistic Facial Expressions? Atypical Production of Emotional Facial Expressions in Autism Spectrum Disorders.

    Science.gov (United States)

    Brewer, Rebecca; Biotti, Federica; Catmur, Caroline; Press, Clare; Happé, Francesca; Cook, Richard; Bird, Geoffrey

    2016-02-01

    The difficulties encountered by individuals with autism spectrum disorder (ASD) when interacting with neurotypical (NT, i.e. nonautistic) individuals are usually attributed to failure to recognize the emotions and mental states of their NT interaction partner. It is also possible, however, that at least some of the difficulty is due to a failure of NT individuals to read the mental and emotional states of ASD interaction partners. Previous research has frequently observed deficits of typical facial emotion recognition in individuals with ASD, suggesting atypical representations of emotional expressions. Relatively little research, however, has investigated the ability of individuals with ASD to produce recognizable emotional expressions, and thus, whether NT individuals can recognize autistic emotional expressions. The few studies which have investigated this have used only NT observers, making it impossible to determine whether atypical representations are shared among individuals with ASD, or idiosyncratic. This study investigated NT and ASD participants' ability to recognize emotional expressions produced by NT and ASD posers. Three posing conditions were included, to determine whether potential group differences are due to atypical cognitive representations of emotion, impaired understanding of the communicative value of expressions, or poor proprioceptive feedback. Results indicated that ASD expressions were recognized less well than NT expressions, and that this is likely due to a genuine deficit in the representation of typical emotional expressions in this population. Further, ASD expressions were equally poorly recognized by NT individuals and those with ASD, implicating idiosyncratic, rather than common, atypical representations of emotional expressions in ASD. © 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.

  11. Genome-wide identification and analysis of expression profiles of maize mitogen-activated protein kinase kinase kinase.

    Directory of Open Access Journals (Sweden)

    Xiangpei Kong

    Full Text Available Mitogen-activated protein kinase (MAPK cascades are highly conserved signal transduction model in animals, yeast and plants. Plant MAPK cascades have been implicated in development and stress responses. Although MAPKKKs have been investigated in several plant species including Arabidopsis and rice, no systematic analysis has been conducted in maize. In this study, we performed a bioinformatics analysis of the entire maize genome and identified 74 MAPKKK genes. Phylogenetic analyses of MAPKKKs from maize, rice and Arabidopsis have classified them into three subgroups, which included Raf, ZIK and MEKK. Evolutionary relationships within subfamilies were also supported by exon-intron organizations and the conserved protein motifs. Further expression analysis of the MAPKKKs in microarray databases revealed that MAPKKKs were involved in important signaling pathways in maize different organs and developmental stages. Our genomics analysis of maize MAPKKK genes provides important information for evolutionary and functional characterization of this family in maize.

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

    OpenAIRE

    Brett Silverstein; Jules Angst

    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 appetit...

  13. Atypical X-linked agammaglobulinaemia caused by a novel BTK mutation in a selective immunoglobulin M deficiency patient.

    Science.gov (United States)

    Lim, Lee-Moay; Chang, Jer-Ming; Wang, I-Fang; Chang, Wei-Chiao; Hwang, Daw-Yang; Chen, Hung-Chun

    2013-09-27

    X-linked agammaglobulinaemia (XLA) is the most common inherited humoural immunodeficiency disorder. Mutations in the gene coding for Bruton's tyrosine kinase (BTK) have been identified as the cause of XLA. Most affected patients exhibit a marked reduction of serum immunoglobulins, mature B cells, and an increased susceptibility to recurrent bacterial infections. However, the diagnosis of XLA can be a challenge in certain patients who have near-normal levels of serum immunoglobulin. Furthermore, reports on XLA with renal involvement are scant. We report an atypical XLA patient who presented with selective immunoglobulin M (IgM) immunodeficiency and nephropathy. He was diagnosed with selective IgM immunodeficiency, based on his normal serum immunoglobulin G (IgG) and immunoglobulin A (IgA) levels but undetectable serum IgM level. Intravenous immunoglobulin was initiated due to increased infections and persistent proteinuria but no improvement in proteinuria was found. A lupus-like nephritis was detected in his kidney biopsy and the proteinuria subsided after receiving a mycophenolate mofetil regimen. Although he had a history of recurrent bacterial infections since childhood, XLA was not diagnosed until B-lymphocyte surface antigen studies and a genetic analysis were conducted. We suggest that B-lymphocyte surface antigen studies and a BTK mutation analysis should be performed in familial patients with selective IgM deficiency to rule out atypical XLA.

  14. Role of laboratory in rapid diagnosis of atypical mumps

    Directory of Open Access Journals (Sweden)

    KE Vandana

    Full Text Available Fairly large number of mumps virus infections present atypically without parotitis leading to delay in diagnosis and increased morbidity. Awareness of such presentations and inclusion of serological test for detecting IgM-specific antibodies could help in solving diagnostic dilemma, especially in unvaccinated individuals from developing countries.

  15. Atypical Chikungunya during pregnancy: Report of the Venezuela final experience

    Directory of Open Access Journals (Sweden)

    Ana Carvajal

    2017-01-01

    Full Text Available Introduction Chikungunya virus (CHIKV is an emerging arbovirus in Latin America and the Caribbean. The virus was detected in the Caribbean territory, at the end of 2013 for the first time. It is known that 1 to 2 % of patients will show atypical symptoms. Methods Three cases of pregnant women with atypical Chikungunya virus are described taking into account epidemiological variables, clinical features, pregnancy progress and laboratory testing parameters. Results Three pregnant women with atypical CHIKV confirmed by RT‐PCR were included. All of them were included at the ICU because of a life‐ threatening disease, 2 of the pregnancies were resolved by caesarean, one at term with a newborn with typical CHIKV and the other one at the 25 week of pregnancy, this result in a stillborn and a neonatal death. Conclusion Chikungunya fever during pregnancy can show atypical and severe course, with adverse evolution of pregnancy and vertical transmission of the infection. We recommend to maximize the medical care in pregnant women with suspicion of CHIKV infection.

  16. Diagnosis and management of atypically presenting slowly-leaking ...

    African Journals Online (AJOL)

    Background: An ectopic pregnancy is a common cause of morbidity and occasionally of mortality in women of reproductive age. Its diagnosis can be difficult with an atypical presentation as the classic symptoms of abdominal pain, amenorrhoea and vaginal bleeding are seen in 50% of women presenting with ectopic ...

  17. Heterogeneous photocatalysis for selected atypical antipsychotic removal from river waters

    OpenAIRE

    Regulska, El?bieta; Karpi?ska, Joanna

    2011-01-01

    Heterogeneous photocatalysis of selected atypical antipsychotic, namely olanzapine, was examined. Photocatalytic degradation of above mentioned pharmaceutic was investigated in deionized and river water solution in the presence of titanium dioxide as a photocatalyst. River water samples were collected from Narew and Marycha, which run in the east of Poland. Studied irradiation sources included ultraviolet radiation and simulated solar light. Photodegradation efficiency and the presen...

  18. Use of atypical antipsychotics in the elderly: a clinical review

    Directory of Open Access Journals (Sweden)

    Gareri P

    2014-08-01

    Full Text Available Pietro Gareri,1 Cristina Segura-García,2 Valeria Graziella Laura Manfredi,1 Antonella Bruni,2 Paola Ciambrone,2 Gregorio Cerminara,2 Giovambattista De Sarro,2 Pasquale De Fazio2 1Elderly Health Care, Azienda Sanitaria Provinciale Catanzaro, Catanzaro, Italy; 2Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy Abstract: The use of atypical antipsychotic drugs in the elderly has become wider and wider in recent years; in fact, these agents have novel receptor binding profiles, good efficacy with regard to negative symptoms, and reduced extrapyramidal symptoms. However, in recent years, the use of both conventional and atypical antipsychotics has been widely debated for concerns about their safety in elderly patients affected with dementia and the possible risks for stroke and sudden death. A MEDLINE search was made using the words elderly, atypical antipsychotics, use, schizophrenia, psychosis, mood disorders, dementia, behavioral disorders, and adverse events. Some personal studies were also considered. This paper reports the receptor binding profiles and the main mechanism of action of these drugs, together with their main use in psychiatry and the possible adverse events in elderly people. Keywords: atypical antipsychotics, dementia, elderly, psychosis, mood disorders, side effects

  19. [Atypical sites of metastatic renal carcinoma. Literature review].

    Science.gov (United States)

    Pérez Fentes, D A; Blanco Parra, M; Toucedo Caamaño, V; Lema Grille, J; Cimadevila García, A; Villar Núñez, M

    2005-01-01

    To review in the literature atypical sites of metastatic renal cell carcinoma, its onset, clinical features, diagnosis, treatment and prognosis. To review, using Medline database, atypical sites of metastatic renal cell carcinoma in the last five years Spanish literature. There have been published 15 spanish articles about atypical metastatic renal cell carcinoma in the last five years. Most patients were male with a mean age of 62,3 years and methacronous metastases. Imaging and pathological diagnosis. Main sites: ocular, renal graft, larynx, suprarenal, brain, penis, gastric and pancreatic. Surgical treatment if the surgeon is able to remove the lesion. Inmunotherapy and radiotherapy in the rest of cases. Renal cell carcinoma represents about 3% of all adult malignancy neoplasms. Its metastatic sites, in order of frequency, are lung, bone and liver, whether synchronic or methacronic. Its location, clinical features, onset, evolution and prognosis is very variable. Individualized diagnostic and therapeutic approach, according to prognostic factors. The knowledge of this atypical sites in patients with renal cell carcinoma in the past can lead us to an earlier diagnosis and treatment which could change the evolution of the illness.

  20. Strategies in an Arts Program for Adults with Atypical Communication

    Science.gov (United States)

    Lukac, Christina

    2017-01-01

    The purpose of this study was to observe and implement strategies and adaptations in an arts program for adults with atypical communication due to developmental and intellectual disabilities. This study was conducted in the field using an action research approach with triangulated methods of data collection including semi-structured interviews,…

  1. Atypical vessels as an early sign of intracardiac myxoma?

    Science.gov (United States)

    Dübel, Hans-Peter; Knebel, Fabian; Gliech, Volker; Konertz, Wolfgang; Rutsch, Wolfgang; Baumann, Gert; Borges, Adrian Constantin

    2004-01-01

    We report on a woman with previously unknown left atrial myxoma, who underwent percutaneous coronary intervention. 45 months after the initial coronary angiography, echocardiography demonstrated a large atrial myxoma, which was not seen echocardiographically before. The retrospective analysis of the pre-intervention coronary angiography revealed atypical vessels in the atrial septum, which are interpreted as early signs of myxoma. PMID:15310408

  2. CASE REPORT CASE Atypical tuberculosis of the knee joint CASE ...

    African Journals Online (AJOL)

    TB caused by atypical mycobacteria is rare; instead, it is predomi- nantly a synovial disease affecting the tendon sheaths rather than bone. Predisposing factors are immunocompromised individuals, including the elderly, alcoholics, those with HIV, diabetes mellitus, malnutrition and other chronic debilitating illnesses, and ...

  3. [HL-A W27 antigen and atypical rheumatic pelvispondylitis].

    Science.gov (United States)

    Sany, J; Serre, H; Seignalet, J

    1976-02-01

    The authors report 26 cases of atypical inflammatory rheumatism in which the discovery of HL-A W27 antigen indicated the possibility of atypical ankylosing spondylarthritis. These patients included 17 men and 9 women with an average age of 35.6 years. The clinical symptoms included :--pelvic or vetebral signs alone in 8 cases,--pelvic or vertebral signs combined with peripheral inflammatory rheumatism, the latter being always cleaarly evident, in 9 cases,--extravertebral signs alone without any involvement of the vertebral column or of the sacroiliac joints in 9 cases (8 cases of peripheral inflammatory rheumatism, 1 case of talalgia). The vertebral radiograms were normal in 84 percent of cases. The sacroiliac joints were clear radiologically in 65 percent of cases. In the other cases the lesions, generally unilateral, were extremely discrete. In all the cases, the Waaler-Rose reaction was negative. The therapeutic test with non-hormonal anti inflammatory products were generally positive. The evolution of the condition confirmed the diagnosis of rheumatic pelvispondylitis in 2 cases. The patients have been under observation for insufficient time to be sure whether all the cases presented represent authentic cases of ankylosing spondylarthritis that were at first atypical. The authors emphasize the high percentage of female cases (38 percent) the high frequency of extra-vertebral manifestations. They also emphasize the value of looking for HL-A W27 antigen in patients with atypical inflammatory rheumatism.

  4. Nonconvulsive Status Epilepticus Resembling Clinical Absence with Atypical EEG Pattern

    Directory of Open Access Journals (Sweden)

    Channaiah Srikanth Mysore

    2017-01-01

    Full Text Available Objective. We are reporting two cases: a patient with steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT and another patient with secondary progressive multiple sclerosis (SPMS, both presenting with altered mental status (AMS and later diagnosed with nonconvulsive atypical absence status epilepticus (AS, with atypical EEG changes. Methods. A report of two cases. Results. A patient with history of SREAT and the other with SPMS had multiple admissions due to AMS. For both, EEG revealed the presence of a high voltage generalized sharply contoured theta activity. A diagnosis of NCSE with clinical features of AS was made based on both clinical and EEG features. There was significant clinical and electrographic improvement with administration of levetiracetam for both patients in addition to sodium valproate and Solumedrol for the SREAT patient. Both patients continued to be seizure free on follow-up few months later. Conclusions. This is a report of two cases of atypical AS, with atypical EEG, in patients with different neurological conditions. Prompt clinical and EEG recovery occurred following appropriate medical treatment. We think that this condition might be underreported and could significantly benefit from prompt treatment when appropriately diagnosed.

  5. Fibrolipomatous hamartoma in the foot: atypical MR imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Breuseghem, I. van; Pans, S.; Geusens, E.; Brys, P. [Department of Radiology, University Hospitals Leuven, Herestraat 49, 3000, Leuven (Belgium); Sciot, R. [Department of Pathology, University Hospitals Leuven (Belgium); Wever, I. de [Department of Oncological Surgery, University Hospitals Leuven (Belgium)

    2003-11-01

    Lipomatosis of a nerve is a well-known but uncommon entity mostly seen in the median nerve. Magnetic resonance imaging (MRI) has been shown to provide pathognomonic features, obviating the need for diagnostic biopsy. We present a case of lipomatosis of a branch of the medial plantar nerve with an atypical appearance on magnetic resonance imaging. (orig.)

  6. Comparing the side effect profile of the Atypical

    African Journals Online (AJOL)

    antipsychotics have greater efficacy (especially for negative symptoms) and fewer EPSE when compared to the typical antipsychotics. Given the lack of studies directly comparing these agents, we used the Physician Desk Reference (PDR) to calculate the treatment emergent placebo adjusted side effects for these atypical ...

  7. 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.

  8. Hereditary atypical retinitis pigmentosa: case report | Omoti | Annals ...

    African Journals Online (AJOL)

    This report presents four generations of hereditary atypical (pericentric) retinitis pigmentosa in an Itsekiri family of Warri, Delta state of Nigeria. The patients presented with nyctalopia, waxy disc pallor, arteriolar attenuation, pigment deposits around the optic nerve and visual field loss. The cases were typically mild with ...

  9. 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 grou...

  10. Atypical teratoid/rhabdoid tumour in a supratentorial location

    African Journals Online (AJOL)

    cerebro spinal fluid seeding, as in our second patient,[4] which led to their death. e entire CNS must therefore be imaged at presentation to identify subarachnoid spread of the tumour. e differential diagnosis for atypical teratoid/rhabdoid tumour includes. PNET, medulloblastoma, high-grade glioma and teratoma.[1,3,6].

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

    African Journals Online (AJOL)

    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 ...

  12. Atypical presentation of systemic lupus erythematosus in a west ...

    African Journals Online (AJOL)

    Systemic lupus erythematosus (SLE) is a chronic, autoimmune multi-system disorder. About seventy to ninety percent of all cases of SLE occur in women. Although the disease is common in black young women residing in Europe and North America, it is reputed to be a very rare diagnosis in West Africa. A case of atypical ...

  13. Atypical tuberculosis of the knee joint | Albuquerque-Jonathan | SA ...

    African Journals Online (AJOL)

    (TB) of the knee joint, caused by Mycobacterium kansasii. Osteoarticular TB caused by atypical mycobacteria is rare; instead, it is predominantly a synovial disease affecting the tendon sheaths rather than bone. Predisposing factors are immunocompromised individuals, including the elderly, alcoholics, those with HIV, ...

  14. Atypical Localizations of Hydatid Disease: Experience from a Single ...

    African Journals Online (AJOL)

    Departments of General Surgery, 1Radiodiagnosis and Imaging and 2Neurosurgery, Sheri Kashmir Institute of Medical. Sciences, Soura, Srinagar, Jammu and ... development of hydatidosis at the primary sites. KEYWORDS: Atypical locations ..... Conflict of Interest: None declared. 24. Senyuz OF, Yesildag E, Celayir S.

  15. Grid Keratotomy for Treatment of Atypical Presenting Indolent ...

    African Journals Online (AJOL)

    Corneal ulcers are one of the highest causes of vision impairment in dogs. The Boxer breed is particularly predisposed to recurrent and refractory corneal ulcers (Whitley and Gigler, 1999). In this report we present an interesting case of indolent corneal ulcer in a Boxer with atypical clinical manifestation and features, and its ...

  16. Atypical basic movement kinematics in autism spectrum conditions

    Science.gov (United States)

    Blakemore, Sarah-Jayne; Press, Clare

    2013-01-01

    Individuals with autism spectrum conditions have difficulties in understanding and responding appropriately to others. Additionally, they demonstrate impaired perception of biological motion and problems with motor control. Here we investigated whether individuals with autism move with an atypical kinematic profile, which might help to explain perceptual and motor impairments, and in principle may contribute to some of their higher level social problems. We recorded trajectory, velocity, acceleration and jerk while adult participants with autism and a matched control group conducted horizontal sinusoidal arm movements. Additionally, participants with autism took part in a biological motion perception task in which they classified observed movements as ‘natural’ or ‘unnatural’. Results show that individuals with autism moved with atypical kinematics; they did not minimize jerk to the same extent as the matched typical control group, and moved with greater acceleration and velocity. The degree to which kinematics were atypical was correlated with a bias towards perceiving biological motion as ‘unnatural’ and with the severity of autism symptoms as measured by the Autism Diagnostic Observation Schedule. We suggest that fundamental differences in movement kinematics in autism might help to explain their problems with motor control. Additionally, developmental experience of their own atypical kinematic profiles may lead to disrupted perception of others’ actions. PMID:23983031

  17. Update on diffusion MRI in Parkinson's disease and atypical parkinsonism

    NARCIS (Netherlands)

    Meijer, F.J.A.; Bloem, B.R.; Mahlknecht, P.; Seppi, K.; Goraj, B.

    2013-01-01

    Differentiating Parkinson's disease (PD) from other types of neurodegenerative atypical parkinsonism (AP) can be challenging, especially in early disease stages. Routine brain magnetic resonance imaging (MRI) can show atrophy or signal changes in several parts of the brain with fairly high

  18. Clinical Profile of Atypical Manifestations of Dengue Fever.

    Science.gov (United States)

    Pothapregada, Sriram; Kamalakannan, Banupriya; Thulasingam, Mahalakshmy

    2016-06-01

    To study the clinical profile and outcome of the atypical manifestations of dengue fever in children. All children (0-12 y of age) diagnosed and confirmed as dengue fever at a tertiary care hospital at Puducherry, between the 1st of August 2012 and January 31st 2015 were reviewed retrospectively from hospital case records as per the revised World Health Organization (WHO) guidelines 2011 for dengue fever. The diagnosis was confirmed by NS1 antigen-based ELISA test or dengue serology for IgM and IgG antibodies and the data was analyzed using SPSS 16.0 statistical software. Out of 254 children admitted with dengue fever, non-severe dengue and severe dengue were seen in 62.6 % and 37.4 % respectively. Atypical manifestations were seen in 106 cases (41.7 %). Mean age of presentation was 6.9(3.3) y. M: F ratio was 1.2:1. The common manifestations of severe dengue infection were shock (37.4 %), bleeding (20.1 %) and multi-organ dysfunction (2.4 %). The most common atypical manifestations of dengue fever were lymphadenopathy (41.7 %), splenomegaly (21.2 %), biphasic fever (18.1 %), hepatitis (11.4 %), febrile diarrhea (6.3 %), refractory shock (2.4 %) and impaired consciousness (1.9 %). The other atypical manifestations present were portal hypertension, acalculous cholecystitis, appendicitis, acute respiratory distress syndrome (ARDS), myocarditis, pericardial effusion, paroxysmal supraventricular tachycardia (PSVT), myositis, acute kidney injury (AKI), hemophagocytic syndrome and disseminated intravascular coagulopathy (DIC). Platelet count did not always correlate well with the severity of bleeding. There were six deaths (2.4 %) and out of them four presented with impaired consciousness (66.6 %). The common causes for poor outcome were multiorgan failure, encephalopathy and refractory shock. The atypical manifestations of dengue fever are no more a rare entity. Clinicians should have a high index of suspicion and vigilance for atypical manifestations of

  19. Venus kinase receptors: prospects in signaling and biological functions of these invertebrate kinases.

    Science.gov (United States)

    Dissous, Colette; Morel, Marion; Vanderstraete, Mathieu

    2014-01-01

    Venus kinase receptors (VKRs) form a family of invertebrate receptor tyrosine kinases (RTKs) initially discovered in the parasitic platyhelminth Schistosoma mansoni. VKRs are single transmembrane receptors that contain an extracellular venus fly trap structure similar to the ligand-binding domain of G protein-coupled receptors of class C, and an intracellular tyrosine kinase domain close to that of insulin receptors. VKRs are found in a large variety of invertebrates from cnidarians to echinoderms and are highly expressed in larval stages and in gonads, suggesting a role of these proteins in embryonic and larval development as well as in reproduction. VKR gene silencing could demonstrate the function of these receptors in oogenesis as well as in spermatogenesis in S. mansoni. VKRs are activated by amino acids and are highly responsive to arginine. As many other RTKs, they form dimers when activated by ligands and induce intracellular pathways involved in protein synthesis and cellular growth, such as MAPK and PI3K/Akt/S6K pathways. VKRs are not present in vertebrates or in some invertebrate species. Questions remain open about the origin of this little-known RTK family in evolution and its role in emergence and specialization of Metazoa. What is the meaning of maintenance or loss of VKR in some phyla or species in terms of development and physiological functions? The presence of VKRs in invertebrates of economical and medical importance, such as pests, vectors of pathogens, and platyhelminth parasites, and the implication of these RTKs in gametogenesis and reproduction processes are valuable reasons to consider VKRs as interesting targets in new programs for eradication/control of pests and infectious diseases, with the main advantage in the case of parasite targeting that VKR counterparts are absent from the vertebrate host kinase panel.

  20. 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).

  1. MAP kinase cascades in Arabidopsis innate immunity

    DEFF Research Database (Denmark)

    Rasmussen, Magnus Wohlfahrt; Roux, Milena Edna; Petersen, Morten

    2012-01-01

    Plant mitogen-activated protein kinase (MAPK) cascades generally transduce extracellular stimuli into cellular responses. These stimuli include the perception of pathogen-associated molecular patterns (PAMPs) by host transmembrane pattern recognition receptors which trigger MAPK-dependent innate...... immune responses. In the model Arabidopsis, molecular genetic evidence implicates a number of MAPK cascade components in PAMP signaling, and in responses to immunity-related phytohormones such as ethylene, jasmonate, and salicylate. In a few cases, cascade components have been directly linked...... to the transcription of target genes or to the regulation of phytohormone synthesis. Thus MAPKs are obvious targets for bacterial effector proteins and are likely guardees of resistance proteins, which mediate defense signaling in response to the action of effectors, or effector-triggered immunity. This mini...

  2. Tyrosine kinases in inflammatory dermatologic disease.

    Science.gov (United States)

    Paniagua, Ricardo T; Fiorentino, David F; Chung, Lorinda; Robinson, William H

    2011-08-01

    Tyrosine kinases (TKs) are enzymes that catalyze the phosphorylation of tyrosine residues on protein substrates. They are key components of signaling pathways that drive an array of cellular responses including proliferation, differentiation, migration, and survival. Specific TKs have recently been identified as critical to the pathogenesis of several autoimmune and inflammatory diseases. Small-molecule inhibitors of TKs are emerging as a novel class of therapy that may provide benefit in certain patient subsets. In this review, we highlight TK signaling implicated in inflammatory dermatologic diseases, evaluate strategies aimed at inhibiting these aberrant signaling pathways, and discuss prospects for future drug development. Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  3. Cutaneous and Subcutaneous Metastases From Atypical Laryngeal Carcinoids

    Science.gov (United States)

    Wang, Kui-Rong; Jia, Yuan-Jing; Zhou, Shui-Hong; Wang, Qin-Ying; Bao, Yang-Yang; Feng, Zhi-Ying; Yao, Hong-Tian; Fan, Jun

    2016-01-01

    Abstract The incidence of cutaneous and subcutaneous metastases from atypical laryngeal carcinoids is approximately 20%. However, the pathogenesis and natural history of, and prognostic factors for, the condition remain poorly understood. We reported a 54-year-old female presented with cutaneous and subcutaneous metastases from atypical laryngeal carcinoid. Laryngoscopy revealed a 0.5 × 1.5-cm reddish mass on the laryngeal surface of the epiglottis. Under general anesthesia, a biopsy sample was obtained via suspension laryngoscopy. Routine pathology revealed atypical laryngeal carcinoid. Immunohistochemical staining of the sections of primary tumor was positive for cytokeratin, chromogranin A, synaptophysin, hypoxia-inducible factor-1α, P53, and CD56. GLUT-1, p-Akt, and PI3K were negative. The Ki-67 index was 15%. Supraglottic laryngectomy and selective right-neck dissection were performed. After 6 months, the patient complained of pain in the right wall of the chest; multiple cutaneous and subcutaneous nodules were evident at that site and in the abdomen. An abdominal nodule was biopsied and pathology revealed that the atypical metastatic carcinoid had metastasized to both cutaneous and subcutaneous areas of the abdomen. Chemotherapy was then prescribed. Currently, the intrathecal drug delivery system remains in place. No local recurrence has been detected. Furthermore, we systematically reviewed clinical manifestations of the disease, pathogenesis, prognostic factors, and treatment. The metastasis rate (cutaneous and subcutaneous) was approximately 12.2%. Thirty patients (62.5%) with cutaneous and subcutaneous metastases exhibited contemporaneous lymph node invasion. The 3-, 5-, and 10-year survival rates were 44.0%, 22.0%, and 13.0%, respectively. The prognosis of patients with atypical laryngeal carcinoids was poor. Relevant prognostic factors included the level of p53, human papilloma virus status, certain hypoxic markers, and distant metastasis. No

  4. Citron kinase - renaissance of a neglected mitotic kinase.

    Science.gov (United States)

    D'Avino, Pier Paolo

    2017-05-15

    Cell division controls the faithful segregation of genomic and cytoplasmic materials between the two nascent daughter cells. Members of the Aurora, Polo and cyclin-dependent (Cdk) kinase families are known to regulate multiple events throughout cell division, whereas another kinase, citron kinase (CIT-K), for a long time has been considered to function solely during cytokinesis, the last phase of cell division. CIT-K was originally proposed to regulate the ingression of the cleavage furrow that forms at the equatorial cortex of the dividing cell after chromosome segregation. However, studies in the last decade have clarified that this kinase is, instead, required for the organization of the midbody in late cytokinesis, and also revealed novel functions of CIT-K earlier in mitosis and in DNA damage control. Moreover, CIT-K mutations have recently been linked to the development of human microcephaly, and CIT-K has been identified as a potential target in cancer therapy. In this Commentary, I describe and re-evaluate the functions and regulation of CIT-K during cell division and its involvement in human disease. Finally, I offer my perspectives on the open questions and future challenges that are necessary to address, in order to fully understand this important and yet unjustly neglected mitotic kinase. © 2017. Published by The Company of Biologists Ltd.

  5. Clinical utilization of atypical antipsychotics in pregnancy and lactation.

    Science.gov (United States)

    Gentile, Salvatore

    2004-01-01

    To analyze the available literature regarding the safety of atypical antipsychotics in pregnancy and lactation in order to recommend evidence-based strategies for pharmacologic management of psychosis in these conditions. We summarized the results from articles identified via MEDLINE/PubMed/TOXNET (1993-January 31, 2004), using the key terms pregnancy, lactation, breast-feeding, human milk, psychotropic drugs, atypical antipsychotics, olanzapine, quetiapine, risperidone, clozapine, ziprasidone, and aripiprazole. Retrospective studies, clinical observations, and case reports regarding the 6 atypical antipsychotics mentioned above were selected and analyzed. Extensive manual review of pertinent journals and textbooks was also performed. Reviewed studies show that olanzapine and clozapine apparently do not increase the teratogenic risk if administered to pregnant women, while evidence on quetiapine, risperidone, aripiprazole, and ziprasidone is still limited. In contrast, available information is not able to exclude unwanted serious effects associated with the use of all atypical antipsychotics on mother-infant dyads. Furthermore, more than a few studies suggest increased hyperglycemic risk for pregnant women related to atypical antipsychotic therapy during gestation. Finally, published evidence about the effects on long-term infant neurodevelopment of drug exposure through both placenta and breast milk is represented only by sporadic case reports. It is well known that potential consequences of an untreated psychotic episode may be severe and may lead to the mother attempting suicide and/or infanticide. For these reasons, clinicians need to help mothers weigh both fetal and neonatal risks of exposure to drugs against the potential risk they and their infant may incur if the psychiatric illness is not treated. On the other hand, atypical antipsychotics in pregnancy and breast-feeding do not show evident advantages in safety when compared with typical neuroleptic

  6. Atypical depression in the structure of organic mental disorders (literature review

    Directory of Open Access Journals (Sweden)

    Leonov S.F.

    2014-09-01

    Full Text Available The review of literature presents current data on cli¬nical picture and diagnostics of atypical depression. Rubric “atypical depression” includes a variety of depressive states characterized by reactively caused changes of mood, sensitivity to interpersonal contacts, inverted vegetative and somatic symptoms such as increased appetite and hypersomnia. The article considers the place of atypical depression in the structure of organic mental disorders. Positions of foreign authors that produce atypical depression as a clinical entity in the structure of Bipolar affective disorder II type are represented, the views of other authors on the structure of atypical depression are considered. The analysis of national concept of non-circular depression is carried out. Questions of atypical affective conditions acquire special significance due to preparation of International Classification of Diseases of the 11th revision, because inclusion in it of Bipolar affective disorder II type, a manifestation of which is considered to be atypical depressions, is under discussion.

  7. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells.

    Science.gov (United States)

    Remsing Rix, L L; Rix, U; Colinge, J; Hantschel, O; Bennett, K L; Stranzl, T; Müller, A; Baumgartner, C; Valent, P; Augustin, M; Till, J H; Superti-Furga, G

    2009-03-01

    The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.

  8. Regulation of Akt(ser473 phosphorylation by Choline kinase in breast carcinoma cells

    Directory of Open Access Journals (Sweden)

    Ullrich Axel

    2009-12-01

    Full Text Available Abstract Background The serine/threonine kinase PKB/Akt plays essential role in various cellular processes including cell growth and proliferation, metabolism and cell survival. The importance of the Akt pathway is highlighted by the mutation of various components of the pathway such as the PTEN and PI3-kinase (P110α in human cancers. In this paper, we employed an RNA interference library targeting all human kinases to screen for kinases involved in the regulation of Akt activation, in particular serine 473 phosphorylation. Here, we transfected the MDA-MB 468 breast cell line with the human kinome siRNA library and measured Akt activation using an antibody specific for phosphoserine 473 of Akt. Results The screen revealed that phosphorylation of Akt(ser473 can be regulated by more than 90 kinases. Interestingly, phosphorylation of Akt(ser473, but not thr308, can be severely reduced by inhibition of Choline kinase activity via siRNA or small molecule inhibitors. We show here that the regulation of Akt phosphorylation by Choline kinase is PI3K-independent. In addition, xenograft tumors treated with Choline kinase inhibitors demonstrated a statistically significant decrease in Akt(ser473 phosphorylation. Importantly, the reduction in phosphorylation correlates with regression of these xenograft tumors in the mouse model. Conclusion High Choline kinase expression and activity has previously been implicated in tumor development and metastasis. The mechanism by which Choline kinase is involved in tumor formation is still not fully resolved. From our data, we proposed that Choline kinase plays a key role in regulating Akt(ser473 phosphorylation, thereby promoting cell survival and proliferation.

  9. Prognostic implications of myocardial creatine kinase and cardiac troponin in coronary artery bypass surgery Implicação prognóstica da creatino-quinase miocárdica e troponina na revascularização do miocárdio

    Directory of Open Access Journals (Sweden)

    Fábio P. Taniguchi

    2003-09-01

    Full Text Available OBJECTIVES: To evaluate the prognostic implications of myocardial creatine kinase and troponin I (cTn I in blood samples from the coronary sinus of patients submitted to coronary artery bypass surgery both with and without ischemic preconditioning. METHODS: From October 1998 to May 1999, 35 patients with coronary artery disease who were submitted to coronary artery bypass surgery were studied. Samples containing creatine kinase and cTn I were obtained from the great cardiac vein during surgery at the onset of cardiopulmonary bypass, at the end of the first anastomosis, and at the end of cardiopulmonary bypass. In May 2002, 29 patients were evaluated in regards to the angina functional class, congestive heart failure, number of hospitalizations, myocardial infarction and death. There were 15 patients in the Preconditioned group and 14 in the Control group. Each group was subdivided into patients with and without cardiovascular symptoms. RESULTS: The Control and Preconditioned groups were not significantly different in relation to frequency of cardiovascular symptoms. There were progressive increases of the creatine kinase and cTn I levels at different Interval s of the study. The cTn I in the Preconditioned group was 1.21 ± 0.64 ng/mL and 3.19 ± 3.21 ng/mL in the Control group (pOBJETIVO: Avaliar a implicação prognóstica da dosagem da creatino-quinase miocárdica (CKMB e Troponina I (cTn I em amostras no seio coronariano, na evolução de pacientes submetidos a revascularização do miocárdio (RM, com e sem o pré-condicionamento isquêmico. MÉTODO: Entre outubro de 1998 e maio de 1999, 35 pacientes com insuficiência coronariana foram submetidos a RM foram estudados. No intra-operatório foram coletadas amostras do seio coronariano para dosagem de CKMB e cTn I. Os momentos de coleta foram: momento 1-no início da circulação extracorpórea (CEC, momento 2- após a primeira anastomose e momento 3- no final da CEC. Em maio de 2002, 29

  10. Early memory formation disrupted by atypical PKC inhibitor ZIP in the medial prefrontal cortex but not hippocampus.

    Science.gov (United States)

    Evuarherhe, Obaro; Barker, Gareth R I; Savalli, Giorgia; Warburton, Elizabeth C; Brown, Malcolm W

    2014-08-01

    Atypical isoforms of protein kinase C (aPKCs; particularly protein kinase M zeta: PKMζ) have been hypothesized to be necessary and sufficient for the maintenance of long-term potentiation (LTP) and long term memory by maintaining postsynaptic AMPA receptors via the GluA2 subunit. A myristoylated PKMζ pseudosubstrate peptide (ZIP) blocks PKMζ activity. We examined the actions of ZIP in medial prefrontal cortex (mPFC) and hippocampus in associative recognition memory in rats during early memory formation and memory maintenance. ZIP infusion in either hippocampus or mPFC impaired memory maintenance. However, early memory formation was impaired by ZIP in mPFC but not hippocampus; and blocking GluA2-dependent removal of AMPA receptors did not affect this impairment caused by ZIP in the mPFC. The findings indicate: (i) a difference in the actions of ZIP in hippocampus and medial prefrontal cortex, and (ii) a GluA2-independent target of ZIP (possibly PKCλ) in the mPFC during early memory formation. © 2014 Wiley Periodicals, Inc.

  11. Atypical Antipsychotics and Inverse Agonism at 5-HT2 Receptors

    Science.gov (United States)

    Sullivan, Laura C.; Clarke, William P.; Berg, Kelly A.

    2017-01-01

    It is now well accepted that receptors can regulate cellular signaling pathways in the absence of a stimulating ligand, and inverse agonists can reduce this ligand-independent or “constitutive” receptor activity. Both the serotonin 5-HT2A and 5-HT2C receptors have demonstrated constitutive receptor activity in vitro and in vivo. Each has been identified as a target for the treatment of schizophrenia. Further, most, if not all, atypical antipsychotic drugs have inverse agonist properties at both 5-HT2A and 5-HT2C receptors. This paper describes our current knowledge of inverse agonism of atypical antipsychotics at 5-HT2A/2C receptor subtypes in vitro and in vivo. Exploiting inverse agonist properties of antipsychotic drugs may provide new avenues for drug development. PMID:26044975

  12. 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.

  13. Transmission of atypical scrapie to homozygous ARQ sheep.

    Science.gov (United States)

    Okada, Hiroyuki; Miyazawa, Kohtaro; Imamura, Morikazu; Iwamaru, Yoshifumi; Masujin, Kentaro; Matsuura, Yuichi; Yokoyama, Takashi

    2016-11-01

    Two Cheviot ewes homozygous for the A136L141R154Q171 (AL141RQ) prion protein (PrP) genotype were exposed intracerebrally to brain pools prepared using four field cases of atypical scrapie from the United Kingdom. Animals were clinically normal until the end of the experiment, when they were culled 7 years post-inoculation. Limited accumulation of disease-associated PrP (PrP(Sc)) was observed in the cerebellar molecular layer by immunohistochemistry, but not by western blot or enzyme-linked immunosorbent assay. In addition, PrP(Sc) was partially localized in astrocytes and microglia, suggesting that these cells have a role in PrP(Sc) processing, degradation or both. Our results indicate that atypical scrapie is transmissible to AL141RQ sheep, but these animals act as clinically silent carriers with long incubation times.

  14. Subacute Sclerosing Panencephalitis with Atypical Clinical and MRI Findings

    Directory of Open Access Journals (Sweden)

    Buse Rahime Hasırcı

    2016-04-01

    Full Text Available Subacute sclerosing panencephalitis (SSPE is a progressive inflammatory disorder of the central nervous system and a slow virus infection caused by aberrant measles virüs. Typical neurological manifestations include psychomotor impairment, progressive intellectual deterioration, myoclonic jerks and behavioral changes, with or without pyramidal symptoms. It usually affecting people aged 10 to 14 year. We report the case of an 17-year-old girl presenting with initial symptom of visual loss, seizures, a lack of SSPE specific EEG pattern, late onset and atypical fast progression of disease. The case highlights the importance of atypical clinical findings of SSPE at onset and also firstly disappearing, then appearing MRI findings at sequential images which can complicate the accurate diagnosis. High suspicion is needed because of its rareness.

  15. [Atypical fractures of the femur: apropos of 3 clinical cases].

    Science.gov (United States)

    Sanduloviciu, Maria; Stoll, Delphine; Lamy, Olivier; Krieg, Marc-Antoine; Aubry-Rozier, Bérengère

    2014-08-06

    Osteoporosis is an increasing public health problem. The bisphophonates are the most useful treatment used through the world to prevent osteoporotic fractures. Their large prescription revealed an unpredictable side effect: the atypical fracture. These fractures appear in the subtrochanteric or diaphysal femoral proximal site, spontaneously or after a low trauma, and could be bilateral. X-rays shows a transversal or oblique fracture with a spur in the cortex and with a diffuse thickening of the cortical of the proximal femur. Expert's recommendations are current in progress to well understand and managed this problem. Here we report three cases of atypical femur fractures occurred in our Centre of bone diseases with some management and treatment propositions.

  16. Learning, plasticity, and atypical generalization in children with autism.

    Science.gov (United States)

    Church, Barbara A; Rice, Courtney L; Dovgopoly, Alexander; Lopata, Christopher J; Thomeer, Marcus L; Nelson, Andrew; Mercado, Eduardo

    2015-10-01

    Individuals with autism spectrum disorder (ASD) show accelerated learning in some tasks, degraded learning in others, and distinct deficits when generalizing to novel situations. Recent simulations with connectionist models suggest that deficits in cortical plasticity mechanisms can account for atypical patterns of generalization shown by some children with ASD. We tested the surprising theoretical prediction, from past simulations, that the children with ASD who show atypical generalization in perceptual categorization tasks will benefit more from training with a single prototypical member of the category than from training with multiple examples, but children with ASD who generalize normally will be comparatively harmed. The experimental results confirmed this prediction, suggesting that plasticity deficits may well underlie the difficulties that some children with ASD have generalizing skills, and these deficits are not specific to the acquisition of social skills, but rather reflect a more general perceptual learning deficit that may impact many abilities.

  17. 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 (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. This work

  18. 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

  19. Atypical brain responses to auditory spatial cues in adults with autism spectrum disorder.

    Science.gov (United States)

    Lodhia, Veema; Hautus, Michael J; Johnson, Blake W; Brock, Jon

    2017-09-09

    The auditory processing atypicalities experienced by many individuals on the autism spectrum disorder might be understood in terms of difficulties parsing the sound energy arriving at the ears into discrete auditory 'objects'. Here, we asked whether autistic adults are able to make use of two important spatial cues to auditory object formation - the relative timing and amplitude of sound energy at the left and right ears. Using electroencephalography, we measured the brain responses of 15 autistic adults and 15 age- and verbal-IQ-matched control participants as they listened to dichotic pitch stimuli - white noise stimuli in which interaural timing or amplitude differences applied to a narrow frequency band of noise typically lead to the perception of a pitch sound that is spatially segregated from the noise. Responses were contrasted with those to stimuli in which timing and amplitude cues were removed. Consistent with our previous studies, autistic adults failed to show a significant object-related negativity (ORN) for timing-based pitch, although their ORN was not significantly smaller than that of the control group. Autistic participants did show an ORN to amplitude cues, indicating that they do not experience a general impairment in auditory object formation. However, their P400 response - thought to indicate the later attention-dependent aspects of auditory object formation - was missing. These findings provide further evidence of atypical auditory object processing in autism with potential implications for understanding the perceptual and communication difficulties associated with the condition. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  20. 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

  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 presentation is dominant and typical for coeliac disease.

    Science.gov (United States)

    Rostami Nejad, Mohammad; Rostami, Kamran; Pourhoseingholi, Mohamad Amin; Nazemalhosseini Mojarad, Ehsan; Habibi, Manijeh; Dabiri, Hossein; Zali, Mohammad Reza

    2009-09-01

    Atypical presentation is the most prevalent form of coeliac disease (CD) and mostly clinically indistinguishable from other gastrointestinal (GI) disorders. The first objective of this study was to determine the prevalence of CD in patients with GI symptoms and the second objective was to characterize the typical manifestations of the atypical forms of CD. This was a cross sectional study comprising 5,176 individuals by random sampling of self-referred people from the Tehran province, during the years 2006-2007 in a primary care setting. From 5,176 individuals, 670 with GI symptoms were selected for coeliac serology including total immunoglobulin A (IgA) and anti-tissue transglutaminase (tTG) antibodies. Those with IgA deficiency were tested with IgG tTG. This study shows that 13% (670/5176) of self-referred patients to a general practice suffer from GI symptoms. Dyspepsia was the most common symptom in 25 seropositive cases similar to the rest of the study group. A positive anti-tTG test was found in 22 from 670 investigated subjects (17 women, 5 men) (95% CI: 1.70-4.30) and 8/670 were IgA deficient. A positive IgG tTG was detected in 3/8 IgA deficient individuals. The prevalence of CD antibodies in serologically screened samples excluding IgA-deficient was 3.3% and 3.7% when including those IgA-deficient with positive tTG-IgG. Non-specific GI symptoms seem to be the typical presentation of atypical CD. This study indicated that there is a high prevalence of CD antibodies among patients with GI symptoms (3.7%). More awareness regarding the atypical presentation of CD could be the key step in identifying asymptomatic patients.

  3. Atypical Histiocyte-Rich Sweet’s Syndrome

    Directory of Open Access Journals (Sweden)

    Sharon Chi

    2017-01-01

    Full Text Available Sweet’s Syndrome is a rare neutrophilic dermatosis thought to be a result of immune dysregulation occurring in the setting of drug exposure, recent infection, pregnancy, and underlying malignancy or idiopathic with specific and widely accepted diagnostic criteria established in the literature. Other organ systems can be involved with varying degrees of severity. An unusual case of Sweet’s Syndrome associated with myopericarditis, acral involvement, and atypical histological findings with predominance of histiocytes is described here.

  4. Use of atypical antipsychotics in the treatment of autistic disorder.

    Science.gov (United States)

    Stachnik, Joan M; Nunn-Thompson, Cheryl

    2007-04-01

    To review clinical trials and reports describing the efficacy and safety of atypical antipsychotics (olanzapine, ziprasidone, quetiapine, aripiprazole) in the treatment of autistic or other pervasive developmental disorders. English-language publications from the MEDLINE database (1966-February 2007) including clinical trials, case reports, and retrospective series were reviewed. Relevant data were extracted from studies of selected atypical antipsychotics in the treatment of autistic disorder in children, adolescents, and adults. Most literature found was in the form of case reports or case series; however, several open-label and double-blind trials were also identified. Autistic disorder is a chronic neurodevelopmental disorder with limited treatment options. Nonpharmacologic approaches may be the most beneficial, but pharmacologic agents are needed for some patients with significant behavioral manifestations of the disorder. The atypical antipsychotics (olanzapine, ziprasidone, quetiapine, aripiprazole) have shown some efficacy in improving certain behavioral symptoms of autistic disorder--primarily aggressiveness, hyperactivity, and self-injurious behavior. Efficacy was based on observation or changes from baseline in behavioral rating scores. Data appear to be strongest for olanzapine compared with quetiapine, with several open-label trials suggesting its efficacy. Weight gain and sedation were frequently reported adverse events with both agents. Aripiprazole has demonstrated efficacy in limited case series, with minimal adverse effects reported. Atypical antipsychotics represent a treatment option for symptoms associated with autistic disorder. However, these drugs do not affect the core symptoms of autistic disorder and are associated with potentially significant adverse effects. In addition, there is a lack of randomized controlled trials to determine the true efficacy and long-term safety of these agents in the pediatric population.

  5. Recurrent Malignancy-Associated Atypical Neutrophilic Dermatosis With Noninfectious Shock.

    Science.gov (United States)

    Kinser, Kathryn Nicole; Panach, Kamaldeep; Dominguez, Arturo Ricardo

    2017-12-01

    Sweet syndrome (SS) or acute febrile neutrophilic dermatosis presents with the sudden onset of fever, leukocytosis and tender, erythematous, edematous, well-demarcated papules and plaques that histopathologically demonstrate a dense neutrophilic infiltrate. A total of 20% of patients with SS have malignancy-associated disease that can present with bullous or atypical skin lesions that mimic pyoderma gangrenosum, another neutrophilic dermatosis. Both entities exist on a spectrum, and in the context of underlying malignancy, these neutrophilic diseases become less clinically distinct. The literature also describes life-threatening cases of neutrophilic dermatoses that mimic severe sepsis. We present a fatal case of a patient with chronic eosinophilic leukemia with recurrent episodes of malignancy-associated atypical neutrophilic dermatosis characterized by necrotic skin lesions, pulmonary infiltrates and noninfectious shock and we also summarize the clinical presentations of an additional 10 patients reported in the literature. We conducted a PubMed search of articles published up to and in 2015, focusing on the English and Spanish literature with SS cross-referenced with the following search terms: neutrophilic dermatosis, pyoderma gangrenosum, shock, multiorgan failure and systemic inflammatory response syndrome. The articles were reviewed and the patients׳ clinical and laboratory findings were summarized. Cases of atypical neutrophilic dermatosis presenting with noninfectious shock syndrome are likely underrecognized clinically and underreported in the literature. Patients with malignancy-associated atypical neutrophilic dermatoses associated with noninfectious shock syndrome typically have multisystem disease characterized by recurrent episodes and typically have poor prognoses. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  6. Primary atypical carcinoid of the parietal pleura expressing KIT.

    Science.gov (United States)

    Terada, Tadashi

    2014-01-01

    The author reports an extremely rare case of atypical carcinoid of the pleura expressing KIT. An 81-year-old Japanese man with emphysema was found to have a mass (3×3×2 cm) in the left parietal pleura by various imaging modalities. Video-assisted tumorectomy was performed, but could not excise it completely. Histologically, the tumor was composed of atypical cells arranged in trabecular, ribbon-like, and rosette patterns. Mitotic figures and necrosis were present. The tumor cells were argyrophil. Immunohistochemically, the tumor cells were positive for pancytokeratins, cytokeratin (CK) 18, chromogranin (focal), p53, KIT, and Ki67 (labeling=17%). In contrast, the tumor cells were negative for CK5/6, CK7, CK19, CK20, CK34βE12, epithelial membrane antigen, vimentin, S100-protein, α-smooth muscle actin, desmin, CEA, TTF-1, CDX-2, AFP, HepPar-1, synaptophysin, CD56, CA19-9, CD15, neuron specific enolase, serotonin, CD34, platelet-derived growth factor-α, calretinin, thrombomodulin, WT-1, B72.3, and D2-40. The pathologic diagnosis was atypical carcinoid of the pleura. The patient was examined by whole body computed tomography, magnetic resonance imaging, and positron emission tomography, but there were no tumors other than the pleural tumor. Endoscopic examinations including upper and lower gastrointestinal tract revealed no tumors. Therefore, the pleural tumor was thought to be primary. Ten months later, the patient developed metastatic lesions in the vertebular and femoral bones, and died of respiratory failure. Autopsy was not performed. To the best of the author's knowledge, there are no cases of primary carcinoid in the pleura in the English literature. This case is also interesting in that the atypical carcinoid expressed KIT.

  7. Acute neck pain, an atypical presentation of subarachnoid haemorrhage

    OpenAIRE

    Ahmed, Julian; Blakeley, Chris; Sakar, Ramy; Aktar, Khalida; Hashemi, Kambiz

    2007-01-01

    Subarachnoid haemorrhage can be a massively debilitating condition with long‐term repercussions. The “classic” presentation of sudden‐onset severe headache normally raises suspicions. However, if the presentation is atypical, the diagnosis may be missed. We report on a 52‐year‐old man who presented with a 1‐day history of progressively worsening right‐sided neck pain spreading to the chest with associated symptoms of autonomic dysfunction. After initial stabilisation, the patient's Glasgow Co...

  8. Atypical Eating Attitudes and Behaviors in Thai Medical Students

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    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.

  9. Electronic brachytherapy management of atypical fibroxanthoma: report of 8 lesions

    OpenAIRE

    Stephen Doggett; James Brazil; Marketa Limova; Leah Press; Sidney Smith; Jeremy Peck

    2017-01-01

    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...

  10. Atypical Pelvic Crescent Fracture Caused by Vertical Shear Force

    OpenAIRE

    Park, Sang-Eun; Lee, Se-Won; Kim, Weon-Yoo; Park, Yong

    2014-01-01

    The crescent fracture consists of a posterior iliac wing fracture with extension into the sacroiliac joint and a dislocation of the sacroiliac joint. This fracture represents a subset of lateral compression injury. The strong posterior ligaments of sacroiliac joint remain intact and a fracture fragment (crescent shape) involving the posterior superior iliac spines remains firmly attached to the sacrum. We report a patient with atypical pelvic crescent fracture that is mainly influenced by ver...

  11. Childhood atypical meningioma with perineural spread: MR findings

    Energy Technology Data Exchange (ETDEWEB)

    Wei, Feng-Yu.; Wong, Alex Mun-Ching; Wong, Ho-Fai; Ng, Shu-Hang [Chang Gung Memorial Hospital, Department of Diagnostic Radiology, Kwei-Shan, Tao-Yuan (Taiwan); Wu, Chieh-Tsai [Chang Gung Memorial Hospital, Department of Neurosurgery, Kwei-Shan, Tao-Yuan (Taiwan); Lin, Kuang-Lin [Chang Gung Memorial Hospital, Division of Pediatric Neurology, Kwei-Shan, Tao-Yuan (Taiwan)

    2005-09-01

    Meningiomas are uncommon in children. When they occur, they are frequently associated with neurofibromatosis type 2. Childhood meningiomas are generally large and commonly associated with cyst formation and an unusual location. Perineural tumor spread, occasionally associated with head and neck malignancies, is very rare in meningiomas. We present the MR findings of an atypical meningioma with perineural spread in a 4.5-year-old girl. (orig.)

  12. Quantitative methods for somatosensory evaluation in atypical odontalgia

    OpenAIRE

    PORPORATTI,André Luís; COSTA,Yuri Martins; STUGINSKI-BARBOSA,Juliana; BONJARDIM,Leonardo Rigoldi; CONTI,Paulo César Rodrigues; SVENSSON,Peter

    2015-01-01

    A systematic review was conducted to identify reliable somatosensory evaluation methods for atypical odontalgia (AO) patients. The computerized search included the main databases (MEDLINE, EMBASE, and Cochrane Library). The studies included used the following quantitative sensory testing (QST) methods: mechanical detection threshold (MDT), mechanical pain threshold (MPT) (pinprick), pressure pain threshold (PPT), dynamic mechanical allodynia with a cotton swab (DMA1) or a brush (DMA2), warm d...

  13. Current Evidence on Atypical Odontalgia: Diagnosis and Clinical Management

    OpenAIRE

    Abiko, Yoshihiro; Matsuoka, Hirofumi; Chiba, Itsuo; Toyofuku, Akira

    2012-01-01

    Patients with atypical odontalgia (AO) complain of medically unexplained toothache. No evidence-based diagnostic criteria or treatment guidelines are yet available. The present paper addresses seven clinical questions about AO based on current knowledge in the literature and discusses diagnostic criteria and guidelines for treatment and management. The questions are (i) What is the prevalence of AO in the community? (ii) What psychological problems are experienced by patients with AO? (iii) A...

  14. 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.

  15. 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.

  16. 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.

  17. Research advance on diagnosis and treatment for atypical optic neuritis

    Directory of Open Access Journals (Sweden)

    Guo-Yan Zeng

    2016-06-01

    Full Text Available Optic neuritis(ONis one of the most common causes of vision loss by neural eye diseases in youth and middle-aged. In the past, the diagnosis simply according to the risk position, which did not distinguish from the pathogenesis and clinical characteristics, can not meet the current clinical diagnosis and treatment needs. Combining with the etiology, clinical characteristics and prognosis, the latest classification of the current international diagnosis of ON are typical and atypical ON. Typical ON relates to multiple sclerosis(MSor demyelinating disease of the central nervous system, it has a relatively good therapeutic effect and prognosis. Rather than, atypical ON has complex etiology, clinical manifestation, and the treatment and prognosis are also different. At present there are many international ON treatment guidelines with level I evidence-based medical evidence, but with different genetic background, geographical environment and ethnic groups, they are not been determined. China lacks of such a multicenter large sample, a wide range of research evidence. In this paper, we will summarize the progress of the diagnosis and treatment about ON, especially about the atypical ON, in order to provide some suggestions to further improve the standardization and individualization for clinical diagnosis and treatment on ON.

  18. Identification and Validation of Small-Gatekeeper Kinases as Drug Targets in Giardia lamblia.

    Science.gov (United States)

    Hennessey, Kelly M; Smith, Tess R; Xu, Jennifer W; Alas, Germain C M; Ojo, Kayode K; Merritt, Ethan A; Paredez, Alexander R

    2016-11-01

    Giardiasis is widely acknowledged to be a neglected disease in need of new therapeutics to address toxicity and resistance issues associated with the limited available treatment options. We examined seven protein kinases in the Giardia lamblia genome that are predicted to share an unusual structural feature in their active site. This feature, an expanded active site pocket resulting from an atypically small gatekeeper residue, confers sensitivity to "bumped" kinase inhibitors (BKIs), a class of compounds that has previously shown good pharmacological properties and minimal toxicity. An initial phenotypic screen for biological activity using a subset of an in-house BKI library found that 5 of the 36 compounds tested reduced trophozoite growth by at least 50% at a concentration of 5 μM. The cellular localization and the relative expression levels of the seven protein kinases of interest were determined after endogenously tagging the kinases. Essentiality of these kinases for parasite growth and infectivity were evaluated genetically using morpholino knockdown of protein expression to establish those that could be attractive targets for drug design. Two of the kinases were critical for trophozoite growth and attachment. Therefore, recombinant enzymes were expressed, purified and screened against a BKI library of >400 compounds in thermal stability assays in order to identify high affinity compounds. Compounds with substantial thermal stabilization effects on recombinant protein were shown to have good inhibition of cell growth in wild-type G. lamblia and metronidazole-resistant strains of G. lamblia. Our data suggest that BKIs are a promising starting point for the development of new anti-giardiasis therapeutics that do not overlap in mechanism with current drugs.

  19. Identification and Validation of Small-Gatekeeper Kinases as Drug Targets in Giardia lamblia

    Science.gov (United States)

    Hennessey, Kelly M.; Smith, Tess R.; Xu, Jennifer W.; Alas, Germain C. M.; Ojo, Kayode K.; Merritt, Ethan A.

    2016-01-01

    Giardiasis is widely acknowledged to be a neglected disease in need of new therapeutics to address toxicity and resistance issues associated with the limited available treatment options. We examined seven protein kinases in the Giardia lamblia genome that are predicted to share an unusual structural feature in their active site. This feature, an expanded active site pocket resulting from an atypically small gatekeeper residue, confers sensitivity to “bumped” kinase inhibitors (BKIs), a class of compounds that has previously shown good pharmacological properties and minimal toxicity. An initial phenotypic screen for biological activity using a subset of an in-house BKI library found that 5 of the 36 compounds tested reduced trophozoite growth by at least 50% at a concentration of 5 μM. The cellular localization and the relative expression levels of the seven protein kinases of interest were determined after endogenously tagging the kinases. Essentiality of these kinases for parasite growth and infectivity were evaluated genetically using morpholino knockdown of protein expression to establish those that could be attractive targets for drug design. Two of the kinases were critical for trophozoite growth and attachment. Therefore, recombinant enzymes were expressed, purified and screened against a BKI library of >400 compounds in thermal stability assays in order to identify high affinity compounds. Compounds with substantial thermal stabilization effects on recombinant protein were shown to have good inhibition of cell growth in wild-type G. lamblia and metronidazole-resistant strains of G. lamblia. Our data suggest that BKIs are a promising starting point for the development of new anti-giardiasis therapeutics that do not overlap in mechanism with current drugs. PMID:27806042

  20. Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

    Science.gov (United States)

    Lupardus, Patrick J.; Ultsch, Mark; Wallweber, Heidi; Bir Kohli, Pawan; Johnson, Adam R.; Eigenbrot, Charles

    2014-01-01

    Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase–kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and “exon 12” JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state. PMID:24843152

  1. Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition.

    Science.gov (United States)

    Lupardus, Patrick J; Ultsch, Mark; Wallweber, Heidi; Bir Kohli, Pawan; Johnson, Adam R; Eigenbrot, Charles

    2014-06-03

    Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase-kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and "exon 12" JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state.

  2. 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.

  3. 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.

  4. 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. PMID:26258131

  5. DETORQUEO, QUIRKY, and ZERZAUST represent novel components involved in organ development mediated by the receptor-like kinase STRUBBELIG in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Lynette Fulton

    2009-01-01

    Full Text Available Intercellular signaling plays an important role in controlling cellular behavior in apical meristems and developing organs in plants. One prominent example in Arabidopsis is the regulation of floral organ shape, ovule integument morphogenesis, the cell division plane, and root hair patterning by the leucine-rich repeat receptor-like kinase STRUBBELIG (SUB. Interestingly, kinase activity of SUB is not essential for its in vivo function, indicating that SUB may be an atypical or inactive receptor-like kinase. Since little is known about signaling by atypical receptor-like kinases, we used forward genetics to identify genes that potentially function in SUB-dependent processes and found recessive mutations in three genes that result in a sub-like phenotype. Plants with a defect in DETORQEO (DOQ, QUIRKY (QKY, and ZERZAUST (ZET show corresponding defects in outer integument development, floral organ shape, and stem twisting. The mutants also show sub-like cellular defects in the floral meristem and in root hair patterning. Thus, SUB, DOQ, QKY, and ZET define the STRUBBELIG-LIKE MUTANT (SLM class of genes. Molecular cloning of QKY identified a putative transmembrane protein carrying four C(2 domains, suggesting that QKY may function in membrane trafficking in a Ca(2+-dependent fashion. Morphological analysis of single and all pair-wise double-mutant combinations indicated that SLM genes have overlapping, but also distinct, functions in plant organogenesis. This notion was supported by a systematic comparison of whole-genome transcript profiles during floral development, which molecularly defined common and distinct sets of affected processes in slm mutants. Further analysis indicated that many SLM-responsive genes have functions in cell wall biology, hormone signaling, and various stress responses. Taken together, our data suggest that DOQ, QKY, and ZET contribute to SUB-dependent organogenesis and shed light on the mechanisms, which are dependent on

  6. Non-Targeted Metabolomics Analysis of the Effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Muscle, Liver and Serum Metabolism In Vivo

    OpenAIRE

    Jensen, Brian C; Parry, Traci L; Wei Huang; Amro Ilaiwy; Bain, James R; Muehlbauer, Michael J.; O’Neal, Sara K.; Cam Patterson; Johnson, Gary L; Monte S. Willis

    2017-01-01

    Background: More than 90 tyrosine kinases have been implicated in the pathogenesis of malignant transformation and tumor angiogenesis. Tyrosine kinase inhibitors (TKIs) have emerged as effective therapies in treating cancer by exploiting this kinase dependency. The TKI erlotinib targets the epidermal growth factor receptor (EGFR), whereas sunitinib targets primarily vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR).TKIs that impact the fun...

  7. 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.

  8. Anticancer Alkaloid Lamellarins Inhibit Protein Kinases

    Directory of Open Access Journals (Sweden)

    Laurent Meijer

    2008-10-01

    Full Text Available Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, display promising anti-tumor activity. They induce apoptotic cell death through multi-target mechanisms, including inhibition of topoisomerase I, interaction with DNA and direct effects on mitochondria. We here report that lamellarins inhibit several protein kinases relevant to cancer such as cyclin-dependent kinases, dualspecificity tyrosine phosphorylation activated kinase 1A, casein kinase 1, glycogen synthase kinase-3 and PIM-1. A good correlation is observed between the effects of lamellarins on protein kinases and their action on cell death, suggesting that inhibition of specific kinases may contribute to the cytotoxicity of lamellarins. Structure/activity relationship suggests several paths for the optimization of lamellarins as kinase inhibitors.

  9. A multisubstrate deoxyribonucleoside kinase from plants

    DEFF Research Database (Denmark)

    Clausen, Anders R.; Girandon, Lenart; Knecht, Wolfgang

    2008-01-01

    Deoxyribonucleoside kinases catalyze the rate limiting step during the salvage of deoxyribonucleosides and convert them into the corresponding monophosphate compounds. We have identified and characterized a unique multisubstrate deoxyribonucleoside kinase from plants. The phylogenetic relationshi...

  10. Mitogen Activated Protein kinase signal transduction pathways in the prostate

    Directory of Open Access Journals (Sweden)

    Koul Sweaty

    2004-06-01

    Full Text Available Abstract The biochemistry of the mitogen activated protein kinases ERK, JNK, and p38 have been studied in prostate physiology in an attempt to elucidate novel mechanisms and pathways for the treatment of prostatic disease. We reviewed articles examining mitogen-activated protein kinases using prostate tissue or cell lines. As with other tissue types, these signaling modules are links/transmitters for important pathways in prostate cells that can result in cellular survival or apoptosis. While the activation of the ERK pathway appears to primarily result in survival, the roles of JNK and p38 are less clear. Manipulation of these pathways could have important implications for the treatment of prostate cancer and benign prostatic hypertrophy.

  11. A multisubstrate deoxyribonucleoside kinase from plants.

    Science.gov (United States)

    Clausen, Anders Ranegaard; Girandon, Lenart; Knecht, Wolfgang; Survery, Sabeen; Andreasson, Erik; Munch-Petersen, Birgitte; Piskur, Jure

    2008-01-01

    Deoxyribonucleoside kinases catalyze the rate limiting step during the salvage of deoxyribonucleosides and convert them into the corresponding monophosphate compounds. We have identified and characterized a unique multisubstrate deoxyribonucleoside kinase from plants. The phylogenetic relationship and biochemical properties suggest that this deoxyribonucleoside kinase represents a living fossil resembling the progenitor of the modern animal deoxycytidine, deoxyguanosine and thymidine 2 kinases. The broad substrate specificity makes this enzyme an interesting candidate to be evaluated as a suicide gene in anti-cancer therapy.

  12. Molecular mechanism of regulation of the atypical protein kinase C by N-terminal domains and an allosteric small compound

    DEFF Research Database (Denmark)

    Zhang, Hua; Neimanis, Sonja; Lopez-Garcia, Laura A

    2014-01-01

    provide structural evidence that the small compound PS315 is an allosteric inhibitor that binds to the PIF-pocket of aPKC. PS315 exploits the physiological dynamics of helix αC for its binding and allosteric inhibition. The results will support research on allosteric mechanisms and selective drug...

  13. 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.

  14. Role of calcium in the expression of MAP kinase kinases (MKKs ...

    African Journals Online (AJOL)

    The mitogen activated protein kinase (MAPK) cascade is an important intracellular signaling module that functions as a convergent point for crosstalk during stress signaling. In this study, we constructed a phylogenetic tree for MAP kinase kinases (MKKs) and MAP kinases (MPKs) in Arabidopsis and Lycopersicon ...

  15. A Mitogen-activated protein kinase kinase kinase mediates reactive oxygen species homeostasis in Arabidopsis.

    Science.gov (United States)

    Nakagami, Hirofumi; Soukupová, Hanka; Schikora, Adam; Zárský, Viktor; Hirt, Heribert

    2006-12-15

    Mitogen-activated protein kinase kinase kinases (MAPKKKs) play key roles in intra- and extracellular signaling in eukaryotes. Here we report that the MAPKKK MEKK1 regulates redox homeostasis in Arabidopsis. We show that MEKK1-deficient plants are misregulated in the expression of a number of genes involved in cellular redox control and accumulate reactive oxygen species (ROS). Most strikingly, homozygous mekk1 mutant plants exhibit a lethal phenotype when developing true leaves. MEKK1 kinase activity and protein stability was regulated by H(2)O(2) in a proteasome-dependent manner and mekk1 plants were compromised in ROS-induced MAPK MPK4 activation. Whereas mpk3 and mpk6 knock out plants showed no defects in development or changes in redox control genes, mpk4 null mutant shared several phenotypic and transcript profile features with mekk1 plants. In agreement with the concept that ROS negatively regulates auxin responses in plants, mekk1 and mpk4 mutants show reduced expression of several auxin-inducible marker genes. Overall, our data defines MPK4 as downstream target of MEKK1 and show that MEKK1 functions in integrating ROS homeostasis with plant development and hormone signaling.

  16. The JAK kinases: not just another kinase drug discovery target.

    Science.gov (United States)

    Wilks, Andrew F

    2008-08-01

    There are four members of the JAK family of protein tyrosine kinases (PTKs) in the human genome. Since their discovery in 1989, great strides have been made in the understanding of their role in normal intracellular signalling. Importantly, their roles in pathologies ranging from cancer to immune deficiencies have placed them front and centre as potential drug targets. The recent discovery of the role of activating mutations in the kinase-like domain (KLD) of JAK2 in the development of polycythemia rubra vera, and the elaboration of KLD mutation as a broader mechanism by which cells might become hyperproliferative has sparked enormous interest in the development of JAK selective drug candidates. I review herein the progress that has been made in the discovery of JAK-targeted inhibitors, and discuss the challenges that face the development of these drugs for use in the clinic.

  17. 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

  18. 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

  19. Reassessing risk models for atypical hyperplasia: age may not matter.

    Science.gov (United States)

    Mazzola, Emanuele; Coopey, Suzanne B; Griffin, Molly; Polubriaginof, Fernanda; Buckley, Julliette M; Parmigiani, Giovanni; Garber, Judy E; Smith, Barbara L; Gadd, Michele A; Specht, Michelle C; Guidi, Anthony; Hughes, Kevin S

    2017-09-01

    The aim of this study was to investigate the influence of age at diagnosis of atypical hyperplasia ("atypia", ductal [ADH], lobular [ALH], or severe ADH) on the risk of developing subsequent invasive breast cancer or ductal carcinoma in situ (DCIS). Using standard survival analysis methods, we retrospectively analyzed 1353 women not treated with chemoprevention among a cohort of 2370 women diagnosed with atypical hyperplasia to determine the risk relationship between age at diagnosis and subsequent breast cancer. For all atypia diagnoses combined, our cohort showed a 5-, 10-, and 15-year risk of invasive breast cancer or DCIS of 0.56, 1.25, and 1.30, respectively, with no significant difference in the (65,75] year age group. For women aged (35,75] years, we observed no significant difference in the 15-year risk of invasive breast cancer or DCIS after atypical hyperplasia, although the baseline risk for a 40-year-old woman is approximately 1/8 the risk of a 70-year-old woman. The risks associated with invasive breast cancer or DCIS for women in our cohort diagnosed with ADH, severe ADH, or ALH, regardless of age, were 7.6% (95% CI 5.9-9.3%) at 5 years, 25.1% (20.7-29.2%) at 10 years, and 40.1% (32.8-46.6%) at 15 years. In contrast to current risk prediction models (e.g., Gail, Tyrer-Cuzick) which assume that the risk of developing breast cancer increases in relation to age at diagnosis of atypia, we found the 15-year cancer risk in our cohort was not significantly different for women between the ages of 35 (excluded) and 75. This implies that the "hits" received by the breast tissue along the "high-risk pathway" to cancer might possibly supersede other factors such as age.

  20. Priming the proteasome by protein kinase G: a novel cardioprotective mechanism of sildenafil

    OpenAIRE

    Zhang, Hanming; Wang, Xuejun

    2015-01-01

    The proteasome mediates the degradation of most cellular proteins including misfolded proteins, pivotal to intracellular protein hemostasis. Proteasome functional insufficiency is implicated in a large subset of human failing hearts. Experimental studies have established proteasome functional insufficiency as a major pathogenic factor, rationalizing proteasome enhancement as a potentially new therapeutic strategy for congestive heart failure. Protein kinase G activation known to be cardioprot...

  1. 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

  2. Pim serine/threonine kinases regulate the stability of Socs-1 protein

    NARCIS (Netherlands)

    Chen, XP; Losman, JA; Cowan, S; Donahue, E; Fay, S; Vuong, BQ; Nawijn, MC; Capece, D; Cohan, VL; Rothman, P

    2002-01-01

    Studies of SOCS-1-deficient mice have implicated Socs-1 in the suppression of JAK-STAT (Janus tyrosine kinase-signal transducers and activators of transcription) signaling and T cell development. It has been suggested that the levels of Socs-1 protein may be regulated through the proteasome pathway.

  3. THE ROLE OF ATYPICAL ANTIPSYCHOTIC DECREASING AGGRESIVENESS IN SCHIZOPHRENIA

    Directory of Open Access Journals (Sweden)

    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.

  4. Unusual imaging presentation of infantile atypical Kawasaki disease.

    Science.gov (United States)

    Kumar, Nishith; Mittal, Mahesh Kumar; Sinha, Mukul; Gupta, Arpita; Thukral, Brij Bhushan

    2016-01-01

    Kawasaki disease is a systemic medium vessel vasculitis of unknown etiology affecting children under 5 years of age. There are no specific diagnostic tests, and thus, the diagnosis of the disease is primarily made on the basis of clinical criteria. Unusual presentations of Kawasaki disease have been variably reported from different parts of the world. However, presentation of the disease in the form of peripheral thromboembolism and florid non-coronary aneurysms has rarely been described This report describes the imaging findings in infantile atypical Kawasaki disease with aneurysms of multiple medium-sized arteries, including coronary arteries, emphasizing the detection of clinically silent aneurysms in the disease.

  5. 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.

  6. Atypical Clavicular Involvement of Nonbacterial Osteitis: An Orthopaedic Enigma

    Directory of Open Access Journals (Sweden)

    Salil Umrani

    2011-12-01

    Full Text Available Nonbacterial osteitis (NBO is an underdiagnosed and poorly understood condition caused by sterile inflammation. It can mimic the presentation of many other orthopaedic conditions, for example, osteomyelitis, septic arthritis, or malignancy, in particular for those patients who have unifocal presentation. Because NBO is a diagnosis by exclusion, it poses much difficulty and confusion to many orthopaedic surgeons in treating such disease. Clavicular involvement is common but it is typically present at the medial aspect of the clavicle. We report a case of NBO with atypical clavicular involvement who presented to our orthopaedic clinic with painful swelling in the left shoulder. Appropriate investigations and management are discussed together with literature review.

  7. 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.

  8. Nephrotic syndrome, hypertension, and adrenal failure in atypical Cockayne syndrome.

    Science.gov (United States)

    Reiss, U; Hofweber, K; Herterich, R; Waldherr, R; Bohnert, E; Jung, E; Schärer, K

    1996-10-01

    This report describes a boy with an atypical severe from of Cockayne syndrome type II manifesting in infancy. He developed nephrotic syndrome at the age of 4.7 years and a hypertensive crisis with hemiparesis at 5.4 years. Renal biopsy revealed focal segmental glomerulosclerosis, which was confirmed at autopsy. Adrenocortical failure was also present. The course was characterized by frequent infections and an episode of myocarditis. The boy died at the age of 6.0 years after rapid neurological deterioration accompanied by renal insufficiency. Autopsy disclosed cerebral leukodystrophy compatible with Cockayne syndrome.

  9. Atypical imaging in a desmoplastic non-infantile astrocytoma.

    Science.gov (United States)

    Gupta, Abhishek; Karthigeyan, Madhivanan; Gupta, Kirti; Salunke, Pravin

    2017-03-01

    Desmoplastic infantile tumors, especially desmoplastic astrocytomas, are uncommon neoplasms that are generally seen within first 2 years of life. Their occurrence in slightly older children is very rare. The typical radiological appearance is a large cystic lesion with small enhancing solid part. In the present report, we describe a 10-year-old child with atypical appearance of desmoplastic non-infantile astrocytoma which was predominantly solid on imaging. Although rare, desmoplastic astrocytomas may present even in older children and should be considered in the differential diagnoses. These tumors may present as predominantly solid enhancing lesions and add to the radiological dilemma.

  10. 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.

  11. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Wong, Bernadette Zhi Ying [Mayo Clinic School of Medicine, Rochester, MN (United States); University College London, Royal Free and University College Medical School, London (United Kingdom); Amrami, Kimberly K.; Wenger, Doris E. [Mayo Clinic, Department of Radiology, Rochester, MN (United States); Dyck, P. James B. [Mayo Clinic, Department of Neurology, Rochester, MN (United States); Scheithauer, Bernd W. [Mayo Clinic, Department of Pathology, Rochester, MN (United States); Spinner, Robert J. [Mayo Clinic, Department of Neurologic Surgery, Rochester, MN (United States); Mayo Clinic, Department of Orthopedics, Rochester, MN (United States)

    2006-03-15

    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.)

  13. A Case of Ramsay Hunt Syndrome with Atypical Presentation.

    Science.gov (United States)

    Kayayurt, Kamil; Yavasi, Ozcan; Bilir, Ozlem; Ersunan, Gokhan; Giakoup, Baris

    2014-09-01

    Ramsay Hunt syndrome is a rare complication of herpes zoster which results from the reactivation of the latent varicella-zoster virus in the geniculate ganglion. Although facial nerve is the most common affected nerve in Ramsay Hunt syndrome, other cranial and cervical nerves can also be affected. We present an atypical case of Ramsay Hunt syndrome in a 42-year-old male, with cervical nerve involvement. As spontaneous recovery rate in Ramsay Hunt syndrome is low, early diagnosis and treatment plays a key role in full recovery of paralysis.

  14. 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.

  15. An atypical porcine proliferative enteropathy of malgrowth piglets.

    Science.gov (United States)

    Sueyoshi, Masuo; Arikawa, Akinobu; Uemura, Ryoko; Nakamori, Kentaro; Nagatomo, Hiroshi

    2010-11-01

    Two 60-day-old pigs showing clinical signs of malgrowth and diarrhea were diagnosed as atypical porcine proliferative enteropathy (PPE). The intestinal mucosal lesions in the piglets were characterized by the adenomatous proliferation of the crypt epithelium together with growth of small curved bacteria within the enterocytes. The lesions could be seen in the ileum and other portions of the intestine histologically, although no significant thickening of the gut wall could be observed grossly in the present case. The macroscopic findings are extremely important for the diagnosis of PPE, however, this paper shows that the histopathological and/or immunohistochemical findings were also critical to identify the disease.

  16. Atypical Findings of Guillain-Barré Syndrome in Children

    OpenAIRE

    KARIMZADEH, Parvaneh; Mohammadkazem BAKHSHANDEH BALI; Mohammad Mahdi Nasehi; Seyedeh Mohaddese Taheri Otaghsara; Mohammad Ghofrani

    2012-01-01

    How to cite this article: Karimzadeh P, Bakhshandeh Bali MK, Nasehi MM, Taheri Otaghsara SM, Ghofrani M. Atypical Findings of Guillain-Barré Syndrome in Children. Iran J Child Neurol Autumn 2012;6(4):17-22. AbstractObjectiveGuillain-Barre syndrome (GBS) is an immune-mediated polyneuropathy that occurs mostly after  prior infection. The diagnosis of this syndrome is dependent heavily on the history and examination, although cerebrospinal fluid analysis and electrodiagnostic testing usually conf...

  17. Multiphasic acute disseminated encephalomyelitis associated with atypical rubella virus infection.

    Science.gov (United States)

    Shinoda, Koji; Asahara, Hideaki; Uehara, Taira; Miyoshi, Katsue; Suzuki, Satoshi O; Iwaki, Toru; Kira, Jun-ichi

    2015-02-01

    We report the first case of an occurrence of multiphasic acute disseminated encephalomyelitis (ADEM) associated with atypical rubella virus infection with no rash and long-term increased titers of serum anti-rubella IgM in a 17-year-old male who had no history of rubella vaccination. He suffered from at least six clinical exacerbations with disseminated hyperintense lesions on FLAIR MR images during the course of 18 months. Repeated methylprednisolone pulse therapy and intravenous immunoglobulin therapy resolved the exacerbations. In patients with multiphasic ADEM of unknown etiology, clinicians should also consider the possibility of preceding infection with rubella virus. © The Author(s), 2015.

  18. [Atypical agents of wound infection and targeted samples].

    Science.gov (United States)

    Kucisec-Tepes, Nastja

    2012-10-01

    All open wounds are primarily contaminated and subsequently colonized by microorganisms, predominantly bacteria. Only about 30% of chronic wounds are also infected. Factors which favor the development of infection are the following: large quantity of bacteria, presence of virulence factors, their quantity and number, predominantly the synergy of aerobic and anaerobic bacteria, and formation of biofilm. Common agents of infection of acute and chronic wounds are Staphylococcus aureus, MRSA, Streptococcus beta-haemolyticus, Pseudomonas aeruginosa, Bacteroides spp., and Candida albicans. Difference between acute and chronic wound is in the predominance of individual agents, with an observation that Staphylococcus aureus is predominant in both cases. Atypical agents of chronic wound infection are rare, unusual, not found in the area in which we live, not proven by standard microbiological methods, but molecular methods are needed instead. They are predominantly opportunists, varying in the expression of virulence factors, or they have changed their phenotype characteristics and are not the agents of primary wound infections. They are the agents of secondary infections. Atypical agents of the chronic wound infection are diverse, from the anaerobe group, Peptoniphilus spp., Anaerococcus spp., Bacteroides ureolyticus, Finegoldia magma, the group of gram positive rods of the Corynebacterium genus, the group of bacteria from aquatic environment Mycobacterium fortuitum complex, and Vibrio alginolyticus. The targeted samples are biopsy sample as the "gold standard" and/or aspirate, when a significant quantity of exudate is present. Targeted samples are obligatory when there is a progression and decomposition of the base of the wound, increase in the size or depth of the wound, isolation of multiresistant microbes, or absence of clinical response to empirical antimicrobial therapy. In the diagnosis of opportunistic pathogens or atypical agents of chronic wound infection, it is

  19. Atypical bacterial infections explained by a concomitant virus infection.

    Science.gov (United States)

    Dagan, R; Hall, C B; Menegus, M A

    1985-09-01

    Because both viral and bacterial infections are common during early childhood, dual infections are not unexpected. However, the clinical manifestation of such combined infections may be, difficult to interpret, and they are often misdiagnosed as "atypical bacterial infection." Five patients with concomitant viral-bacterial infections are described. In all five cases, virus detection enabled the physicians to better understand an otherwise puzzling clinical presentation. In view of the recent progress in rapid viral diagnoses and the potential of antiviral drugs, the possibility of dual infection should be investigated more often.

  20. The Atypical Response Regulator AtvR Is a New Player in Pseudomonas aeruginosa Response to Hypoxia and Virulence.

    Science.gov (United States)

    Kaihami, Gilberto Hideo; Breda, Leandro Carvalho Dantas; de Almeida, José Roberto Fogaça; de Oliveira Pereira, Thays; Nicastro, Gianlucca Gonçalves; Boechat, Ana Laura; de Almeida, Sandro Rogério; Baldini, Regina Lúcia

    2017-08-01

    Two-component systems are widespread in bacteria, allowing adaptation to environmental changes. The classical pathway is composed of a histidine kinase that phosphorylates an aspartate residue in the cognate response regulator (RR). RRs lacking the phosphorylatable aspartate also occur, but their function and contribution during host-pathogen interactions are poorly characterized. AtvR (PA14_26570) is the only atypical response regulator with a DNA-binding domain in the opportunistic pathogen Pseudomonas aeruginosa Macrophage infection with the atvR mutant strain resulted in higher levels of tumor necrosis factor alpha secretion as well as increased bacterial clearance compared to those for macrophages infected with the wild-type strain. In an acute pneumonia model, mice infected with the atvR mutant presented increased amounts of proinflammatory cytokines, increased neutrophil recruitment to the lungs, reductions in bacterial burdens, and higher survival rates in comparison with the findings for mice infected with the wild-type strain. Further, several genes involved in hypoxia/anoxia adaptation were upregulated upon atvR overexpression, as seen by high-throughput transcriptome sequencing (RNA-Seq) analysis. In addition, atvR was more expressed in hypoxia in the presence of nitrate and required for full expression of nitrate reductase genes, promoting bacterial growth under this condition. Thus, AtvR would be crucial for successful infection, aiding P. aeruginosa survival under conditions of low oxygen tension in the host. Taken together, our data demonstrate that the atypical response regulator AtvR is part of the repertoire of transcriptional regulators involved in the lifestyle switch from aerobic to anaerobic conditions. This finding increases the complexity of regulation of one of the central metabolic pathways that contributes to Pseudomonas ubiquity and versatility. Copyright © 2017 American Society for Microbiology.

  1. Inhibitors of unactivated p38 MAP kinase.

    Science.gov (United States)

    Bullington, James; Argentieri, Dennis; Averill, Kristin; Carter, Demetrius; Cavender, Druie; Fahmy, Bohumila; Fan, Xiaodong; Hall, Daniel; Heintzelman, Geoffrey; Jackson, Paul; Leung, Wai-Ping; Li, Xun; Ling, Ping; Olini, Gilbert; Razler, Thomas; Reuman, Michael; Rupert, Kenneth; Russell, Ronald; Siekierka, John; Wadsworth, Scott; Wolff, Russell; Xiang, Bangping; Zhang, Yue-Mei

    2006-12-01

    Inhibition of the p38 map kinase pathway has been shown to be beneficial in the treatment of inflammatory diseases. The first class of potent p38 kinase inhibitors was the pyridinylimidazole compounds from SKB. Since then several pyridinylimidazole-based compounds have been shown to inhibit activated p38 kinase in vitro and in vivo. We have developed a novel series of pyridinylimidazole-based compounds, which potently inhibit the p38 pathway by binding to unactivated p38 kinase and only weakly inhibiting activated p38 kinase activity in vitro.

  2. Abi1/Hssh3bp1 pY213 links Abl kinase signaling to p85 regulatory subunit of PI-3 kinase in regulation of macropinocytosis in LNCaP cells.

    Science.gov (United States)

    Dubielecka, Patrycja M; Machida, Kazuya; Xiong, Xiaoling; Hossain, Sajjad; Ogiue-Ikeda, Mari; Carrera, Ana C; Mayer, Bruce J; Kotula, Leszek

    2010-08-04

    Macropinocytosis is regulated by Abl kinase via an unknown mechanism. We previously demonstrated that Abl kinase activity is, itself, regulated by Abi1 subsequent to Abl kinase phosphorylation of Abi1 tyrosine 213 (pY213) [1]. Here we show that blocking phosphorylation of Y213 abrogated the ability of Abl to regulate macropinocytosis, implicating Abi1 pY213 as a key regulator of macropinocytosis. Results from screening the human SH2 domain library and mapping the interaction site between Abi1 and the p85 regulatory domain of PI-3 kinase, coupled with data from cells transfected with loss-of-function p85 mutants, support the hypothesis that macropinocytosis is regulated by interactions between Abi1 pY213 and the C-terminal SH2 domain of p85-thereby linking Abl kinase signaling to p85-dependent regulation of macropinocytosis. Copyright (c) 2010 Federation of European Biochemical Societies. All rights reserved.

  3. A novel protein kinase-like domain in a selenoprotein, widespread in the tree of life.

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    Małgorzata Dudkiewicz

    Full Text Available Selenoproteins serve important functions in many organisms, usually providing essential oxidoreductase enzymatic activity, often for defense against toxic xenobiotic substances. Most eukaryotic genomes possess a small number of these proteins, usually not more than 20. Selenoproteins belong to various structural classes, often related to oxidoreductase function, yet a few of them are completely uncharacterised.Here, the structural and functional prediction for the uncharacterised selenoprotein O (SELO is presented. Using bioinformatics tools, we predict that SELO protein adopts a three-dimensional fold similar to protein kinases. Furthermore, we argue that despite the lack of conservation of the "classic" catalytic aspartate residue of the archetypical His-Arg-Asp motif, SELO kinases might have retained catalytic phosphotransferase activity, albeit with an atypical active site. Lastly, the role of the selenocysteine residue is considered and the possibility of an oxidoreductase-regulated kinase function for SELO is discussed.The novel kinase prediction is discussed in the context of functional data on SELO orthologues in model organisms, FMP40 a.k.a.YPL222W (yeast, and ydiU (bacteria. Expression data from bacteria and yeast suggest a role in oxidative stress response. Analysis of genomic neighbourhoods of SELO homologues in the three domains of life points toward a role in regulation of ABC transport, in oxidative stress response, or in basic metabolism regulation. Among bacteria possessing SELO homologues, there is a significant over-representation of aquatic organisms, also of aerobic ones. The selenocysteine residue in SELO proteins occurs only in few members of this protein family, including proteins from Metazoa, and few small eukaryotes (Ostreococcus, stramenopiles. It is also demonstrated that enterobacterial mchC proteins involved in maturation of bactericidal antibiotics, microcins, form a distant subfamily of the SELO proteins.The new

  4. 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....

  5. 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.

  6. DMPD: Bruton's tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling? [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15081522 Bruton's tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signall...ruton's tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling? PubmedID 15081522 Title Bruton...'s tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling? Authors

  7. MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA-Dependent Mechanism.

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    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. Structural basis of ligand interaction with atypical chemokine receptor 3

    Science.gov (United States)

    Gustavsson, Martin; Wang, Liwen; van Gils, Noortje; Stephens, Bryan S.; Zhang, Penglie; Schall, Thomas J.; Yang, Sichun; Abagyan, Ruben; Chance, Mark R.; Kufareva, Irina; Handel, Tracy M.

    2017-01-01

    Chemokines drive cell migration through their interactions with seven-transmembrane (7TM) chemokine receptors on cell surfaces. The atypical chemokine receptor 3 (ACKR3) binds chemokines CXCL11 and CXCL12 and signals exclusively through β-arrestin-mediated pathways, without activating canonical G-protein signalling. This receptor is upregulated in numerous cancers making it a potential drug target. Here we collected over 100 distinct structural probes from radiolytic footprinting, disulfide trapping, and mutagenesis to map the structures of ACKR3:CXCL12 and ACKR3:small-molecule complexes, including dynamic regions that proved unresolvable by X-ray crystallography in homologous receptors. The data are integrated with molecular modelling to produce complete and cohesive experimentally driven models that confirm and expand on the existing knowledge of the architecture of receptor:chemokine and receptor:small-molecule complexes. Additionally, we detected and characterized ligand-induced conformational changes in the transmembrane and intracellular regions of ACKR3 that elucidate fundamental structural elements of agonism in this atypical receptor.

  9. Structural basis of ligand interaction with atypical chemokine receptor 3

    Energy Technology Data Exchange (ETDEWEB)

    Gustavsson, Martin; Wang, Liwen; van Gils, Noortje; Stephens, Bryan S.; Zhang, Penglie; Schall, Thomas J.; Yang, Sichun; Abagyan, Ruben; Chance, Mark R.; Kufareva, Irina; Handel, Tracy M.

    2017-01-18

    Chemokines drive cell migration through their interactions with seven-transmembrane (7TM) chemokine receptors on cell surfaces. The atypical chemokine receptor 3 (ACKR3) binds chemokines CXCL11 and CXCL12 and signals exclusively through β-arrestin-mediated pathways, without activating canonical G-protein signalling. This receptor is upregulated in numerous cancers making it a potential drug target. Here we collected over 100 distinct structural probes from radiolytic footprinting, disulfide trapping, and mutagenesis to map the structures of ACKR3:CXCL12 and ACKR3:small-molecule complexes, including dynamic regions that proved unresolvable by X-ray crystallography in homologous receptors. The data are integrated with molecular modelling to produce complete and cohesive experimentally driven models that confirm and expand on the existing knowledge of the architecture of receptor:chemokine and receptor:small-molecule complexes. Additionally, we detected and characterized ligand-induced conformational changes in the transmembrane and intracellular regions of ACKR3 that elucidate fundamental structural elements of agonism in this atypical receptor.

  10. Typical and atypical clinical presentation of uterine myomas

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    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.

  11. Atypical lung carcinoid metastasis to the pituitary gland

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    Xiao-ling YAN

    2017-09-01

    Full Text Available Objective To study clinicopathological features, diagnosis and differential diagnosis of atypical lung carcinoid metastasis to the pituitary gland based on clinical data of one patient. Methods and Results A 81-year-old female presented headache and sudden blindness, and head MRI showed that there was a lesion at the saddle area. The tumor was detected at intrasellar and in grayish red during surgery. The diameter of tumor was 2 cm. The tumor was soft with no envelop at and well-defined margins, and insufficiency in blood supply. The tumor was removed completely along its edge. Under optical microscopy, the tumor was consisted of small round cells of the same size. Tumor cells were distributed around blood vessels in a nest manner or diffuse manner with brisk mitotic activity and focal necrosis. By using immunohistochemical staining, the tumor cells were diffusely positive for synaptophysin (Syn, CD56 and thyoid transcription factor - 1 (TTF - 1, focal positive for cytokeratin (CK and P53, and negative for growth hormone (GH, prolactin (PRL, adrenocorticotropic hormone (ACTH, follicle stimulating hormone (FSH, thyroid stimulating hormone (TSH, luteinizing hormone (LH, S-100 protein (S-100, thyroglobulin (TG and calcitonin. Ki?67 labeling index was about 33%. Conclusions Pituitary metastasis is a rare tumor, and only a few cases of atypical lung carcinoid metastasis to the pituitary gland have been reported. Definite diagnosis could be made by history, typical histopathological characteristics and immunohistochemical expressions. DOI: 10.3969/j.issn.1672-6731.2017.09.010

  12. Differentiation of regions with atypical oligonucleotide composition in bacterial genomes

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    Reva Oleg N

    2005-10-01

    Full Text Available Abstract Background Complete sequencing of bacterial genomes has become a common technique of present day microbiology. Thereafter, data mining in the complete sequence is an essential step. New in silico methods are needed that rapidly identify the major features of genome organization and facilitate the prediction of the functional class of ORFs. We tested the usefulness of local oligonucleotide usage (OU patterns to recognize and differentiate types of atypical oligonucleotide composition in DNA sequences of bacterial genomes. Results A total of 163 bacterial genomes of eubacteria and archaea published in the NCBI database were analyzed. Local OU patterns exhibit substantial intrachromosomal variation in bacteria. Loci with alternative OU patterns were parts of horizontally acquired gene islands or ancient regions such as genes for ribosomal proteins and RNAs. OU statistical parameters, such as local pattern deviation (D, pattern skew (PS and OU variance (OUV enabled the detection and visualization of gene islands of different functional classes. Conclusion A set of approaches has been designed for the statistical analysis of nucleotide sequences of bacterial genomes. These methods are useful for the visualization and differentiation of regions with atypical oligonucleotide composition prior to or accompanying gene annotation.

  13. Clinical and molecular review of atypical congenital adrenal hyperplasia

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    Taninee Sahakitrungruang

    2015-03-01

    Full Text Available Congenital adrenal hyperplasia (CAH is one of the most common inherited metabolic disorders. It comprises a group of autosomal recessive disorders caused by the mutations in the genes encoding for steroidogenic enzymes that involved cortisol synthesis. More than 90% of cases are caused by a defect in the enzyme 21-hydroxylase. Four other enzyme deficiencies (cholesterol side-chain cleavage, 17α-hydroxylase [P450c17], 11β-hydroxylase [P450c11β], 3β-hydroxysteroid dehydrogenase in the steroid biosynthesis pathway, along with one cholesterol transport protein defect (steroidogenic acute regulatory protein, and one electrontransfer protein (P450 oxidoreductase account for the remaining cases. The clinical symptoms of the different forms of CAH result from the particular hormones that are deficient and those that are produced in excess. A characteristic feature of CAH is genital ambiguity or disordered sex development, and most variants are associated with glucocorticoid deficiency. However, in the rare forms of CAH other than 21-hydroxylase deficiency so-called "atypical CAH", the clinical and hormonal phenotypes can be more complicated, and are not well recognized. This review will focus on the atypical forms of CAH, including the genetic analyses, and phenotypic correlates.

  14. Atypical antipsychotics in the treatment of early-onset schizophrenia

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    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

  15. Atypical dermatophilosis of sheep in Kenya : clinical communication

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    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.

  16. Clinical and molecular review of atypical congenital adrenal hyperplasia

    Science.gov (United States)

    2015-01-01

    Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders. It comprises a group of autosomal recessive disorders caused by the mutations in the genes encoding for steroidogenic enzymes that involved cortisol synthesis. More than 90% of cases are caused by a defect in the enzyme 21-hydroxylase. Four other enzyme deficiencies (cholesterol side-chain cleavage, 17α-hydroxylase [P450c17], 11β-hydroxylase [P450c11β], 3β-hydroxysteroid dehydrogenase) in the steroid biosynthesis pathway, along with one cholesterol transport protein defect (steroidogenic acute regulatory protein), and one electrontransfer protein (P450 oxidoreductase) account for the remaining cases. The clinical symptoms of the different forms of CAH result from the particular hormones that are deficient and those that are produced in excess. A characteristic feature of CAH is genital ambiguity or disordered sex development, and most variants are associated with glucocorticoid deficiency. However, in the rare forms of CAH other than 21-hydroxylase deficiency so-called "atypical CAH", the clinical and hormonal phenotypes can be more complicated, and are not well recognized. This review will focus on the atypical forms of CAH, including the genetic analyses, and phenotypic correlates. PMID:25883920

  17. 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.

  18. Multiple forms of atypical rearrangements generating supernumerary derivative chromosome 15

    Directory of Open Access Journals (Sweden)

    Sigman Marian

    2008-01-01

    Full Text Available Abstract Background Maternally-derived duplications that include the imprinted region on the proximal long arm of chromosome 15 underlie a complex neurobehavioral disorder characterized by cognitive impairment, seizures and a substantial risk for autism spectrum disorders1. The duplications most often take the form of a supernumerary pseudodicentric derivative chromosome 15 [der(15] that has been called inverted duplication 15 or isodicentric 15 [idic(15], although interstitial rearrangements also occur. Similar to the deletions found in most cases of Angelman and Prader Willi syndrome, the duplications appear to be mediated by unequal homologous recombination involving low copy repeats (LCR that are found clustered in the region. Five recurrent breakpoints have been described in most cases of segmental aneuploidy of chromosome 15q11-q13 and previous studies have shown that most idic(15 chromosomes arise through BP3:BP3 or BP4:BP5 recombination events. Results Here we describe four duplication chromosomes that show evidence of atypical recombination events that involve regions outside the common breakpoints. Additionally, in one patient with a mosaic complex der(15, we examined homologous pairing of chromosome 15q11-q13 alleles by FISH in a region of frontal cortex, which identified mosaicism in this tissue and also demonstrated pairing of the signals from the der(15 and the normal homologues. Conclusion Involvement of atypical BP in the generation of idic(15 chromosomes can lead to considerable structural heterogeneity.

  19. [The case of temporal lobes dysfunction in atypical psychiatric episodes].

    Science.gov (United States)

    Gabison-Hermann, D; Pelletier, A; Taleb, M; Bouleau, J-H

    2009-10-01

    A thirty-seven-year-old man, with temporal epilepsy, had transient, atypical psychiatric states with periods of time without any symptom. These episodes included hypersexuality with qualitative changes of sex drive, obscene behavior, exhibitionism, masturbation and modified sexual orientation. Blunted affect, inability to recognize significant persons (visual agnosia) were also detected. Magnetic resonance imaging was normal and interictal single-photon emission computed tomography (SPECT) showed decreased cerebral perfusion in both temporal lobes. The principal hypothesis is a Klüver-Bucy syndrome (KBS). In animals and human beings, this syndrome can be produced by bilateral temporal lobectomy. It is characterised by hypersexuality, visual agnosia, strong oral tendency, dietary changes, hypermetamorphosis and blunted affect. A minimum of three KBS elements suggests bilateral temporal dysfunction and supports the diagnosis. The syndrome may occur in herpes encephalitis, head trauma, Pick disease and temporal epilepsy. A single case of a patient, without any evidence for structural lesion in temporal lobes, is presented with many KBS symptoms, behavioral changes being due to complex partial seizure. Bitemporal dysfunction for this patient was confirmed by SPECT scan. On the other hand, the detected behavioral changes cannot be explained by temporal epilepsy alone. Postictal hypersexuality in temporal epilepsy consists in sexual arousal but not sexual aberrations as found in KBS. KBS following complex partial status epilepticus is a rare phenomenum. The case described here shows how atypical psychiatric episodes can cover complex neurologic disorders.

  20. 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