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Sample records for acquired c1 inhibitor

  1. Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment.

    PubMed

    Zeerleder, Sacha; Levi, Marcel

    2016-01-01

    Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. A decreased activity of C1-inhibitor is the hallmark of C1-INH-HAE (types 1 and 2) due to a mutation in the C1-inhibitor gene, whereas the deficiency in C1-inhibitor in C1-INH-AAE is the result of autoimmune phenomena. In HAE with normal C1-inhibitor, a significant percentage of patients have an increased activity of factor XIIa due to a FXII mutation (FXII-HAE). Treatment of C1-inhibitor-dependent angioedema focuses on restoring control of BK generation by inhibition of CP proteases by correcting the balance between CP inhibitors and BK breakdown or by inhibition of BK-mediated effects at the BKR2 on endothelial cells. This review will address the pathophysiology, clinical picture, diagnosis and available treatment in C1-inhibitor-dependent angioedema focusing on BK-release and its regulation. Key Messages Inadequate control of bradykinin formation results in the formation of characteristic subcutaneous and submucosal edemas of the skin, upper airways, facial structures, abdomen and extremities as seen in hereditary and acquired C1-inhibitor-dependent angioedema. Diagnosis of hereditary and acquired C1-inhibitor-dependent angioedema may be troublesome as illustrated by the fact that there is a significant delay in diagnosis; a certain grade of suspicion is therefore crucial for quick diagnosis. Submucosal edema formation in

  2. The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity.

    PubMed

    Wu, Maddalena Alessandra; Castelli, Roberto

    2016-02-01

    Several clinical and biological features of lymphoproliferative diseases have been associated with an increased risk of developing autoimmune manifestations. Acquired deficiency of C1-inhibitor (C1-INH) (AAE) is a rare syndrome clinically similar to hereditary angioedema (HAE) characterized by local increase in vascular permeability (angioedema) of the skin and the gastrointestinal and oro-pharyngo-laryngeal mucosa. Bradykinin, a potent vasoactive peptide, released from high molecular weight kininogen when it is cleaved by plasma kallikrein (a serine protease controlled by C1-INH), is the mediator of symptoms. In total 46% of AAE patients carry an underlying hematological disorder including monoclonal gammopathy of uncertain significance (MGUS) or B cell malignancies. However, 74% of AAE patients have anti-C1-INH autoantibodies without hematological, clinical or instrumental evidence of lymphoproliferative disease. Unlike HAE patients, AAE patients usually have late-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hypercatabolism of C1-INH. Experiments show that C1-INH and/or the classical complement pathway were consumed by the neoplastic lymphatic tissues and/or anti-C1-INH neutralizing autoantibodies. Therapy of AAE follows two directions: 1) prevention/reversal of the symptoms of angioedema; and 2) treatment of the associated disease. Different forms of B cell disorders coexist and/or evolve into each other in AAE and seem to be dominated by an altered control of B cell proliferation, thus AAE represents an example of the strict link between autoimmunity and lymphoproliferation.

  3. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema.

    PubMed

    Zuraw, Bruce L; Bernstein, Jonathan A; Lang, David M; Craig, Timothy; Dreyfus, David; Hsieh, Fred; Khan, David; Sheikh, Javed; Weldon, David; Bernstein, David I; Blessing-Moore, Joann; Cox, Linda; Nicklas, Richard A; Oppenheimer, John; Portnoy, Jay M; Randolph, Christopher R; Schuller, Diane E; Spector, Sheldon L; Tilles, Stephen A; Wallace, Dana

    2013-06-01

    These parameters were developed by the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the JTFPP, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. The Joint Task Force on Practice Parameters understands that the cost of diagnostic tests and therapeutic agents is an important concern that might appropriately influence the work-up and treatment chosen for a given patient. The JTFPP recognizes that the emphasis of our primary recommendations regarding a medication might vary, for example, depending on third-party payer issues and product patent expiration dates. However, because the cost of a given test or agent is so widely variable and there is a paucity of pharmacoeconomic data, the JTFPP generally does not consider cost when formulating practice parameter recommendations. In some instances the cost benefit of an intervention is considered relevant, and commentary might be provided. These parameters are not designed for use by pharmaceutical companies in drug promotion

  4. Acquired Factor V Inhibitor

    PubMed Central

    Hirai, Daisuke; Yamashita, Yugo; Masunaga, Nobutoyo; Katsura, Toshiaki; Akao, Masaharu; Okuno, Yoshiaki; Koyama, Hiroshi

    2016-01-01

    Inhibitors directed against factor V rarely occur, and the clinical symptoms vary. We herein report the case of a patient who presented with a decreased factor V activity that had decreased to <3 %. We administered vitamin K and 6 units of fresh frozen plasma, but she thereafter developed an intracerebral hemorrhage. It is unclear whether surgery >10 years earlier might have caused the development of a factor V inhibitor. The treatment of acquired factor V inhibitors is mainly the transfusion of platelet concentrates and corticosteroids. Both early detection and the early initiation of the treatment of factor V inhibitor are thus considered to be important. PMID:27746446

  5. C1 inhibitor: quantification and purification.

    PubMed

    Varga, Lilian; Dobó, József

    2014-01-01

    C1 inhibitor is a multipotent serpin capable of inhibiting the classical and the lectin pathways of complement, the fibrinolytic system, and contact/kinin system of coagulation. Deficiency of C1 inhibitor manifest as hereditary angioedema (HAE), an autosomal dominant hereditary disease. Measuring the C1 inhibitor level is of vital importance for the diagnosis of HAE and also for monitoring patients receiving C1 inhibitor for therapy. Determination of the antigenic C1 inhibitor level by the radial immunodiffusion (RID) technique is described in detail in this chapter. The presented purification method of plasma C1 inhibitor is primarily based on its high carbohydrate content and its affinity to the lectin jacalin.

  6. [Acquired coagulant factor inhibitors].

    PubMed

    Nogami, Keiji

    2015-02-01

    Acquired coagulation factor inhibitors are an autoimmune disease causing bleeding symptoms due to decreases in the corresponding factor (s) which result from the appearance of autoantibodies against coagulation factors (inhibitor). This disease is quite different from congenital coagulation factor deficiencies based on genetic abnormalities. In recent years, cases with this disease have been increasing, and most have anti-factor VIII autoantibodies. The breakdown of the immune control mechanism is speculated to cause this disease since it is common in the elderly, but the pathology and pathogenesis are presently unclear. We herein describe the pathology and pathogenesis of factor VIII and factor V inhibitors. Characterization of these inhibitors leads to further analysis of the coagulation process and the activation mechanisms of clotting factors. In the future, with the development of new clotting examination method (s), we anticipate that further novel findings will be obtained in this field through inhibitor analysis. In addition, detailed elucidation of the coagulation inhibitory mechanism possibly leading to hemostatic treatment strategies for acquired coagulation factor disorders will be developed.

  7. Hereditary angioedema with normal C1 inhibitor.

    PubMed

    Bork, Konrad

    2013-11-01

    Until recently it was assumed that hereditary angioedema was a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity, and protein in plasma were described. Since then, numerous patients and families with that condition have been reported. Most of the patients were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. In some families mutations in the coagulation factor XII (Hageman factor) gene were detected.

  8. C1 inhibitor functional deficiency in systemic lupus erythematosus (SLE).

    PubMed Central

    Jazwinska, E C; Gatenby, P A; Dunckley, H; Serjeantson, S W

    1993-01-01

    C1 inhibitor (C1-inh) was assayed in eight SLE patients presenting with consistently low levels of intact C4. C1-inh antigenic levels were normal in all patients; however, the function of the C1-inh tested against C1s and C1r was variable and outside the normal functional range in seven of the eight patients. The molecular weight of patients' C1-inh protein was 105 kD, corresponding to the size of the intact molecule. The C1-inh gene was analysed in all patients. Restriction fragments generated with TaqI, PstI and HgiAI gave no indication of a major C1-inh gene rearrangement. Direct genomic sequencing of exon VIII revealed three polymorphic point mutations, but there were no changes from the normal gene in or around the reactive-centre residue of C1-inh. Furthermore, we found no evidence for a C1-inh autoantibody in patients which could affect normal C1-inh function in vitro. These results indicate that the etiology of C1-inh dysfunction in SLE is heterogeneous and distinct from that reported in either hereditary or acquired angioedema. PMID:8485912

  9. Characterization of C1 inhibitor binding to neutrophils.

    PubMed Central

    Chang, N S; Boackle, R J; Leu, R W

    1991-01-01

    In a previous study we have isolated neutrophil membrane proteins that non-covalently bind to native C1-INH (105,000 MW) and a non-functional, degraded C1-INH (88,000 MW; C1-INH-88). To further characterize the binding nature, we have designed a novel kinetic C1 titration assay which enables not only a quantification of the removal of fluid-phase C1-INH by neutrophils, but also a concomitant measure of residual C1-INH function. Native C1-INH, when adsorbed to EDTA-pretreated neutrophils, lost its function in the inhibition of fluid-phase C1. The non-functional C1-INH-88, which is probably devoid of a reactive centre, was found to block the binding of native C1-INH to neutrophils. Pretreatment of neutrophils with serine esterase inhibitors did not abrogate binding capacity of the cells for C1-INH, whereas the binding affinity for C1-INH was lost when the cells were pretreated with trypsin. An array of human peripheral blood leucocytes and several lymphoid cell lines has surface binding sites for C1-INH, but not on human erythrocytes and U937 cells. Binding was further confirmed using (i) C1-INH-microsphere beads to neutrophils, in which the binding was blocked when pretreating neutrophils with excess C1-INH or with trypsin, and (ii) radiolabelled C1-INH to neutrophils, which was competitively blocked by unlabelled non-functional C1-INH-88. Desialylation of C1-INH significantly reduced its binding affinity for neutrophils, indicating that the membrane receptor sites on neutrophils could be specific for the binding of sialic acid residues on C1-INH. Overall, our studies indicate that neutrophils or other leucocytes possess specific surface binding sites for the sialic acid-containing portion of C1-INH. PMID:2045131

  10. Terminal complement complexes and C1/C1 inhibitor complexes in autoimmune thyroid disease.

    PubMed Central

    Weetman, A P; Cohen, S B; Oleesky, D A; Morgan, B P

    1989-01-01

    The potential role of complement activation and the membrane attack complex in the pathogenesis of Graves' disease and Hashimoto's thyroiditis has been investigated by measuring serum concentrations of the C1r-C1s-C1 inhibitor complex (C1/C1-inh) and the terminal complement complex (TCC), and by studying the binding to thyroid tissue of monoclonal and polyclonal antibodies against TCC neoantigens. Serum C1/C1-inh and TCC concentrations were significantly increased in 29 patients with untreated Graves' disease compared with 47 healthy subjects (P less than 0.001 for both), and decreased significantly after carbimazole treatment in 18 of these patients for whom post-treatment samples were available (P less than 0.01 and P less than 0.02, respectively). The serum TCC concentration, but not that of C1/C1-inh, was also significantly increased in 15 patients with Hashimoto's thyroiditis compared with the 47 healthy subjects (P less than 0.001). TCCs were identified by immunohistochemical staining around the thyroid follicles in thyroidectomy specimens from patients with Graves' disease (six out of six) and Hashimoto's thyroiditis (two out of two); normal thyroid tissue from two subjects showed no staining. These results suggest a role for complement, in particular the membrane attack complex in the pathogenesis of autoimmune thyroid disease. Images Fig. 3 PMID:2766576

  11. C1 inhibitor deficiency: 2014 United Kingdom consensus document.

    PubMed

    Longhurst, H J; Tarzi, M D; Ashworth, F; Bethune, C; Cale, C; Dempster, J; Gompels, M; Jolles, S; Seneviratne, S; Symons, C; Price, A; Edgar, D

    2015-06-01

    C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life-threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor-deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi-disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organization.

  12. C1 inhibitor deficiency: 2014 United Kingdom consensus document

    PubMed Central

    Longhurst, H J; Tarzi, M D; Ashworth, F; Bethune, C; Cale, C; Dempster, J; Gompels, M; Jolles, S; Seneviratne, S; Symons, C; Price, A; Edgar, D

    2015-01-01

    C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life-threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor-deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi-disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organization. PMID:25605519

  13. Complement, Kinins, and Hereditary Angioedema: Mechanisms of Plasma Instability when C1 Inhibitor is Absent.

    PubMed

    Kaplan, Allen P; Joseph, Kusumam

    2016-10-01

    Plasma of patients with types I and II hereditary angioedema is unstable if incubated in a plastic (i.e., inert) vessel at 37 °C manifested by progressively increasing formation of bradykinin. There is also a persistent low level of C4 in 95 % of patients even when they are symptomatic. These phenomena are due to the properties of the C1r subcomponent of C1, factor XII, and the bimolecular complex of prekallikrein with high molecular weight kininogen (HK). Purified C1r auto-activates in physiologic buffers, activates C1s, which in turn depletes C4. This occurs when C1 inhibitor is deficient. The complex of prekallikrein-HK acquires an inducible active site not present in prekallikrein which in Tris-type buffers cleaves HK stoichiometrically to release bradykinin, or in phosphate buffer auto-activates to generate kallikrein and bradykinin. Thus immunologic depletion of C1 inhibitor from factor XII-deficient plasma (phosphate is the natural buffer) auto-activates on incubation to release bradykinin. Normal C1 inhibitor prevents this from occurring. During attacks of angioedema, if factor XII auto-activates on surfaces, the initial factor XIIa formed converts prekallikrein to kallikrein, and kallikrein cleaves HK to release bradykinin. Kallikrein also rapidly activates most remaining factor XII to factor XIIa. Additional cleavages convert factor XIIa to factor XIIf and factor XIIf activates C1r enzymatically so that C4 levels approach zero, and C2 is depleted. There is also a possibility that kallikrein is generated first as a result of activation of the prekallikrein-HK complex by heat shock protein 90 released from endothelial cells, followed by kallikrein activation of factor XII.

  14. [Clinical cases of acquired coagulation inhibitors].

    PubMed

    Yamane, T; Hino, M; Ota, K; Akahori, M; Hirai, M; Inoue, T; Mugitani, A; Tatsumi, N

    2000-12-01

    The acquired coagulation factor inhibitors are classified into alloantibodies, which appear in association with supplementary treatment for congenital coagulation factor deficiency, and autoantibodies, which are spontaneously produced. We report here 2 cases of acquired factor VIII inhibitor and 1 case of factor V inhibitor. Case 1: A 52-year-old woman noted swelling of the right parotid region in March 1988. Though contrast examination was scheduled, she was admitted for detailed examination due to a markedly prolonged coagulation time. An APTT correction test suggested that decreased factor VIII activity was due to the presence of an inhibitor. Since antinuclear antibody and SS-A antibody were positive and infiltration by lymphocytes in the salivary gland acini in a lip biopsy specimen was detected, Sjögren's syndrome was diagnosed. Case 2: A 33-year-old woman had normal delivery of her second child in February 1998. In June 1998, she suffered slight contusion in the left lower limb. The affected site became swollen and painful, making walking difficult. Since both upper limbs became markedly swollen after 1 week, she visited our hospital. Prolonged APTT and a marked decrease in factor VIII activity were observed. Factor VIII inhibitor titer was high at 19 Bethesda units. Case 3: A 64-year-old man had had asymptomatic macroscopic hematuria since the beginning of August 1998 but was placed under observation since no abnormal findings were observed on various imaging tests. However, he was admitted to Osaka City General Medical Center because of vesicular tamponade. Factor V activity was markedly decreased to 1.0%. PT correction test suggested that decreased factor V activity was due to the presence of an inhibitor. The underlying disease could not be determined in this case. In patients with acquired coagulation inhibitors, bleeding symptoms are reported to be mild in many cases, and severe bleeding is rare. However, cases of death without severe bleeding or

  15. Hereditary angioedema with normal C1 inhibitor: clinical characteristics and treatment response with plasma-derived human C1 inhibitor concentrate (Berinert(®)) in a French cohort.

    PubMed

    Bouillet, Laurence; Boccon-Gibod, Isabelle; Gompel, Anne; Floccard, Bernard; Martin, Ludovic; Blanchard-Delaunay, Claire; Launay, David; Fain, Olivier

    2017-03-01

    Hereditary angioedema (HAE) is a rare genetic disorder characterised by episodes of swelling without urticaria. Berinert® (CSL Behring) is a plasma-derived human C1 inhibitor (C1-INH) concentrate, approved for the treatment of HAE with C1-INH deficiency (C1-INH-HAE), however, it is often used off-label in Europe to treat HAE with normal C1-INH.

  16. A 'de novo' arisen case of angioedema C1-inhibitor deficiency dependent: possible mutagenic effect of azathioprine?

    PubMed

    Guastafierro, S; D'Apuzzo, A; Verrazzo, G; Lucivero, G; Coppola, L

    1999-06-01

    It is reported that a C1-inhibitor (CI-INH) deficiency dependent angiodema case arose 'de novo' in a child without a family history of this disease. His mother was undergoing immunosuppressive therapy (50 mg of azathioprine plus 8 mg of methyl-prednisolone daily) during pregnancy, uninterrupted for seven years because of a kidney transplant. All the other known causes of acquired C1-INH deficiency were excluded. An involvement of an azathioprine-induced C1-INH gene mutation is hypothised.

  17. [Acquired angioedema with C1-INH deficiency and accompanying chronic spontaneous urticaria in a patient with chronic lymphatic B cell leukemia].

    PubMed

    Klossowski, N; Braun, S A; von Gruben, V; Losem, C; Plewe, D; Homey, B; Meller, S

    2015-10-01

    Acquired angioedema due to C1 inhibitor deficiency (C1-INH-AAE) is characterized by recurrent edema of the subcutaneous and/or submucosal tissue without wheals and negative family history of angioedema. Here, we present the case of a patient with a chronic lymphatic B cell leukemia who suffered from both C1-INH-AAE and chronic spontaneous urticaria. Oral corticosteroids, antihistamines, and the anti-IgE antibody omalizumab were applied to treat the chronic urticaria in combination with the plasma-derived C1 esterase inhibitor concentrate Berinert® and the bradykinin B2 receptor antagonist icatibant, but the symptoms did not improved significantly. Thus, polychemotherapy targeting the slow-growing lymphoproliferative disease including rituximab was initiated, which resulted in remission of both the urticaria and the angioedema.

  18. Overview of hereditary angioedema caused by C1-inhibitor deficiency: assessment and clinical management.

    PubMed

    Bork, K; Davis-Lorton, M

    2013-02-01

    Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a rare, autosomal-dominant disease. HAE-C1-INH is characterized by recurrent attacks of marked, diffuse, nonpitting and nonpruritic skin swellings, painful abdominal attacks, and laryngeal edema. The extremities and the gastrointestinal tract are most commonly affected. Swelling of the upper respiratory mucosa poses the greatest risk because death from asphyxiation can result from laryngealedema. HAE-C1-INH attacks are variable, unpredictable, and may be induced by a variety of stimuli, including stress or physical trauma. Because the clinical presentation of HAE-C1-INH is similar to other types of angioedema, the condition may be a challenge to diagnose. Accurate identification of HAE-C1-INH is critical in order to avoid asphyxiation by laryngeal edema and to improve the burden of disease. Based on an understanding of the underlying pathophysiology of IHAE-C1-INH, drugs targeted specifically to the disease, such as C1-inhibitor therapy, bradykinin B2-receptor antagonists, and kallikrein-inhibitors, have become available for both treatment and prevention of angioedema attacks. This article reviews the clinical features, differential diagnosis, and current approaches to management of HAE-C1-INH.

  19. Therapeutic management of hereditary angioedema due to C1 inhibitor deficiency.

    PubMed

    Zanichelli, Andrea; Mansi, Marta; Periti, Giulia; Cicardi, Marco

    2013-05-01

    Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a rare genetic disease characterized by recurrent swellings of the subcutaneous and submucosal tissues that can manifest as cutaneous edema, abdominal pain and laryngeal edema with airway obstruction. These symptoms have a significant impact on patients' quality of life. The reduction in C1-INH function leads to uncontrolled activation of the contact system and generation of bradykinin, the mediator of increased vascular permeability and edema formation. In the past, few treatment options were available; however, several new therapies with proven efficacy have recently become available to treat and prevent HAE attacks, such as plasma-derived and recombinant C1-INHs that replace the deficient protein, bradykinin receptor antagonist (icatibant) that blocks bradykinin activity and kallikrein inhibitor (ecallantide) that prevents bradykinin release. Such therapies can improve disease outcome. This article reviews the therapeutic management of HAE, which involves the treatment of acute attacks and prophylaxis.

  20. Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency.

    PubMed

    Moldovan, Dumitru; Bernstein, Jonathan A; Cicardi, Marco

    2015-01-01

    Hereditary angioedema is a rare genetic condition transmitted as an autosomal dominant trait and characterized most commonly by the production of either inadequate or nonfunctioning C1 esterase inhibitor (C1-INH), a blood protein that regulates proteases in the complement, fibrinolytic and contact systems. Patients with hereditary angioedema suffer from episodic, unpredictable manifestations of edema affecting multiple anatomical locations, including the GI tract, facial tissue, the upper airway, oropharynx, urogenital region and/or the arms and legs. A rational approach to treatment is replacement of C1-INH protein, to normalize the levels of C1-INH activity and halt the progression of the biochemical activation processes underlying the edema formation. Ruconest is a highly purified recombinant human C1-INH. This article will focus on the results of ten clinical studies demonstrating the efficacy and safety of Ruconest(®) (Pharming Group NV, Leiden, the Netherlands), which is now approved for use in Europe, Israel and the USA.

  1. Membranous nephropathy with acquired factor V inhibitor: a case report

    PubMed Central

    2013-01-01

    Background Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. In contrast, acquired factor V inhibitor is a rare bleeding disorder. Case presentation A 62-year-old Asian man with a history of cerebral hemorrhage, purpura, eosinophilia and hyper immunoglobulin E syndrome developed proteinuria. The bleeding disorder was diagnosed with acquired factor V inhibitors. A renal biopsy revealed that he suffered from membranous nephropathy with glomerular endothelial damage which is reported to be involved in another factor disorder. After the steroid administration, the coagulation test and proteinuria were improved. Conclusions The presence of factor V inhibitors may have been involved in the development of membranous nephropathy. PMID:24360027

  2. Rituximab in the treatment of acquired factor VIII inhibitors.

    PubMed

    Wiestner, Adrian; Cho, Hearn J; Asch, Adam S; Michelis, Mary Ann; Zeller, Jack A; Peerschke, Ellinor I B; Weksler, Babette B; Schechter, Geraldine P

    2002-11-01

    Autoantibodies against factor VIII (FVIII) are rare but can cause life-threatening bleeding requiring costly factor replacement and prolonged immunosuppression. We report 4 consecutively treated patients whose acquired FVIII inhibitors responded rapidly to immunosuppressive regimens that included rituximab, a monoclonal antibody against CD20(+) B cells. Three patients had spontaneously occurring inhibitors. The fourth, a patient with mild hemophilia A, developed both an autoantibody and an alloantibody following recombinant FVIII treatment. Pretreatment FVIII activities ranged from less than 1% to 4% and inhibitor titers from 5 to 60 Bethesda units (BU). One patient with polymyalgia rheumatica who developed the inhibitor while receiving prednisone responded to single agent rituximab. The hemophilia patient had rapid resolution of the autoantibody, whereas the alloantibody persisted for months. Responses continue off treatment from more than 7 to more than 12 months. This report adds to the growing evidence that rituximab has efficacy in immune disorders resulting from autoantibody formation.

  3. Idiopathic Acquired Hemophilia A with Undetectable Factor VIII Inhibitor

    PubMed Central

    Abt, Nicholas B.; Streiff, Michael B.; Gocke, Christian B.; Kickler, Thomas S.; Lanzkron, Sophie M.

    2014-01-01

    Objective. We present the case of a 73-year-old female, with no family or personal history of a bleeding disorder, who had a classic presentation for acquired hemophilia A. Factor VIII activity was low but detectable and a factor VIII inhibitor was undetectable. Methods. The patient's plasma was comprehensively studied to determine the cause of the acquired coagulopathy. Using the Nijmegen modification of the Bethesda assay, no factor VIII autoantibody was measureable despite varying the incubation time from 1 to 3 hours. Results. The aPTT was prolonged at 46.8 seconds, which did not correct in the 4 : 1 mix but did with 1 : 1 mix. Using a one stage factor VIII activity assay, the FVIII activity was 16% and chromogenic FVIII activity was also 16%. The patient was treated with recombinant FVII and transfusion, significantly reducing bleeding. Long-term therapy was initiated with cyclophosphamide and prednisone with normalization of FVIII activity. Conclusions. Physicians can be presented with the challenging clinical picture of an acquired factor VIII inhibitor without a detectable inhibitor by the Bethesda assay. Standard therapy for an acquired hemophilia A should be considered. PMID:24955264

  4. C1 inhibitor-mediated myocardial protection from chronic intermittent hypoxia-induced injury

    PubMed Central

    Fu, Jinrong; Guo, Furong; Chen, Cheng; Yu, Xiaoman; Hu, Ke; Li, Mingjiang

    2016-01-01

    The optimal treatment for chronic intermittent hypoxia (CIH)-induced cardiovascular injuries has yet to be determined. The aim of the current study was to explore the potential protective effect and mechanism of a C1 inhibitor in CIH in the myocardium. The present study used a rat model of CIH in which complement regulatory protein, known as C1 inhibitor (C1INH), was administered to the rats in the intervention groups. Cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. The expression of proteins associated with the apoptotic pathway, such as B-cell lymphoma 2 (Bcl-2), Bax and caspase-3 were detected by western blot analysis. The expression of complement C3 protein and RNA were also analyzed. C1INH was observed to improve the cardiac function in rats with CIH. Myocardial myeloperoxidase activity, a marker of neutrophil infiltration, was significantly decreased in the C1INH intervention group compared with the CIH control group, and cardiomyocyte apoptosis was significantly attenuated (P<0.05). Western blotting and reverse transcription-polymerase chain reaction analysis indicated that the protein expression levels of Bcl-2 were decreased and those of Bax were increased in the CIH group compared with the normal control group, but the protein expression levels of Bcl-2 were increased and those of Bax were decreased in the C1INH intervention group, as compared with the CIH group. Furthermore, the CIH-induced expression and synthesis of complement C3 in the myocardium were also reduced in the C1INH intervention group. C1INH, in addition to inhibiting complement activation and inflammation, preserved cardiac function in CIH-mediated myocardial cell injury through an anti-apoptotic mechanism. PMID:27698713

  5. An update on the diagnosis and management of hereditary angioedema with abnormal C1 inhibitor.

    PubMed

    Davis-Lorton, Mark

    2015-02-01

    Hereditary angioedema (HAE) is a rare genetic disease caused by a deficiency in functional C1-esterase inhibitor characterized by recurrent episodes of angioedema in the absence of associated urticaria. Subcutaneous swellings are experienced by virtually all patients with HAE, and dermatologists are likely to encounter this manifestation, requiring that they be knowledgeable about diagnosis and treatment options. Diagnosis of HAE is often delayed because several of the symptoms can mimic other disease states. Delays in diagnosis can lead to increased inappropriate treatment and decreased patient quality of life. Once a proper diagnosis is made, treatment needs to be targeted to the individual patient and includes on-demand therapy and an option for short- and long-term prophylaxis. On-demand therapy is required for all patients who are diagnosed with HAE and effective options include plasma-derived and recombinant C1 inhibitors, kallikrein inhibitors, and bradykinin B2-receptor antagonists. Options available for prophylaxis include plasma-derived C1 inhibitors, attenuated androgens, and antifibrinolytic agents, although the latter 2 options are associated with significant adverse events. This article reviews the diagnosis and options for effective management of patients with HAE.

  6. Population pharmacokinetics of recombinant human C1 inhibitor in patients with hereditary angioedema

    PubMed Central

    Farrell, Colm; Hayes, Siobhan; Relan, Anurag; van Amersfoort, Edwin S; Pijpstra, Rienk; Hack, C Erik

    2013-01-01

    Aims To characterize the pharmacokinetics (PK) of recombinant human C1 inhibitor (rhC1INH) in healthy volunteers and hereditary angioedema (HAE) patients. Methods Plasma levels of C1INH following 294 administrations of rhC1INH in 133 subjects were fitted using nonlinear mixed-effects modelling. The model was used to simulate maximal C1INH levels for the proposed dosing scheme. Results A one-compartment model with Michaelis–Menten elimination kinetics described the data. Baseline C1INH levels were 0.901 [95% confidence interval (CI): 0.839–0.968] and 0.176 U ml−1 (95% CI: 0.154–0.200) in healthy volunteers and HAE patients, respectively. The volume of distribution of rhC1INH was 2.86 l (95% CI: 2.68–3.03). The maximal rate of elimination and the concentration corresponding to half this maximal rate were 1.63 U ml−1 h−1 (95% CI: 1.41–1.88) and 1.60 U ml−1 (95% CI: 1.14–2.24), respectively, for healthy volunteers and symptomatic HAE patients. The maximal elimination rate was 36% lower in asymptomatic HAE patients. Peak C1INH levels did not change upon repeated administration of rhC1INH. Bodyweight was found to be an important predictor of the volume of distribution. Simulations of the proposed dosing scheme predicted peak C1INH concentrations above the lower level of the normal range (0.7 U ml−1) for at least 94% of all patients. Conclusions The population PK model for C1INH supports a dosing scheme on a 50 U kg−1 basis up to 84 kg, with a fixed dose of 4200 U above 84 kg. The PK of rhC1INH following repeat administration are consistent with the PK following the first administration. PMID:23594263

  7. Effects of C1 inhibitor on tissue damage in a porcine model of controlled hemorrhage.

    PubMed

    Dalle Lucca, Jurandir J; Li, Yansong; Simovic, Milomir; Pusateri, Anthony E; Falabella, Michael; Dubick, Michael A; Tsokos, George C

    2012-07-01

    Activation of the complement system has been associated with tissue injury after hemorrhage and resuscitation in animals. We investigated whether administration of recombinant human C1-esterase inhibitor (rhC1-INH), a regulator of complement and contact activation systems, reduces tissue damage and cytokine release and improves metabolic acidosis in a porcine model of hemorrhagic shock. Male Yorkshire swine were assigned to experimental groups and subjected to controlled, isobaric hemorrhage to a target mean arterial pressure of 35 mmHg. Hypotension was maintained for 20 min followed by a bolus intravenous injection of rhC1-INH or vehicle; animals were then observed for 3 h. Blood chemistry and physiologic parameters were recorded. Lung and small intestine tissue samples were subjected to histopathologic evaluation and immunohistochemistry to determine the extent of injury and deposition of complement proteins. Cytokine levels and quantitative assessment of renal and hepatic function were measured via enzyme-linked immunosorbent assay and chemistry analyzer, respectively. Pharmacokinetics of rhC1-INH revealed dose proportionality for maximum concentration, half-life, and the time span in which the functional C1-INH level was greater than 1 IU/mL. Recombinant human C1-INH significantly reduced renal, intestinal, and lung tissue damage in a dose-dependent manner (100 and 250 IU/kg). In addition, rhC1-INH (250 IU/kg) markedly improved hemorrhage-induced metabolic acidosis and circulating tumor necrosis factor α. The tissue-protective effects of rhC1-INH appear to be related to its ability to reduce tissue complement activation and deposition. Recombinant human C1-INH decreased tissue complement activation and deposition in hemorrhaged animals, improved metabolic acidosis, reduced circulating tumor necrosis factor α, and attenuated tissue damage in this model. The observed beneficial effects of rhC1-INH treatment on tissue injury 20 min into severe hypotension

  8. Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

    PubMed

    Longhurst, Hilary; Cicardi, Marco; Craig, Timothy; Bork, Konrad; Grattan, Clive; Baker, James; Li, Huamin H; Reshef, Avner; Bonner, James; Bernstein, Jonathan A; Anderson, John; Lumry, William R; Farkas, Henriette; Katelaris, Constance H; Sussman, Gordon L; Jacobs, Joshua; Riedl, Marc; Manning, Michael E; Hebert, Jacques; Keith, Paul K; Kivity, Shmuel; Neri, Sergio; Levy, Donald S; Baeza, Maria L; Nathan, Robert; Schwartz, Lawrence B; Caballero, Teresa; Yang, William; Crisan, Ioana; Hernandez, María D; Hussain, Iftikhar; Tarzi, Michael; Ritchie, Bruce; Králíčková, Pavlina; Guilarte, Mar; Rehman, Syed M; Banerji, Aleena; Gower, Richard G; Bensen-Kennedy, Debra; Edelman, Jonathan; Feuersenger, Henrike; Lawo, John-Philip; Machnig, Thomas; Pawaskar, Dipti; Pragst, Ingo; Zuraw, Bruce L

    2017-03-23

    Background Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. Methods We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. Results Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0

  9. C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation.

    PubMed

    Albert-Weissenberger, Christiane; Mencl, Stine; Schuhmann, Michael K; Salur, Irmak; Göb, Eva; Langhauser, Friederike; Hopp, Sarah; Hennig, Nelli; Meuth, Sven G; Nolte, Marc W; Sirén, Anna-Leena; Kleinschnitz, Christoph

    2014-01-01

    Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings.

  10. Suppression of complement regulatory protein C1 inhibitor in vascular endothelial activation by inhibiting vascular cell adhesion molecule-1 action

    SciTech Connect

    Zhang, Haimou; Qin, Gangjian; Liang, Gang; Li, Jinan; Chiu, Isaac; Barrington, Robert A.; Liu, Dongxu . E-mail: dxliu001@yahoo.com

    2007-07-13

    Increased expression of adhesion molecules by activated endothelium is a critical feature of vascular inflammation associated with the several diseases such as endotoxin shock and sepsis/septic shock. Our data demonstrated complement regulatory protein C1 inhibitor (C1INH) prevents endothelial cell injury. We hypothesized that C1INH has the ability of an anti-endothelial activation associated with suppression of expression of adhesion molecule(s). C1INH blocked leukocyte adhesion to endothelial cell monolayer in both static assay and flow conditions. In inflammatory condition, C1INH reduced vascular cell adhesion molecule (VCAM-1) expression associated with its cytoplasmic mRNA destabilization and nuclear transcription level. Studies exploring the underlying mechanism of C1INH-mediated suppression in VCAM-1 expression were related to reduction of NF-{kappa}B activation and nuclear translocation in an I{kappa}B{alpha}-dependent manner. The inhibitory effects were associated with reduction of inhibitor I{kappa}B kinase activity and stabilization of the NF-{kappa}B inhibitor I{kappa}B. These findings indicate a novel role for C1INH in inhibition of vascular endothelial activation. These observations could provide the basis for new therapeutic application of C1INH to target inflammatory processes in different pathologic situations.

  11. Human inhibitor of the first component of complement, C1: characterization of cDNA clones and localization of the gene to chromosome 11.

    PubMed Central

    Davis, A E; Whitehead, A S; Harrison, R A; Dauphinais, A; Bruns, G A; Cicardi, M; Rosen, F S

    1986-01-01

    C1 inhibitor is a heavily glycosylated plasma protein that regulates the activity of the first component of complement (C1) by inactivation of the serine protease subcomponents, C1r and C1s. C1 inhibitor cDNA clones have been isolated, and one of these (pC1INH1, 950 base pairs) has been partially sequenced. Sequence analysis demonstrates that the C1 inhibitor is a member of the serpin "superfamily" of protease inhibitors. In the region sequenced, C1 inhibitor has 22% identity with antithrombin III, 26% with alpha 1-antitrypsin and alpha 1-antichymotrypsin, and 18% with human angiotensinogen. C1 inhibitor has a larger amino-terminal extension than do the other plasma protease inhibitors. In addition, inspection of residues that are invariant among the other protease inhibitors shows that C1 inhibitor differs at 14 of 41 of these positions. Thus, it appears that C1 inhibitor diverged from the group relatively early in evolution, although probably after the divergence of angiotensinogen. Southern blot analysis of BamHI-digested DNA from normal individuals and from rodent-human somatic cell hybrid cell lines (that contain a limited but varied human chromosome complement) was used to localize the human C1 inhibitor gene to chromosome 11. Images PMID:3458172

  12. Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal.

    PubMed

    Lipski, Samuel Michael; Casimir, Georges; Vanlommel, Martine; Jeanmaire, Mathieu; Dolhen, Pierre

    2015-02-01

    C1 esterase inhibitor (Berinert®) is generally used to treat severe attack of hereditary angioedema. We describe here the case of a patient who presented with a severe angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) endangering her life. It could be successfully treated with that medicine.

  13. Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection

    PubMed Central

    Côté, Marceline; Misasi, John; Ren, Tao; Bruchez, Anna; Lee, Kyungae; Filone, Claire Marie; Hensley, Lisa; Li, Qi; Ory, Daniel; Chandran, Kartik; Cunningham, James

    2011-01-01

    Summary Ebolavirus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection1 and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV2. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that the anti-viral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the N-terminal domain3–7, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit8. Thus, NPC1 is essential for EboV entry and a target for anti-viral therapy. PMID:21866101

  14. Purification of human ceruloplasmin as a by-product of C1-inhibitor.

    PubMed

    Kouoh Elombo, F; Radosevich, M; Poulle, M; Descamps, J; Chtourou, S; Burnouf, T; Catteau, J P; Bernier, J L; Cotelle, N

    2000-12-01

    Human ceruloplasmin (Cp) has been purified from cryoprecipitate-poor plasma as a by-product of the C1-inhibitor production chain. Highly purified Cp was obtained by subsequent ion-exchange chromatography on sulfate-Fractogel EMD and TMAE-Fractogel EMD. Treatments for viral safety included application of the solvent-detergent method and two nanofiltration steps using 35- and 15-nm pore size filters at the end of the process. Overall antigen yield was 95 (+/-5) %. Purified human ceruloplasmin was studied by electron spin resonance (ESR) to characterize its different types of copper complexes and to check its antioxidant properties. We distinguished three types of complexes: one type-2 Cu(II) with g// = 2.25 and A// = 180 G and two type-I Cu(II) exhibiting different narrow hyperfine splitting (A// = 72 G and A// = 90 G) with close g// (2.20 and 2.21). Purified Cp has a specific activity of 24.5+/-0.2 mU/mg of proteins. This process provides a method for Cp purification that could be easily integrated into modern plasma fractionation.

  15. Lack of increased prevalence of immunoregulatory disorders in hereditary angioedema due to C1-inhibitor deficiency.

    PubMed

    Farkas, Henriette; Csuka, Dorottya; Gács, Judit; Czaller, Ibolya; Zotter, Zsuzsanna; Füst, George; Varga, Lilian; Gergely, Péter

    2011-10-01

    Hereditary angioedema due to deficiency of C1-INH (HAE-C1-INH) is associated with enhanced consumption of the early complement components, which may predispose for autoimmune disease. We assessed the prevalence of such disorders among HAE- C1-INH patients and their impact on the natural course of HAE-C1-INH. Clinical data and immunoserological parameters of 130 HAE-C1-INH and 174 non-C1-INH-deficient patients with angioedema were analyzed. In our study, the incidence of immunoregulatory disorders was 11.5% in the population of HAE-C1-INH patients and 5.2% among non-C1-INH-deficient controls with angioedema. Immunoserology screening revealed a greater prevalence of anticardiolipin IgM (p=0.0118) among HAE-C1-INH patients, than in those with non-C1-INH-deficient angioedema. We did not find higher prevalence of immunoregulatory disorders among our HAE-C1-INH patients. However, in patients with confirmed immunoregulatory disorders, the latter influenced both the severity of HAE-C1-INH and the effectiveness of its long-term management. Appropriate management of the immunoregulatory disease thus identified improves the symptoms of HAE-C1-INH.

  16. Effects of C1 Inhibitor on Tissue Damage in a Porcine Model of Controlled Hemorrhage

    DTIC Science & Technology

    2012-07-01

    glucose, hematocrit (Hct), hemoglobin ( Hb ), sodium (Na+), potassium (K+), and ionized calcium (Ca2+) using i STAT cartridges (Abbott Laboratories, Abbott...Shock Society. Unauthorized reproduction of this article is prohibited. (Princeton, NJ). MicroVue C1 INH enzyme immunoassay (EIA) kit was purchased from...TABLE 3. Prehemorrhage and posthemorrhage metabolic data of hemorrhaged animals Group PSham H H + C1-100 H + C1-250 n 5 5 6 4 5 4 5 Prehemorrhage Hb , g

  17. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors

    PubMed Central

    Batsuli, Glaivy; Deng, Wei; Healey, John F.; Parker, Ernest T.; Baldwin, W. Hunter; Cox, Courtney; Nguyen, Brenda; Kahle, Joerg; Königs, Christoph; Li, Renhao; Lollar, Pete

    2016-01-01

    Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance. PMID:27381905

  18. Hereditary angioedema in a Jordanian family with a novel missense mutation in the C1-inhibitor N-terminal domain.

    PubMed

    Jaradat, Saied A; Caccia, Sonia; Rawashdeh, Rifaat; Melhem, Motasem; Al-Hawamdeh, Ali; Carzaniga, Thomas; Haddad, Hazem

    2016-03-01

    Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) is an autosomal dominant disease caused by mutations in the SERPING1 gene. A Jordanian family, including 14 individuals with C1-INH-HAE clinical symptoms, was studied. In the propositus and his parents, SERPING1 had four mutations leading to amino acid substitutions. Two are known polymorphic variants (c.167T>C; p.Val34Ala and c.1438G>A; p.Val458Met), the others are newly described. One (c.203C>T; p.Thr46Ile) is located in the N-terminal domain of the C1-inhibitor protein and segregates with angioedema symptoms in the family. The other (c.800C>T; p.Ala245Val) belongs to the serpin domain, and derives from the unaffected father. DNA from additional 24 family members were screened for c.203C>T mutation in the target gene. All individuals heterozygous for the c.203C>T mutation had antigenic and functional plasma levels of C1-inhibitor below 50% of normal, confirming the diagnosis of type I C1-INH-HAE. Angioedema symptoms were present in 14 of 16 subjects carrier for the c.203T allele. Among these subjects, those carrying the c.800T variation had more severe and frequent symptoms than subjects without this mutation. This family-based study provides the first evidence that multiple amino acid substitutions in SERPING1 could influence C1-INH-HAE phenotype.

  19. Hereditary angioedema with normal C1 inhibitor in a French cohort: Clinical characteristics and response to treatment with icatibant

    PubMed Central

    Boccon‐Gibod, Isabelle; Launay, David; Gompel, Anne; Kanny, Gisele; Fabien, Vincent; Fain, Oliver

    2017-01-01

    Abstract Introduction The clinical characteristics and icatibant‐treatment outcomes of patients with hereditary angioedema with normal C1 inhibitor (HAE‐nC1 INH) are limited. Methods We retrospectively analyzed data from French HAE patients enrolled in the Icatibant Outcome Survey registry (from July 2009 to September 2013) to compare disease characteristics and the effectiveness and safety of acute icatibant‐treated angioedema attacks in patients with HAE‐nC1 INH, HAE with C1 INH deficiency (type I), or dysfunction (type II). Results One center in Grenoble contributed 22 patients with HAE‐nC1 INH and a family history of HAE while 15 centers across France contributed 153 patients with HAE type I and seven patients with HAE type II. Patients with HAE‐nC1 INH compared to HAE type I, respectively, were more likely to be female (88.1% vs. 63.4%), older at median age of disease onset (21 years vs. 15 years), and have a greater rate of abdominal (80% vs. 61%) and laryngeal (23% vs. 14%) attacks. Icatibant was effective in both groups though the median time to resolution of attack was significantly longer in the HAE‐nC1 INH group (20.0 h, 37 attacks) versus the HAE type I group (14.0 h, 67 attacks). Icatibant was self‐administered for 96.1% of attacks in patients with HAE‐nC1 INH and 75.8% in patients with HAE type I. No serious adverse side effects related to icatibant were reported. Conclusions These data help further define the disease characteristics of HAE‐nC1 INH in the French population and extend the limited data reporting the safe and effective use of icatibant in acute treatment of angioedema in French patients diagnosed with HAE‐nC1 INH. PMID:28250922

  20. Endothelial targeting with C1-inhibitor reduces complement activation in vitro and during ex vivo reperfusion of pig liver

    PubMed Central

    Bergamaschini, L; Gobbo, G; Gatti, S; Caccamo, L; Prato, P; Maggioni, M; Braidotti, P; Di Stefano, R; Fassati, L R

    2001-01-01

    Tissue damage during cold storage and reperfusion remains a major obstacle to wider use of transplantation. Vascular endothelial cells and complement activation are thought to be involved in the inflammatory reactions following reperfusion, so endothelial targeting of complement inhibitors is of great interest. Using an in vitro model of human umbilical vein endothelial cells (HUVEC) cold storage and an animal model of ex vivo liver reperfusion after cold ischaemia, we assessed the effect of C1-INH on cell functions and liver damage. We found that in vitro C1-INH bound to HUVEC in a manner depending on the duration of cold storage. Cell-bound C1-INH was functionally active since retained the ability to inhibit exogenous C1s. To assess the ability of cell-bound C1-INH to prevent complement activation during organ reperfusion, we added C1-INH to the preservation solution in an animal model of extracorporeal liver reperfusion. Ex vivo liver reperfusion after 8 h of cold ischaemia resulted in plasma C3 activation and reduction of total serum haemolytic activity, and at tissue level deposition of C3 associated with variable level of inflammatory cell infiltration and tissue damage. These findings were reduced when livers were stored in preservation solution containing C1-INH. Immunohistochemical analysis of C1-INH-treated livers showed immunoreactivity localized on the sinusoidal pole of the liver trabeculae, linked to sinusoidal endothelium, so it is likely that the protective effect was due to C1-INH retained by the livers. These results suggest that adding C1-INH to the preservation solution may be useful to reduce complement activation and tissue injury during the reperfusion of an ischaemic liver. PMID:11737055

  1. Endothelial targeting with C1-inhibitor reduces complement activation in vitro and during ex vivo reperfusion of pig liver.

    PubMed

    Bergamaschini, L; Gobbo, G; Gatti, S; Caccamo, L; Prato, P; Maggioni, M; Braidotti, P; Di Stefano, R; Fassati, L R

    2001-12-01

    Tissue damage during cold storage and reperfusion remains a major obstacle to wider use of transplantation. Vascular endothelial cells and complement activation are thought to be involved in the inflammatory reactions following reperfusion, so endothelial targeting of complement inhibitors is of great interest. Using an in vitro model of human umbilical vein endothelial cells (HUVEC) cold storage and an animal model of ex vivo liver reperfusion after cold ischaemia, we assessed the effect of C1-INH on cell functions and liver damage. We found that in vitro C1-INH bound to HUVEC in a manner depending on the duration of cold storage. Cell-bound C1-INH was functionally active since retained the ability to inhibit exogenous C1s. To assess the ability of cell-bound C1-INH to prevent complement activation during organ reperfusion, we added C1-INH to the preservation solution in an animal model of extracorporeal liver reperfusion. Ex vivo liver reperfusion after 8 h of cold ischaemia resulted in plasma C3 activation and reduction of total serum haemolytic activity, and at tissue level deposition of C3 associated with variable level of inflammatory cell infiltration and tissue damage. These findings were reduced when livers were stored in preservation solution containing C1-INH. Immunohistochemical analysis of C1-INH-treated livers showed immunoreactivity localized on the sinusoidal pole of the liver trabeculae, linked to sinusoidal endothelium, so it is likely that the protective effect was due to C1-INH retained by the livers. These results suggest that adding C1-INH to the preservation solution may be useful to reduce complement activation and tissue injury during the reperfusion of an ischaemic liver.

  2. Adaptive and Acquired Resistance to EGFR Inhibitors Converge on the MAPK Pathway

    PubMed Central

    Ma, Pengfei; Fu, Yujie; Chen, Minjiang; Jing, Ying; Wu, Jie; Li, Ke; Shen, Ying; Gao, Jian-Xin; Wang, Mengzhao; Zhao, Xiaojing; Zhuang, Guanglei

    2016-01-01

    Both adaptive and acquired resistance significantly limits the efficacy of the epidermal growth factor receptor (EGFR) kinase inhibitors. However, the distinct or common mechanisms of adaptive and acquired resistance have not been fully characterized. Here, through systematic modeling of erlotinib resistance in lung cancer, we found that feedback reactivation of MAPK signaling following erlotinib treatment, which was dependent on the MET receptor, contributed to the adaptive resistance of EGFR inhibitors. Interestingly, acquired resistance to erlotinib was also associated with the MAPK pathway activation as a result of CRAF or NRAS amplification. Consequently, combined inhibition of EGFR and MAPK impeded the development of both adaptive and acquired resistance. These observations demonstrate that adaptive and acquired resistance to EGFR inhibitors can converge on the same pathway and credential cotargeting EGFR and MAPK as a promising therapeutic approach in EGFR mutant tumors. PMID:27279914

  3. Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia.

    PubMed

    de Beer, Friso; Lagrand, Wim; Glas, Gerie J; Beurskens, Charlotte J P; van Mierlo, Gerard; Wouters, Diana; Zeerleder, Sacha; Roelofs, Joris J T H; Juffermans, Nicole P; Horn, Janneke; Schultz, Marcus J

    2016-12-01

    Complement activation plays an important role in the pathogenesis of pneumonia. We hypothesized that inhibition of the complement system in the lungs by repeated treatment with nebulized plasma-derived human C1-esterase inhibitor reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation. This was investigated in a rat model of severe Streptococcus pneumoniae pneumonia. Rats were intra-tracheally challenged with S. pneumoniae to induce pneumonia. Nebulized C1-esterase inhibitor or saline (control animals) was repeatedly administered to rats, 30 min before induction of pneumonia and every 6 h thereafter. Rats were sacrificed 20 or 40 h after inoculation with bacteria. Brochoalveolar lavage fluid and lung tissue were obtained for measuring levels of complement activation (C4b/c), lung injury and inflammation. Induction of pneumonia was associated with pulmonary complement activation (C4b/c at 20 h 1.24 % [0.56-2.59] and at 40 h 2.08 % [0.98-5.12], compared to 0.50 % [0.07-0.59] and 0.03 % [0.03-0.03] in the healthy control animals). The functional fraction of C1-INH was detectable in BALF, but no effect was found on pulmonary complement activation (C4b/c at 20 h 0.73 % [0.16-1.93] and at 40 h 2.38 % [0.54-4.19]). Twenty hours after inoculation, nebulized C1-esterase inhibitor treatment reduced total histology score, but this effect was no longer seen at 40 h. Nebulized C1-esterase inhibitor did not affect other markers of lung injury or lung inflammation. In this negative experimental animal study, severe S. pneumoniae pneumonia in rats is associated with pulmonary complement activation. Repeated treatment with nebulized C1-esterase inhibitor, although successfully delivered to the lungs, does not affect pulmonary complement activation, lung inflammation or lung injury.

  4. C1-transport in gastric micorsomes. An ATP-dependent influx sensitive to membrane potential and to protein kinase inhibitor.

    PubMed

    Soumarmon, A; Abastado, M; Bonfils, S; Lewin, M J

    1980-12-25

    Uptakes of radioactive C1- or 1- by gastric microsomal vesicles were stimulated 2- to 8-fold by AtP. The sensitivity of those uptakes to a C1- in equilibrium OH- ionophore and to osmotic swelling suggested they were due to transport rather than to binding. The ATP effect was labile, but dithiothreitol and methanol improved its stability. The stimulation of anion transport required magnesium; GTP and UTP were less potent than ATP whereas ADP and AMP had no effect. The apparent Km for ATP was estimated to be 2 X 10(-4) M at 22 degrees C. The rate of the ATP-dependent transport showed saturation-type kinetics, with half-maximal uptake at 10 mM for I- and 15 mM for C1-. Nonradioactive C1-, I-, and SCN- competed with 125I- uptake while SO42- did not. K+ valinomycin increased the ATP-dependent C1- uptake. The thermostable inhibitor of cAMP-dependent protein kinases inhibited the effect of ATP. These results suggest the existence of an anion conductance, permeant to C1-, I-, and SCN- and nonpermeant to SO42-, which could be linked to a cAMP-dependent protein kinase.

  5. 84 Immuno-Safety of Recombinant Human C1 Inhibitor in Patients With Hereditary Angioedema: An Integrated Analysis

    PubMed Central

    Hack, Erik; Relan, Anurag; Kaufman, Leonard; Pijpstra, Rienk

    2012-01-01

    Background Recombinant C1 inhibitor (rhC1INH) is a novel therapeutic option for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE). The amino acid sequence of rhC1INH is identical to that of endogenous C1INH. However, any recombinant protein may elicit antibodies against the protein and/or host related impurities (HRI). Clinical consequences of these antibodies can theoretically range from no clinical symptoms to allergic reactions and reduced C1INH activity due to neutralizing antibodies. Objective To analyze the immuno-safety of rhC1INH in symptomatic patients with HAE. Methods Plasma samples were collected pre-treatment and 22 and 90 days post-treatment of an acute angioedema attack. Plasma samples were tested for the presence of antibodies against plasma-derived C1INH and rhC1INH using 6 different, validated enzyme-linked immunosorbent assays (ELISAs), to detect IgM, IgG and IgA antibodies against plasma-derived C1INH or rhC1INH. Antibodies against HRI in plasma samples were measured in an ELISA testing for all antibody classes. Plasma samples from normal healthy controls and HAE patients, never exposed to rhC1INH, were used to estimate cut off levels of the assays. Plasma samples with antibody levels above the cut-off level in the screening assays were tested in confirmatory displacement assay in case of anti-HRI antibodies and in an assay for neutralizing antibodies in case of antibodies against C1INH. Results Data from 155 symptomatic HAE patients having received a total of 424 administrations of rhC1INH were analyzed. The frequency of anti-C1INH antibody levels above the assay cut-off was low and similar in pre- and post-exposure samples (1.7 and 1.8%, respectively). Results above the assay cut-off were sporadic and transient. Occurrence of anti-C1INH antibodies did not correlate with repeated treatment or time since last treatment. No neutralizing antibodies were detected. A total of 5/155 (3%) rhC1INH-treated patients

  6. Elucidating the Mechanism of Gain of Toxic Function From Mutant C1 Inhibitor Proteins in Hereditary Angioedema

    DTIC Science & Technology

    2015-10-01

    AD______________ AWARD NUMBER: W81XWH-14-1-0506 TITLE: Elucidating the Mechanism of Gain of Toxic Function From Mutant C1 Inhibitor Proteins...REPORT TYPE Annual 3. DATES COVERED 30 Sept 2014 – 29 Sept 2015 4. TITLE AND SUBTITLE Elucidating the Mechanism of Gain of Toxic Function From Mutant ...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT HAE is autosomal dominant. Cells, heterozygous for the SERPING1 mutation, express both mutant and WT

  7. Acquired factor V inhibitor after exposure to topical human thrombin related to an otorhinolaryngological procedure.

    PubMed

    Donohoe, K; Levine, R

    2015-10-01

    Acquired factor V (FV) inhibitors occur rarely and classically develop after exposure to bovine thrombin. The clinical presentation is variable, ranging from asymptomatic with incidental laboratory abnormalities to significant bleeding. With the development of human-derived thrombin agents, bovine thrombin is less frequently used. We report a case of an acquired FV inhibitor that developed in a patient after exposure to human thrombin used as a hemostatic agent during an otorhinolaryngology surgical procedure. Our review of the literature revealed only one prior reported case of FV inhibitor after exposure to human thrombin. Hematologists and surgeons should be aware of this rare, but potentially life-threatening, complication in the postprocedural setting.

  8. Acquired chemotactic inhibitors during infection with guinea pig cytomegalovirus.

    PubMed Central

    Tannous, R; Myers, M G

    1983-01-01

    Factors involved in neutrophil and monocyte migrations were serially studied in strain 2 guinea pigs undergoing initial cytomegalovirus infection and sham-inoculated controls. All studies remained unchanged in uninfected animals. Monocyte migrations and neutrophil spontaneous migration remained unchanged in infected animals. However, transient abnormalities occurred early in infection, comprising a decrease in neutrophil-directed migration towards C5-derived chemotactic fractions (C5-fr) and a decrease in the chemotactic activity of zymosan-activated plasma. Consequently, the presence of neutrophil- and chemotaxin-directed inhibitors in plasma was investigated. Normal neutrophils, C5-fr, Escherichia coli-derived bacterial factor, and the synthetic peptide F-met-leu-phe were first incubated with control or infected plasmas and then assayed for directed migration and lysosomal enzyme release. Results indicated the de novo appearance of both neutrophil- and chemotaxin-directed inhibitory activities in plasma during early infection. The neutrophil-directed inhibition was heat stable (56 degrees C for 120 min) and nonspecific (responses to all chemotaxins were inhibited). The chemotaxin-directed inhibition was heat stable and C5-fr specific. The cytomegalovirus-induced inhibitors may be important in the enhanced susceptibility to concurrent opportunistic infections. PMID:6305847

  9. Efficacy and safety of an intravenous C1-inhibitor concentrate for long-term prophylaxis in hereditary angioedema

    PubMed Central

    Craig, Timothy; Shapiro, Ralph; Vegh, Arthur; Baker, James W.; Bernstein, Jonathan A.; Busse, Paula; Magerl, Markus; Martinez-Saguer, Inmaculada; Riedl, Marc A.; Lumry, William; Williams-Herman, Debora; Edelman, Jonathan; Feuersenger, Henrike; Machnig, Thomas

    2017-01-01

    Background: The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis. Objective: This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP). Methods: The international registry (2010–2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason. Results: The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500–3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH–treated attack of 72.0 hours (range, 0.0–166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH–treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port). Conclusion: In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration. PMID:28381322

  10. Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance

    PubMed Central

    Li, Huamin Henry

    2016-01-01

    Hereditary angioedema (HAE) is a rare genetic disease characterized by episodic subcutaneous or submucosal swelling. The primary cause for the most common form of HAE is a deficiency in functional C1 esterase inhibitor (C1-INH). The swelling caused by HAE can be painful, disfiguring, and life-threatening. It reduces daily function and compromises the quality of life of affected individuals and their caregivers. Among different treatment strategies, replacement with C1-INH concentrates is employed for on-demand treatment of acute attacks and long-term prophylaxis. Three human plasma-derived C1-INH preparations are approved for HAE treatment in the US, the European Union, or both regions: Cinryze®, Berinert®, and Cetor®; however, only Cinryze is approved for long-term prophylaxis. Postmarketing studies have shown that home therapy (self-administered or administered by a caregiver) is a convenient and safe option preferred by many HAE patients. In this review, we summarize the role of self-administered plasma-derived C1-INH concentrate therapy with Cinryze at home in the prophylaxis of HAE. PMID:27660422

  11. Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association

    PubMed Central

    Andrejević, Slađana; Korošec, Peter; Šilar, Mira; Košnik, Mitja; Mijanović, Radovan; Bonači-Nikolić, Branka; Rijavec, Matija

    2015-01-01

    Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect

  12. Molecular phylogeny of C1 inhibitor depicts two immunoglobulin-like domains fusion in fishes and ray-finned fishes specific intron insertion after separation from zebrafish

    SciTech Connect

    Kumar, Abhishek; Bhandari, Anita; Sarde, Sandeep J.; Goswami, Chandan

    2014-07-18

    Highlights: • C1 inhibitors of fishes have two Ig domains fused in the N-terminal end. • Spliceosomal introns gain in two Ig domains of selected ray-finned fishes. • C1 inhibitors gene is maintained from 450 MY on the same locus. • C1 inhibitors gene is missing in frog and lampreys. • C1 inhibitors of tetrapod and fishes differ in the RCL region. - Abstract: C1 inhibitor (C1IN) is a multi-facet serine protease inhibitor in the plasma cascades, inhibiting several proteases, notably, regulates both complement and contact system activation. Despite huge advancements in the understanding of C1IN based on biochemical properties and its roles in the plasma cascades, the phylogenetic history of C1IN remains uncharacterized. To date, there is no comprehensive study illustrating the phylogenetic history of C1IN. Herein, we explored phylogenetic history of C1IN gene in vertebrates. Fishes have C1IN with two immunoglobulin like domains attached in the N-terminal region. The RCL regions of CIIN from fishes and tetrapod genomes have variations at the positions P2 and P1′. Gene structures of C1IN gene from selected ray-finned fishes varied in the Ig domain region with creation of novel intron splitting exon Im2 into Im2a and Im2b. This intron is limited to ray-finned fishes with genome size reduced below 1 Gb. Hence, we suggest that genome compaction and associated double-strand break repairs are behind this intron gain. This study reveals the evolutionary history of C1IN and confirmed that this gene remains the same locus for ∼450 MY in 52 vertebrates analysed, but it is not found in frogs and lampreys.

  13. Acquired subglottic stenosis caused by methicillin resistant Staphylococcus aureus that produce epidermal cell differentiation inhibitor

    PubMed Central

    Yamada, Y; Sugai, M; Woo, M; Nishida, N; Sugimoto, T

    2001-01-01

    Local infection of the trachea in intubated neonates is one of the main risk factors for development of acquired subglottic stenosis, although its role in the pathogenesis is unclear. Methicillin resistant Staphylococcus aureus (MRSA) is often the cause of critical illness in neonatal patients. Two cases are reported of acquired subglottic stenosis following bacterial infection of the trachea, suggesting an association with the staphylococcal exotoxin, epidermal cell differentiation inhibitor (EDIN). EDIN-producing MRSA were isolated from purulent tracheal secretions from both infants. Acquired subglottic stenosis in both cases was probably caused by delayed wound healing as the result of EDIN inhibition of epithelial cell migration.

 PMID:11124922

  14. Cleavage of the second component of complement by plasma proteases: implications in hereditary C1-inhibitor deficiency.

    PubMed Central

    Smith, M A; Kerr, M A

    1985-01-01

    EDTA plasma from patients with hereditary angioedema (HAE), the genetic deficiency of C1-inhibitor, when incubated at 37 degrees produces a kinin-like activity which can induce contraction of oestrus rat uterus. The second component of complement (C2) has previously been suggested to be the source of this kinin-like activity, with the implication that C2-kinin is a normal product of complement activation. Our results show that purified human C2 is cleaved rapidly to C2a and C2b when added to HAE plasma, but not normal plasma or plasma from a danazol-treated HAE patient. However, the addition to HAE plasma of C2 at 20 X normal plasma concentration had no effect on the kinin activity generated on incubation at 37 degrees. In the presence of soya bean trypsin inhibitor, the rate of C2 cleavage and products were unaltered but no kinin activity was generated. C2 was cleaved by purified C1s to C2a and C2b. Incubation of C2 with trypsin resulted in cleavage to C2a and C2b followed by more extensive cleavage of both C2a and C2b. Kallikrein cleaved C2 to C2a and C2b but plasmin had no effect on C2. In no case was kinin activity generated. When C2 was cleaved by C1s to C2a and C2b then incubated with trypsin, kallikrein, or plasmin, no kinin activity was generated: only trypsin cleaved the C2 fragments further. The results suggest that C2 is not the source of the kinin-like activity generated in hereditary angioedema plasma. Images Figure 4 Figure 5 Figure 6 Figure 7 PMID:2934317

  15. Inhibition of Myeloperoxidase Activity in Cystic Fibrosis Sputum by Peptide Inhibitor of Complement C1 (PIC1)

    PubMed Central

    Hair, Pamela S.; Sass, Laura A.; Krishna, Neel K.

    2017-01-01

    Myeloperoxidase is the major peroxidase enzyme in neutrophil granules and implicated in contributing to inflammatory lung damage in cystic fibrosis. Free myeloperoxidase is present in cystic fibrosis lung fluid and generates hypochlorous acid. Here we report a new inhibitor of myeloperoxidase activity, Peptide Inhibitor of Complement C1 (PIC1). Using TMB as the oxidizing substrate, PIC1 inhibited myeloperoxidase activity in cystic fibrosis sputum soluble fractions by an average of a 3.4-fold decrease (P = 0.02). PIC1 also dose-dependently inhibited myeloperoxidase activity in a neutrophil lysate or purified myeloperoxidase by up to 28-fold (P < 0.001). PIC1 inhibited myeloperoxidase activity similarly, on a molar basis, as the specific myeloperoxidase inhibitor 4-Aminobenzoic acid hydrazide (ABAH) for various oxidizing substrates. PIC1 was able to protect the heme ring of myeloperoxidase from destruction by NaOCl, assayed by spectral analysis. PIC1 incubated with oxidized TMB reversed the oxidation state of TMB, as measured by absorbance at 450 nm, with a 20-fold reduction in oxidized TMB (P = 0.02). This result was consistent with an antioxidant mechanism for PIC1. In summary, PIC1 inhibits the peroxidase activity of myeloperoxidase in CF sputum likely via an antioxidant mechanism. PMID:28135312

  16. A novel mutation in exon 8 of C1 inhibitor (C1INH) gene leads to abolish its physiological stop codon in a large Chinese family with hereditary angioedema type I.

    PubMed

    Qu, Le; Wei, Bin; Liu, Mei; Zhang, Lili; Xiao, Ting; Chen, Hong-Duo; Zhou, Li; Mi, Qing-Sheng; He, Chundi

    2012-10-01

    C1 inhibitor (C1INH) plays an important role in the classical pathway of the complement system. Mutations in C1INH gene cause quantitative or qualitative deficiencies in C1INH, which can lead to hereditary angioedema (HAE) type I or II. Here, we identified a novel frame-shift mutation c.1391-1445del55 (p.v464fsx556) in exon 8 in a large Chinese family with HAE type I. This 55 base pairs deletion abolishes the original stop codon and introduces a new stop codon 220 bp downstream of the original one, and leads to mutated C1INH protein prolonged from 500 to 556 amino acids. The levels of C4 and C1INH as well as C1INH activity in serum were significantly reduced in affected individuals. This is the first report of a novel mutation abolishing the physiological stop codon of C1INH gene in a large Chinese family with HAE type I.

  17. C1 esterase inhibitor

    MedlinePlus

    ... algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol . 2010;6:24. PMID: ... chap 6. Read More Cirrhosis Complement Glomerulonephritis Hepatitis Hereditary angioedema Kidney transplant Lupus nephritis Systemic lupus erythematosus Ulcerative ...

  18. Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

    PubMed Central

    Schoenfeld, Ann-Kathrin; Lahrsen, Eric; Alban, Susanne

    2016-01-01

    The serpin C1 inhibitor (C1-INH) is the only regulator of classical complement activation as well as the major regulator of the contact system. Its importance is demonstrated by hereditary angioedema (HAE), a severe disease with potentially life-threatening attacks due to deficiency or dysfunction of C1-INH. C1-INH replacement is the therapy of choice in HAE. In addition, C1-INH showed to have beneficial effects in other diseases characterized by inappropriate complement and contact system activation. Due to some limitations of its clinical application, there is a need for improving the efficacy of therapeutically applied C1-INH or to enhance the activity of endogenous C1-INH. Given the known potentiating effect of heparin on C1-INH, sulfated glycans (SG) may be such candidates. The aim of this study was to characterize suitable SG by evaluating structure-activity relationships. For this, more than 40 structurally distinct SG were examined for their effects on C1-INH, C1s and FXIIa. The SG turned out to potentiate the C1s inhibition by C1-INH without any direct influence on C1s. Their potentiating activity proved to depend on their degree of sulfation, molecular mass as well as glycan structure. In contrast, the SG had no effect on the FXIIa inhibition by C1-INH, but structure-dependently modulated the activity of FXIIa. Among the tested SG, β-1,3-glucan sulfates with a Mr ≤ 10 000 were identified as most promising lead candidates for the development of a glycan-based C1-INH amplifier. In conclusion, the obtained information on structural characteristics of SG favoring C1-INH potentiation represent an useful elementary basis for the development of compounds improving the potency of C1-INH in diseases and clinical situations characterized by inappropriate activation of complement and contact system. PMID:27783665

  19. Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study.

    PubMed

    Montgomery, R A; Orandi, B J; Racusen, L; Jackson, A M; Garonzik-Wang, J M; Shah, T; Woodle, E S; Sommerer, C; Fitts, D; Rockich, K; Zhang, P; Uknis, M E

    2016-05-16

    Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

  20. Peptide Inhibitor of Complement C1 (PIC1) Rapidly Inhibits Complement Activation after Intravascular Injection in Rats

    PubMed Central

    Sharp, Julia A.; Hair, Pamela S.; Pallera, Haree K.; Kumar, Parvathi S.; Mauriello, Clifford T.; Nyalwidhe, Julius O.; Phelps, Cody A.; Park, Dalnam; Thielens, Nicole M.; Pascal, Stephen M.; Chen, Waldon; Duffy, Diane M.; Lattanzio, Frank A.; Cunnion, Kenji M.; Krishna, Neel K.

    2015-01-01

    The complement system has been increasingly recognized to play a pivotal role in a variety of inflammatory and autoimmune diseases. Consequently, therapeutic modulators of the classical, lectin and alternative pathways of the complement system are currently in pre-clinical and clinical development. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement and is referred to as Peptide Inhibitor of Complement C1 (PIC1). In this study, we determined that the lead PIC1 variant demonstrates a salt-dependent binding to C1q, the initiator molecule of the classical pathway. Additionally, this peptide bound to the lectin pathway initiator molecule MBL as well as the ficolins H, M and L, suggesting a common mechanism of PIC1 inhibitory activity occurs via binding to the collagen-like tails of these collectin molecules. We further analyzed the effect of arginine and glutamic acid residue substitution on the complement inhibitory activity of our lead derivative in a hemolytic assay and found that the original sequence demonstrated superior inhibitory activity. To improve upon the solubility of the lead derivative, a pegylated, water soluble variant was developed, structurally characterized and demonstrated to inhibit complement activation in mouse plasma, as well as rat, non-human primate and human serum in vitro. After intravenous injection in rats, the pegylated derivative inhibited complement activation in the blood by 90% after 30 seconds, demonstrating extremely rapid function. Additionally, no adverse toxicological effects were observed in limited testing. Together these results show that PIC1 rapidly inhibits classical complement activation in vitro and in vivo and is functional for a variety of animal species, suggesting its utility in animal models of classical complement-mediated diseases. PMID:26196285

  1. Molecular phylogeny of C1 inhibitor depicts two immunoglobulin-like domains fusion in fishes and ray-finned fishes specific intron insertion after separation from zebrafish.

    PubMed

    Kumar, Abhishek; Bhandari, Anita; Sarde, Sandeep J; Goswami, Chandan

    2014-07-18

    C1 inhibitor (C1IN) is a multi-facet serine protease inhibitor in the plasma cascades, inhibiting several proteases, notably, regulates both complement and contact system activation. Despite huge advancements in the understanding of C1IN based on biochemical properties and its roles in the plasma cascades, the phylogenetic history of C1IN remains uncharacterized. To date, there is no comprehensive study illustrating the phylogenetic history of C1IN. Herein, we explored phylogenetic history of C1IN gene in vertebrates. Fishes have C1IN with two immunoglobulin like domains attached in the N-terminal region. The RCL regions of CIIN from fishes and tetrapod genomes have variations at the positions P2 and P1'. Gene structures of C1IN gene from selected ray-finned fishes varied in the Ig domain region with creation of novel intron splitting exon Im2 into Im2a and Im2b. This intron is limited to ray-finned fishes with genome size reduced below 1 Gb. Hence, we suggest that genome compaction and associated double-strand break repairs are behind this intron gain. This study reveals the evolutionary history of C1IN and confirmed that this gene remains the same locus for ∼450 MY in 52 vertebrates analysed, but it is not found in frogs and lampreys.

  2. Acquired Factor V Inhibitors in a Patient with End-stage Renal Disease

    PubMed Central

    Kitazawa, Atsushi; Misawa, Hideo; Nagahori, Katsuhiro; Koda, Ryo; Yoshino, Atsunori; Kawamoto, Shinya; Takeda, Tetsuro

    2016-01-01

    We report a case of acquired factor V inhibitors (AFVIs) in a patient with end-stage renal disease receiving warfarin therapy for atrial fibrillation. A 72-year-old Japanese man was admitted to our hospital complaining of tarry stools and abdominal pain. The laboratory findings revealed eosinophilia (52.1%), prolonged activated partial thromboplastin time (APTT) (98 s), PT (84 s), a factor V (FV) activity of <3%, and an FV inhibitor level of 6 Bethesda units/mL. After administration of prednisolone was started, his coagulation findings improved. However, his renal failure progressed, and he ultimately required chronic hemodialysis. This is the first case of AFVIs in a patient starting hemodialysis for end-stage renal disease. PMID:27904118

  3. Acquired Factor V Inhibitors in a Patient with End-stage Renal Disease.

    PubMed

    Kitazawa, Atsushi; Misawa, Hideo; Nagahori, Katsuhiro; Koda, Ryo; Yoshino, Atsunori; Kawamoto, Shinya; Takeda, Tetsuro

    We report a case of acquired factor V inhibitors (AFVIs) in a patient with end-stage renal disease receiving warfarin therapy for atrial fibrillation. A 72-year-old Japanese man was admitted to our hospital complaining of tarry stools and abdominal pain. The laboratory findings revealed eosinophilia (52.1%), prolonged activated partial thromboplastin time (APTT) (98 s), PT (84 s), a factor V (FV) activity of <3%, and an FV inhibitor level of 6 Bethesda units/mL. After administration of prednisolone was started, his coagulation findings improved. However, his renal failure progressed, and he ultimately required chronic hemodialysis. This is the first case of AFVIs in a patient starting hemodialysis for end-stage renal disease.

  4. Recent developments in the treatment of acute abdominal and facial attacks of hereditary angioedema: focus on human C1 esterase inhibitor

    PubMed Central

    Cardona, Lourdes Pastó; Bellfill, Ramon Lleonart; Caus, Joaquim Marcoval

    2010-01-01

    Hereditary angioedema (HAE) is a potentially fatal genetic disorder typified by a deficiency (type I) or dysfunction (type II) of the C1-inhibitor (C1-INH) and characterized by swelling of the extremities, face, trunk, abdominal viscera, and upper airway. Type III is normal estrogen-sensitive C1-INH HAE. Bradykinin, the main mediator of HAE, binds to endothelial B2 receptors, increasing vascular permeability and resulting in edema. HAE management includes short- and long-term prophylaxis. For treating acute episodes, C1-INH concentrate is recommended with regression of symptoms achieved in 30–90 min. Infusions of 500–1000 U have been used in Europe for years. Two plasma-derived C1-INH concentrates have been licensed recently in the United States: Berinert® for treating acute attacks and Cinryze® for prophylaxis in adolescent/adult patients. A recombinant C1-INH that is being considered for approval (conestat alfa) exhibited significant superiority versus placebo. Ecallantide (Kalbitor®) is a selective kallikrein inhibitor recently licensed in the United States for treating acute attacks in patients aged >16 years. It is administered in three 10-mg subcutaneous injections with the risk of anaphylactic reactions. Icatibant (Firazyr®) is a bradykinin B2 receptor competitor. It is administered subcutaneously as a 30-mg injection and approved in Europe but not in the United States. PMID:23776358

  5. Epitope specificity of anti-factor VIII antibodies from inhibitor positive acquired and congenital haemophilia A patients using synthetic peptides spanning A and C domains.

    PubMed

    Gharagozlou, Soheila; Sharifian, Ramazan A; Khoshnoodi, Jalal; Karimi, Katayoon; Milani, Monica; Okita, David K; Shokri, Fazel; Conti-Fine, Bianca M

    2009-05-01

    Development of antibodies (Ab) that either block the function of coagulation factor VIII (FVIII) (inhibitors) or clear it from circulation, seriously complicate the treatment of haemophilia A patients with FVIII products. Autoantibodies which develop in subjects without congenital FVIII defects, cause acquired haemophilia, a rare but life-threatening coagulopathy. Identification of the FVIII epitopes to which inhibitor Abs bind will help understanding the mechanisms of inhibitor activity, and perhaps development of new therapies. Here, we examined the FVIII peptide sequence regions recognised by anti-FVIII Ab in the plasma of six congenital and one acquired haemophilia patients with high inhibitor titers (24.4-2000 BU/ml). We used indirect ELISA and overlapping synthetic peptides, 20 residues long, spanning the sequence of the A and C FVIII domains. None of the plasma samples reacted with A1, A3 or C1 domain peptides. Six plasmas reacted with A2 and/or C2 peptides. Peptides spanning residues A2-521-690 and C2-2251-2332 were recognised most frequently and strongly. They include residues that contribute to the binding sites for activated factor IX and phosphatidyl serine/von Willebrand factor. These results suggest that anti-FVIII Abs share a pattern of antigen specificity in our panel of patients, and that exposed regions of the FVIII molecule that form functionally important binding sites elicit an intense Ab response.

  6. Novel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold.

    PubMed

    Leiva, Rosana; Seira, Constantí; McBride, Andrew; Binnie, Margaret; Luque, F Javier; Bidon-Chanal, Axel; Webster, Scott P; Vázquez, Santiago

    2015-10-01

    The adamantane scaffold is found in several marketed drugs and in many investigational 11β-HSD1 inhibitors. Interestingly, all the clinically approved adamantane derivatives are C-1 substituted. We demonstrate that, in a series of paired adamantane isomers, substitution of the adamantane in C-2 is preferred over the substitution at C-1 and is necessary for potency at human 11β-HSD1. Furthermore, the introduction of an oxygen atom in the hydrocarbon scaffold of adamantane is deleterious to 11β-HSD1 inhibition. Molecular modeling studies provide a basis to rationalize these features.

  7. Diketo acids derivatives as integrase inhibitors: the war against the acquired immunodeficiency syndrome.

    PubMed

    Henao-Mejia, Jorge; Góez, Yenny; Patiño, Pablo; Rugeles, Maria T

    2006-06-01

    Since the human immunodeficiency virus was identified as etiological agent of the acquired immunodeficiency syndrome, great advances have been accomplished in the therapeutic field leading to reduced morbidity and mortality among infected patients. However, the high mutation rate of the viral genome generates strains resistant to multiple drugs, pointing to the importance of finding new therapeutic targets. Among the HIV structural genes, the POL gene codes for three essential enzymes: reverse transcriptase, protease, and integrase; nineteen of the twenty drugs currently approved by the Food and Drug Administration to treat this viral infection, inhibit the reverse transcriptase and the protease. Although intense research has been carried out in this area during the last 10 years, HIV integrase inhibitors are not yet approved for clinical use; however the fact that presence of this enzyme is a sine qua non for a productive HIV life cycle joined to its unique properties makes it a promissory target for anti-HIV therapy. Many compounds have been claimed to inhibit integrase in vitro; however, few of them have proven to have antiviral activity and low cytotoxicity in cell systems. Diketoacid derivatives are the most promising integrase inhibitors so far reported. Initially discovered independently by Shionogi & Co. and the Merck Research Laboratories, these compounds are highly specific for the integrase with potent antiviral activity in vitro and in vivo, and low cytotoxicity in cell cultures. Some of these compounds have recently entered clinical trials. Due to the high relevance of integrase inhibitors, and specifically of diketoacid derivatives, we review the latest findings and patents in this important field of research.

  8. Targeting MAGE-C1/CT7 Expression Increases Cell Sensitivity to the Proteasome Inhibitor Bortezomib in Multiple Myeloma Cell Lines

    PubMed Central

    de Carvalho, Fabricio; Costa, Erico T.; Camargo, Anamaria A.; Gregorio, Juliana C.; Masotti, Cibele; Andrade, Valeria C.C.; Strauss, Bryan E.; Caballero, Otavia L.; Atanackovic, Djordje; Colleoni, Gisele W.B.

    2011-01-01

    The MAGE-C1/CT7 encodes a cancer/testis antigen (CTA), is located on the chromosomal region Xq26–27 and is highly polymorphic in humans. MAGE-C1/CT7 is frequently expressed in multiple myeloma (MM) that may be a potential target for immunotherapy in this still incurable disease. MAGEC1/CT7 expression is restricted to malignant plasma cells and it has been suggested that MAGE-C1/CT7 might play a pathogenic role in MM; however, the exact function this protein in the pathophysiology of MM is not yet understood. Our objectives were (1) to clarify the role of MAGE-C1/CT7 in the control of cellular proliferation and cell cycle in myeloma and (2) to evaluate the impact of silencing MAGE-C1/CT7 on myeloma cells treated with bortezomib. Myeloma cell line SKO-007 was transduced for stable expression of shRNA-MAGE-C1/CT7. Downregulation of MAGE-C1/CT7 was confirmed by real time quantitative PCR and western blot. Functional assays included cell proliferation, cell invasion, cell cycle analysis and apoptosis. Western blot showed a 70–80% decrease in MAGE-C1/CT7 protein expression in inhibited cells (shRNA-MAGE-C1/CT7) when compared with controls. Functional assays did not indicate a difference in cell proliferation and DNA synthesis when inhibited cells were compared with controls. However, we found a decreased percentage of cells in the G2/M phase of the cell cycle among inhibited cells, but not in the controls (p<0.05). When myeloma cells were treated with bortezomib, we observed a 48% reduction of cells in the G2/M phase among inhibited cells while controls showed 13% (empty vector) and 9% (ineffective shRNA) reduction, respectively (p<0.01). Furthermore, inhibited cells treated with bortezomib showed an increased percentage of apoptotic cells (Annexin V+/PI-) in comparison with bortezomib-treated controls (p<0.001). We found that MAGE-C1/CT7 protects SKO-007 cells against bortezomib-induced apoptosis. Therefore, we could speculate that MAGE-C1/CT7 gene therapy could be

  9. Multi-Kinase Inhibitor C1 Triggers Mitotic Catastrophe of Glioma Stem Cells Mainly through MELK Kinase Inhibition

    PubMed Central

    Joshi, Kaushal; Nakano-Okuno, Mariko; Hong, Christopher; Nguyen, Chi-Hung; Kornblum, Harley I.; Molla, Annie; Nakano, Ichiro

    2014-01-01

    Glioblastoma multiforme (GBM) is a highly lethal brain tumor. Due to resistance to current therapies, patient prognosis remains poor and development of novel and effective GBM therapy is crucial. Glioma stem cells (GSCs) have gained attention as a therapeutic target in GBM due to their relative resistance to current therapies and potent tumor-initiating ability. Previously, we identified that the mitotic kinase maternal embryonic leucine-zipper kinase (MELK) is highly expressed in GBM tissues, specifically in GSCs, and its expression is inversely correlated with the post-surgical survival period of GBM patients. In addition, patient-derived GSCs depend on MELK for their survival and growth both in vitro and in vivo. Here, we demonstrate evidence that the role of MELK in the GSC survival is specifically dependent on its kinase activity. With in silico structure-based analysis for protein-compound interaction, we identified the small molecule Compound 1 (C1) is predicted to bind to the kinase-active site of MELK protein. Elimination of MELK kinase activity was confirmed by in vitro kinase assay in nano-molar concentrations. When patient-derived GSCs were treated with C1, they underwent mitotic arrest and subsequent cellular apoptosis in vitro, a phenotype identical to that observed with shRNA-mediated MELK knockdown. In addition, C1 treatment strongly induced tumor cell apoptosis in slice cultures of GBM surgical specimens and attenuated growth of mouse intracranial tumors derived from GSCs in a dose-dependent manner. Lastly, C1 treatment sensitizes GSCs to radiation treatment. Collectively, these data indicate that targeting MELK kinase activity is a promising approach to attenuate GBM growth by eliminating GSCs in tumors. PMID:24739874

  10. Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors.

    PubMed

    Zang, Yan; Kirk, Christopher J; Johnson, Daniel E

    2014-09-01

    Acquired resistance to proteasome inhibitors represents a considerable impediment to their effective clinical application. Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors. However, the mechanisms of acquired resistance to carfilzomib and oprozomib are incompletely understood, and effective strategies for overcoming this resistance are needed. Here, we developed models of acquired resistance to carfilzomib in two head and neck squamous cell carcinoma cell lines, UMSCC-1 and Cal33, through gradual exposure to increasing drug concentrations. The resistant lines R-UMSCC-1 and R-Cal33 demonstrated 205- and 64-fold resistance, respectively, relative to the parental lines. Similarly, a high level of cross-resistance to oprozomib, as well as paclitaxel, was observed, whereas only moderate resistance to bortezomib (8- to 29-fold), and low level resistance to cisplatin (1.5- to 5-fold) was seen. Synergistic induction of apoptosis signaling and cell death, and inhibition of colony formation followed co-treatment of acquired resistance models with carfilzomib and the histone deacetylase inhibitor (HDACi) vorinostat. Synergism was also seen with other combinations, including oprozomib plus vorinostat, or carfilzomib plus the HDACi entinostat. Synergism was accompanied by upregulation of proapoptotic Bik, and suppression of Bik attenuated the synergy. The acquired resistance models also exhibited elevated levels of MDR-1/P-gp. Inhibition of MDR-1/P-gp with reversin 121 partially overcame carfilzomib resistance in R-UMSCC-1 and R-Cal33 cells. Collectively, these studies indicate that combining carfilzomib or oprozomib with HDAC or MDR-1/P-gp inhibitors may be a useful strategy for overcoming acquired resistance to these proteasome inhibitors.

  11. A Nationwide Study of Norwegian Patients with Hereditary Angioedema with C1 Inhibitor Deficiency Identified Six Novel Mutations in SERPING1

    PubMed Central

    Johnsrud, Irene; Kulseth, Mari Ann; Rødningen, Olaug Kristin; Landrø, Linn; Helsing, Per; Waage Nielsen, Erik; Heimdal, Ketil

    2015-01-01

    Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is characterized by relapsing, non-pruritic swelling in skin and submucosal tissue. Symptoms can appear in early infancy when diagnosis is more difficult. In the absence of a correct diagnosis, treatment of abdominal attacks often lead to unnecessary surgery, and laryngeal edema can cause asphyxiation. A cohort study of 52 patients from 25 unrelated families in Norway was studied. Diagnosis of C1-INH-HAE was based on international consensus criteria including low functional and/or antigenic C1-INH values and antigenic C4. As SERPING1 mutations in Norwegian patients with C1-INH-HAE are largely undescribed and could help in diagnosis, we aimed to find and describe these mutations. Mutation analysis of the SERPING1 gene was performed by Sanger sequencing of all protein coding exons and exon-intron boundaries. Samples without detected mutation were further analyzed by multiplex ligation-dependent probe amplification to detect deletions and duplications. Novel mutations suspected to lead to splice defects were analyzed on the mRNA level. Fifty-two patients from 25 families were included. Forty-four (84,6%) suffered from C1-INH-HAE type I and eight (15,4%) suffered from C1-INH-HAE type II. Pathogenic or likely pathogenic mutations were found in 22/25 families (88%). Thirteen unique mutations were detected, including six previously undescribed. There were three missense mutations including one mutation affecting the reactive center loop at codon 466, three nonsense mutations, three small deletions/duplications, three gross deletions, and one splice mutation. PMID:26154504

  12. Inhibitors of the mitochondrial cytochrome b-c1 complex inhibit the cyanide-insensitive respiration of Trypanosoma brucei.

    PubMed

    Turrens, J F; Bickar, D; Lehninger, A L

    1986-06-01

    The cyanide-insensitive respiration of bloodstream trypomastigote forms of Trypanosoma brucei (75 +/- 8 nmol O2 min-1(mg protein)-1) is completely inhibited by the mitochondrial ubiquinone-like inhibitors 2-hydroxy-3-undecyl-1,4-naphthoquinone (UHNQ) and 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT). The Ki values for UHDBT (30 nM) and UHNQ (2 microM) are much lower than the reported Ki for salicylhydroxamic acid (SHAM) (5 microM), a widely used inhibitor of the cyanide-insensitive oxidase. UHNQ also stimulated the glycerol-3-phosphate-dependent reduction of phenazine methosulfate, demonstrating that the site of UHNQ inhibition is on the terminal oxidase of the cyanide-insensitive respiration of T. brucei. These results suggest that a ubiquinone-like compound may act as an electron carrier between the two enzymatic components of the cyanide-insensitive glycerol-3-phosphate oxidase.

  13. Myeloid cells that impair immunotherapy are restored in melanomas which acquire resistance to BRAF inhibitors.

    PubMed

    Steinberg, Shannon M; Shabaneh, Tamer; Zhang, Peisheng; Martyanov, Viktor; Li, Zhenghui; Malik, Brian; Wood, Tammara; Boni, Andrea; Molodtsov, Aleksey; Angeles, Christina V; Curiel, Tyler J; Whitfield, Michael; Turk, Mary Jo

    2017-02-15

    Acquired resistance to BRAFV600E inhibitors (BRAFi) in melanoma remains a common clinical obstacle, as is the case for any targeted drug therapy that can be developed given the plastic nature of cancers. While there has been significant focus on the cancer cell-intrinsic properties of BRAFi resistance, the impact of BRAFi resistance on host immunity has not been explored. Here we provide preclinical evidence that resistance to BRAFi in an autochthonous mouse model of melanoma is associated with restoration of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment initially reduced by BRAFi treatment. In contrast to restoration of MDSC, levels of T regulatory cells remained reduced in BRAFi-resistant tumors. Accordingly, tumor gene expression signatures specific for myeloid cell chemotaxis and homeostasis reappeared in BRAFi-resistant tumors. Notably, MDSC restoration relied upon MAPK pathway reactivation and downstream production of the myeloid attractant CCL2 in BRAFi-resistant melanoma cells. Strikingly, while combination checkpoint blockade (anti-CTLA-4 + anti-PD-1) was ineffective against BRAFi-resistant melanomas, the addition of MDSC depletion/blockade (anti-Gr-1 + CCR2 antagonist) prevented outgrowth of BRAFi-resistant tumors. Our results illustrate how extrinsic pathways of immunosuppression elaborated by melanoma cells dominate the tumor microenvironment and highlight the need to target extrinsic as well as intrinsic mechanisms of drug resistance.

  14. Plasma-derived human C1-esterase inhibitor does not prevent mechanical ventilation-induced pulmonary complement activation in a rat model of Streptococcus pneumoniae pneumonia.

    PubMed

    de Beer, F M; Aslami, H; Hoeksma, J; van Mierlo, G; Wouters, D; Zeerleder, S; Roelofs, J J T H; Juffermans, N P; Schultz, M J; Lagrand, W K

    2014-11-01

    Mechanical ventilation has the potential to cause lung injury, and the role of complement activation herein is uncertain. We hypothesized that inhibition of the complement cascade by administration of plasma-derived human C1-esterase inhibitor (C1-INH) prevents ventilation-induced pulmonary complement activation, and as such attenuates lung inflammation and lung injury in a rat model of Streptococcus pneumoniae pneumonia. Forty hours after intratracheal challenge with S. pneumoniae causing pneumonia rats were subjected to ventilation with lower tidal volumes and positive end-expiratory pressure (PEEP) or high tidal volumes without PEEP, after an intravenous bolus of C1-INH (200 U/kg) or placebo (saline). After 4 h of ventilation blood, broncho-alveolar lavage fluid and lung tissue were collected. Non-ventilated rats with S. pneumoniae pneumonia served as controls. While ventilation with lower tidal volumes and PEEP slightly amplified pneumonia-induced complement activation in the lungs, ventilation with higher tidal volumes without PEEP augmented local complement activation more strongly. Systemic pre-treatment with C1-INH, however, failed to alter ventilation-induced complement activation with both ventilation strategies. In accordance, lung inflammation and lung injury were not affected by pre-treatment with C1-INH, neither in rats ventilated with lower tidal volumes and PEEP, nor rats ventilated with high tidal volumes without PEEP. Ventilation augments pulmonary complement activation in a rat model of S. pneumoniae pneumonia. Systemic administration of C1-INH, however, does not attenuate ventilation-induced complement activation, lung inflammation, and lung injury.

  15. Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema.

    PubMed

    Deroux, A; Boccon-Gibod, I; Fain, O; Pralong, P; Ollivier, Y; Pagnier, A; Djenouhat, K; Du-Thanh, A; Gompel, A; Faisant, C; Launay, D; Bouillet, L

    2016-09-01

    Hereditary angioedema (HAE) is a rare disease associated with either a quantitative or qualitative deficiency in C1-inhibitor (C1-INH) or normal C1-INH. HAE with normal C1-INH is associated in 20% of cases with mutations in the gene for factor XII (FXII) or FXII-HAE. A recent review described 41 families, including 14 German and 15 Spanish families. We have constructed a register of French patients and their characteristics. A national survey was launched through the French National Center of Reference for Angioedema (CREAK) to study the clinical, biological and therapeutic characteristics of patients with HAE linked to a mutation of FXII gene. Fifty-seven patients were identified from 24 different families. In most cases they were young women (mean age at diagnosis: 31 years, mean age at first symptom: 21 years, female/male ratio: 76%). Twenty-one per cent of the patients experienced angioedema attacks only during pregnancy or when on oestrogen contraception. Sixty-three per cent had attacks at all times, but they were more severe during these same periods. Male carriers of the mutation were more frequently asymptomatic than females (P = 0·003). C1-INH concentrate and icatibant were both effective for treating attacks. The prophylactic use of tranexamic acid led to a 64% decrease in the number of attacks. This is one of the largest series reported of HAE patients with FXII mutation. The therapeutic management appeared to be identical to that of HAE with C1-INH deficiency.

  16. Antithrombin III, but not C1 esterase inhibitor reduces inflammatory response in lipopolysaccharide-stimulated human monocytes in an ex-vivo whole blood setting.

    PubMed

    Kellner, Patrick; Nestler, Frank; Leimert, Anja; Bucher, Michael; Czeslick, Elke; Sablotzki, Armin; Raspè, Christoph

    2014-12-01

    In order to examine the immunomodulatory effects of antithrombin III (AT-III) and C1 esterase inhibitor (C1-INH) in human monocytes, we investigated the intracellular expression of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in an ex-vivo laboratory study in a whole blood setting. Heparinized whole blood samples from 23 healthy male and female volunteers (mean age: 27±7years) were pre-incubated with clinically relevant concentrations of AT-III (n=11) and C1-INH (n=12), then stimulated with 0.2 ng/mL lipopolysaccharide (LPS) for 3h. After phenotyping CD14⁺ monocytes, intracellular expression of IL-6, IL-8, and TNF-α was assessed using flow cytometry. In addition, 12 whole blood samples (AT-III and C1-INH, n=6 each) were examined using hirudin for anticoagulation; all samples were processed in the same way. To exclude cytotoxicity effects, 7-amino-actinomycin D and Nonidet P40 staining were used to investigate probes. This study is the first to demonstrate the influence of C1-INH and AT-III on the monocytic inflammatory response in a whole blood setting, which mimics the optimal physiological setting. Cells treated with AT-III exhibited significant downregulation of the proportion of gated CD14⁺ monocytes for IL-6 and IL-8, in a dose-dependent manner; downregulation for TNF-α did not reach statistical significance. There were no significant effects on mean fluorescence intensity (MFI). In contrast, C1-INH did not significantly reduce the proportion of gated CD14⁺ monocytes or the MFI regarding IL-6, TNF-α, and IL-8. When using hirudin for anticoagulation, no difference in the anti-inflammatory properties of AT-III and C1-INH in monocytes occurs. Taken together, in contrast to TNF-α, IL-6 and IL-8 were significantly downregulated in monocytes in an ex-vivo setting of human whole blood when treated with AT-III. This finding implicates monocytes as an important point of action regarding the anti-inflammatory properties of AT-III in sepsis. C1

  17. Ruthenium complexes as inhibitors of the aldo-keto reductases AKR1C1-1C3.

    PubMed

    Traven, Katja; Sinreih, Maša; Stojan, Jure; Seršen, Sara; Kljun, Jakob; Bezenšek, Jure; Stanovnik, Branko; Turel, Iztok; Rižner, Tea Lanišnik

    2015-06-05

    The human aldo-keto reductases (AKRs) from the 1C subfamily are important targets for the development of new drugs. In this study, we have investigated the possible interactions between the recombinant AKR1C enzymes AKR1C1-AKR1C3 and ruthenium(II) complexes; in particular, we were interested in the potential inhibitory actions. Five novel ruthenium complexes (1a, 1b, 2a, 2b, 2c), two precursor ruthenium compounds (P1, P2), and three ligands (a, b, c) were prepared and included in this study. Two different types of novel ruthenium(II) complexes were synthesized. First, bearing the sulphur macrocycle [9]aneS3, S-bonded dimethylsulphoxide (dmso-S), and an N,N-donor ligand, with the general formula of [Ru([9]aneS3)(dmso)(N,N-ligand)](PF6)2 (1a, 1b), and second, with the general formula of [(η(6)-p-cymene)RuCl(N,N-ligand)]Cl (2a, 2b, 2c). All of these synthesized compounds were characterized by high-resolution NMR spectroscopy, X-ray crystallography (compounds a, b, c, 1a, 1b) and other standard physicochemical methods. To evaluate the potential inhibitory actions of these compounds on the AKR1C enzymes, we followed enzymatically catalyzed oxidation of the substrate 1-acenaphthenol by NAD(+) in the absence and presence of various micromolar concentrations of the individual compounds. Among 10 compounds, one ruthenium complex (2b) and two precursor ruthenium compounds (P1, P2) inhibited all three AKR1C enzymes, and one ruthenium complex (2a) inhibited only AKR1C3. Ligands a, b and c revealed no inhibition of the AKR1C enzymes. All four of the active compounds showed multiple binding with the AKR1C enzymes that was characterized by an initial instantaneous inhibition followed by a slow quasi-irreversible step. To the best of our knowledge, this is the first study that has examined interactions between these AKR1C enzymes and ruthenium(II) complexes.

  18. Unmasking Heavily O-Glycosylated Serum Proteins Using Perchloric Acid: Identification of Serum Proteoglycan 4 and Protease C1 Inhibitor as Molecular Indicators for Screening of Breast Cancer

    PubMed Central

    Lee, Cheng-Siang; Taib, Nur Aishah Mohd; Ashrafzadeh, Ali; Fadzli, Farhana; Harun, Faizah; Rahmat, Kartini; Hoong, See Mee; Abdul-Rahman, Puteri Shafinaz; Hashim, Onn Haji

    2016-01-01

    Heavily glycosylated mucin glycopeptides such as CA 27.29 and CA 15–3 are currently being used as biomarkers for detection and monitoring of breast cancer. However, they are not well detected at the early stages of the cancer. In the present study, perchloric acid (PCA) was used to enhance detection of mucin-type O-glycosylated proteins in the serum in an attempt to identify new biomarkers for early stage breast cancer. Sensitivity and specificity of an earlier developed sandwich enzyme-linked lectin assay were significantly improved with the use of serum PCA isolates. When a pilot case-control study was performed using the serum PCA isolates of normal participants (n = 105) and patients with stage 0 (n = 31) and stage I (n = 48) breast cancer, higher levels of total O-glycosylated proteins in sera of both groups of early stage breast cancer patients compared to the normal control women were demonstrated. Further analysis by gel-based proteomics detected significant inverse altered abundance of proteoglycan 4 and plasma protease C1 inhibitor in both the early stages of breast cancer patients compared to the controls. Our data suggests that the ratio of serum proteoglycan 4 to protease C1 inhibitor may be used for screening of early breast cancer although this requires further validation in clinically representative populations. PMID:26890881

  19. Bleeding associated with acquired factor V inhibitor in a patient on warfarin treated successfully with prednisolone

    PubMed Central

    Khalafallah, Alhossain; Grabek, Julian; Hayes, Robert; Mohamed, Muhajir

    2013-01-01

    An 85-year-old man on warfarin for atrial fibrillation presented with skin bleeding. International normalised ratio (INR) and activated partial thromboplastin time (APTT) were elevated and did not correct even after warfarin reversal with vitamin K, prothrombin complex concentrate (PCC) and fresh frozen plasma. Mixing coagulation studies with normal plasma suggested the presence of an inhibitor rather than the multiple coagulation factor deficiencies expected with warfarin. Assays of the common-pathway coagulation factors revealed factor V concentration <2% with inhibitor level elevated to 11 Bethesda units. The bleeding resolved following a course of corticosteroids. Coagulation studies and factor V level returned to normal along with resolution of the inhibitor. We report the case of the diagnostic dilemma posed and successful therapy implemented despite the limited evidence-based data being available for the treatment of this rare condition. PMID:23921688

  20. Acquired factor V inhibitor in a patient receiving venous-venous extracorporeal membrane oxygenation for Legionella pneumonia.

    PubMed

    Leung, Anne K H; Ng, George W Y; Sin, K C; Au, S Y; Lai, K Y; Lee, K L; Law, K I

    2015-04-01

    We report a rare complication of factor V deficiency in a patient having Legionella pneumonia. This patient also had other complications like severe acute respiratory distress syndrome, acute kidney injury, and septic shock that required venous-venous extracorporeal membrane oxygenation support. This is the first reported case of acquired factor V deficiency in a patient receiving extracorporeal membrane oxygenation for Legionella pneumonia. With the combined use of intravenous immunoglobulin, rituximab and plasma exchange, we achieved rapid clearance of the factor V inhibitor within 1 week so as to allow safe decannulation of extracorporeal membrane oxygenation.

  1. EGFR inhibitor and chemotherapy combinations for acquired TKI resistance in EGFR-mutant NSCLC models.

    PubMed

    Laurila, Niina; Koivunen, Jussi P

    2015-07-01

    Acquired resistance to EGFR TKIs is the most important limiting factor for treatment efficiency in EGFR-mutant NSCLC. Although the continuation of EGFR TKI beyond disease progression in combination with chemotherapy is often suggested as a strategy for treating acquired resistance, the optimal treatment sequence for EGFR TKI and chemotherapy is unknown. In the current work, NSCLC cell lines PC9ER, H1975 and HCC827GR, representing the acquired TKI resistance genotypes (T790M, cMET), were exposed to a chemotherapeutic agent, cisplatin or paclitaxel, in combination with EGFR TKIs (erlotinib, WZ4002) in vitro and analysed for cytotoxicity and apoptotic response. The result showed that all the combinations of EGFR TKIs with a chemotherapeutic agent tested had a synergistic effect on cytotoxicity and increased the apoptotic response. The sequences involving a chemotherapeutic agent concurrently with an EGFR TKI or preceding it were the most efficient strategies. Our in vitro models suggest that the combination of an EGFR TKI and chemotherapy is beneficial in cases of acquired EGFR TKI resistance. Furthermore, the sequence of chemotherapy followed by EGFR TKI is significantly more powerful than the reversed order, so that an intercalated approach is likely to be the most active strategy in clinical use and ought to be tested in a randomized clinical trial.

  2. Isolation and study of an acquired inhibitor of human coagulation factor V.

    PubMed Central

    Nesheim, M E; Nichols, W L; Cole, T L; Houston, J G; Schenk, R B; Mann, K G; Bowie, E J

    1986-01-01

    A coagulation Factor V inhibitor developed in a man 75 yr of age in association with an anaplastic malignancy and drug treatment (including the aminoglycoside antibiotic, gentamicin). The patient did not bleed abnormally, despite both surgical challenge and plasma Factor V activity of less than 1%. The inhibited plasma had grossly prolonged prothrombin and activated partial thromboplastin times, but a normal thrombin time. Mixing studies indicated progressive coagulation inhibition with normal plasma, but not with Factor V-deficient plasma, and reversal of coagulation inhibition by the addition of bovine Factor V to the patient's plasma. 1 ml of patient plasma inhibited the Factor V activity of 90 ml of normal human plasma. The inhibitor was isolated by sequential affinity chromatography on protein A-Sepharose and Factor V-Sepharose. The IgG isolate markedly inhibits the activity of prothrombinase assembled from purified Factors Xa and Va, calcium ion, and phospholipid vesicles, and partially inhibits prothrombinase assembled from purified Factor Xa, calcium ion, and normal platelets. The Factor V of platelets, however, appears relatively inaccessible to the antibody, inasmuch as platelets isolated from whole blood supplemented for 8 h with the antibody functioned normally with respect to platelet Factor V-mediated prothrombinase function. The absence of obvious hemorrhagic difficulties in the patient, the total inhibition of plasma Factor V by the inhibitor, and the apparent inaccessibility of platelet Factor V to the inhibitor specifically implicate platelet Factor V in the maintenance of hemostasis. Images PMID:3944265

  3. XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IκBα and overcomes acquired proteasome inhibitor resistance in human multiple myeloma.

    PubMed

    Turner, Joel G; Kashyap, Trinayan; Dawson, Jana L; Gomez, Juan; Bauer, Alexis A; Grant, Steven; Dai, Yun; Shain, Kenneth H; Meads, Mark; Landesman, Yosef; Sullivan, Daniel M

    2016-11-29

    Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired resistance in MM. PI-resistant myeloma cell lines both in vitro and in vivo and refractory myeloma patient biopsies were treated with selinexor/bortezomib or carfilzomib and assayed for apoptosis. Mechanistic studies included NFκB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assays. IκBα knockdown and NFκB activity were measured in selinexor/bortezomib-treated MM cells. We found that selinexor restored sensitivity of PI-resistant MM to bortezomib and carfilzomib. Selinexor/bortezomib treatment inhibited PI-resistant MM tumor growth and increased survival in mice. Myeloma cells from PI-refractory MM patients were sensitized by selinexor to bortezomib and carfilzomib without affecting non-myeloma cells. Immunofluorescence microscopy, Western blot, and ImageStream analyses of MM cells showed increases in total and nuclear IκBα by selinexor/bortezomib. Proximity ligation found increased IκBα-NFκB complexes in treated MM cells. IκBα knockdown abrogated selinexor/bortezomib-induced cytotoxicity in MM cells. Selinexor/bortezomib treatment decreased NFκB transcriptional activity. Selinexor, when used with bortezomib or carfilzomib, has the potential to overcome PI drug resistance in MM. Sensitization may be due to inactivation of the NFκB pathway by IκBα.

  4. The novel ATP-competitive MEK/Aurora kinase inhibitor BI-847325 overcomes acquired BRAF inhibitor resistance through suppression of Mcl-1 and MEK expression

    PubMed Central

    Phadke, Manali S.; Sini, Patrizia; Smalley, Keiran S. M.

    2015-01-01

    Resistance to BRAF inhibitors is a major clinical problem. Here we evaluate BI-847325, an ATP-competitive inhibitor of MEK and Aurora kinases, in treatment-naïve and drug-resistant BRAF-mutant melanoma models. BI-847325 potently inhibited growth and survival of melanoma cell lines that were both BRAF inhibitor naïve and resistant in 2D culture, 3D cell culture conditions and in colony formation assays. Western blot studies showed BI-847325 to reduce expression of phospho-ERK and phospho-histone 3 in multiple models of vemurafenib resistance. Mechanistically, BI-847325 decreased the expression of MEK and Mcl-1 while increasing the expression of the pro-apoptotic protein BIM. Strong suppression of MEK expression was observed after 48 h of treatment, with no recovery following >72 h of washout. siRNA mediated knockdown of Mcl-1 enhanced the effects of BI-847325, whereas Mcl-1 overexpression reversed this in both 2D cell culture and 3D spheroid melanoma models. In vivo, once weekly BI-847325 (70 mg/kg) led to durable regression of BRAF-inhibitor naive xenografts with no regrowth seen (>65 days of treatment). In contrast, treatment with the vemurafenib analog PLX4720 was associated with tumor relapse at >30 days. BI-847325 also suppressed the long-term growth of xenografts with acquired PLX4720 resistance. Analysis of tumor samples revealed BI-847325 to induce apoptosis associated with suppression of phospho-ERK, total MEK, phospho-Histone3 and Mcl-1 expression. Our studies indicate that BI-847325 is effective in overcoming BRAF inhibitor resistance and has long-term inhibitory effects upon BRAF-mutant melanoma in vivo, through a mechanism associated with the decreased expression of both MEK and Mcl-1. PMID:25873592

  5. Model-based evaluation of similarity in pharmacokinetics of two formulations of the blood-derived plasma product c1 esterase inhibitor.

    PubMed

    Keizer, Ron J; Budde, Ilona Kleine; Sprengers, Paul F W; Levi, M; Beijnen, Jos H; Huitema, Alwin D R

    2012-02-01

    A novel formulation of C1 esterase inhibitor concentrate, a plasma product used in the treatment of hereditary angioedema (HAE), was studied in a clinical trial for similarity in pharmacokinetics (PK) compared with the reference product. Direct trial data were limited given the availability of patients, and therefore a modeling approach was used to study similarity. Type I error of the study was evaluated using simulations based on retrospective data. A population PK modeling analysis was performed on data from the trial. Analysis of variance was carried out on results of a noncompartmental PK analysis (NCA) of the clinical data. Simulations showed that type I error was inflated to 62% (P < .05) when bioequivalence criteria (confidence intervals within 80%-125%) were adhered to strictly. In the clinical trial, 13 HAE patients were evaluable. The population PK analysis showed no significant differences in PK parameters, whereas confidence intervals for all parameters were within 80% to 125%. The relative differences in area under the curve, incremental recovery, and mean residence time estimated using NCA were all close to 1. The novel formulation showed similar PK characteristics to the original formulation. The model-based approach showed that strict criteria for PK comparison could not be applied in this analysis.

  6. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance

    PubMed Central

    Song, Zilan; Wang, Meining; Zhang, Ao

    2015-01-01

    The development of inhibitors for the tyrosine anaplastic lymphoma kinase (ALK) has advanced rapidly, driven by biology and medicinal chemistry. The first generation ALK inhibitor crizotinib was granted US FDA approval with only four years of preclinical and clinical testing. Although this drug offers significant clinical benefit to the ALK-positive patients, resistance has been developed through a variety of mechanisms. In addition to ceritinib, alectinib is another second-generation ALK inhibitor launched in 2014 in Japan. This drug has a unique chemical structure bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold with an IC50 value of 1.9 nmol/L, and is highly potent against ALK bearing the gatekeeper mutation L1196M with an IC50 of 1.56 nmol/L. In the clinic, alectinib is highly efficacious in treatment of ALK-positive non-small cell lung cancer (NSCLC), and retains potency to combat crizotinib-resistant ALK mutations L1196M, F1174L, R1275Q and C1156Y. PMID:26579422

  7. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.

    PubMed

    Jackman, David; Pao, William; Riely, Gregory J; Engelman, Jeffrey A; Kris, Mark G; Jänne, Pasi A; Lynch, Thomas; Johnson, Bruce E; Miller, Vincent A

    2010-01-10

    Ten percent of North American patients with non-small-cell lung cancer have tumors with somatic mutations in the gene for the epidermal growth factor receptor (EGFR). Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of EGFR experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, the overwhelming majority of these patients inevitably acquire resistance to either drug. Currently, the clinical definition of such secondary or acquired resistance is not clear. We propose the following criteria be used to define more precisely acquired resistance to EGFR TKIs. All patients should have the following criteria: previous treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib); either or both of the following: a tumor that harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benefit from treatment with an EGFR TKI; systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or WHO) while on continuous treatment with gefitinib or erlotinib within the last 30 days; and no intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of new therapy. The relatively simple definition proposed here will lead to a more uniform approach to investigating the problem of acquired resistance to EGFR TKIs in this unique patient population. These guidelines should minimize reporting of false-positive and false-negative activity in these clinical trials and would facilitate the identification of agents that truly overcome acquired resistance to gefitinib and erlotinib.

  8. XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IκBα and overcomes acquired proteasome inhibitor resistance in human multiple myeloma

    PubMed Central

    Turner, Joel G.; Kashyap, Trinayan; Dawson, Jana L.; Gomez, Juan; Bauer, Alexis A.; Grant, Steven; Dai, Yun; Shain, Kenneth H.; Meads, Mark; Landesman, Yosef; Sullivan, Daniel M.

    2016-01-01

    Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired resistance in MM. PI-resistant myeloma cell lines both in vitro and in vivo and refractory myeloma patient biopsies were treated with selinexor/bortezomib or carfilzomib and assayed for apoptosis. Mechanistic studies included NFκB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assays. IκBα knockdown and NFκB activity were measured in selinexor/bortezomib-treated MM cells. We found that selinexor restored sensitivity of PI-resistant MM to bortezomib and carfilzomib. Selinexor/bortezomib treatment inhibited PI-resistant MM tumor growth and increased survival in mice. Myeloma cells from PI-refractory MM patients were sensitized by selinexor to bortezomib and carfilzomib without affecting non-myeloma cells. Immunofluorescence microscopy, Western blot, and ImageStream analyses of MM cells showed increases in total and nuclear IκBα by selinexor/bortezomib. Proximity ligation found increased IκBα-NFκB complexes in treated MM cells. IκBα knockdown abrogated selinexor/bortezomib-induced cytotoxicity in MM cells. Selinexor/bortezomib treatment decreased NFκB transcriptional activity. Selinexor, when used with bortezomib or carfilzomib, has the potential to overcome PI drug resistance in MM. Sensitization may be due to inactivation of the NFκB pathway by IκBα. PMID:27806331

  9. Exocytosis of polyubiquitinated proteins in bortezomib-resistant leukemia cells: a role for MARCKS in acquired resistance to proteasome inhibitors

    PubMed Central

    Franke, Niels E.; Kaspers, Gertjan L.; Assaraf, Yehuda G.; van Meerloo, Johan; Niewerth, Denise; Kessler, Floortje L.; Poddighe, Pino J.; Kole, Jeroen; Smeets, Serge J.; Ylstra, Bauke; Bi, Chonglei; Chng, Wee Joo; Horton, Terzah M.; Menezes, Rene X.; Musters, Renée J.P.; Zweegman, Sonja; Jansen, Gerrit; Cloos, Jacqueline

    2016-01-01

    PSMB5 mutations and upregulation of the β5 subunit of the proteasome represent key determinants of acquired resistance to the proteasome inhibitor bortezomib (BTZ) in leukemic cells in vitro. We here undertook a multi-modality (DNA, mRNA, miRNA) array-based analysis of human CCRF-CEM leukemia cells and BTZ-resistant subclones to determine whether or not complementary mechanisms contribute to BTZ resistance. These studies revealed signatures of markedly reduced expression of proteolytic stress related genes in drug resistant cells over a broad range of BTZ concentrations along with a high upregulation of myristoylated alanine-rich C-kinase substrate (MARCKS) gene expression. MARCKS upregulation was confirmed on protein level and also observed in other BTZ-resistant tumor cell lines as well as in leukemia cells with acquired resistance to other proteasome inhibitors. Moreover, when MARCKS protein expression was demonstrated in specimens derived from therapy-refractory pediatric leukemia patients (n = 44), higher MARCKS protein expression trended (p = 0.073) towards a dismal response to BTZ-containing chemotherapy. Mechanistically, we show a BTZ concentration-dependent association of MARCKS protein levels with the emergence of ubiquitin-containing vesicles in BTZ-resistant CEM cells. These vesicles were found to be extruded and taken up in co-cultures with proteasome-proficient acceptor cells. Consistent with these observations, MARCKS protein associated with ubiquitin-containing vesicles was also more prominent in clinical leukemic specimen with ex vivo BTZ resistance compared to BTZ-sensitive leukemia cells. Collectively, we propose a role for MARCKS in a novel mechanism of BTZ resistance via exocytosis of ubiquitinated proteins in BTZ-resistant cells leading to quenching of proteolytic stress. PMID:27542283

  10. Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors

    PubMed Central

    Baker, Theresa; Nerle, Sujata; Pritchard, Justin; Zhao, Boyang; Rivera, Victor M.

    2015-01-01

    Although targeted therapies have revolutionized cancer treatment, overcoming acquired resistance remains a major clinical challenge. EZH2 inhibitors (EZH2i), EPZ-6438 and GSK126, are currently in the early stages of clinical evaluation and the first encouraging signs of efficacy have recently emerged in the clinic. To anticipate mechanisms of resistance to EZH2i, we used a forward genetic platform combining a mutagenesis screen with next generation sequencing technology and identified a hotspot of secondary mutations in the EZH2 D1 domain (Y111 and I109). Y111D mutation within the WT or A677G EZH2 allele conferred robust resistance to both EPZ-6438 and GSK126, but it only drove a partial resistance within the Y641F allele. EZH2 mutants required histone methyltransferase (HMT) catalytic activity and the polycomb repressive complex 2 (PRC2) components, SUZ12 and EED, to drive drug resistance. Furthermore, D1 domain mutations not only blocked the ability of EZH2i to bind to WT and A677G mutant, but also abrogated drug binding to the Y641F mutant. These data provide the first cellular validation of the mechanistic model underpinning the oncogenic function of WT and mutant EZH2. Importantly, our findings suggest that acquired-resistance to EZH2i may arise in WT and mutant EZH2 patients through a single mutation that remains targetable by second generation EZH2i. PMID:26360609

  11. Inhibition of ABCB1 Overcomes Cancer Stem Cell-like Properties and Acquired Resistance to MET Inhibitors in Non-Small Cell Lung Cancer.

    PubMed

    Sugano, Teppei; Seike, Masahiro; Noro, Rintaro; Soeno, Chie; Chiba, Mika; Zou, Fenfei; Nakamichi, Shinji; Nishijima, Nobuhiko; Matsumoto, Masaru; Miyanaga, Akihiko; Kubota, Kaoru; Gemma, Akihiko

    2015-11-01

    Patients with non-small cell lung cancer (NSCLC) EGFR mutations have shown a dramatic response to EGFR inhibitors (EGFR-TKI). EGFR T790M mutation and MET amplification have been recognized as major mechanisms of acquired resistance to EGFR-TKI. Therefore, MET inhibitors have recently been used in NSCLC patients in clinical trials. In this study, we tried to identify the mechanism of acquired resistance to MET inhibitors. We analyzed the antitumor effects of two MET inhibitors, PHA-665752 and crizotinib, in 10 NSCLC cell lines. EBC-1 cells with MET amplification were the only cells that were sensitive to both MET inhibitors. We established PHA-665752-resistant EBC-1 cells, namely EBC-1R cells. Activation of KRAS, EGFR, and FGFR2 signaling was observed in EBC-1R cells by FISH and receptor tyrosine kinase phosphorylation antibody arrays. EBC-1R cells also showed overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) as well as phosphorylation of MET. EBC-1R cells grew as cell spheres that exhibited cancer stem cell-like (CSC) properties and epithelial-mesenchymal transition (EMT). The level of miR-138 that targeted ABCB1 was decreased in EBC-1R cells. ABCB1 siRNA and the ABCB1 inhibitor elacridar could reduce sphere numbers and suppress EMT. Elacridar could also reverse resistance to PHA-665752 in EBC-1R cells. Our study demonstrated that ABCB1 overexpression, which was associated with CSC properties and EMT, was involved in the acquired resistance to MET inhibitors. Inhibition of ABCB1 might be a novel therapeutic strategy for NSCLC patients with acquired resistance to MET inhibitors.

  12. A Naturally-Occurring Histone Acetyltransferase Inhibitor Derived from Garcinia indica Impairs Newly Acquired and Reactivated Fear Memories

    PubMed Central

    Maddox, Stephanie A.; Watts, Casey S.; Doyère, Valérie; Schafe, Glenn E.

    2013-01-01

    The study of the cellular and molecular mechanisms underlying the consolidation and reconsolidation of traumatic fear memories has progressed rapidly in recent years, yet few compounds have emerged that are readily useful in a clinical setting for the treatment of anxiety disorders such as post-traumatic stress disorder (PTSD). Here, we use a combination of biochemical, behavioral, and neurophysiological methods to systematically investigate the ability of garcinol, a naturally-occurring histone acetyltransferase (HAT) inhibitor derived from the rind of the fruit of the Kokum tree (Garcina indica), to disrupt the consolidation and reconsolidation of Pavlovian fear conditioning, a widely studied rodent model of PTSD. We show that local infusion of garcinol into the rat lateral amygdala (LA) impairs the training and retrieval-related acetylation of histone H3 in the LA. Further, we show that either intra-LA or systemic administration of garcinol within a narrow window after either fear conditioning or fear memory retrieval significantly impairs the consolidation and reconsolidation of a Pavlovian fear memory and associated neural plasticity in the LA. Our findings suggest that a naturally-occurring compound derived from the diet that regulates chromatin function may be useful in the treatment of newly acquired or recently reactivated traumatic memories. PMID:23349897

  13. Feasibility of home infusion and self-administration of nanofiltered C1 esterase inhibitor for routine prophylaxis in patients with hereditary angioedema and characterization of a training and support program.

    PubMed

    Gregory, Cherylann; Landmesser, Ladonna M; Corrigan, Larry; Mariano, David

    2014-01-01

    Hereditary angioedema (HAE) is a rare, chronic disease of C1 inhibitor deficiency. Study researchers evaluated the prevalence of home and self-administration of nanofiltered, human-derived C1 esterase inhibitor infusions and the implementation of a nursing training and support program. Home administration rate increased from 49.0% to 75.8%. The percentage who self-administered increased from 20.3% to 43.9%. Doses per week averaged 1.85 at home compared with 1.40 in infusion centers and physicians' offices. Patients required an average of 5 visits to be trained. Self-administration is a viable, feasible option in the management of HAE, which is facilitated by a nurse-managed training and support program.

  14. Successful use of daily intravenous infusion of C1 esterase inhibitor concentrate in the treatment of a hereditary angioedema patient with ascites, hypovolemic shock, sepsis, renal and respiratory failure.

    PubMed

    Pham, Hoang; Santucci, Stephanie; Yang, William H

    2014-01-01

    Hereditary angioedema (HAE) is a rare autosomal dominant disease most commonly associated with defects in C1 esterase inhibitor (C1-INH). HAE manifests as recurrent episodes of edema in various body locations. Atypical symptoms, such as ascites, acute respiratory distress syndrome, and hypovolemic shock, have also been reported. Management of HAE conventionally involves the treatment of acute attacks, as well as short- and long-term prophylaxis. Since attacks can be triggered by several factors, including stress and physical trauma, prophylactic therapy is recommended for patients undergoing surgery. Human plasma-derived C1-INH (pdC1-INH) concentrate is indicated for the treatment of both acute HAE attacks and pre-procedure prevention of HAE episodes in patients undergoing medical, dental, or surgical procedures. We report the first case of a patient with HAE who experienced an abdominal attack precipitated by a retroperitoneal bleed while being converted from warfarin to heparin in preparation for surgery. Subsequently, the patient had a protracted course in hospital with other complications, which included hypovolemic shock, ascites, severe sepsis from nosocomial pneumonia, renal and respiratory failure. Despite intensive interventions, the patient remained in a critical state for months; however, after a trial of daily intravenous infusion of pdC1-INH concentrate (Berinert®, CSL Behring GmbH, Marburg, Germany), clinical status improved, particularly renal function. Therefore, pdC1-INH concentrate may be an effective treatment option to consider for critically-ill patients with HAE.

  15. PI3Kδ inhibitor idelalisib in combination with BTK inhibitor ONO/GS-4059 in diffuse large B cell lymphoma with acquired resistance to PI3Kδ and BTK inhibitors

    PubMed Central

    Sorensen, Rick A.; Cui, Zhi-Hua; Keegan, Kathleen S.; Brockett, Robert; Chen, Guang; Quéva, Christophe; Li, Li; Tannheimer, Stacey L.

    2017-01-01

    Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton’s tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma. Significant tumor regression was observed with a combination of PI3Kδ and Bruton’s tyrosine kinase inhibitors in the mouse TMD8 xenograft. Acquired resistance to idelalisib in the TMD8 cell line occurred by loss of phosphatase and tensin homolog and phosphoinositide 3-kinase pathway upregulation, but not by mutation of PIK3CD. Sensitivity to idelalisib could be restored by combining idelalisib and ONO/GS-4059. Further evaluation of targeted inhibitors revealed that the combination of idelalisib and the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 or the AKT inhibitor MK-2206 could partially overcome resistance. Characterization of acquired Bruton’s tyrosine kinase inhibitor resistance revealed a novel tumor necrosis factor alpha induced protein 3 mutation (TNFAIP3 Q143*), which led to a loss of A20 protein, and increased p-IκBα. The combination of idelalisib and ONO/GS-4059 partially restored sensitivity in this resistant line. Additionally, a mutation in Bruton’s tyrosine kinase at C481F was identified as a mechanism of resistance. The combination activity observed with idelalisib and ONO/GS-4059, taken together with the ability to overcome resistance, could lead to a new therapeutic option in activated B-cell-like diffuse large B-cell lymphoma. A clinical trial is currently underway to evaluate the

  16. Evolution of pre-existing versus acquired resistance to platinum drugs and PARP inhibitors in BRCA-associated cancers.

    PubMed

    Yamamoto, Kimiyo N; Hirota, Kouji; Takeda, Shunichi; Haeno, Hiroshi

    2014-01-01

    Platinum drugs and PARP inhibitors ("PARPis") are considered to be effective in BRCA-associated cancers with impaired DNA repair. These agents cause stalled and collapsed replication forks and create double-strand breaks effectively in the absence of repair mechanisms, resulting in arrest of the cell cycle and induction of cell death. However, recent studies have shown failure of these chemotherapeutic agents due to emerging drug resistance. In this study, we developed a stochastic model of BRCA-associated cancer progression in which there are four cancer populations: those with (i) functional BRCA, (ii) dysfunctional BRCA, (iii) functional BRCA and a growth advantage, and (iv) dysfunctional BRCA and a growth advantage. These four cancer populations expand from one cancer cell with normal repair function until the total cell number reaches a detectable amount. We derived formulas for the probability and expected numbers of each population at the time of detection. Furthermore, we extended the model to consider the tumor dynamics during treatment. Results from the model were validated and showed good agreement with clinical and experimental evidence in BRCA-associated cancers. Based on the model, we investigated conditions in which drug resistance during the treatment course originated from either a pre-existing drug-resistant population or a de novo population, due to secondary mutations. Finally, we found that platinum drugs and PARPis were effective if (i) BRCA inactivation is present, (ii) the cancer was diagnosed early, and (iii) tumor growth is rapid. Our results indicate that different types of cancers have a preferential way of acquiring resistance to platinum drugs and PARPis according to their growth and mutational characteristics.

  17. Are proton pump inhibitors associated with the development of community-acquired pneumonia? A meta-analysis.

    PubMed

    Giuliano, Christopher; Wilhelm, Sheila M; Kale-Pradhan, Pramodini B

    2012-05-01

    This study was presented at the American College of Chest Physicians meeting in Pittsburgh (PA, USA) in October 2011. The study objective was to evaluate the association of proton pump inhibitors (PPIs) and community-acquired pneumonia (CAP). The design was a meta-analysis of nine case-controlled and cohort studies. 120,863 pneumonia cases from 1987 to 2006 were included in the meta-analysis. PubMed and Ovid Medline were searched from inception through May 2011 by two investigators independently using keywords: PPI, pneumonia, CAP, anti-ulcer, antacid, omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. This meta-analysis only included case-controlled and cohort studies that were published in full in English and evaluated PPI use and CAP incidence. Studies were excluded if they included the following patients: pediatric, Helicobacter pylori treatment and critically ill. Bibliographies of recent review articles and systematic reviews were hand-searched. Quality of studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Two investigators independently extracted data into standardized data collection forms that were confirmed by a third investigator. Data were analyzed based on current use of PPIs, duration of PPI use (<30 days or >180 days) and PPI dose (high vs low). Overall association of PPI and CAP was analyzed using the random effects model (Comprehensive Meta analysis(®) Version 2.0). Nine studies met all criteria for the primary outcome. Newcastle-Ottawa Quality Assessment Scale scores ranged from 4 to 8 out of 9. Current use of PPIs (odds ratio [OR]: 1.39; 95% CI: 1.09-1.76), PPI use <30 days (OR: 1.65; 95% CI: 1.25-2.19), PPI high dose (OR: 1.50; 95% CI: 1.33-1.68) and PPI low dose (OR: 1.17; 95% CI: 1.11-1.24) were significantly associated with CAP. There was no association between CAP and PPI use >180 days (OR: 1.10; 95% CI: 1.00-1.21). In conclusion, patients currently receiving PPIs, particularly <30 days or high dose

  18. THE ENZYMATIC NATURE OF C'1r

    PubMed Central

    Naff, George B.; Ratnoff, Oscar D.

    1968-01-01

    Human C'1, a macromolecular complex composed of three subunits, is the zymogen for at least two distinct enzymes. Preparations of one subunit, C'1r, functioned as a protease which converted another subunit, C'1s, to C'1 esterase. The conversion of C'1s to C'1 esterase by C'1r was blocked by Liquoid, phenyl methylsulfonyl fluoride, and calcium ions, but not by soybean trypsin inhibitor, hirudin, or heparin. Preparations of C'1r also possessed two additional functions, i.e., the ability to hydrolyze certain synthetic amino acid esters and to participate in immune hemolysis. Evidence was presented which indicates that these three functions are properties of a single entity, C'1r, but not of the same portion of its molecular structure. These observations suggest that C'1r has at least two active sites, one for its reaction with C'1q, an additional subunit of C'1, and one for its reaction with C'1s; together, the three subcomponents, C'1q, C'1r, and C'1s, form a single functional unit, the first component of complement. PMID:5675434

  19. HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors.

    PubMed

    Sottile, Rosa; Pangigadde, Pradeepa N; Tan, Thomas; Anichini, Andrea; Sabbatino, Francesco; Trecroci, Francesca; Favoino, Elvira; Orgiano, Laura; Roberts, James; Ferrone, Soldano; Kärre, Klas; Colucci, Francesco; Carbone, Ennio

    2016-02-01

    The frequent development of drug resistance to targeted therapies in cancer patients has stimulated interest in strategies counteracting resistance. Combining immunotherapies with targeted therapies is one such strategy. In this context, we asked whether human NK cells can target melanoma cells that have acquired resistance to selective inhibitors targeting activating mutants of the B-Raf kinase (BRAF inhibitors, BRAFi). We generated drug-resistant cell variants in vitro from human BRAF-mutant melanoma cell lines MEL-HO, COLO-38, SK-MEL-37, 1520 and from primary melanoma cells freshly isolated from two patients. All drug-resistant cell variants remained susceptible to lysis by IL-2-activated NK cells; and two BRAFi-resistant lines (BRAFi-R) became significantly more susceptible to NK-cell lysis than their parental lines. This was associated with significant HLA class I antigen downregulation and PD-L1 upregulation on the drug-resistant lines. Although blocking HLA class I enhanced the extent of lysis of both BRAFi-R and parental cells to NK-cell-mediated lysis, antibody-mediated inhibition of PD1-PD-L1 interactions had no detectable effect. HLA class I antigen expression on BRAFi-R melanoma variants thus appears to play a major role in their susceptibility to NK-cell cytotoxicity. These findings suggest that NK-cell-based immunotherapy may be a viable approach to treat melanoma patients with acquired resistance to BRAF inhibitors.

  20. HLA class I downregulation is associated with enhanced NK‐cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors

    PubMed Central

    Sottile, Rosa; Pangigadde, Pradeepa N.; Tan, Thomas; Anichini, Andrea; Sabbatino, Francesco; Trecroci, Francesca; Favoino, Elvira; Orgiano, Laura; Roberts, James; Ferrone, Soldano; Kärre, Klas; Colucci, Francesco

    2015-01-01

    The frequent development of drug resistance to targeted therapies in cancer patients has stimulated interest in strategies counteracting resistance. Combining immunotherapies with targeted therapies is one such strategy. In this context, we asked whether human NK cells can target melanoma cells that have acquired resistance to selective inhibitors targeting activating mutants of the B‐Raf kinase (BRAF inhibitors, BRAFi). We generated drug‐resistant cell variants in vitro from human BRAF‐mutant melanoma cell lines MEL‐HO, COLO‐38, SK‐MEL‐37, 1520 and from primary melanoma cells freshly isolated from two patients. All drug‐resistant cell variants remained susceptible to lysis by IL‐2‐activated NK cells; and two BRAFi‐resistant lines (BRAFi‐R) became significantly more susceptible to NK‐cell lysis than their parental lines. This was associated with significant HLA class I antigen downregulation and PD‐L1 upregulation on the drug‐resistant lines. Although blocking HLA class I enhanced the extent of lysis of both BRAFi‐R and parental cells to NK‐cell‐mediated lysis, antibody‐mediated inhibition of PD1–PD‐L1 interactions had no detectable effect. HLA class I antigen expression on BRAFi‐R melanoma variants thus appears to play a major role in their susceptibility to NK‐cell cytotoxicity. These findings suggest that NK‐cell‐based immunotherapy may be a viable approach to treat melanoma patients with acquired resistance to BRAF inhibitors. PMID:26564811

  1. Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 Genes Are Associated with the Response to TNF Inhibitors in Patients with Rheumatoid Arthritis

    PubMed Central

    Politi, Cristina; Triggianese, Paola; Rufini, Sara; Kroegler, Barbara; Perricone, Carlo; Latini, Andrea; Novelli, Giuseppe; Borgiani, Paola; Perricone, Roberto

    2017-01-01

    Objective Rheumatoid Arthritis (RA) is a progressive autoimmune disease characterized by chronic joint inflammation and structural damage. Remission or at least low disease activity (LDA) represent potentially desirable goals of RA treatment. Single nucleotide polymorphisms (SNPs) in several genes might be useful for prediction of response to therapy. We aimed at exploring 4 SNPs in candidate genes (STAT4, PTPN2, PSORS1C1 and TRAF3IP2) in order to investigate their potential role in the response to therapy with tumor necrosis factor inhibitors (TNF-i) in RA patients. Methods In 171 RA patients we investigated the following SNPs: rs7574865 (STAT4), rs2233945 (PSORS1C1), rs7234029 (PTPN2) and rs33980500 (TRAF3IP2). Remission, LDA, and EULAR response were registered at 6 months and 2 years after initiation of first line TNF-i [Adalimumab (ADA) and Etanercept (ETN)]. Results STAT4 variant allele was associated with the absence of a good/moderate EULAR response at 2 years of treatment in the whole RA group and in ETN treated patients. The PTPN2 SNP was associated with no good/moderate EULAR response at 6 months in ADA treated patients. Patients carrying PSORS1C1 variant allele did not reach LDA at 6 months in both the whole RA group and ETN treated patients. TRAF3IP2 variant allele was associated with the lack of LDA and remission achievement at 6 months in all RA cohort while an association with no EULAR response at 2 years of treatment occurred only in ETN treated patients. Conclusions For the first time, we reported that SNPs in STAT4, PTPN2, PSORS1C1, and TRAF3IP2 are associated with response to TNF-i treatment in RA patients; however, these findings should be validated in a larger population. PMID:28107378

  2. ZEB1 Mediates Acquired Resistance to the Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer

    PubMed Central

    Yoshida, Takeshi; Song, Lanxi; Bai, Yun; Kinose, Fumi; Li, Jiannong; Ohaegbulam, Kim C.; Muñoz-Antonia, Teresita; Qu, Xiaotao; Eschrich, Steven; Uramoto, Hidetaka; Tanaka, Fumihiro; Nasarre, Patrick; Gemmill, Robert M.; Roche, Joëlle; Drabkin, Harry A.; Haura, Eric B.

    2016-01-01

    Epithelial-mesenchymal transition (EMT) is one mechanism of acquired resistance to inhibitors of the epidermal growth factor receptor-tyrosine kinases (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The precise mechanisms of EMT-related acquired resistance to EGFR-TKIs in NSCLC remain unclear. We generated erlotinib-resistant HCC4006 cells (HCC4006ER) by chronic exposure of EGFR-mutant HCC4006 cells to increasing concentrations of erlotinib. HCC4006ER cells acquired an EMT phenotype and activation of the TGF-β/SMAD pathway, while lacking both T790M secondary EGFR mutation and MET gene amplification. We employed gene expression microarrays in HCC4006 and HCC4006ER cells to better understand the mechanism of acquired EGFR-TKI resistance with EMT. At the mRNA level, ZEB1 (TCF8), a known regulator of EMT, was >20-fold higher in HCC4006ER cells than in HCC4006 cells, and increased ZEB1 protein level was also detected. Furthermore, numerous ZEB1 responsive genes, such as CDH1 (E-cadherin), ST14, and vimentin, were coordinately regulated along with increased ZEB1 in HCC4006ER cells. We also identified ZEB1 overexpression and an EMT phenotype in several NSCLC cells and human NSCLC samples with acquired EGFR-TKI resistance. Short-interfering RNA against ZEB1 reversed the EMT phenotype and, importantly, restored erlotinib sensitivity in HCC4006ER cells. The level of micro-RNA-200c, which can negatively regulate ZEB1, was significantly reduced in HCC4006ER cells. Our results suggest that increased ZEB1 can drive EMT-related acquired resistance to EGFR-TKIs in NSCLC. Attempts should be made to explore targeting ZEB1 to resensitize TKI-resistant tumors. PMID:26789630

  3. Ten-year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan.

    PubMed

    Takedani, H; Shima, M; Horikoshi, Y; Koyama, T; Fukutake, K; Kuwahara, M; Ishiguro, N

    2015-05-01

    Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries.

  4. Development of a disease-specific quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-QoL): Spanish multi-centre research project

    PubMed Central

    2012-01-01

    Background There is a need for a disease-specific instrument for assessing health-related quality of life in adults with hereditary angioedema due to C1 inhibitor deficiency, a rare, disabling and life-threatening disease. In this paper we report the protocol for the development and validation of a specific questionnaire, with details on the results of the process of item generation, domain selection, and the expert and patient rating phase. Methods/Design Semi-structured interviews were completed by 45 patients with hereditary angioedema and 8 experts from 8 regions in Spain. A qualitative content analysis of the responses was carried out. Issues raised by respondents were grouped into categories. Content analysis identified 240 different responses, which were grouped into 10 conceptual domains. Sixty- four items were generated. A total of 8 experts and 16 patients assessed the items for clarity, relevance to the disease, and correct dimension assignment. The preliminary version of the specific health-related quality of life questionnaire for hereditary angioedema (HAE-QoL v 1.1) contained 44 items grouped into 9 domains. Discussion To the best of our knowledge, this is the first multi-centre research project that aims to develop a specific health-related quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency. A preliminary version of the specific HAE-QoL questionnaire was obtained. The qualitative analysis of interviews together with the expert and patient rating phase helped to ensure content validity. A pilot study will be performed to assess the psychometric properties of the questionnaire and to decide on the final version. PMID:22817696

  5. Usefulness of plasma HGF level for monitoring acquired resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer.

    PubMed

    Umeguchi, Hitomi; Sueoka-Aragane, Naoko; Kobayashi, Naomi; Nakamura, Tomomi; Sato, Akemi; Takeda, Yuji; Hayashi, Shinichiro; Sueoka, Eisaburo; Kimura, Shinya

    2015-01-01

    Monitoring of molecular markers is indispensable for deciding subsequent treatment after acquired resistance to molecular-targeted therapy. According to results using re-biopsy, EGFR T790M mutation and overexpression of hepatocyte growth factor (HGF) are major mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The aim of the present study was to assess whether quantification of HGF using peripheral blood in addition to detection of T790M with plasma DNA is useful for monitoring as an alternative to invasive re-biopsy. HGF levels in plasma were determined using ELISA and T790M mutation was detected using mutation-biased PCR and quenched probe system (MBP-QP). The median level of HGF in plasma at baseline was 140 pg/ml and was significantly higher in the advanced stage of cancer and in smokers and predicted poor survival as determined using 315 plasma samples from 225 lung cancer patients. T790M was detected with plasma DNA in 9 of 16 patients who acquired resistance to EGFR-TKIs and a greater than 1.5-fold elevation compared with pretreatment HGF levels was observed in 6 patients after acquired resistance. Eleven of 16 patients (69%) showed either HGF elevation or T790M in plasma samples, with both outcomes observed in 25% of patients; this is consistent with results based on re-biopsy reported from other laboratories. Considering these results, assessing HGF and T790M using peripheral blood could be useful for monitoring mechanisms of acquired resistance to EGFR-TKIs.

  6. A platinum-based hybrid drug design approach to circumvent acquired resistance to molecular targeted tyrosine kinase inhibitors

    NASA Astrophysics Data System (ADS)

    Wei, Yuming; Poon, Daniel C.; Fei, Rong; Lam, Amy S. M.; Au-Yeung, Steve C. F.; To, Kenneth K. W.

    2016-05-01

    Three molecular targeted tyrosine kinase inhibitors (TKI) were conjugated to classical platinum-based drugs with an aim to circumvent TKI resistance, predominately mediated by the emergence of secondary mutations on oncogenic kinases. The hybrids were found to maintain specificity towards the same oncogenic kinases as the original TKI. Importantly, they are remarkably less affected by TKI resistance, presumably due to their unique structure and the observed dual mechanism of anticancer activity (kinase inhibition and DNA damage). The study is also the first to report the application of a hybrid drug approach to switch TKIs from being efflux transporter substrates into non-substrates. TKIs cannot penetrate into the brain for treating metastases because of efflux transporters at the blood brain barrier. The hybrids were found to escape drug efflux and they accumulate more than the original TKI in the brain in BALB/c mice. Further development of the hybrid compounds is warranted.

  7. A platinum-based hybrid drug design approach to circumvent acquired resistance to molecular targeted tyrosine kinase inhibitors

    PubMed Central

    Wei, Yuming; Poon, Daniel C.; Fei, Rong; Lam, Amy S. M.; Au-Yeung, Steve C. F.; To, Kenneth K. W.

    2016-01-01

    Three molecular targeted tyrosine kinase inhibitors (TKI) were conjugated to classical platinum-based drugs with an aim to circumvent TKI resistance, predominately mediated by the emergence of secondary mutations on oncogenic kinases. The hybrids were found to maintain specificity towards the same oncogenic kinases as the original TKI. Importantly, they are remarkably less affected by TKI resistance, presumably due to their unique structure and the observed dual mechanism of anticancer activity (kinase inhibition and DNA damage). The study is also the first to report the application of a hybrid drug approach to switch TKIs from being efflux transporter substrates into non-substrates. TKIs cannot penetrate into the brain for treating metastases because of efflux transporters at the blood brain barrier. The hybrids were found to escape drug efflux and they accumulate more than the original TKI in the brain in BALB/c mice. Further development of the hybrid compounds is warranted. PMID:27150583

  8. Acquired BRAF inhibitor resistance: a multicenter meta-analysis of the spectrum and frequencies, clinical behavior, and phenotypic associations of resistance mechanisms

    PubMed Central

    Johnson, Douglas B.; Menzies, Alexander M.; Zimmer, Lisa; Eroglu, Zeynep; Ye, Fei; Zhao, Shilin; Rizos, Helen; Sucker, Antje; Scolyer, Richard A.; Gutzmer, Ralf; Gogas, Helen; Kefford, Richard F.; Thompson, John F.; Becker, Jürgen C.; Berking, Carola; Egberts, Friederike; Loquai, Carmen; Goldinger, Simone M.; Pupo, Gulietta M.; Hugo, Willy; Kong, Xiangju; Garraway, Levi A.; Sosman, Jeffrey A.; Ribas, Antoni; Lo, Roger S.; Long, Georgina V.; Schadendorf, Dirk

    2015-01-01

    Background Acquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance. Methods We compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole exome sequencing and/or PCR-based genetic testing. Results Among 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAFV600E/K amplifications (13%), MEK1/2 mutations (7%), and non-MAPK pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with >1 progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p=0.045) and intracranial metastases (p=0.036), and MEK1/2 mutations correlated with hepatic progression (p=0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi resistance mechanisms. Conclusions This is the first study to systematically characterize the clinical implications of particular acquired BRAFi resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement. PMID:26608120

  9. Discovery of methyl 4'-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1'-biphenyl]-3-carboxylate, an improved small-molecule inhibitor of c-Myc-max dimerization.

    PubMed

    Chauhan, Jay; Wang, Huabo; Yap, Jeremy L; Sabato, Philip E; Hu, Angela; Prochownik, Edward V; Fletcher, Steven

    2014-10-01

    c-Myc is a basic helix-loop-helix-leucine zipper (bHLH-ZIP) transcription factor that is responsible for the transcription of a wide range of target genes involved in many cancer-related cellular processes. Over-expression of c-Myc has been observed in, and directly contributes to, a variety of human cancers including those of the hematopoietic system, lung, prostate and colon. To become transcriptionally active, c-Myc must first dimerize with Myc-associated factor X (Max) via its own bHLH-ZIP domain. A proven strategy towards the inhibition of c-Myc oncogenic activity is to interfere with the structural integrity of the c-Myc-Max heterodimer. The small molecule 10074-G5 is an inhibitor of c-Myc-Max dimerization (IC50 =146 μM) that operates by binding and stabilizing c-Myc in its monomeric form. We have identified a congener of 10074-G5, termed 3jc48-3 (methyl 4'-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1'-biphenyl]-3-carboxylate), that is about five times as potent (IC50 =34 μM) at inhibiting c-Myc-Max dimerization as the parent compound. 3jc48-3 exhibited an approximate twofold selectivity for c-Myc-Max heterodimers over Max-Max homodimers, suggesting that its mode of action is through binding c-Myc. 3jc48-3 inhibited the proliferation of c-Myc-over-expressing HL60 and Daudi cells with single-digit micromolar IC50 values by causing growth arrest at the G0 /G1 phase. Co-immunoprecipitation studies indicated that 3jc48-3 inhibits c-Myc-Max dimerization in cells, which was further substantiated by the specific silencing of a c-Myc-driven luciferase reporter gene. Finally, 3jc48-3's intracellular half-life was >17 h. Collectively, these data demonstrate 3jc48-3 to be one of the most potent, cellularly active and stable c-Myc inhibitors reported to date.

  10. Gallic acid inhibition of Src-Stat3 signaling overcomes acquired resistance to EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer

    PubMed Central

    Phan, Ai N.H.; Hua, Tuyen N.M.; Kim, Min-Kyu; Vo, Vu T.A.; Choi, Jong-Whan; Kim, Hyun-Won; Rho, Jin Kyung; Kim, Ki Woo; Jeong, Yangsik

    2016-01-01

    Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have clinically benefited to lung cancer patients harboring a subset of activating EGFR mutations. However, even with the remarkable therapeutic response at the initial TKI treatment, most lung cancer patients eventually have relapsed aggressive tumors due to acquired resistance to the TKIs. Here, we report that 3, 4, 5-trihydroxybenzoic acid or gallic acid (GA), a natural polyphenolic compound, shows anti-tumorigenic effects in TKI-resistant non-small cell lung cancer (NSCLC). Using both in vitro growth assay and in vivo xenograft animal model, we demonstrated tumor suppressive effect of GA was more selective for the TKI-resistant cancer compared to the TKI-sensitive one. Mechanistically, GA treatment inhibited Src-Stat3-mediated signaling and decreased the expression of Stat3-regulated tumor promoting genes, subsequently inducing apoptosis and cell cycle arrest in the TKI-resistant lung cancer but not in the TKI-sensitive one. Consistent with the in vitro results, in vivo xenograft experiments showed the TKI-resistant tumor-selective growth inhibition and suppression of Src-Stat3-dependent signaling in the GA-treated tumors isolated from the xenograft model. This finding identified an importance of Src-Stat3 signaling cascade in GA-mediated tumor-suppression activity and, more importantly, provides a novel therapeutic insight of GA for advanced TKI-resistant lung cancer. PMID:27419630

  11. Significant Differences in the Development of Acquired Resistance to the MDM2 Inhibitor SAR405838 between In Vitro and In Vivo Drug Treatment

    PubMed Central

    Hoffman-Luca, C. Gianna; Yang, Chao-Yie; Lu, Jianfeng; Ziazadeh, Daniel; McEachern, Donna; Debussche, Laurent; Wang, Shaomeng

    2015-01-01

    SAR405838 is a potent and specific MDM2 inhibitor currently being evaluated in Phase I clinical trials for the treatment of human cancer. Using the SJSA-1 osteosarcoma cell line which harbors an amplified MDM2 gene and wild-type p53, we have investigated the acquired resistance mechanisms both in vitro and in vivo to SAR405838. Treatment of SJSA-1 cells with SAR405838 in vitro leads to dose-dependent cell growth inhibition, cell cycle arrest and robust apoptosis. However, prolonged treatment of SJSA-1 cells in vitro with SAR405838 results in profound acquired resistance to the drug. Analysis of in vitro-derived resistant cell lines showed that p53 is mutated in the DNA binding domain and can no longer be activated by SAR405838. Treatment of the parental SJSA-1 xenograft tumors with SAR405838 in mice yields rapid tumor regression but the tumors eventually regrow. Culturing the regrown tumors established a number of sublines, which showed only modest (3–5 times) loss of sensitivity to SAR405838 in vitro. Sequencing of the p53 showed that it retains its wild-type status in these in vivo sublines, with the exception of one subline, which harbors a single heterozygous C176F p53 mutation. Using xenograft models of two in vivo derived sublines, which has either wild-type p53 or p53 containing a single heterozygous C176F mutation, we showed that while SAR405838 effectively achieves partial tumor regression in these models, it no longer induces complete tumor regression and tumors resume growth once the treatment is stopped. Harvesting and culturing tumors obtained from a prolonged treatment with SAR405838 in mice established additional in vivo sublines, which all contain a single heterozygous C176F mutation with no additional p53 mutation detected. Interestingly, SAR405838 can still effectively activate p53 in all sublines containing a single heterozygous C176F mutation, with a moderately reduced potency as compared to that in the parental cell line. Consistently, SAR

  12. Acquired Hypothyroidism as a Predictive Marker of Outcome in Patients With Metastatic Renal Cell Carcinoma Treated With Tyrosine Kinase Inhibitors: A Literature-Based Meta-Analysis.

    PubMed

    Nearchou, Andreas; Valachis, Antonis; Lind, Pehr; Akre, Olof; Sandström, Per

    2015-08-01

    Hypothyroidism in patients with metastatic renal cell carcinoma (mRCC) during treatment with the tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib is a well-established side effect. Furthermore, the potential role of hypothyroidism as predictive marker of outcome has been studied but with conflicting results. The aim of the present meta-analysis was to assess the predictive value of hypothyroidism for progression-free (PFS) and overall survival (OS) in patients with mRCC during TKI therapy. We searched PubMed and the electronic abstract databases of the major international congresses' proceedings to identify all eligible studies that reported a correlation between the development of hypothyroidism during TKI treatment and outcome in patients with mRCC. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS and OS were obtained from these publications and pooled in a meta-analysis. Eleven studies with a total of 500 patients fulfilled the inclusion criteria. We found no statistical significant difference in PFS between patients who developed hypothyroidism during sunitinib therapy and unaffected patients (HR, 0.82; 95% CI, 0.59-1.13; P = .22; 6 studies; 250 patients). The HR for OS was 0.52 (95% CI, 0.31-0.87; P = .01) for patients who developed hypothyroidism during sunitinib therapy compared with patients who did not (4 studies; 147 patients). The development of hypothyroidism during TKI therapy is not clearly shown to be predictive of efficacy in patients with mRCC. The observed advantage in OS for the patients with acquired hypothyroidism should be interpreted with caution.

  13. Chapter 22: Hereditary and acquired angioedema.

    PubMed

    Georgy, Mary S; Pongracic, Jacqueline A

    2012-01-01

    Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema (AAE) is caused by either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and AAE can be life-threatening. The screening test for both conditions is complement component C4, which is low to absent at times of angioedema or during quiescent periods. A useful test to differentiate HAE from AAE is C1q protein, which is normal in HAE and low in AAE. There are three types of HAE: type 1 HAE is most common, occurring in ∼85% of patients and characterized by decreased production of C1-INH, resulting in reduced functional activity to 5-30% of normal. In type 2, which occurs in 15% of cases, C1-INH is detectable in normal or elevated quantities but is dysfunctional. Finally, type 3, which is rare and almost exclusively occurs in women, is estrogen dependent and associated with normal CI-INH and C4 levels. One-third of these patients have a gain-of-function mutation in clotting factor XII leading to kallikrein-driven bradykinin production. Although the anabolic steroid, danazol, is useful in increasing the concentration of C4 and reducing the episodes of angioedema in HAE and AAE, it has expected adverse effects. Fortunately, disease-specific therapies are available and include C1-INH enzyme for i.v. infusion either acutely or empirically, ecallantide, an inhibitor of kallikrein, and icatibant, a bradykinin B2-receptor antagonist, both approved for acute angioedema and administered, subcutaneously.

  14. Influence of factor VIII level and its inhibitor titer on the therapeutic response to corticosteroids alone in the management of acquired hemophilia

    PubMed Central

    Vautier, Mathieu; de Boysson, Hubert; Creveuil, Christian; Repesse, Yohan; Borel-Derlon, Annie; Troussard, Xavier; Damaj, Gandhi L.; Bienvenu, Boris; Gautier, Philippe; Aouba, Achille

    2016-01-01

    Abstract The treatment of acquired hemophilia (AH) involves discussing whether corticosteroids should be administered alone or combined with immunosuppressant drugs, which increase the risk of infection especially in elderly patients and/or those with autoimmunity or neoplastic diseases, who represent the target population of the disease. Prognostic factors highlighting adequate responses to corticosteroids alone must be identified for satisfactory clinical response and lower infectious risk. We aimed to evaluating the efficacy of corticosteroids alone in the management of AH depending on factor VIII (FVIII, ≥ or <1 IU/dL) levels and/or inhibitor (INH, ≤ or >20 Bethesda units per milliliter [BU/mL]) titer. We conducted a retrospective single-center study including 24 patients treated for AH with corticosteroids alone. Time to achieve partial remission (PR: absence of hemorrhage and FVIII levels >50 IU/dL) was significantly shorter in the FVIII ≥ 1 IU/dL group than in the FVIII < 1 IU/dL group (20 [10–55] vs 39 [20–207] days, P = 0.044) and in the INH ≤ 20 BU/mL and FVIII ≥ 1 IU/dL group than in the FVIII < 1 IU/dL and/or INH > 20 BU/mL group (15 [11–35] vs 41 [20–207] days, P = 0.003). In both subgroups, time to achieve complete remission (CR: negative INH and corticosteroids below 10 mg/d) was also significantly shorter than that observed in the opposite subgroups. INH titer, considered alone, did not affect the length of time to onset of PR or CR. CR and PR rates did not differ significantly depending on these variables. Our study suggests that in AH, patients with FVIII levels ≥1 IU/dL considered alone or combined with INH titer ≤20 BU/mL could be treated by corticosteroids alone, given that this subgroup of patients displayed faster therapeutic responses to this strategy. PMID:27902587

  15. Clinical presentation, pathophysiology, diagnosis, and treatment of acquired and hereditary angioedema: Exploring state-of-the-art therapies in RI.

    PubMed

    Guo, Canting; Settipane, Russell A

    2016-06-01

    Hereditary and acquired angioedema are potentially life-threatening diseases characterized by spontaneous episodes of subcutaneous and submucosal swelling of face, lips, oral cavity, larynx, and GI tract. Hereditary angioedema (HAE) usually presents within the first and second decades of life, whereas acquired angioedema presents in adults after 40 years of age. These clinical symptoms together with reduced C1 inhibitor levels and/or activity can usually confirm the diagnosis. In recent years, multiple novel therapies for treating hereditary angioedema have emerged including C1 inhibitor concentrates, ecallantide/kallikrein inhibitor, and icatibant/bradykinin receptor antagonist. This article reviews the clinical presentation, diagnosis, treatment, and prophylaxis of HAE. Lastly, this article takes into consideration that, in reality, acute care treatment can often be limited by each hospital's formulary, included is a review of HAE treatments available at the nine major hospitals in Rhode Island. [Full article available at http://rimed.org/rimedicaljournal-2016-06.asp, free with no login].

  16. BI-97C1, an Optically Pure Apogossypol Derivative as Pan-Active Inhibitor of Anti-apoptotic B-cell lymphoma/leukemia-2 (Bcl-2) Family Proteins

    PubMed Central

    Wei, Jun; Stebbins, John L.; Kitada, Shinichi; Dash, Rupesh; Placzek, William; Rega, Michele F.; Wu, Bainan; Cellitti, Jason; Zhai, Dayong; Yang, Li; Dahl, Russell; Fisher, Paul B.; Reed, John C.; Pellecchia, Maurizio

    2010-01-01

    In our continued attempts to identify novel and effective pan-Bcl-2 antagonists, we have recently reported a series of compound 2 (Apogossypol) derivatives, resulting in the chiral compound 4 (8r). We report here on synthesis and evaluation on its optically pure individual isomers. Compound 11 (BI-97C1), the most potent diastereoisomer of compound 4, inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2, Mcl-1 and Bfl-1 with IC50 values of 0.31, 0.32, 0.20 and 0.62 μM, respectively. The compound also potently inhibits cell growth of human prostate cancer, lung cancer and lymphoma cell lines with EC50 values of 0.13, 0.56 and 0.049 μM, respectively and shows little cytotoxicity against bax−/−bak−/− cells. Compound 11 displays in vivo efficacy in transgenic mice models and also demonstrated superior single-agent antitumor efficacy in a prostate cancer mouse xenograft model. Therefore, compound 11 represents a potential drug lead for the development of novel apoptosis-based therapies against cancer. PMID:20443627

  17. Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors

    PubMed Central

    Vandamme, Timon; Beyens, Matthias; de Beeck, Ken Op; Dogan, Fadime; van Koetsveld, Peter M; Pauwels, Patrick; Mortier, Geert; Vangestel, Christel; de Herder, Wouter; Van Camp, Guy; Peeters, Marc; Hofland, Leo J

    2016-01-01

    Background: The mTOR-inhibitor everolimus improves progression-free survival in advanced pancreatic neuroendocrine tumours (PNETs). However, adaptive resistance to mTOR inhibition is described. Methods: QGP-1 and BON-1, two human PNET cell lines, were cultured with increasing concentrations of everolimus up to 22 weeks to reach a dose of 1 μM everolimus, respectively, 1000-fold and 250-fold initial IC50. Using total DNA content as a measure of cell number, growth inhibitory dose–response curves of everolimus were determined at the end of resistance induction and over time after everolimus withdrawal. Response to ATP-competitive mTOR inhibitors OSI-027 and AZD2014, and PI3K-mTOR inhibitor NVP-BEZ235 was studied. Gene expression of 10 PI3K-Akt-mTOR pathway-related genes was evaluated using quantitative real-time PCR (RT–qPCR). Results: Long-term everolimus-treated BON-1/R and QGP-1/R showed a significant reduction in everolimus sensitivity. During a drug holiday, gradual return of everolimus sensitivity in BON-1/R and QGP-1/R led to complete reversal of resistance after 10–12 weeks. Treatment with AZD2014, OSI-027 and NVP-BEZ235 had an inhibitory effect on cell proliferation in both sensitive and resistant cell lines. Gene expression in BON-1/R revealed downregulation of MTOR, RICTOR, RAPTOR, AKT and HIF1A, whereas 4EBP1 was upregulated. In QGP-1/R, a downregulation of HIF1A and an upregulation of ERK2 were observed. Conclusions: Long-term everolimus resistance was induced in two human PNET cell lines. Novel PI3K-AKT-mTOR pathway-targeting drugs can overcome everolimus resistance. Differential gene expression profiles suggest different mechanisms of everolimus resistance in BON-1 and QGP-1. PMID:26978006

  18. Acquired hyperpigmentations*

    PubMed Central

    Cestari, Tania Ferreira; Dantas, Lia Pinheiro; Boza, Juliana Catucci

    2014-01-01

    Cutaneous hyperpigmentations are frequent complaints, motivating around 8.5% of all dermatological consultations in our country. They can be congenital, with different patterns of inheritance, or acquired in consequence of skin problems, systemic diseases or secondary to environmental factors. The vast majority of them are linked to alterations on the pigment melanin, induced by different mechanisms. This review will focus on the major acquired hyperpigmentations associated with increased melanin, reviewing their mechanisms of action and possible preventive measures. Particularly prominent aspects of diagnosis and therapy will be emphasized, with focus on melasma, post-inflammatory hyperpigmentation, periorbital pigmentation, dermatosis papulosa nigra, phytophotodermatoses, flagellate dermatosis, erythema dyschromicum perstans, cervical poikiloderma (Poikiloderma of Civatte), acanthosis nigricans, cutaneous amyloidosis and reticulated confluent dermatitis PMID:24626644

  19. A preclinical evaluation of the PI3K alpha/delta dominant inhibitor BAY 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2-targeted therapies trastuzumab and lapatinib.

    PubMed

    Elster, N; Cremona, M; Morgan, C; Toomey, S; Carr, A; O'Grady, A; Hennessy, B T; Eustace, A J

    2015-01-01

    The PI3K pathway is a key mechanism of trastuzumab resistance, but early attempts to indirectly target this pathway with mTOR inhibitors have had limited success. We present the results of a preclinical study of the selective alpha/delta isoform dominant PI3K inhibitor BAY 80-6946 tested alone and in combination with HER2-targeted therapies in HER2-positive cell lines, including models with acquired resistance to trastuzumab and/or lapatinib. A panel of HER2-positive breast cancer cells were profiled for their mutational status using Sequenom MassARRAY, PTEN status by Western blot, and anti-proliferative response to BAY 80-6946 alone and in combination with the HER2-targeted therapies trastuzumab, lapatinib and afatinib. Reverse phase protein array was used to determine the effect of BAY 80-6946 on expression and phosphorylation of 68 proteins including members of the PI3K and MAPK pathways. The Boyden chamber method was used to determine if BAY 80-6946 affected cellular invasion and migration. BAY 80-6946 has anti-proliferative and anti-invasive effects when used alone in our panel of cell lines (IC50s 3.9-29.4 nM). BAY 80-6946 inhibited PI3K signalling and was effective in cells regardless of their PI3K, P53 or PTEN status. The combination of HER2-targeted therapies and BAY 80-6946 inhibited growth more effectively than either therapy used alone (with clear synergism in many cases), and can restore sensitivity to trastuzumab and lapatinib in cells with acquired resistance to either trastuzumab and/or lapatinib. The addition of BAY 80-6946 to HER2-targeted therapy could represent an improved treatment strategy for patients with refractory metastatic HER2-positive breast cancer, and should be considered for clinical trial evaluation.

  20. Comparing acquired angioedema with hereditary angioedema (types I/II): findings from the Icatibant Outcome Survey.

    PubMed

    Longhurst, H J; Zanichelli, A; Caballero, T; Bouillet, L; Aberer, W; Maurer, M; Fain, O; Fabien, V; Andresen, I

    2017-04-01

    Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1-INH-HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1-INH-AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1-INH-AAE and compare disease characteristics with those with C1-INH-HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6-month intervals during patient follow-up visits. In the icatibant-treated population, 16 patients with C1-INH-AAE had 287 attacks and 415 patients with C1-INH-HAE types I/II had 2245 attacks. Patients with C1-INH-AAE versus C1-INH-HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset [57·9 (51·33-64·53) versus 14·0 (12·70-15·26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1-INH-AAE versus C1-INH-HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1-INH-AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1-INH-HAE types I/II versus C1-INH-AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1-INH-AAE versus C1-INH-HAE types I/II, respectively.

  1. Comparing acquired angioedema with hereditary angioedema (types I/II): findings from the Icatibant Outcome Survey

    PubMed Central

    Zanichelli, A.; Caballero, T.; Bouillet, L.; Aberer, W.; Maurer, M.; Fain, O.; Fabien, V.; Andresen, I.

    2017-01-01

    Summary Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1‐INH‐HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1‐INH‐AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1‐INH‐AAE and compare disease characteristics with those with C1‐INH‐HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6‐month intervals during patient follow‐up visits. In the icatibant‐treated population, 16 patients with C1‐INH‐AAE had 287 attacks and 415 patients with C1‐INH‐HAE types I/II had 2245 attacks. Patients with C1‐INH‐AAE versus C1‐INH‐HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset [57·9 (51·33–64·53) versus 14·0 (12·70–15·26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1‐INH‐AAE versus C1‐INH‐HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1‐INH‐AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1‐INH‐HAE types I/II versus C1‐INH‐AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1‐INH‐AAE versus C1‐INH‐HAE types I/II, respectively. PMID:27936514

  2. Hereditary angioedema with normal C1-INH (HAE type III).

    PubMed

    Riedl, Marc A

    2013-01-01

    Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH), also known as HAE type III, is a familial condition only clinically recognized within the past three decades. Similar to HAE from C1-INH deficiency (HAE types I and II), affected individuals experience unpredictable angioedema episodes of the skin, gastrointestinal tract, and airway. Unique clinical features of HAE with normal C1-INH include the predominance of affected women, frequent exacerbation by estrogen, and a prominence of angioedema that involves the face and oropharynx. The underlying pathophysiology of HAE with normal C1-INH is poorly understood, but indirect evidence points to contact pathway dysregulation with bradykinin-mediated angioedema. Currently, evaluation is complicated by a lack of confirmatory laboratory testing such that clinical criteria must often be used to make the diagnosis of HAE with normal C1-INH. Factor XII mutations have been identified in only a minority of persons affected by HAE with normal C1-INH, limiting the utility of such analysis. To date, no controlled clinical studies have examined the efficacy of therapeutic agents for HAE with normal C1-INH, although published evidence supports frequent clinical benefit with medications shown effective in HAE due to C1-INH deficiency.

  3. Selective Serotonin Reuptake Inhibitor and Substance P Antagonist Enhancement of Natural Killer Cell Innate Immunity in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

    PubMed Central

    Evans, Dwight L.; Lynch, Kevin G.; Benton, Tami; Dubé, Benoit; Gettes, David R.; Tustin, Nancy B.; Lai, Jian Ping; Metzger, David; Douglas, Steven D.

    2010-01-01

    Background Natural killer (NK) cells play an important role in innate immunity and are involved in the host defense against human immunodeficiency virus (HIV) infection. This study examines the potential role of three underlying regulatory systems that have been under investigation in central nervous system research as well as immune and viral research: serotonin, neurokinin, and glucocorticoid systems. Methods Fifty-one HIV-seropositive subjects were recruited to achieve a representative sample of depressed and nondepressed women. The effects of a selective serotonin reuptake inhibitor (SSRI), a substance P (SP) antagonist, and a glucocorticoid antagonist on NK cell function were assessed in a series of ex vivo experiments of peripheral blood mononuclear cells from each HIV-seropositive subject. Results Natural killer cell cytolytic activity was significantly increased by the SSRI citalopram and by the substance P antagonist CP-96345 relative to control conditions; the glucocorticoid antagonist, RU486, showed no effect on NK cytotoxicity. Our results suggest that the effects of the three agents did not differ as a function of depression. Conclusions Our findings provide evidence that NK cell function in HIV infection may be enhanced by serotonin reuptake inhibition and by substance P antagonism. It remains to be determined if HIV-related impairment in not only NK cytolytic activity but also NK noncytolytic activity can be improved by an SSRI or an SP antagonist. Clinical studies are warranted to address these questions and the potential roles of serotonergic agents and SP antagonists in improving NK cell immunity, delaying HIV disease progression, and extending survival with HIV infection. PMID:17945197

  4. Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity.

    PubMed

    Colonna, Lucrezia; Parry, Graham C; Panicker, Sandip; Elkon, Keith B

    2016-02-01

    Complement activation contributes to inflammation in many diseases, yet it also supports physiologic apoptotic cells (AC) clearance and its downstream immunosuppressive effects. The roles of individual complement components in AC phagocytosis have been difficult to dissect with artificially depleted sera. Using human in vitro systems and the novel antibody complement C1s inhibitor TNT003, we uncoupled the role of the enzymatic activation of the classical pathway from the opsonizing role of C1q in mediating a) the phagocytosis of early and late AC, and b) the immunosuppressive capacity of early AC. We found that C1s inhibition had a small impact on the physiologic clearance of early AC, leaving their immunosuppressive properties entirely unaffected, while mainly inhibiting the phagocytosis of late apoptotic/secondary necrotic cells. Our data suggest that C1s inhibition may represent a valuable therapeutic strategy to control classical pathway activation without causing significant AC accumulation in diseases without defects in AC phagocytosis.

  5. Detection of the T790M mutation of EGFR in plasma of advanced non–small cell lung cancer patients with acquired resistance to tyrosine kinase inhibitors (West Japan oncology group 8014LTR study)

    PubMed Central

    Azuma, Koichi; Hida, Toyoaki; Hirabayashi, Masataka; Oguri, Tetsuya; Tanaka, Hiroshi; Ebi, Noriyuki; Sawa, Toshiyuki; Bessho, Akihiro; Tachihara, Motoko; Akamatsu, Hiroaki; Bandoh, Shuji; Himeji, Daisuke; Ohira, Tatsuo; Shimokawa, Mototsugu; Nakanishi, Yoichi; Nakagawa, Kazuhiko; Nishio, Kazuto

    2016-01-01

    Introduction Next-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to overcome resistance to earlier generations of such drugs mediated by a secondary T790M mutation of EGFR, but the performance of a second tumor biopsy to assess T790M mutation status can be problematic. Methods We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation–positive non–small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. Results A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites fluid from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M. Conclusions Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment. PMID:27542267

  6. Curtiss XSO3C-1 Seagull

    NASA Technical Reports Server (NTRS)

    1940-01-01

    Curtiss XSO3C-1 Seagull: Although drag reduction was very important to radial engined aircraft, it was no less important to aircraft such as this inline Ranger powered Curtiss XSO3C-1 Seagull. Here the Seagull is shown in the 30 x 60 Full Scale Tunnel in October of 1940. The XSO3C-1 was also undergoing study to improve engine cooling. Published in Aircraft; FST; Curtiss XSO3C-1 Seagull; Full Scale Tunnel; Nicklas

  7. Cell Surface Expression and Function of the Macromolecular C1 Complex on the Surface of Human Monocytes

    PubMed Central

    Hosszu, Kinga K.; Valentino, Alisa; Ji, Yan; Matkovic, Mara; Pednekar, Lina; Rehage, Nina; Tumma, Nithin; Peerschke, Ellinor I. B.; Ghebrehiwet, Berhane

    2011-01-01

    The synthesis of the subunits of the C1 complex (C1q, C1s, C1r), and its regulator C1 inhibitor (C1-Inh) by human monocytes has been previously established. However, surface expression of these molecules by monocytes has not been shown. Using flow cytometry and antigen-capture enzyme-linked immunosorbent assay, we show here for the first time that, in addition to C1q, peripheral blood monocytes, and the monocyte-derived U937 cells express C1s and C1r, as well as Factor B and C1-Inh on their surface. C1s and C1r immunoprecipitated with C1q, suggesting that at least some of the C1q on these cells is part of the C1 complex. Furthermore, the C1 complex on U937 cells was able to trigger complement activation via the classical pathway. The presence of C1-Inh may ensure that an unwarranted autoactivation of the C1 complex does not take place. Since C1-Inh closely monitors the activation of the C1 complex in a sterile or infectious inflammatory environment, further elucidation of the role of C1 complex is crucial to dissect its function in monocyte, dendritic cell, and T cell activities, and its implications in host defense and tolerance. PMID:22566921

  8. 29 CFR 2575.502c-1 - Adjusted civil penalty under section 502(c)(1).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Adjusted civil penalty under section 502(c)(1). 2575.502c-1 Section 2575.502c-1 Labor Regulations Relating to Labor (Continued) EMPLOYEE BENEFITS SECURITY... ERISA Title I § 2575.502c-1 Adjusted civil penalty under section 502(c)(1). In accordance with...

  9. Acquired Cystic Kidney Disease

    MedlinePlus

    ... They Work Kidney Disease A-Z Acquired Cystic Kidney Disease What is acquired cystic kidney disease? Acquired cystic kidney disease happens when a ... cysts. What are the differences between acquired cystic kidney disease and polycystic kidney disease? Acquired cystic kidney ...

  10. Update on laboratory tests for the diagnosis and differentiation of hereditary angioedema and acquired angioedema.

    PubMed

    Frazer-Abel, Ashley; Giclas, Patricia C

    2011-01-01

    The importance of laboratory testing in the diagnosis of hereditary angioedema (HAE) has increased with the advent of new treatment options in recent years. It has been 50 years since HAE was linked to a decrease of C1INH (the inhibitor of complement enzyme, C1 esterase), a link that provided for the first laboratory test available for this disorder. HAE is subdivided into types that can be differentiated only by laboratory testing. The Type I form is characterized by low levels and function of C1INH in the circulation. The Type II form is characterized by normal levels of C1INH, but low function. Sample collection and handling is critical for the functional assays. The serum samples for the functional analysis must be collected, separated, and frozen at less than -60°C within 2 hours of the blood draw. Additionally some suspected Type II patients may benefit from looking closely at what method is used for the functional testing. The acquired forms of angioedema (AAE) can benefit from the same clinical testing, because most are ultimately due to decreased C1INH. Measurement of C1q levels and testing for anti-C1INH autoantibodies can help differentiate AAE from HAE. Diagnostic testing for the third hereditary form, alternately called estrogen-dependent HAE, HAE with Normal C1INH or HAE Type III, still presents challenges, and definitive testing may have to wait until there is a more complete understanding of this mixed group of patients. The next steps will include genetic analysis of C1INH and other proteins involved in HAE.

  11. A UK national audit of hereditary and acquired angioedema.

    PubMed

    Jolles, S; Williams, P; Carne, E; Mian, H; Huissoon, A; Wong, G; Hackett, S; Lortan, J; Platts, V; Longhurst, H; Grigoriadou, S; Dempster, J; Deacock, S; Khan, S; Darroch, J; Simon, C; Thomas, M; Pavaladurai, V; Alachkar, H; Herwadkar, A; Abinun, M; Arkwright, P; Tarzi, M; Helbert, M; Bangs, C; Pastacaldi, C; Phillips, C; Bennett, H; El-Shanawany, T

    2014-01-01

    Hereditary angioedema (HAE) and acquired angioedema (AAE) are rare life-threatening conditions caused by deficiency of C1 inhibitor (C1INH). Both are characterized by recurrent unpredictable episodes of mucosal swelling involving three main areas: the skin, gastrointestinal tract and larynx. Swelling in the gastrointestinal tract results in abdominal pain and vomiting, while swelling in the larynx may be fatal. There are limited UK data on these patients to help improve practice and understand more clearly the burden of disease. An audit tool was designed, informed by the published UK consensus document and clinical practice, and sent to clinicians involved in the care of HAE patients through a number of national organizations. Data sets on 376 patients were received from 14 centres in England, Scotland and Wales. There were 55 deaths from HAE in 33 families, emphasizing the potentially lethal nature of this disease. These data also show that there is a significant diagnostic delay of on average 10 years for type I HAE, 18 years for type II HAE and 5 years for AAE. For HAE the average annual frequency of swellings per patient affecting the periphery was eight, abdomen 5 and airway 0·5, with wide individual variation. The impact on quality of life was rated as moderate or severe by 37% of adult patients. The audit has helped to define the burden of disease in the UK and has aided planning new treatments for UK patients.

  12. 29 CFR 2575.502c-1 - Adjusted civil penalty under section 502(c)(1).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... ACT OF 1974 ADJUSTMENT OF CIVIL PENALTIES UNDER ERISA TITLE I Adjustment of Civil Penalties Under ERISA Title I § 2575.502c-1 Adjusted civil penalty under section 502(c)(1). In accordance with the... section 502(c)(1) of the Employee Retirement Income Security Act of 1974, as amended (ERISA), is...

  13. 29 CFR 2575.502c-1 - Adjusted civil penalty under section 502(c)(1).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... ACT OF 1974 ADJUSTMENT OF CIVIL PENALTIES UNDER ERISA TITLE I Adjustment of Civil Penalties Under ERISA Title I § 2575.502c-1 Adjusted civil penalty under section 502(c)(1). In accordance with the... section 502(c)(1) of the Employee Retirement Income Security Act of 1974, as amended (ERISA), is...

  14. 29 CFR 2575.502c-1 - Adjusted civil penalty under section 502(c)(1).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... ACT OF 1974 ADJUSTMENT OF CIVIL PENALTIES UNDER ERISA TITLE I Adjustment of Civil Penalties Under ERISA Title I § 2575.502c-1 Adjusted civil penalty under section 502(c)(1). In accordance with the... section 502(c)(1) of the Employee Retirement Income Security Act of 1974, as amended (ERISA), is...

  15. 29 CFR 2575.502c-1 - Adjusted civil penalty under section 502(c)(1).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... ACT OF 1974 ADJUSTMENT OF CIVIL PENALTIES UNDER ERISA TITLE I Adjustment of Civil Penalties Under ERISA Title I § 2575.502c-1 Adjusted civil penalty under section 502(c)(1). In accordance with the... section 502(c)(1) of the Employee Retirement Income Security Act of 1974, as amended (ERISA), is...

  16. SLE and C1q: A quantitative ELISA for determining C1q levels in serum

    PubMed Central

    Dillon, Skyler P.; D’Souza, Anil; Kurien, Biji T.; Scofield, R. Hal

    2010-01-01

    C1q is of interest in SLE research due to deficiencies in its activity being associated with the disease. Current published protocols for measuring C1q vary greatly in their results and ease of reproducibility. Due to this, average C1q concentrations have been reported between 56 and 276 µg/ml in non-SLE serum. We present an improved method for quantifying C1q concentrations that employs a sandwich ELISA. This method has improved precision, cost efficiency, up-scaling, reproducibility, and uses significantly lesser volumes of serum sample when compared to RID and other methods for quantifying C1q. We report an average concentration of 113±40 µg/ml for C1q in non-SLE serum. The assay designed here will be useful in the high-throughput measurement of serum C1q in SLE cases. PMID:19370710

  17. A correction to the research article titled: "Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells" by A. S. Little, K. Balmanno, M. J. Sale, S. Newman, J. R. Dry, M. Hampson, P. A. W. Edwards, P. D. Smith, S. J. Cook.

    PubMed

    Little, Annette S; Balmanno, Kathryn; Sale, Matthew J; Newman, Scott; Dry, Jonathan R; Hampson, Mark; Edwards, Paul A W; Smith, Paul D; Cook, Simon J

    2011-01-01

    The acquisition of resistance to protein kinase inhibitors is a growing problem in cancer treatment. We modeled acquired resistance to the MEK1/2 (mitogen-activated or extracellular signal–regulated protein kinase kinases 1 and 2) inhibitor selumetinib (AZD6244) in colorectal cancer cell lines harboring mutations in BRAF (COLO205 and HT29 lines) or KRAS (HCT116 and LoVo lines). AZD6244-resistant derivatives were refractory to AZD6244-induced cell cycle arrest and death and exhibited a marked increase in ERK1/2 (extracellular signal–regulated kinases 1 and 2) pathway signaling and cyclin D1 abundance when assessed in the absence of inhibitor. Genomic sequencing revealed no acquired mutations in MEK1 or MEK2, the primary target of AZD6244. Rather, resistant lines showed a marked up-regulation of their respective driving oncogenes, BRAF600E or KRAS13D, due to intrachromosomal amplification. Inhibition of BRAF reversed resistance to AZD6244 in COLO205 cells, which suggested that combined inhibition of MEK1/2 and BRAF may reduce the likelihood of acquired resistance in tumors with BRAF600E. Knockdown of KRAS reversed AZD6244 resistance in HCT116 cells as well as reduced the activation of ERK1/2 and protein kinase B; however, the combined inhibition of ERK1/2 and phosphatidylinositol 3-kinase signaling had little effect on AZD6244 resistance, suggesting that additional KRAS effector pathways contribute to this process. Microarray analysis identified increased expression of an 18-gene signature previously identified as reflecting MEK1/2 pathway output in resistant cells. Thus, amplification of the driving oncogene (BRAF600E or KRAS13D) can drive acquired resistance to MEK1/2 inhibitors by increasing signaling through the ERK1/2 pathway. However, up-regulation of KRAS13D leads to activation of multiple KRAS effector pathways, underlining the therapeutic challenge posed by KRAS mutations. These results may have implications for the use of combination therapies.

  18. MECHANISMS OF ACTIVATION OF C'1 ESTERASE IN HEREDITARY ANGIONEUROTIC EDEMA PLASMA IN VITRO

    PubMed Central

    Donaldson, Virginia H.

    1968-01-01

    The generation of C'1 esterase activity in siliconed plasma obtained from individuals with hereditary angioneurotic edema in remission tends to occur spontaneously, but can be hastened during its incubation with preparations of activated Hageman factor. This effect of activated Hageman factor could not be shown during its incubation with normal siliconed plasma, nor could consumption of normal serum inhibition of C'1 esterase be clearly shown. Soy bean trypsin inhibitor and heparin could impair this enhanced generation of C'1 esterase but neither inhibits the esterolytic function of C'1 esterase once formed. Trasylol was less effective in blocking this effect of activated Hageman factor. While the mechanism of the effect of activated Hageman factor upon C'1 activation remains obscure, it is apparent that some intermediate steps, possibly involving a kinin-forming system of plasma, may play a role. PMID:5299945

  19. Acquired Idiopathic Generalized Anhidrosis.

    PubMed

    Gangadharan, Geethu; Criton, Sebastian; Surendran, Divya

    2015-01-01

    Acquired idiopathic generalized anhidrosis is a rare condition, where the exact pathomechanism is unknown. We report a case of acquired idiopathic generalized anhidrosis in a patient who later developed lichen planus. Here an autoimmune-mediated destruction of sweat glands may be the probable pathomechanism.

  20. LABORATORY-ACQUIRED MYCOSES

    DTIC Science & Technology

    laboratory- acquired mycoses . Insofar as possible, the etiological fungus, type of laboratory, classification of personnel, type of work conducted, and other...pertinent data have been listed in this study. More than 288 laboratory- acquired mycoses are described here, including 108 cases of

  1. Combined traumatic occiput-C1 and C1-C2 dissociation: 2 case reports.

    PubMed

    Gould, Stephen; Hishmeh, Shuriz; McKinney, Bart; Stephen, Mark

    2010-08-01

    Occiput-C1 and C1-C2 dissociations and dislocations have been well documented in the literature. However, after thorough review of the literature, we found very little in the literature regarding combined occiput-C1 and C1-C2 dissociations in adults who survived. We present 2 case reports describing the clinical presentation, initial management, operative treatment, and postoperative course of 2 patients who sustained traumatic combined occiput-C1 and C1-C2 dissociations. After initial stabilization, both patients underwent open reduction and posterior occipital-cervical fusion with segmental fixation. At recent follow-up, both patients maintain good sagittal alignment without loss of reduction, and they have radiographic progression to fusion, minimal pain, and improved neurologic function. Combined occiput-C1 and C1-C2 dissociations are rare but serious injuries. Incomplete dissociations may not be evident on initial radiographs. Computed tomography or magnetic resonance imaging is recommended for formal diagnosis. A traumatic dural tear may be present. We recommend open reduction and posterior occipital-cervical fusion with segmental fixation for these patients.

  2. Cooperative Research in C1 Chemistry

    SciTech Connect

    Gerald P. Huffman

    2000-10-27

    C1 chemistry refers to the conversion of simple carbon-containing materials that contain one carbon atom per molecule into valuable products. The feedstocks for C1 chemistry include natural gas, carbon dioxide, carbon monoxide, methanol and synthesis gas (a mixture of carbon monoxide and hydrogen). Synthesis gas, or syngas, is produced primarily by the reaction of natural gas, which is principally methane, with steam. It can also be produced by gasification of coal, petroleum coke, or biomass. The availability of syngas from coal gasification is expected to increase significantly in the future because of increasing development of integrated gasification combined cycle (IGCC) power generation. Because of the abundance of remote natural gas, the advent of IGCC, and environmental advantages, C1 chemistry is expected to become a major area of interest for the transportation fuel and chemical industries in the relatively near future. The CFFLS will therefore perform a valuable national service by providing science and engineering graduates that are trained in this important area. Syngas is the source of most hydrogen. Approximately 10 trillion standard cubic feet (SCF) of hydrogen are manufactured annually in the world. Most of this hydrogen is currently used for the production of ammonia and in a variety of refining and chemical operations. However, utilization of hydrogen in fuel cells is expected to grow significantly in the next century. Syngas is also the feedstock for all methanol and Fischer-Tropsch plants. Currently, world consumption of methanol is over 25 million tons per year. There are many methanol plants in the U.S. and throughout the world. Methanol and oxygenated transportation fuel products play a significant role in the CFFLS C1 program. Currently, the only commercial Fischer-Tropsch plants are overseas, principally in South Africa (SASOL). However, new plants are being built or planned for a number of locations. One possible location for future F

  3. Acquired inflammatory demyelinating neuropathies.

    PubMed

    Ensrud, E R; Krivickas, L S

    2001-05-01

    The acquired demyelinating neuropathies can be divided into those with an acute onset and course and those with a more chronic course. The acute neuropathies present as Guillain-Barré syndrome and include acute inflammatory demyelinating polyradiculoneuropathy (AIDP), Miller Fisher syndrome, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and acute pandysautonomia. The chronic neuropathies are collectively known as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and include MADSAM (multifocal acquired demyelinating sensory and motor neuropathy, also know as Lewis-Sumner syndrome) and DADS (distal acquired demyelinating symmetric neuropathy) as variants. The clinical features, pathology, pathogenesis, diagnosis, treatment, rehabilitation, and prognosis of these neuropathies are discussed.

  4. 21 CFR 866.5250 - Complement C2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  5. 21 CFR 866.5250 - Complement C2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  6. 21 CFR 866.5250 - Complement C2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  7. 21 CFR 866.5250 - Complement C 2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  8. 21 CFR 866.5250 - Complement C 2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  9. Acquired color vision deficiency.

    PubMed

    Simunovic, Matthew P

    2016-01-01

    Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations.

  10. COOPERATIVE RESEARCH IN C1 CHEMISTRY

    SciTech Connect

    Gerald P. Huffman

    2001-04-30

    Faculty and students from five universities (Kentucky, West Virginia, Utah, Pittsburgh and Auburn) are collaborating on a basic research program to develop novel C1 chemistry processes for the production of clean, high quality transportation fuel. An Industrial Advisory Board (IAB) with members from Chevron, Eastman Chemical, Energy International, Teir Associates, and the Department of Defense has been formed to provide practical guidance to the program. The program has two principal objectives. (1) Develop technology for conversion of C1 source materials (natural gas, synthesis gas, carbon dioxide and monoxide, and methanol) into clean, high efficiency transportation fuel. (2) Develop novel processes for producing hydrogen from natural gas and other hydrocarbons. Some of the principal accomplishments of the program in its first two years are: (1) The addition of acetylenic compounds in Fischer-Tropsch synthesis is found to produce significant amounts of oxygenated products in FT diesel fuels. Such oxygenated products should decrease particulate matter (PM) emissions. (2) Nanoscale, binary, Fe-based catalysts supported on alumina have been shown to have significant activity for the decomposition of methane into pure hydrogen and potentially valuable multi-walled carbon nanotubes. (3) Catalytic synthesis processes have been developed for synthesis of diethyl carbonate, higher ethers, and higher alcohols from C1 source materials. Testing of the effect of adding these oxygenates to diesel fuel on PM emissions has begun using a well-equipped small diesel engine test facility. (4) Supercritical fluid (SCF) FT synthesis has been conducted under SCF hexane using both Fe and Co catalysts. There is a marked effect on the hydrocarbon product distribution, with a shift to higher carbon number products. These and other results are summarized.

  11. Theoretical Insights into C1 Surface Chemistry

    NASA Astrophysics Data System (ADS)

    Neurock, Matthew

    2008-03-01

    Reforming and partial oxidation of methane as well as other C1 fuels are important processes in the production of hydrogen and synthesis gas and will likely play important roles future energy strategies. Herein we use theory and simulation to examine the reactivity of methane, methanol and dimethyl ether with CO2, H2O, or O2 over supported transition metals. We systematically probe the elementary C-H bond activation as well as the oxidation pathways involved in both reforming as the oxidation of methane and other C1 intermediates over well defined transition metal surfaces, metal alloys and metal nanoparticles. The calculations demonstrate well-established trends in C-H bond activation as the result of changes in the metal, the activating molecule (methane, methanol, and DME) as well as the reaction conditions. The reaction conditions ultimately dictate the surface coverage of carbon and oxygen which have important consequences on the surface reactivity. The theoretical and simulation results are compared with well defined experiments carried out at Berkeley over supported particles.

  12. Expression of recombinant human complement C1q allows identification of the C1r/C1s-binding sites

    PubMed Central

    Bally, Isabelle; Ancelet, Sarah; Moriscot, Christine; Gonnet, Florence; Mantovani, Alberto; Daniel, Régis; Schoehn, Guy; Arlaud, Gérard J.; Thielens, Nicole M.

    2013-01-01

    Complement C1q is a hexameric molecule assembled from 18 polypeptide chains of three different types encoded by three genes. This versatile recognition protein senses a wide variety of immune and nonimmune ligands, including pathogens and altered self components, and triggers the classical complement pathway through activation of its associated proteases C1r and C1s. We report a method for expression of recombinant full-length human C1q involving stable transfection of HEK 293-F mammalian cells and fusion of an affinity tag to the C-terminal end of the C chain. The resulting recombinant (r) C1q molecule is similar to serum C1q as judged from biochemical and structural analyses and exhibits the characteristic shape of a bunch of flowers. Analysis of its interaction properties by surface plasmon resonance shows that rC1q retains the ability of serum C1q to associate with the C1s-C1r-C1r-C1s tetramer, to recognize physiological C1q ligands such as IgG and pentraxin 3, and to trigger C1r and C1s activation. Functional analysis of rC1q variants carrying mutations of LysA59, LysB61, and/or LysC58, in the collagen-like stems, demonstrates that LysB61 and LysC58 each play a key role in the interaction with C1s-C1r-C1r-C1s, with LysA59 being involved to a lesser degree. We propose that LysB61 and LysC58 both form salt bridges with outer acidic Ca2+ ligands of the C1r and C1s CUB (complement C1r/C1s, Uegf, bone morphogenetic protein) domains. The expression method reported here opens the way for deciphering the molecular basis of the unusual binding versatility of C1q by mapping the residues involved in the sensing of its targets and the binding of its receptors. PMID:23650384

  13. Acquired hypofibrinogenemia: current perspectives

    PubMed Central

    Besser, Martin W; MacDonald, Stephen G

    2016-01-01

    Acquired hypofibrinogenemia is most frequently caused by hemodilution and consumption of clotting factors. The aggressive replacement of fibrinogen has become one of the core principles of modern management of massive hemorrhage. The best method for determining the patient’s fibrinogen level remains controversial, and particularly in acquired dysfibrinogenemia, could have major therapeutic implications depending on which quantification method is chosen. This review introduces the available laboratory and point-of-care methods and discusses the relative advantages and limitations. It also discusses current strategies for the correction of hypofibrinogenemia. PMID:27713652

  14. Community-acquired pneumonia.

    PubMed

    Falguera, M; Ramírez, M F

    2015-11-01

    This article not only reviews the essential aspects of community-acquired pneumonia for daily clinical practice, but also highlights the controversial issues and provides the newest available information. Community-acquired pneumonia is considered in a broad sense, without excluding certain variants that, in recent years, a number of authors have managed to delineate, such as healthcare-associated pneumonia. The latter form is nothing more than the same disease that affects more frail patients, with a greater number of risk factors, both sharing an overall common approach.

  15. Hereditary C1q deficiency: a new family with C1qA deficiency.

    PubMed

    Sun-Tan, Cağman; Ozgür, Tuba Turul; Kilinç, Gamze; Topaloğlu, Rezan; Gököz, Ozay; Ersoy-Evans, Sibel; Sanal, Ozden

    2010-01-01

    Hereditary deficiency of complement component C1q is a rare genetic disorder with susceptibility to recurrent infections with polysaccharide-containing encapsulated microorganisms and a high prevalence of autoimmune diseases, most often systemic lupus erythematosus (SLE). Here, we report a 29-month-old boy who presented with facial rash and history of early death of a sibling with infections, who was found to have a selective deficiency of C1q. The facial rash was composed of patchy erythematous plaques and centrally hypopigmented macules and desquamation. Two siblings had died of severe bacterial infections and his uncle had died of meningitis. Molecular study disclosed a homozygous point mutation in the C1qA chain gene. Five members of the family, including the parents and three healthy siblings, were heterozygous for this mutation.

  16. Acquired Brain Injury Program.

    ERIC Educational Resources Information Center

    Schwartz, Stacey Hunter

    This paper reviews the Acquired Brain Injury (ABI) Program at Coastline Community College (California). The ABI Program is a two-year, for-credit educational curriculum designed to provide structured cognitive retraining for adults who have sustained an ABI due to traumatic (such as motor vehicle accident or fall) or non-traumatic(such as…

  17. Classical complement pathway component C1q: purification of human C1q, isolation of C1q collagen-like and globular head fragments and production of recombinant C1q-derivatives. Functional characterization.

    PubMed

    Kojouharova, Mihaela

    2014-01-01

    The classical complement pathway (CCP) activation is a multimolecular complex, composed of three subcomponents namely C1q, C1r, and C1s. C1q is the recognition subunit of this complex and its binding to the specific targets leads to the formation of active C1, which in turn activates the CCP in an immunoglobulin-dependent or -independent manner. C1q is a hexameric glycoprotein composed of 18 polypeptide chains of three different types (A, B, and C), organized in two fragments-collagen-like (CLR) and globular head (gC1q) possessing different functional activity. The contemporary knowledge of the C1q structure allows the isolation and purification of a C1q molecule from serum by combination of different chromatography procedures including ion-exchange, size-exclusion, and affinity chromatography, as well as the isolation of CLR and gC1q by limited enzymatic hydrolysis of the native C1q molecule. In this chapter, we described methods for purification of human C1q and its CLR and gC1q fragments, as well as methods for their biochemical and functional characterization. The production and purification of recombinant C1q derivatives ghA, ghB, and ghC (globular fragments of the individual C1q chains) are also presented.

  18. Hospital-acquired thrombocytopenia.

    PubMed

    McMahon, Christine M; Cuker, Adam

    2014-10-01

    The development of thrombocytopenia is common in hospitalized patients and is associated with increased mortality. Frequent and important causes of thrombocytopenia in hospitalized patients include etiologies related to the underlying illness for which the patient is admitted, such as infection and disseminated intravascular coagulation, and iatrogenic etiologies such as drug-induced immune thrombocytopenia, heparin-induced thrombocytopenia, posttransfusion purpura, hemodilution, major surgery, and extracorporeal circuitry. This review presents a brief discussion of the pathophysiology, distinguishing clinical features, and management of these etiologies, and provides a diagnostic approach to hospital-acquired thrombocytopenia that considers the timing and severity of the platelet count fall, the presence of hemorrhage or thrombosis, the clinical context, and the peripheral blood smear. This approach may offer guidance to clinicians in distinguishing among the various causes of hospital-acquired thrombocytopenia and providing management appropriate to the etiology.

  19. Desmosomes in acquired disease

    PubMed Central

    Stahley, Sara N.; Kowalczyk, Andrew P.

    2015-01-01

    Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement functions to integrate adhesion and cytoskeletal elements of adjacent cells. The importance of this robust adhesion system is evident in numerous human diseases, both inherited and acquired, that occur when desmosome function is compromised. This review focuses on autoimmune and infectious diseases that impair desmosome function. In addition, we discuss emerging evidence that desmosomal genes are often misregulated in cancer. The emphasis of our discussion is placed on how human diseases inform our understanding of basic desmosome biology, and in turn, how fundamental advances in the cell biology of desmosomes may lead to new treatments for acquired diseases of the desmosome. PMID:25795143

  20. Desmosomes in acquired disease.

    PubMed

    Stahley, Sara N; Kowalczyk, Andrew P

    2015-06-01

    Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement integrates adhesion and cytoskeletal elements of adjacent cells. The importance of this robust adhesion system is evident in numerous human diseases, both inherited and acquired, which occur when desmosome function is compromised. This review focuses on autoimmune and infectious diseases that impair desmosome function. In addition, we discuss emerging evidence that desmosomal genes are often misregulated in cancer. The emphasis of our discussion is placed on the way in which human diseases can inform our understanding of basic desmosome biology and in turn, the means by which fundamental advances in the cell biology of desmosomes might lead to new treatments for acquired diseases of the desmosome.

  1. Acquired hemophilia A in a patient with systemic lupus erythematosus.

    PubMed

    Ishikawa, T; Tsukamoto, N; Suto, M; Uchiumi, H; Mitsuhashi, H; Yokohama, A; Maesawa, A; Nojima, Y; Naruse, T

    2001-06-01

    A patient with systemic lupus erythematosus (SLE) developed acquired hemophilia A. The patient, a 24-year-old Japanese woman, was referred to our hospital because of uncontrollable bleeding following a tooth extraction. Laboratory examination revealed prolonged APTT (116 seconds), reduced factor VIII activity (2.8 %) and the presence of factor VIII inhibitor at a titer of 46.5 Bethesda units/ml. Transfusion of prothrombin complex concentrate and activated prothrombin complex concentrate followed by administration of prednisolone and cyclophosphamide successfully arrested bleeding and reduced the factor VIII inhibitor level. Acquired hemophilia A is a rare but lethal condition. Rapid diagnosis and introduction of adequate therapies are critical.

  2. Acquired Localized Hypertrichosis Induced by Rivastigmine

    PubMed Central

    Imbernón-Moya, Adrian; Podlipnik, Sebastian; Burgos, Fernando; Vargas-Laguna, Elena; Aguilar-Martínez, Antonio; Fernández-Cogolludo, Eva; Gallego-Valdes, Miguel Angel

    2016-01-01

    Hypertrichosis is the excessive hair growth in any area of the skin surface. Acquired localized hypertrichosis may be secondary to multiple causes and there is a secondary form due to several drugs, which is usually reversible with discontinuation of the causative agent. Rivastigmine is a reversible and competitive inhibitor of acetylcholinesterase and butyrylcholinesterase used for symptomatic treatment of Alzheimer dementia and Parkinson's disease. It has an adequate safety profile and cutaneous side effects are unusual. Irritant contact dermatitis, allergic dermatitis, baboon syndrome, and cutaneous rash due to rivastigmine have been reported. We report on a Caucasian 80-year-old male with personal history of Alzheimer's disease. The patient started therapy with oral rivastigmine one month prior to clinical presentation of localized hypertrichosis on both forearms. Norgalanthamine has been shown to promote hair growth activity via the proliferation of dermal papilla. Acetylcholinesterase inhibitors can induce hair growth. PMID:27073702

  3. The neural guidance receptor Plexin C1 delays melanoma progression

    PubMed Central

    Chen, Y; Soong, J; Mohanty, S; Xu, L; Scott, G

    2013-01-01

    Plexin C1 is a type I transmembrane receptor with intrinsic R-Ras GTPase activity, which regulates cytoskeletal remodeling and adhesion in normal human melanocytes. Melanocytes are pigment-producing cells of the epidermis, precursors for melanoma, and express high levels of Plexin C1, which is lost in melanoma in vitro and in vivo. To determine if Plexin C1 is a tumor suppressor for melanoma, we introduced Plexin C1 into a primary human melanoma cell line, and phenotypes including migration, apoptosis, proliferation and tumor growth in mice were analyzed. Complimentary studies in which Plexin C1 was silenced in human melanocytes were performed. Plexin C1 significantly inhibited migration and proliferation in melanoma, whereas in melanocytes, loss of Plexin C1 increased migration and proliferation. In mouse xenografts, Plexin C1 delayed tumor growth of melanoma at early time points, but tumors eventually escaped the suppressive effects of Plexin C1, due to Plexin C1-dependent activation of the pro-survival protein Akt. R-Ras activation stimulates melanoma migration. Plexin C1 lowered R-Ras activity in melanoma and melanocytes, consistent with inhibitory effects of Plexin C1 on migration of melanocytes and melanoma. To determine if R-Ras is expressed in melanocytic lesions in vivo, staining of tissue microarrays of nevi and melanoma were performed. R-Ras expression was highly limited in melanocytic lesions, being essentially confined to primary melanoma, and almost completely absent in nevi and metastatic melanoma. These data suggest that loss of Plexin C1 in melanoma may promote early steps in melanoma progression through suppression of migration and proliferation, but pro-survival effects of Plexin C1 ultimately abrogate the tumor suppressive effects of Plexin C1. In primary melanoma, loss of Plexin C1 may function in early steps of melanoma progression by releasing inhibition of R-Ras activation, and stimulating migration. PMID:23160370

  4. The neural guidance receptor Plexin C1 delays melanoma progression.

    PubMed

    Chen, Y; Soong, J; Mohanty, S; Xu, L; Scott, G

    2013-10-10

    Plexin C1 is a type I transmembrane receptor with intrinsic R-Ras GTPase activity, which regulates cytoskeletal remodeling and adhesion in normal human melanocytes. Melanocytes are pigment-producing cells of the epidermis, precursors for melanoma, and express high levels of Plexin C1, which is lost in melanoma in vitro and in vivo. To determine if Plexin C1 is a tumor suppressor for melanoma, we introduced Plexin C1 into a primary human melanoma cell line, and phenotypes including migration, apoptosis, proliferation and tumor growth in mice were analyzed. Complimentary studies in which Plexin C1 was silenced in human melanocytes were performed. Plexin C1 significantly inhibited migration and proliferation in melanoma, whereas in melanocytes, loss of Plexin C1 increased migration and proliferation. In mouse xenografts, Plexin C1 delayed tumor growth of melanoma at early time points, but tumors eventually escaped the suppressive effects of Plexin C1, due to Plexin C1-dependent activation of the pro-survival protein Akt. R-Ras activation stimulates melanoma migration. Plexin C1 lowered R-Ras activity in melanoma and melanocytes, consistent with inhibitory effects of Plexin C1 on migration of melanocytes and melanoma. To determine if R-Ras is expressed in melanocytic lesions in vivo, staining of tissue microarrays of nevi and melanoma were performed. R-Ras expression was highly limited in melanocytic lesions, being essentially confined to primary melanoma, and almost completely absent in nevi and metastatic melanoma. These data suggest that loss of Plexin C1 in melanoma may promote early steps in melanoma progression through suppression of migration and proliferation, but pro-survival effects of Plexin C1 ultimately abrogate the tumor suppressive effects of Plexin C1. In primary melanoma, loss of Plexin C1 may function in early steps of melanoma progression by releasing inhibition of R-Ras activation, and stimulating migration.

  5. 26 CFR 1.682(c)-1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Definitions. 1.682(c)-1 Section 1.682(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Miscellaneous § 1.682(c)-1 Definitions. For definitions of the terms “husband” and “wife”...

  6. C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus

    PubMed Central

    van Schaarenburg, Rosanne A.; Magro-Checa, César; Bakker, Jaap A.; Teng, Y. K. Onno; Bajema, Ingeborg M.; Huizinga, Tom W.; Steup-Beekman, Gerda M.; Trouw, Leendert A.

    2016-01-01

    C1q deficiency is a rare immunodeficiency, which is strongly associated with the development of systemic lupus erythematosus (SLE). A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q. Patients with C1q deficiency mainly present with cutaneous and renal involvement. Although less frequent, neuropsychiatric (NP) involvement has also been reported in 20% of the C1q-deficient patients. This involvement appears to be absent in other deficiencies of early components of the complement classical pathway (CP) (C1r/C1s, C2, or C4 deficiencies). We describe a new case with C1q deficiency with a homozygous G34R mutation in C1qC-producing LMW-C1q presenting with a severe SLE flare with NP involvement. The serum of this patient contained very low levels of a LMW variant of C1q polypeptides. Cell lysates contained the three chains of C1q, but no intact C1q was detected, consistent with the hypothesis of the existence of a LMW-C1q. Furthermore, we provide a literature overview of NP-SLE in C1q deficiency and hypothesize about the potential role of C1q in the pathogenesis of NP involvement in these patients. The onset of NP-SLE in C1q-deficient individuals is more severe when compared with complement competent NP-SLE patients. An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis. A defective CP, because of non-functional C1q, does not protect against NP involvement in SLE. The absence of C1q and, subsequently, some of its biological functions may be associated with more severe NP-SLE. PMID:28082982

  7. The Genome of the Anaerobic Fungus Orpinomyces sp. Strain C1A Reveals the Unique Evolutionary History of a Remarkable Plant Biomass Degrader

    PubMed Central

    Youssef, Noha H.; Couger, M. B.; Struchtemeyer, Christopher G.; Liggenstoffer, Audra S.; Prade, Rolf A.; Najar, Fares Z.; Atiyeh, Hasan K.; Wilkins, Mark R.

    2013-01-01

    Anaerobic gut fungi represent a distinct early-branching fungal phylum (Neocallimastigomycota) and reside in the rumen, hindgut, and feces of ruminant and nonruminant herbivores. The genome of an anaerobic fungal isolate, Orpinomyces sp. strain C1A, was sequenced using a combination of Illumina and PacBio single-molecule real-time (SMRT) technologies. The large genome (100.95 Mb, 16,347 genes) displayed extremely low G+C content (17.0%), large noncoding intergenic regions (73.1%), proliferation of microsatellite repeats (4.9%), and multiple gene duplications. Comparative genomic analysis identified multiple genes and pathways that are absent in Dikarya genomes but present in early-branching fungal lineages and/or nonfungal Opisthokonta. These included genes for posttranslational fucosylation, the production of specific intramembrane proteases and extracellular protease inhibitors, the formation of a complete axoneme and intraflagellar trafficking machinery, and a near-complete focal adhesion machinery. Analysis of the lignocellulolytic machinery in the C1A genome revealed an extremely rich repertoire, with evidence of horizontal gene acquisition from multiple bacterial lineages. Experimental analysis indicated that strain C1A is a remarkable biomass degrader, capable of simultaneous saccharification and fermentation of the cellulosic and hemicellulosic fractions in multiple untreated grasses and crop residues examined, with the process significantly enhanced by mild pretreatments. This capability, acquired during its separate evolutionary trajectory in the rumen, along with its resilience and invasiveness compared to prokaryotic anaerobes, renders anaerobic fungi promising agents for consolidated bioprocessing schemes in biofuels production. PMID:23709508

  8. A case of HPV and acquired genital lymphangioma: over-lapping clinical features.

    PubMed

    Cestaro, Giovanni; De Rosa, Michele; Gentile, Maurizio; Massa, Salvatore

    2015-03-25

    Lymphatic malformation or lymphangioma is a benign proliferation of the lymphatics accounting for 4% of all vascular malformations and 26% of all benign vascular tumors. There are several reports about genital lymphangiomas mimicking venereal lesions, such as genital warts. Hereby we described a case of a 24 year old man affected by multiple vesicles and warts in genital area. All hematological and biochemical parameters, Human Immunodeficiency Virus (HIV) and Treponema Pallidum tests, C1-Inhibitor and C1-Q values were within limits. An accurate fulguration and wide excision of bigger lesions were performed. Histological examination showed numerous dilated lymphatic vessels in the superficial dermis with infiltration of inflammatory cells, that is a histopathological picture compatible with genital lymphangioma. Considering our clinical suspicion of condylomatosis, HPV (Human Papilloma Virus) Polimerase Chain Reaction (PCR) Genotyping, named INNOLiPA test, was performed, that revealed a genital infection by HPV - genotype 6. We think that our case can be considered an example of HPV infection and acquired genital lymphangioma overlap clinical syndrome. The patient presented any lesions one year after the procedure at follow-up examination.

  9. Acquired epidermodysplasia verruciformis.

    PubMed

    Rogers, Heather D; Macgregor, Jennifer L; Nord, Kristin M; Tyring, Stephen; Rady, Peter; Engler, Danielle E; Grossman, Marc E

    2009-02-01

    Epidermodysplasia verruciformis (EV) is a rare autosomal recessive genodermatosis with an increased susceptibility to specific human papillomavirus (HPV) genotypes. Classically, this viral infection leads to the development of tinea versicolor-like macules on the trunk, neck, arms, and face during childhood, and over time, these lesions can progress to squamous cell carcinoma. More recently, an EV-like syndrome has been described in patients with impaired cell-mediated immunity. We describe two cases of EV-like syndrome in HIV-positive patients, review all previously reported cases of EV in patients with impaired cell-mediated immunity, introduce the term "acquired epidermodysplasia verruciformis" to describe EV developing in the immunocompromised host and examine the limited treatment options for these patients.

  10. AIDS: acquired immunodeficiency syndrome.

    PubMed Central

    Gilmore, N. J.; Beaulieu, R.; Steben, M.; Laverdière, M.

    1983-01-01

    Acquired immunodeficiency syndrome, or AIDS, is a new illness that occurs in previously healthy individuals. It is characterized by immunodeficiency, opportunistic infections and unusual malignant diseases. Life-threatening single or multiple infections with viruses, mycobacteria, fungi or protozoa are common. A rare neoplasm, Kaposi's sarcoma, has developed in approximately one third of patients with AIDS. More than 800 cases of AIDS have been reported in North America, over 24 of them in Canada. The majority of patients are male homosexuals, although AIDS has also developed in abusers of intravenously administered drugs, Haitian immigrants, individuals with hemophilia, recipients of blood transfusions, prostitutes, and infants, spouses and partners of patients with AIDS. The cause of AIDS is unknown, but the features are consistent with an infectious process. Early diagnosis can be difficult owing to the nonspecific symptoms and signs of the infections and malignant diseases. Therefore, vigilance by physicians is of utmost importance. PMID:6342737

  11. AIDS: acquired immunodeficiency syndrome *

    PubMed Central

    Gilmore, N.J.; Beaulieu, R.; Steben, M.; Laverdière, M.

    1992-01-01

    Acquired immunodeficiency syndrome, or AIDS, is a new illness that occurs in previously healthy individuals. It is characterized by immunodeficiency, opportunistic infections and unusual malignant diseases. Life-threatening single or multiple infections with viruses, mycobacteria, fungi or protozoa are common. A rare neoplasm, Kaposi's sarcoma, has developed in approximately one third of patients with AIDS. More than 800 cases of AIDS have been reported in North America, over 24 of them in Canada. The majority of patients are male homosexuals, although AIDS has also developed in abusers of intravenously administered drugs, Haitian immigrants, individuals with hemophilia, recipients of blood transfusions, prostitutes, and infants, spouses and partners of patients with AIDS. The cause of AIDS is unknown, but the features are consistent with an infectious process. Early diagnosis can be difficult owing to the nonspecific symptoms and signs of the infections and malignant diseases. Therefore, vigilance by physicians is of the utmost importance. PMID:1544049

  12. EGFR inhibitors and autophagy in cancer treatment.

    PubMed

    Cui, Jie; Hu, Yun-Feng; Feng, Xie-Min; Tian, Tao; Guo, Ya-Huan; Ma, Jun-Wei; Nan, Ke-Jun; Zhang, Hong-Yi

    2014-12-01

    Epidermal growth factor receptor (EGFR) inhibitor treatment is a strategy for cancer therapy. However, innate and acquired resistance is a major obstacle of the efficacy. Autophagy is a self-digesting process in cells, which is considered to be associated with anti-cancer drug resistance. The activation of EGFR can regulate autophagy through multiple signal pathways. EGFR inhibitors can induce autophagy, but the specific function of the induction of autophagy by EGFR inhibitors remains biphasic. On the one hand, autophagy induced by EGFR inhibitors acts as a cytoprotective response in cancer cells, and autophagy inhibitors can enhance the cytotoxic effects of EGFR inhibitors. On the other hand, a high level of autophagy after treatment of EGFR inhibitors can also result in autophagic cell death lacking features of apoptosis, and the combination of EGFR inhibitors with an autophagy inducer might be beneficial. Thus, autophagy regulation represents a promising approach for improving the efficacy of EGFR inhibitors in the treatment of cancer patients.

  13. Caspase cleavage of cytochrome c1 disrupts mitochondrial function and enhances cytochrome c release.

    PubMed

    Zhu, Yushan; Li, Min; Wang, Xiaohui; Jin, Haijing; Liu, Shusen; Xu, Jianxin; Chen, Quan

    2012-01-01

    Mitochondrial catastrophe can be the cause or consequence of apoptosis and is associated with a number of pathophysiological conditions. The exact relationship between mitochondrial catastrophe and caspase activation is not completely understood. Here we addressed the underlying mechanism, explaining how activated caspase could feedback to attack mitochondria to amplify further cytochrome c (cyto.c) release. We discovered that cytochrome c1 (cyto.c1) in the bc1 complex of the mitochondrial respiration chain was a novel substrate of caspase 3 (casp.3). We found that cyto.c1 was cleaved at the site of D106, which is critical for binding with cyto.c, following apoptotic stresses or targeted expression of casp.3 into the mitochondrial intermembrane space. We demonstrated that this cleavage was closely linked with further cyto.c release and mitochondrial catastrophe. These mitochondrial events could be effectively blocked by expressing non-cleavable cyto.c1 (D106A) or by caspase inhibitor z-VAD-fmk. Our results demonstrate that the cleavage of cyto.c1 represents a critical step for the feedback amplification of cyto.c release by caspases and subsequent mitochondrial catastrophe.

  14. A single-center study of C1q nephropathy in children.

    PubMed

    Roberti, Isabel; Baqi, Noosha; Vyas, Shefali; Kim, Dae Un

    2009-01-01

    C1q nephropathy (C1qN) is a rare idiopathic glomerulopathy typically seen in adolescents and young adults. All kidney biopsies done from 2002 to 2007 were analyzed (264). Thirteen cases of C1qN from 212 (6.6%) native biopsies and one case out of 52 (1.9%) transplant biopsies were reviewed regarding demographic features, clinical presentation, histopathology, treatment, and outcome. Age varied from 1 to 18 years; half were boys. Ten children (71.4%) presented with nephrotic syndrome (NS). The most common histopathology found was diffuse mesangial proliferative glomerulonephritis (DMP) by light microscopy (LM), with diffuse granular staining for C1q predominantly in the mesangium. Children with either NS or persistent gross hematuria received prednisone and angiotensin-converting enzyme inhibitors (ACEi) (11). Median follow-up was 36 months. Steroid response was complete in 6 patients (54.5%). Those with steroid resistance (5) or steroid dependence (2) received further immunosuppression with mycophenolate mofetil (MMF) or tacrolimus (Tac). Three children achieved complete remission and four partial remission. Frequent relapses were seen in 4/14 patients. Renal survival was 100%. Our report reveals a high incidence of C1qN in pediatric patients, with variable clinical presentation. Despite a high incidence of steroid resistance among those with NS, an excellent response was observed with the addition of further immunosuppression.

  15. Angioedema Related to Angiotensin-Converting Enzyme Inhibitors

    PubMed Central

    Javaud, Nicolas; Achamlal, Jallal; Reuter, Paul-George; Lapostolle, Frédéric; Lekouara, Akim; Youssef, Mustapha; Hamza, Lilia; Karami, Ahmed; Adnet, Frédéric; Fain, Olivier

    2015-01-01

    Abstract The number of cases of acquired angioedema related to angiotensin converting enzyme inhibitors induced (ACEI-AAE) is on the increase, with a potential concomitant increase in life-threatening attacks of laryngeal edema. Our objective was to determine the main characteristics of ACEI-AAE attacks and, in doing so, the factors associated with likelihood of hospital admission from the emergency department (ED) after a visit for an attack. A prospective, multicenter, observational study (April 2012–December 2014) was conducted in EDs of 4 French hospitals in collaboration with emergency services (SAMU 93) and a reference center for bradykinin-mediated angioedema. For each patient presenting with an attack, emergency physicians collected demographic and clinical presentation data, treatments, and clinical course. They recorded time intervals from symptom onset to ED arrival and to treatment decision, from ED arrival to specific treatment with plasma-derived C1-inhibitor (C1-INH) or icatibant, and from specific treatment to onset of symptom relief. Attacks requiring hospital admission were compared with those not requiring admission. Sixty-two eligible patients with ACEI-AAE (56% men, median age 63 years) were included. Symptom relief occurred significantly earlier in patients receiving specific treatment than in untreated patients (0.5 [0.5–1.0] versus 3.9 [2.5–7.0] hours; P < 0.0001). Even though icatibant was injected more promptly than plasma-derived C1-INH, there, however, was no significant difference in median time to onset of symptom relief between the 2 drugs (0.5 [0.5–1.3] versus 0.5 [0.4–1.0] hours for C1-INH and icatibant, respectively, P = 0.49). Of the 62 patients, 27 (44%) were admitted to hospital from the ED. In multivariate analysis, laryngeal involvement and progressive swelling at ED arrival were independently associated with admission (Odds ratio [95% confidence interval] = 6.2 [1.3–28.2] and 5.9 [1.3–26

  16. Motion-preserving reduction and fixation of C1 Jefferson fracture using a C1 lateral mass screw construct.

    PubMed

    Jo, Kwang-Wook; Park, Ik-Seong; Hong, Jae Taek

    2011-05-01

    The treatment of C1 Jefferson fractures is controversial. Non-surgical treatment with halo fixation always bears the risk of insufficient healing with further instability and increasing neck pain. However, a C1-2 fusion can markedly decrease the rotatory motion of the neck. The aim of this report is to describe a new treatment for C1 Jefferson fractures. We used open reduction and C1 fixation using a bilateral C1 lateral mass screw construct. The screws were connected with a rod and nuts to reduce lateral spread of the lateral masses. This method is an alternative surgical option for C1 Jefferson fractures in select patients and can maintain important C1-2 joint motion.

  17. Acquired aplastic anemia.

    PubMed

    Keohane, Elaine M

    2004-01-01

    Acquired aplastic anemia (AA) is a disorder characterized by a profound deficit of hematopoietic stem and progenitor cells, bone marrow hypocellularity, and peripheral blood pancytopenia. It primarily affects children, young adults, and those over 60 years of age. The majority of cases are idiopathic; however, idiosyncratic reactions to some drugs, chemicals, and viruses have been implicated in its etiology. An autoimmune T-cell reaction likely causes the stem cell depletion, but the precise mechanism, as well as the eliciting and target antigens, is unknown. Symptoms vary from severe life-threatening cytopenias to moderate or non-severe disease that does not require transfusion support. The peripheral blood typically exhibits pancytopenia, reticulocytopenia, and normocytic or macrocytic erythrocytes. The bone marrow is hypocellular and may exhibit dysplasia of the erythrocyte precursors. First line treatment for severe AA consists of hematopoietic stem cell transplantation in young patients with HLA identical siblings, while immunosuppression therapy is used for older patients and for those of any age who lack a HLA matched donor. Patients with AA have an increased risk of developing paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), or acute leukemia. Further elucidation of the pathophysiology of this disease will result in a better understanding of the interrelationship among AA, PNH, and MDS, and may lead to novel targeted therapies.

  18. Acquired spatial dyslexia.

    PubMed

    Siéroff, E

    2015-08-10

    Acquired spatial dyslexia is a reading disorder frequently occurring after left or right posterior brain lesions. This article describes several types of spatial dyslexia with an attentional approach. After right posterior lesions, patients show left neglect dyslexia with errors on the left side of text, words, and non-words. The deficit is frequently associated with left unilateral spatial neglect. Severe left neglect dyslexia can be detected with unlimited exposure duration of words or non-words. Minor neglect dyslexia is detected with brief presentation of bilateral words, one in the left and one in the right visual field (phenomenon of contralesional extinction). Neglect dyslexia can be explained as a difficulty in orienting attention to the left side of verbal stimuli. With left posterior lesions, spatial dyslexia is also frequent but multiform. Right neglect dyslexia is frequent, but right unilateral spatial neglect is rare. Attentional dyslexia represents difficulty in selecting a stimulus, letter or word among other similar stimuli; it is a deficit of attentional selection, and the left hemisphere plays a crucial role in selection. Two other types of spatial dyslexia can be found after left posterior lesions: paradoxical ipsilesional extinction and stimulus-centred neglect dyslexia. Disconnections between left or right parietal attentional areas and the left temporal visual word form area could explain these deficits. Overall, a model of attention dissociating modulation, selection control, and selection positioning can help in understanding these reading disorders.

  19. Acquired reactive perforating collagenosis

    PubMed Central

    Fei, Chengwen; Wang, Yao; Gong, Yu; Xu, Hui; Yu, Qian; Shi, Yuling

    2016-01-01

    Abstract Background: Reactive perforating collagenosis (RPC) is a rare form of transepithelial elimination, in which altered collagen is extruded through the epidermis. There are 2 types of RPC, acquired RPC (ARPC) and inherited RPC, while the latter is extremely rare. Here we report on 1 case of ARPC. Methods: A 73-year-old female was presented with strongly itchy papules over her back and lower limbs for 3 months. She denied the history of oozing or vesiculation. A cutaneous examination showed diffusely distributed multiple well-defined keratotic papules, 4 to 10 mm in diameter, on the bilateral lower limbs and back as well as a few papules on her chest and forearm. Scratching scars were over the resolved lesions while Koebner phenomenon was negative. The patient had a history of type 2 diabetes for 15 years. Laboratory examinations showed elevated blood glucose level. Skin lesion biopsy showed a well-circumscribed area of necrosis filled with a keratotic plug. Parakeratotic cells and lymphocytic infiltration could be seen in the necrosed area. In dermis, sparse fiber bundles were seen perforating the epidermis. These degenerated fiber bundles were notarized as collagen fiber by elastic fiber stain, suggesting a diagnosis of RPC. Results: Then a diagnosis of ARPC was made according to the onset age and the history of diabetes mellitus. She was treated with topical application of corticosteroids twice a day and oral antihistamine once a day along with compound glycyrrhizin tablets 3 times a day. And the blood glucose was controlled in a satisfying range. Two months later, a significant improvement was seen in this patient. Conclusion: Since there is no efficient therapy to RPC, moreover, ARPC is considered to be associated with some systemic diseases, the management of the coexisting disease is quite crucial. The patient in this case received a substantial improvement due to the control of blood glucose and application of compound glycyrrhizin tablets. PMID

  20. Altered transition metal homeostasis in Niemann-Pick disease, Type C1

    PubMed Central

    Hung, Ya Hui; Faux, Noel G.; Killilea, David W.; Yanjanin, Nicole; Firnkes, Sally; Volitakis, Irene; Ganio, George; Walterfang, Mark; Hastings, Caroline; Porter, Forbes D.; Ory, Daniel S.; Bush, Ashley I.

    2014-01-01

    The loss of NPC1 protein function is the predominant cause of Niemann-Pick type C1 disease (NP-C1), a systemic and neurodegenerative disorder characterized by late-endosomal/lysosomal accumulation of cholesterol and other lipids. Limited evidence from post-mortem human tissues, an Npc1−/− mouse model, and cell culture studies also suggest failure of metal homeostasis in NP-C1. To investigate these findings, we performed a comprehensive transition metal analysis of cerebrospinal fluid (CSF), plasma and tissue samples from human NP-C1 patients and an Npc1−/− mouse model. NPC1 deficiency in the Npc1−/− mouse model resulted in a perturbation of transition metal homeostasis in the plasma and key organs (brain, liver, spleen, heart, lungs, and kidneys). Analysis of human patient CSF, plasma and post-mortem brain tissues also indicated disrupted metal homeostasis. There was a disparity in the direction of metal changes between the human and the Npc1−/− mouse samples, which may reflect species-specific metal metabolism. Nevertheless, common to both species is brain zinc accumulation. Furthermore, treatment with the glucosylceramide synthase inhibitor miglustat, the only drug shown in a controlled clinical trial to have some efficacy for NP-C1, did not correct the alterations in CSF and plasma transition metal and ceruloplasmin (CP) metabolism in NP-C1 patients. These findings highlight the importance of NPC1 function in metal homeostasis, and indicate that metal-targeting therapy may be of value as a treatment for NP-C. PMID:24343124

  1. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Acquiring and acquired persons. 801.2 Section 801.2 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976 COVERAGE RULES § 801.2...

  2. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Acquiring and acquired persons. 801.2 Section 801.2 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976 COVERAGE RULES § 801.2...

  3. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Acquiring and acquired persons. 801.2 Section 801.2 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976 COVERAGE RULES § 801.2...

  4. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Acquiring and acquired persons. 801.2 Section 801.2 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976 COVERAGE RULES § 801.2...

  5. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Acquiring and acquired persons. 801.2 Section 801.2 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976 COVERAGE RULES § 801.2...

  6. Missed C1 posterior arch fracture: a case report

    PubMed Central

    Munro, Donald S

    1990-01-01

    A case of a C1 posterior arch fracture following a fall is presented. The need to perform a thorough history and examination, regardless of previous examination findings, is emphasized. This is especially true when there is a history of recent trauma. A brief discussion of the characteristics and management of C1 fractures follows. ImagesFigure 1Figure 2Figure 3

  7. Anti-C1q in systemic lupus erythematosus.

    PubMed

    Stojan, G; Petri, M

    2016-07-01

    C1q is the first component of the classical complement pathway. Both clinically validated in-house ELISA assays as well as commercial ELISA kits are used for detection of anti-C1q antibodies. Anti-C1q autoantibodies can be detected in a wide range of autoimmune diseases and are highly sensitive for hypocomplementemic uticarial vasculitis. In SLE, anti-C1q are strongly associated with proliferative lupus nephritis, and their absence carries a negative predictive value for development of lupus nephritis of close to 100%. Anti-C1q in combination with anti-dsDNA and low complement has the strongest serological association with renal involvement. The anti-C1q titers correlate with global disease activity scores in patients with renal involvement, and higher titers seem to precede renal flares. After the successful treatment of a renal flare, anti-C1q has the tendency to decrease or even become undetectable. The main obstacle to the inclusion of anti-C1q in the classification criteria and clinical management of SLE is the lack of standardized laboratory assays.

  8. 26 CFR 1.661(c)-1 - Limitation on deduction.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Limitation on deduction. 1.661(c)-1 Section 1.661(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Estates and Trusts Which May Accumulate Income Or Which Distribute Corpus §...

  9. 26 CFR 1.662(c)-1 - Different taxable years.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Different taxable years. 1.662(c)-1 Section 1.662(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Estates and Trusts Which May Accumulate Income Or Which Distribute Corpus §...

  10. 26 CFR 1.678(c)-1 - Trusts for support.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Trusts for support. 1.678(c)-1 Section 1.678(c... (CONTINUED) INCOME TAXES Grantors and Others Treated As Substantial Owners § 1.678(c)-1 Trusts for support... cotrustee, to apply the income of the trust to the support or maintenance of a person whom the holder...

  11. 26 CFR 1.1092(c)-1 - Qualified covered calls.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 11 2010-04-01 2010-04-01 true Qualified covered calls. 1.1092(c)-1 Section 1... (CONTINUED) INCOME TAXES Wash Sales of Stock Or Securities § 1.1092(c)-1 Qualified covered calls. (a) In...), however, writing a qualified covered call option and owning the optioned stock is not treated as...

  12. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

    PubMed

    Collins, Peter; Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

    2012-07-05

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

  13. Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.

    PubMed

    Kapferer-Seebacher, Ines; Pepin, Melanie; Werner, Roland; Aitman, Timothy J; Nordgren, Ann; Stoiber, Heribert; Thielens, Nicole; Gaboriaud, Christine; Amberger, Albert; Schossig, Anna; Gruber, Robert; Giunta, Cecilia; Bamshad, Michael; Björck, Erik; Chen, Christina; Chitayat, David; Dorschner, Michael; Schmitt-Egenolf, Marcus; Hale, Christopher J; Hanna, David; Hennies, Hans Christian; Heiss-Kisielewsky, Irene; Lindstrand, Anna; Lundberg, Pernilla; Mitchell, Anna L; Nickerson, Deborah A; Reinstein, Eyal; Rohrbach, Marianne; Romani, Nikolaus; Schmuth, Matthias; Silver, Rachel; Taylan, Fulya; Vandersteen, Anthony; Vandrovcova, Jana; Weerakkody, Ruwan; Yang, Margaret; Pope, F Michael; Byers, Peter H; Zschocke, Johannes

    2016-11-03

    Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

  14. Stereotypic movement disorder after acquired brain injury.

    PubMed

    McGrath, Cynthia M; Kennedy, Richard E; Hoye, Wayne; Yablon, Stuart A

    2002-05-01

    Stereotypic movement disorder (SMD) consists of repetitive, non-functional motor behaviour that interferes with daily living or causes injury to the person. It is most often described in patients with mental retardation. However, recent evidence indicates that this condition is common among otherwise normal individuals. This case study describes a patient with new-onset SMD occurring after subdural haematoma and brain injury. SMD has rarely been reported after acquired brain injury, and none have documented successful treatment. The current psychiatric literature regarding neurochemistry, neuroanatomy, and treatment of SMD are reviewed with particular application to one patient. Treatment options include serotonin re-uptake inhibitors, opioid antagonists and dopamine antagonists. SMD has been under-appreciated in intellectually normal individuals, and may also be unrecognized after brain injury. Further investigation is needed in this area, which may benefit other individuals with SMD as well.

  15. Cbln and C1q family proteins: new transneuronal cytokines.

    PubMed

    Yuzaki, M

    2008-06-01

    The C1q family is characterized by a C-terminal conserved global C1q domain, which is structurally very similar to the tumor necrosis factor homology domain. Although some C1q family members are expressed in the central nervous system, their functions have not been well characterized. Cbln1, a member of the Cbln subfamily of the C1q family, is predominantly expressed in cerebellar granule cells. Interestingly, Cbln1 was recently shown to play two unique roles at excitatory synapses formed between cerebellar granule cells and Purkinje cells: the formation and stabilization of synaptic contact, and the control of functional synaptic plasticity by regulating the postsynaptic endocytosis pathway. Since other Cbln subfamily members, Cbln2-Cbln4, are expressed in various regions of developing and mature brains, Cbln subfamily proteins may generally serve as a new class of transneuronal regulators of synapse development and synaptic plasticity in various brain regions.

  16. Expression of staphylococcal enterotoxin C1 in Escherichia coli.

    PubMed Central

    Bohach, G A; Schlievert, P M

    1987-01-01

    The structural gene encoding staphylococcal enterotoxin C1 was cloned into Escherichia coli and localized on a 1.5-kilobase HindIII-ClaI DNA fragment by subcloning. The toxin was partially purified from E. coli clones and shown to be immunologically identical to enterotoxin C1 from Staphylococcus aureus. The cloned toxin also had the same molecular weight (26,000) and charge heterogeneity as staphylococcus-derived enterotoxin. Toxins from both sources were equally biologically active. Images PMID:3542834

  17. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 12 2010-04-01 2010-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or business, either as...

  18. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 12 2012-04-01 2012-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or...

  19. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 12 2013-04-01 2013-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or...

  20. [Report of 2 cases with acquired von Willebrand disease and one with acquired hemophilia A].

    PubMed

    Martínez-Murillo, C; Quintana González, S; Ambriz Fernández, R; Domínguez García, V; Rodríguez Moyado, H; Arias Aranda, A; Collazo Jaloma, J; Gutiérrez Romero, M

    1995-01-01

    We report three patients with acquired inhibitors against F VIII:C/F vW:Ag complex. Two patients had acquired hemophilia A. The three patients presented with bleeding diathesis. Case 1 was a 19 years old woman with Graves-Basedow disease; case 2 was a 40 years old woman with systemic lupus erythematosus of four years; and case 3 a 38 years old woman who had had rheumatoid arthritis for five years and was in her 3d month postpartum. The F VIII:C level was below 8 U/dL in all cases. The F vW:Ag, ristocetin cofactor and platelet aggregation with ristocetin were diminished in the two cases with von Willebrand. Inhibitor to F VIII:C was 50, 38 and 20 Bethesda units, respectively, for cases 1, 2 and 3. The three patients showed clinical response to DDAVP and cryoprecipitates with partial response in laboratory tests. All patients responded to corticosteroid treatment, but immunosuppressive treatment was necessary in case 3.

  1. SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis.

    PubMed

    Ferreira, Viviana P; Fazito Vale, Vladimir; Pangburn, Michael K; Abdeladhim, Maha; Mendes-Sousa, Antonio Ferreira; Coutinho-Abreu, Iliano V; Rasouli, Manoochehr; Brandt, Elizabeth A; Meneses, Claudio; Lima, Kolyvan Ferreira; Nascimento Araújo, Ricardo; Pereira, Marcos Horácio; Kotsyfakis, Michalis; Oliveira, Fabiano; Kamhawi, Shaden; Ribeiro, Jose M C; Gontijo, Nelder F; Collin, Nicolas; Valenzuela, Jesus G

    2016-01-13

    Blood-feeding insects inject potent salivary components including complement inhibitors into their host's skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases.

  2. SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis

    PubMed Central

    Ferreira, Viviana P.; Fazito Vale, Vladimir; Pangburn, Michael K.; Abdeladhim, Maha; Ferreira Mendes-Sousa, Antonio; Coutinho-Abreu, Iliano V.; Rasouli, Manoochehr; Brandt, Elizabeth A.; Meneses, Claudio; Lima, Kolyvan Ferreira; Nascimento Araújo, Ricardo; Horácio Pereira, Marcos; Kotsyfakis, Michalis; Oliveira, Fabiano; Kamhawi, Shaden; Ribeiro, Jose M. C.; Gontijo, Nelder F.; Collin, Nicolas; Valenzuela, Jesus G.

    2016-01-01

    Blood-feeding insects inject potent salivary components including complement inhibitors into their host’s skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases. PMID:26758086

  3. Acquired haemophilia A in a woman with autoimmune hepatitis and systemic lupus erythematosus; review of literature.

    PubMed

    Rezaieyazdi, Zahra; Sharifi-Doloui, Davood; Hashemzadeh, Kamila; Shirdel, Abbas; Mansouritorghabeh, Hassan

    2012-01-01

    Acquired haemophilia A, secondary to systemic lupus erythematosus (SLE) is a rare bleeding diathesis. Here we report a 37-year-old woman with autoimmune hepatitis who developed SLE and acquired haemophilia caused by factor VIII inhibitors. She presented with spontaneous ecchymosis and haematuria. There were a prolongation of the activated partial thromboplastin time, reduced factor VIII activity and a high titer of FVIII inhibitors. Therapeutic regimen was started with intravenous methylprednisolone pulse, continued with prednisolone, intravenous pulse cyclophosphamide and fresh frozen plasma. After 8 weeks, factor VIII inhibitor assay was negative.

  4. Acquired haemophilia A in a woman with autoimmune hepatitis and systemic lupus erythematosus: review of literature.

    PubMed

    Rezaieyazdi, Zahra; Sharifi-Doloui, Davood; Hashemzadeh, Kamila; Shirdel, Abbas; Mansouritorghabeh, Hassan

    2011-12-01

    Acquired haemophilia A, secondary to systemic lupus erythematosus (SLE), is a rare bleeding diathesis. Here we report a 37-year-old woman with autoimmune hepatitis who developed SLE and acquired haemophilia caused by factor VIII (fVIII) inhibitors. She presented with spontaneous ecchymosis and haematuria. There were a prolongation of the activated partial thromboplastin time, reduced fVIII activity and a high titre of fVIII inhibitors. Therapeutic regimen was started with intravenous methylprednisolone pulse, continued with prednisolone, intravenous pulse cyclophosphamide and fresh frozen plasma. After 8 weeks, fVIII inhibitor assay was negative.

  5. Acquired antiprothrombin antibodies: an unusual cause of bleeding

    PubMed Central

    Carvalho, Cristiana; Viveiro, Carolina; Maia, Paulo; Rezende, Teresa

    2013-01-01

    Acquired inhibitors of coagulation causing bleeding manifestations are rare in children. They emerge, normally in the context of autoimmune diseases or drug ingestion, but transient and self-limiting cases can occur after viral infection. We describe, an otherwise healthy, 7-year-old girl who had gingival bleeding after a tooth extraction. The prothrombin time (PT) and the activated partial thromboplastin time (APTT) were both prolonged with evidence of an immediate acting inhibitor (lupic anticoagulant). Further coagulation studies demonstrated prothrombin (FII) deficiency and prothrombin directed (FII) antibodies. The serological tests to detect an underlying autoimmune disease were all negative. The coagulation studies normalised alongside the disappearance of the antibody. This article presents lupus anticoagulant hypoprothrombinaemia syndrome (LAHS) as a rare case of acquired bleeding diathesis in childhood. PMID:23299692

  6. Acquired antiprothrombin antibodies: an unusual cause of bleeding.

    PubMed

    Carvalho, Cristiana; Viveiro, Carolina; Maia, Paulo; Rezende, Teresa

    2013-01-07

    Acquired inhibitors of coagulation causing bleeding manifestations are rare in children. They emerge, normally in the context of autoimmune diseases or drug ingestion, but transient and self-limiting cases can occur after viral infection. We describe, an otherwise healthy, 7-year-old girl who had gingival bleeding after a tooth extraction. The prothrombin time (PT) and the activated partial thromboplastin time (APTT) were both prolonged with evidence of an immediate acting inhibitor (lupic anticoagulant). Further coagulation studies demonstrated prothrombin (FII) deficiency and prothrombin directed (FII) antibodies. The serological tests to detect an underlying autoimmune disease were all negative. The coagulation studies normalised alongside the disappearance of the antibody. This article presents lupus anticoagulant hypoprothrombinaemia syndrome (LAHS) as a rare case of acquired bleeding diathesis in childhood.

  7. The Crystal Structure Analysis of Group B Streptococcus Sortase C1: A Model for the ;Lid; Movement upon Substrate Binding

    SciTech Connect

    Khare, Baldeep; Fu, Zheng-Qing; Huang, I-Hsiu; Ton-That, Hung; Narayana, Sthanam V.L.

    2012-02-07

    A unique feature of the class-C-type sortases, enzymes essential for Gram-positive pilus biogenesis, is the presence of a flexible 'lid' anchored in the active site. However, the mechanistic details of the 'lid' displacement, suggested to be a critical prelude for enzyme catalysis, are not yet known. This is partly due to the absence of enzyme-substrate and enzyme-inhibitor complex crystal structures. We have recently described the crystal structures of the Streptococcus agalactiae SAG2603 V/R sortase SrtC1 in two space groups (type II and type III) and that of its 'lid' mutant and proposed a role of the 'lid' as a protector of the active-site hydrophobic environment. Here, we report the crystal structures of SAG2603 V/R sortase C1 in a different space group (type I) and that of its complex with a small-molecule cysteine protease inhibitor. We observe that the catalytic Cys residue is covalently linked to the small-molecule inhibitor without lid displacement. However, the type I structure provides a view of the sortase SrtC1 lid displacement while having structural elements similar to a substrate sorting motif suitably positioned in the active site. We propose that these major conformational changes seen in the presence of a substrate mimic in the active site may represent universal features of class C sortase substrate recognition and enzyme activation.

  8. The crystal structure analysis of group B Streptococcus sortase C1: a model for the "lid" movement upon substrate binding.

    PubMed

    Khare, Baldeep; Fu, Zheng-Qing; Huang, I-Hsiu; Ton-That, Hung; Narayana, Sthanam V L

    2011-12-09

    A unique feature of the class-C-type sortases, enzymes essential for Gram-positive pilus biogenesis, is the presence of a flexible "lid" anchored in the active site. However, the mechanistic details of the "lid" displacement, suggested to be a critical prelude for enzyme catalysis, are not yet known. This is partly due to the absence of enzyme-substrate and enzyme-inhibitor complex crystal structures. We have recently described the crystal structures of the Streptococcus agalactiae SAG2603 V/R sortase SrtC1 in two space groups (type II and type III) and that of its "lid" mutant and proposed a role of the "lid" as a protector of the active-site hydrophobic environment. Here, we report the crystal structures of SAG2603 V/R sortase C1 in a different space group (type I) and that of its complex with a small-molecule cysteine protease inhibitor. We observe that the catalytic Cys residue is covalently linked to the small-molecule inhibitor without lid displacement. However, the type I structure provides a view of the sortase SrtC1 lid displacement while having structural elements similar to a substrate sorting motif suitably positioned in the active site. We propose that these major conformational changes seen in the presence of a substrate mimic in the active site may represent universal features of class C sortase substrate recognition and enzyme activation.

  9. Total synthesis of (-)-CP2-disorazole C1.

    PubMed

    Hopkins, Chad D; Schmitz, John C; Chu, Edward; Wipf, Peter

    2011-08-05

    The total synthesis of a bis-cyclopropane analog of the antimitotic natural product (-)-disorazole C(1) was accomplished in 23 steps and 1.1% overall yield. A vinyl cyclopropane cross-metathesis reaction generated a key (E)-alkene segment of the target molecule. IC(50) determinations of (-)-CP(2)-disorazole C(1) in human colon cancer cell lines indicated low nanomolar cytotoxic properties. Accordingly, this synthetic bioisostere represents the first biologically active disorazole analog not containing a conjugated diene or polyene substructure element.

  10. Kinetic modeling of hyperpolarized 13C 1-pyruvate metabolism in normal rats and TRAMP mice

    NASA Astrophysics Data System (ADS)

    Zierhut, Matthew L.; Yen, Yi-Fen; Chen, Albert P.; Bok, Robert; Albers, Mark J.; Zhang, Vickie; Tropp, Jim; Park, Ilwoo; Vigneron, Daniel B.; Kurhanewicz, John; Hurd, Ralph E.; Nelson, Sarah J.

    2010-01-01

    PurposeTo investigate metabolic exchange between 13C 1-pyruvate, 13C 1-lactate, and 13C 1-alanine in pre-clinical model systems using kinetic modeling of dynamic hyperpolarized 13C spectroscopic data and to examine the relationship between fitted parameters and dose-response. Materials and methodsDynamic 13C spectroscopy data were acquired in normal rats, wild type mice, and mice with transgenic prostate tumors (TRAMP) either within a single slice or using a one-dimensional echo-planar spectroscopic imaging (1D-EPSI) encoding technique. Rate constants were estimated by fitting a set of exponential equations to the dynamic data. Variations in fitted parameters were used to determine model robustness in 15 mm slices centered on normal rat kidneys. Parameter values were used to investigate differences in metabolism between and within TRAMP and wild type mice. ResultsThe kinetic model was shown here to be robust when fitting data from a rat given similar doses. In normal rats, Michaelis-Menten kinetics were able to describe the dose-response of the fitted exchange rate constants with a 13.65% and 16.75% scaled fitting error (SFE) for kpyr→lac and kpyr→ala, respectively. In TRAMP mice, kpyr→lac increased an average of 94% after up to 23 days of disease progression, whether the mice were untreated or treated with casodex. Parameters estimated from dynamic 13C 1D-EPSI data were able to differentiate anatomical structures within both wild type and TRAMP mice. ConclusionsThe metabolic parameters estimated using this approach may be useful for in vivo monitoring of tumor progression and treatment efficacy, as well as to distinguish between various tissues based on metabolic activity.

  11. In silico structural characteristics and α-amylase inhibitory properties of Ric c 1 and Ric c 3, allergenic 2S albumins from Ricinus communis seeds.

    PubMed

    Do Nascimento, Viviane Veiga; Castro, Helena Carla; Abreu, Paula Alvarez; Oliveira, Antônia Elenir Amâncio; Fernandez, Jorge Hernandez; Araújo, Jucélia Da Silva; Machado, Olga Lima Tavares

    2011-05-11

    The major Ricinus communis allergens are the 2S albumins, Ric c 1 and Ric c 3. These proteins contain a trypsin/α-amylase inhibitor family domain, suggesting that they have a role in insect resistance. In this study, we verified that Ric c 1 and Ric c 3 inhibited the α-amylase activity of Callosobruchus maculatus, Zabrotes subfasciatus, and Tenebrio molitor (TMA) larvae as well as mammalian α-amylase. The toxicity of 2S albumin was determined through its incorporation in C. maculatus larvae as part of an artificial diet. Bioassays revealed that 2S albumin reduced larval growth by 20%. We also analyzed the tridimensional structures of Ric c 1 and Ric c 3 by (a) constructing a comparative model of Ric c 1 based on Ric c 3 NMR structure and (b) constructing the theoretical structure of the Ric c 1-TMA and Ric c 3-TMA complexes. Our biological and theoretical results revealed that Ric c 1 and Ric c 3 are a new class of α-amylase inhibitors. They could potentially be used to help design inhibitors that would be useful in diverse fields, ranging from diabetes treatment to crop protection.

  12. 26 CFR 1.1092(c)-1 - Qualified covered calls.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 11 2013-04-01 2013-04-01 false Qualified covered calls. 1.1092(c)-1 Section 1... stock price of $14.84. Using the bench marks for an equity option with standardized terms with an adjusted applicable stock price of $14.84, the highest available strike price less than the...

  13. 26 CFR 1.1092(c)-1 - Qualified covered calls.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 11 2014-04-01 2014-04-01 false Qualified covered calls. 1.1092(c)-1 Section 1... stock price of $14.84. Using the bench marks for an equity option with standardized terms with an adjusted applicable stock price of $14.84, the highest available strike price less than the...

  14. Angiogenesis Inhibitors

    MedlinePlus

    ... inhibitors: current strategies and future prospects. CA: A Cancer Journal for Clinicians 2010; 60(4):222–243. [PubMed Abstract] Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nature Reviews Clinical Oncology 2009; 6(8):465– ...

  15. Carboxylesterase inhibitors

    PubMed Central

    Hatfield, M. Jason; Potter, Philip M.

    2011-01-01

    Introduction Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis. Areas covered This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors. Expert opinion The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties, and potential uses of such agents, are discussed here. PMID:21609191

  16. Musicality: instinct or acquired skill?

    PubMed

    Marcus, Gary F

    2012-10-01

    Is the human tendency toward musicality better thought of as the product of a specific, evolved instinct or an acquired skill? Developmental and evolutionary arguments are considered, along with issues of domain-specificity. The article also considers the question of why humans might be consistently and intensely drawn to music if musicality is not in fact the product of a specifically evolved instinct.

  17. Duplicated Information Acquired by Libraries.

    ERIC Educational Resources Information Center

    White, Carl M.

    The object of this study is to make a start toward determining the extent of duplicated information that is being acquired in spite of customary precautions to avoid it. Referring to a specific case, the percentages in Table II show the frequency of appearance in five other works of 19 items in Mitchell's "Encyclopedia of American Politics." While…

  18. Acquired aplastic anemia in children.

    PubMed

    Hartung, Helge D; Olson, Timothy S; Bessler, Monica

    2013-12-01

    This article provides a practice-based and concise review of the etiology, diagnosis, and management of acquired aplastic anemia in children. Bone marrow transplantation, immunosuppressive therapy, and supportive care are discussed in detail. The aim is to provide the clinician with a better understanding of the disease and to offer guidelines for the management of children with this uncommon yet serious disorder.

  19. Caudally directed Inferior facetal and transfacetal screws for C1-C2 and C1-2-3 fixation.

    PubMed

    Goel, Atul

    2017-01-13

    An alternative caudally directed C2 inferior facetal screw is described. Such screw insertion can form the axial stabilization point in cases undergoing atlantoaxial lateral mass plate/rod and screw fixation and those undergoing C1-2and C1-2-3 spinal fixation. The C2 screw courses from the medial point of pedicle-laminar junction and travels caudally and laterally towards the C2-3 articulation. Deploying a longer screw that traverses in a transarticular fashion into the facetal mass of C3 vertebra one can perform C1-2-3 stabilization.Sixteen patients underwent C2 inferior facetal or C2-3 transarticular screw in combination with C1 screw for atlantoaxial fixation. Three of these patients with multilevel spinal instability underwent atlantoaxial and C2-3 fixation using the discussed technique. The technical issues, anatomical subtleties and indication for the use of the C2 inferior facetal screws are discussed. With an average follow-up of 9 months, all screws have successfully provided stability that resulted in arthrodesis of the treated spinal segments. Caudally directed C2 inferior facetal screw can enhance the armamentarium of the surgeon, provide an alternative to conventional techniques or a bailout option and add to safety of the procedure of atlantoaxial lateral mass fixation in anatomically challenged situations.

  20. The effect of excision of the posterior arch of C1 on C1/C2 fusion using transarticular screws.

    PubMed

    Chang, K C; Samartzis, D; Fuego, S M; Dhatt, S S; Wong, Y W; Cheung, W Y; Luk, K D K; Cheung, K M C

    2013-07-01

    Transarticular screw fixation with autograft is an established procedure for the surgical treatment of atlantoaxial instability. Removal of the posterior arch of C1 may affect the rate of fusion. This study assessed the rate of atlantoaxial fusion using transarticular screws with or without removal of the posterior arch of C1. We reviewed 30 consecutive patients who underwent atlantoaxial fusion with a minimum follow-up of two years. In 25 patients (group A) the posterior arch of C1 was not excised (group A) and in five it was (group B). Fusion was assessed on static and dynamic radiographs. In selected patients CT imaging was also used to assess fusion and the position of the screws. There were 15 men and 15 women with a mean age of 51.2 years (23 to 77) and a mean follow-up of 7.7 years (2 to 11.6). Stable union with a solid fusion or a stable fibrous union was achieved in 29 patients (97%). In Group A, 20 patients (80%) achieved a solid fusion, four (16%) a stable fibrous union and one (4%) a nonunion. In Group B, stable union was achieved in all patients, three having a solid fusion and two a stable fibrous union. There was no statistically significant difference between the status of fusion in the two groups. Complications were noted in 12 patients (40%); these were mainly related to the screws, and included malpositioning and breakage. The presence of an intact or removed posterior arch of C1 did not affect the rate of fusion in patients with atlantoaxial instability undergoing C1/C2 fusion using transarticular screws and autograft.

  1. C1 Hermite shape preserving polynomial splines in R3

    NASA Astrophysics Data System (ADS)

    Gabrielides, Nikolaos C.

    2012-06-01

    The C 2 variable degree splines1-3 have been proven to be an efficient tool for solving the curve shape-preserving interpolation problem in two and three dimensions. Based on this representation, the current paper proposes a Hermite interpolation scheme, to construct C 1 shape-preserving splines of variable degree. After this, a slight modification of the method leads to a C 1 shape-preserving Hermite cubic spline. Both methods can easily be developed within a CAD system, since they compute directly (without iterations) the B-spline control polygon. They have been implemented and tested within the DNV Software CAD/CAE system GeniE. [Figure not available: see fulltext.

  2. Acquired Hemophilia A: A Frequently Overlooked Autoimmune Hemorrhagic Disorder

    PubMed Central

    Takeda, Tomohiro

    2014-01-01

    Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII-) neutralizing antibodies (inhibitors) impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed. PMID:24741588

  3. Acquired hemophilia A: a frequently overlooked autoimmune hemorrhagic disorder.

    PubMed

    Sakurai, Yoshihiko; Takeda, Tomohiro

    2014-01-01

    Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII-) neutralizing antibodies (inhibitors) impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed.

  4. Nursing home-acquired pneumonia.

    PubMed

    El Solh, Ali A

    2009-02-01

    Nursing home-acquired pneumonia (NHAP) was first described in 1978. Since then there has been much written regarding NHAP and its management despite the lack of well-designed studies in this patient population. The most characteristic features of patients with NHAP are the atypical presentation, which may lead to delay in diagnosis and therapy. The microbial etiology of pneumonia encompasses a wide spectrum that spans microbes recovered from patients with community-acquired pneumonia to organisms considered specific only to nosocomial settings. Decision to transfer a nursing home patient to an acute care facility depends on a host of factors, which include the level of staffing available at the nursing home, patients' advance directives, and complexity of treatment. The presence of risk factors for multidrug-resistant pathogens dictates approach to therapy. Prevention remains the cornerstone of reducing the incidence of disease. Despite the advance in medical services, mortality from NHAP remains high.

  5. Occupationally Acquired American Cutaneous Leishmaniasis

    PubMed Central

    Felinto de Brito, Maria Edileuza; Andrade, Maria Sandra; de Almeida, Éricka Lima; Medeiros, Ângela Cristina Rapela; Werkhäuser, Roberto Pereira; de Araújo, Ana Isabele Freitas; Brandão-Filho, Sinval Pinto; Paiva de Almeida, Alzira Maria; Gomes Rodrigues, Eduardo Henrique

    2012-01-01

    We report two occupationally acquired cases of American cutaneous leishmaniasis (ACL): one accidental laboratory autoinoculation by contaminated needlestick while handling an ACL lesion sample, and one acquired during field studies on bird biology. Polymerase chain reaction (PCR) assays of patient lesions were positive for Leishmania, subgenus Viannia. One isolate was obtained by culture (from patient 2 biopsy samples) and characterized as Leishmania (Viannia) naiffi through an indirect immunofluorescence assay (IFA) with species-specific monoclonal antibodies (mAbs) and by multilocus enzyme electrophoresis (MLEE). Patients were successfully treated with N-methyl-glucamine. These two cases highlight the potential risks of laboratory and field work and the need to comply with strict biosafety procedures in daily routines. The swab collection method, coupled with PCR detection, has greatly improved ACL laboratory diagnosis. PMID:23227369

  6. [Acquired disorders of color vision].

    PubMed

    Lascu, Lidia; Balaş, Mihaela

    2002-01-01

    This article is a general view of acquired disorders of color vision. The revision of the best known methods and of the etiopathogenic classification is not very important in ophthalmology but on the other hand, the detection of the blue defect advertise and associated ocular pathology. There is a major interest in serious diseases as multiple sclerosis, AIDS, diabetes melitus, when the first ocular sign can be a defect in the color vision.

  7. Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system.

    PubMed Central

    Garnier, Gérard; Circolo, Antonella; Xu, Yuanyuan; Volanakis, John E

    2003-01-01

    C1r and C1s are the serine proteases that form the catalytic unit of the C1 complex, the first component of complement. In the present study, we found that the genes encoding murine C1r and C1s are duplicated. One set of these genes, referred to as c1rA and c1sA, are primarily expressed in the liver and are therefore the homologues of the human C1r and C1s genes. The other two genes, termed c1rB and c1sB, are expressed exclusively in male reproductive tissues, specifically the coagulating gland and the prostate. The predicted C1rB and C1sB proteins share 96 and 93% amino acid identity with C1rA and C1sA respectively. Most of the substitutions are clustered in the serine protease domains, suggesting differences in catalytic efficiencies and/or substrate specificities or alternatively adaptation to different physiological environments. The high homology of C1rB and C1sB with C1rA and C1sA in the non-catalytic regions indicates that they are probably capable of assembling the C1 complex. The expression of alternative genes encoding isomorphs of activating components of complement in male reproductive tissues raises the possibility of new mechanisms of complement activation in the male genital tract or of novel functions for complement proteases in reproduction. PMID:12513694

  8. Reduction of CO2 to C1 products and fuel

    USGS Publications Warehouse

    Mill, T.; Ross, D.

    2002-01-01

    Photochemical semiconductor processes readily reduced CO2 to a broad range of C1 products. However the intrinsic and solar efficiencies for the processes were low. Improved quantum efficiencies could be realized utilizing quantum-sized particles, but at the expense of using less of the visible solar spectrum. Conversely, semiconductors with small bandgaps used more of the visible solar spectrum at the expense of quantum efficiency. Thermal reduction of CO2 with Fe(II) was thermodynamically favored for forming many kinds of organic compounds and occurred readily with olivine and other Fe(II) minerals above 200??C to form higher alkanes and alkenes. No added hydrogen was required.

  9. C1-Cx revisited: intramolecular synergism in a cellulase.

    PubMed Central

    Din, N; Damude, H G; Gilkes, N R; Miller, R C; Warren, R A; Kilburn, D G

    1994-01-01

    Endoglucanase A (CenA) from the bacterium Cellulomonas fimi is composed of a catalytic domain and a nonhydrolytic cellulose-binding domain that can function independently. The individual domains interact synergistically in the disruption and hydrolysis of cellulose fibers. This intramolecular synergism is distinct from the well-known intermolecular synergism between individual cellulases. The catalytic domain corresponds to the hydrolytic Cx system and the cellulose-binding domain corresponds to the nonhydrolytic C1 system postulated by Reese et al. [Reese, E. T., Sui, R. G. H. & Levinson, H. S. (1950) J. Bacteriol. 59, 485-497] to be required for the hydrolysis of cellulose. PMID:7972069

  10. Refinable C(1) spline elements for irregular quad layout.

    PubMed

    Nguyen, Thien; Peters, Jörg

    2016-03-01

    Building on a result of U. Reif on removable singularities, we construct C(1) bi-3 splines that may include irregular points where less or more than four tensor-product patches meet. The resulting space complements PHT splines, is refinable and the refined spaces are nested, preserving for example surfaces constructed from the splines. As in the regular case, each quadrilateral has four degrees of freedom, each associated with one spline and the splines are linearly independent. Examples of use for surface construction and isogeometric analysis are provided.

  11. Posterior arch C-1 screw technique: a cadaveric comparison study.

    PubMed

    Moisi, Marc; Fisahn, Christian; Tkachenko, Lara; Jeyamohan, Shiveindra; Reintjes, Stephen; Grunert, Peter; Norvell, Daniel C; Tubbs, R Shane; Page, Jeni; Newell, David W; Nora, Peter; Oskouian, Rod J; Chapman, Jens

    2017-03-17

    OBJECTIVE Posterior atlantoaxial stabilization and fusion using C-1 lateral mass screw fixation has become commonly used in the treatment of instability and for reconstructive indications since its introduction by Goel and Laheri in 1994 and modification by Harms in 2001. Placement of such lateral mass screws can be challenging because of the proximity to the spinal cord, vertebral artery, an extensive venous plexus, and the C-2 nerve root, which overlies the designated starting point on the posterior center of the lateral mass. An alternative posterior access point starting on the posterior arch of C-1 could provide a C-2 nerve root-sparing starting point for screw placement, with the potential benefit of greater directional control and simpler trajectory. The authors present a cadaveric study comparing an alternative strategy (i.e., a C-1 screw with a posterior arch starting point) to the conventional strategy (i.e., using the lower lateral mass entry site), specifically assessing the safety of screw placement to preserve the C-2 nerve root. METHODS Five US-trained spine fellows instrumented 17 fresh human cadaveric heads using the Goel/Harms C-1 lateral mass (GHLM) technique on the left and the posterior arch lateral mass (PALM) technique on the right, under fluoroscopic guidance. After screw placement, a CT scan was obtained on each specimen to assess for radiographic screw placement accuracy. Four faculty spine surgeons, blinded to the surgeon who instrumented the cadaver, independently graded the quality of screw placement using a modified Upendra classification. RESULTS Of the 17 specimens, the C-2 nerve root was anatomically impinged in 13 (76.5%) of the specimens. The GHLM technique was graded Type 1 or 2, which is considered "acceptable," in 12 specimens (70.6%), and graded Type 3 or 4 ("unacceptable") in 5 specimens (29.4%). In contrast, the PALM technique had 17 (100%) of 17 graded Type 1 or 2 (p = 0.015). There were no vertebral artery injuries found

  12. Centrosomal localisation of the cancer/testis (CT) antigens NY-ESO-1 and MAGE-C1 is regulated by proteasome activity in tumour cells.

    PubMed

    Pagotto, Anna; Caballero, Otavia L; Volkmar, Norbert; Devalle, Sylvie; Simpson, Andrew J G; Lu, Xin; Christianson, John C

    2013-01-01

    The Cancer/Testis (CT) antigen family of genes are transcriptionally repressed in most human tissues but are atypically re-expressed in many malignant tumour types. Their restricted expression profile makes CT antigens ideal targets for cancer immunotherapy. As little is known about whether CT antigens may be regulated by post-translational processing, we investigated the mechanisms governing degradation of NY-ESO-1 and MAGE-C1 in selected cancer cell lines. Inhibitors of proteasome-mediated degradation induced the partitioning of NY-ESO-1 and MAGE-C1 into a detergent insoluble fraction. Moreover, this treatment also resulted in increased localisation of NY-ESO-1 and MAGE-C1 at the centrosome. Despite their interaction, relocation of either NY-ESO-1 or MAGE-C1 to the centrosome could occur independently of each other. Using a series of truncated fragments, the regions corresponding to NY-ESO-1(91-150) and MAGE-C1(900-1116) were established as important for controlling both stability and localisation of these CT antigens. Our findings demonstrate that the steady state levels of NY-ESO-1 and MAGE-C1 are regulated by proteasomal degradation and that both behave as aggregation-prone proteins upon accumulation. With proteasome inhibitors being increasingly used as front-line treatment in cancer, these data raise issues about CT antigen processing for antigenic presentation and therefore immunogenicity in cancer patients.

  13. Acquired Upper Extremity Growth Arrest.

    PubMed

    Gauger, Erich M; Casnovsky, Lauren L; Gauger, Erica J; Bohn, Deborah C; Van Heest, Ann E

    2016-09-29

    This study reviewed the clinical history and management of acquired growth arrest in the upper extremity in pediatric patients. The records of all patients presenting from 1996 to 2012 with radiographically proven acquired growth arrest were reviewed. Records were examined to determine the etiology and site of growth arrest, management, and complications. Patients with tumors or hereditary etiology were excluded. A total of 44 patients (24 boys and 20 girls) with 51 physeal arrests who presented at a mean age of 10.6 years (range, 0.8-18.2 years) were included in the study. The distal radius was the most common site (n=24), followed by the distal humerus (n=8), metacarpal (n=6), distal ulna (n=5), proximal humerus (n=4), radial head (n=3), and olecranon (n=1). Growth arrest was secondary to trauma (n=22), infection (n=11), idiopathy (n=6), inflammation (n=2), compartment syndrome (n=2), and avascular necrosis (n=1). Twenty-six patients (59%) underwent surgical intervention to address deformity caused by the physeal arrest. Operative procedures included ipsilateral unaffected bone epiphysiodesis (n=21), shortening osteotomy (n=10), lengthening osteotomy (n=8), excision of physeal bar or bone fragment (n=2), angular correction osteotomy (n=1), and creation of single bone forearm (n=1). Four complications occurred; 3 of these required additional procedures. Acquired upper extremity growth arrest usually is caused by trauma or infection, and the most frequent site is the distal radius. Growth disturbances due to premature arrest can be treated effectively with epiphysiodesis or osteotomy. In this series, the specific site of anatomic growth arrest was the primary factor in determining treatment. [Orthopedics. 201x; xx(x):xx-xx.].

  14. The inhibition of acquired fear.

    PubMed

    Izquierdo, Iván; Cammarota, Martín; Vianna, Mónica M R; Bevilaqua, Lía R M

    2004-01-01

    A conditioned stimulus (CS) associated with a fearsome unconditioned stimulus (US) generates learned fear. Acquired fear is at the root of a variety of mental disorders, among which phobias, generalized anxiety, the posttraumatic stress disorder (PTSD) and some forms of depression. The simplest way to inhibit learned fear is to extinguish it, which is usually done by repeatedly presenting the CS alone, so that a new association, CS-"no US", will eventually overcome the previously acquired CS-US association. Extinction was first described by Pavlov as a form of "internal inhibition" and was recommended by Freud and Ferenczi in the 1920s (who called it "habituation") as the treatment of choice for phobic disorders. It is used with success till this day, often in association with anxiolytic drugs. Extinction has since then been applied, also successfully and also often in association with anxiolytics, to the treatment of panic, generalized anxiety disorders and, more recently, PTSD. Extinction of learned fear involves gene expression, protein synthesis, N-methyl-D-aspartate (NMDA) receptors and signaling pathways in the hippocampus and the amygdala at the time of the first CS-no US association. It can be enhanced by increasing the exposure to the "no US" component at the time of behavioral testing, to the point of causing the complete uninstallment of the original fear response. Some theorists have recently proposed that reiteration of the CS alone may induce a reconsolidation of the learned behavior instead of its extinction. Reconsolidation would preserve the original memory from the labilization induced by its retrieval. If true, this would of course be disastrous for the psychotherapy of fear-motivated disorders. Here we show that neither the CS nor retrieval cause anything remotely like reconsolidation, but just extinction. In fact, our findings indicate that the reconsolidation hypothesis is essentially incorrect, at least for the form of contextual fear most

  15. Analysis of the Interaction between Globular Head Modules of Human C1q and Its Candidate Receptor gC1qR

    PubMed Central

    Pednekar, Lina; Pathan, Ansar A.; Paudyal, Basudev; Tsolaki, Anthony G.; Kaur, Anuvinder; Abozaid, Suhair M.; Kouser, Lubna; Khan, Haseeb A.; Peerschke, Ellinor I.; Shamji, Mohamed H.; Stenbeck, Gudrun; Ghebrehiwet, Berhane; Kishore, Uday

    2016-01-01

    The heterotrimeric globular head (gC1q) domain of human C1q is made up of the C-terminal ends of the three individual chains, ghA, ghB, and ghC. A candidate receptor for the gC1q domain is a multi-functional pattern recognition protein, gC1qR. Since understanding of gC1qR and gC1q interaction could provide an insight into the pleiotropic functions of gC1qR, this study was undertaken to identify the gC1qR-binding site on the gC1q domain, using the recombinant ghA, ghB, and ghC modules and their substitution mutants. Our results show that ghA, ghB, and ghC modules can interact with gC1qR independently, thus reinforcing the notion of modularity within the gC1q domain of human C1q. Mutational analysis revealed that while Arg162 in the ghA module is central to interaction between gC1qR and C1q, a single amino acid substitution (arginine to glutamate) in residue 114 of the ghB module resulted in enhanced binding. Expression of gC1qR and C1q in adherent monocytes with or without pro-inflammatory stimuli was also analyzed by qPCR; it showed an autocrine/paracrine basis of C1q and gC1qR interaction. Microscopic studies revealed that C1q and gC1qR are colocalized on PBMCs. Cell proliferation assays indicated that ghA, ghB, and ghC modules were able to attenuate phytohemagglutinin-stimulated proliferation of PBMCs. Addition of gC1qR had an additive effect on the anti-proliferative effect of globular head modules. In summary, our results identify residues involved in C1q-gC1qR interaction and explain, to a certain level, their involvement on the immune cell surface, which is relevant for C1q-induced functions including inflammation, infection, and immunity. PMID:28018340

  16. Analysis of the Interaction between Globular Head Modules of Human C1q and Its Candidate Receptor gC1qR.

    PubMed

    Pednekar, Lina; Pathan, Ansar A; Paudyal, Basudev; Tsolaki, Anthony G; Kaur, Anuvinder; Abozaid, Suhair M; Kouser, Lubna; Khan, Haseeb A; Peerschke, Ellinor I; Shamji, Mohamed H; Stenbeck, Gudrun; Ghebrehiwet, Berhane; Kishore, Uday

    2016-01-01

    The heterotrimeric globular head (gC1q) domain of human C1q is made up of the C-terminal ends of the three individual chains, ghA, ghB, and ghC. A candidate receptor for the gC1q domain is a multi-functional pattern recognition protein, gC1qR. Since understanding of gC1qR and gC1q interaction could provide an insight into the pleiotropic functions of gC1qR, this study was undertaken to identify the gC1qR-binding site on the gC1q domain, using the recombinant ghA, ghB, and ghC modules and their substitution mutants. Our results show that ghA, ghB, and ghC modules can interact with gC1qR independently, thus reinforcing the notion of modularity within the gC1q domain of human C1q. Mutational analysis revealed that while Arg162 in the ghA module is central to interaction between gC1qR and C1q, a single amino acid substitution (arginine to glutamate) in residue 114 of the ghB module resulted in enhanced binding. Expression of gC1qR and C1q in adherent monocytes with or without pro-inflammatory stimuli was also analyzed by qPCR; it showed an autocrine/paracrine basis of C1q and gC1qR interaction. Microscopic studies revealed that C1q and gC1qR are colocalized on PBMCs. Cell proliferation assays indicated that ghA, ghB, and ghC modules were able to attenuate phytohemagglutinin-stimulated proliferation of PBMCs. Addition of gC1qR had an additive effect on the anti-proliferative effect of globular head modules. In summary, our results identify residues involved in C1q-gC1qR interaction and explain, to a certain level, their involvement on the immune cell surface, which is relevant for C1q-induced functions including inflammation, infection, and immunity.

  17. Resolution of C1q deposition but not of the clinical nephrotic syndrome after immunomodulating therapy in focal sclerosis

    PubMed Central

    Tibor Fülöp, Tibor; Csongrádi, Éva; Lerant, Anna A.; Lewin, Matthew; Lewin, Jack R.

    2015-01-01

    Background: The natural evolution of C1q nephropathy (C1qNP) during immunosuppressive treatment is relatively little studied or understood. Case Presentation: A 30 year-old Caucasian female was referred to us for further management of biopsy-proven C1qNP and severe nephrotic syndrome. Serologic work-up remained negative, including complement C3 and C4 levels and repeated testing for antinuclear antibodies. A renal biopsy revealed minimal change nephropathy vs. focal sclerosis on light microscopy and C1qNP on immunopathology. She has failed trials of high-dose oral prednisone, mycophenolate mofetil 1,500 mg twice a day and a subsequent regimen of monthly IV cyclophosphamide 750 mg × 9 cycles. She also received the maximum tolerated angiotensin-converting enzyme inhibitor and spironolactone therapy. Random urine protein-to-creatinine (UPC) ratio predicted proteinuria in the range between 5-35 gm/day, while serum creatinine rose progressively from 1.0 mg/dL to 1.4 mg/dL (to convert to μmol/L, multiply by 88.4). A decision was made to repeat renal biopsy to reassess the underlying histology. The biopsy revealed focal sclerosis but no C1q deposition. Conclusions: Our case illustrates at least two points: first, an established pathologic diagnosis does not obviate the need for repeated renal biopsy later on, should diagnostic uncertainty persist. Second, histological diagnoses may evolve over time, especially in a patient receiving active and powerful immune-modulating treatment. In our case, the clinical nephrosis did not change with immunosuppressive therapy while C1q deposition ceased, making this latter entity likely the immunologically mediated process. PMID:25964890

  18. Foodborne listeriosis acquired in hospitals.

    PubMed

    Silk, Benjamin J; McCoy, Morgan H; Iwamoto, Martha; Griffin, Patricia M

    2014-08-15

    Listeriosis is characterized by bacteremia or meningitis. We searched for listeriosis case series and outbreak investigations published in English by 2013, and assessed the strength of evidence for foodborne acquisition among patients who ate hospital food. We identified 30 reports from 13 countries. Among the case series, the median proportion of cases considered to be hospital-acquired was 25% (range, 9%-67%). The median number of outbreak-related illnesses considered to be hospital-acquired was 4.0 (range, 2-16). All patients were immunosuppressed in 18 of 24 (75%) reports with available data. Eight outbreak reports with strong evidence for foodborne acquisition in a hospital implicated sandwiches (3 reports), butter, precut celery, Camembert cheese, sausage, and tuna salad (1 report each). Foodborne acquisition of listeriosis among hospitalized patients is well documented internationally. The number of listeriosis cases could be reduced substantially by establishing hospital policies for safe food preparation for immunocompromised patients and by not serving them higher-risk foods.

  19. [Acquired platelet function disorders: pathogenesis, classification, frequency, diagnosis, clinical management].

    PubMed

    Scharf, R E

    2008-12-01

    Given the high consumption of pharmacological agents in western societies, it is not surprising at all that drugs represent the most common cause of acquired platelet dysfunction. While acetylsalicylic acid, clopigogrel and integrin alphaIIbbeta3 (GPIIb-IIIa) receptor antagonists are well-known as prototypes of antiplatelet drugs, other widely used agents including non-steroidal anti-inflammatory drugs, antibiotics, serotonin reuptake inhibitors, and volume expanders can also impair platelet function and cause or aggravate haemorrhages. Besides pharmacological agents, certain clinical conditions are often associated with qualitative platelet disorders and bleeding diathesis. Consequently, in contrast to inherited platelet disorders, acquired platelet function defects are much more frequent in clinical practice and deserve special attention. Their pathogenesis is widespread and heterogeneous with various, sometimes overlapping abnormalities. Moreover, acquired platelet dysfunctions can occur at any age and range in severity from mild to life-threatening haemorrhages. Due to their heterogeneity, acquired platelet function disorders will be classified and discussed according to the underlying clinical setting or disease.

  20. Interaction of HmC1q with leech microglial cells: involvement of C1qBP-related molecule in the induction of cell chemotaxis

    PubMed Central

    2012-01-01

    Background In invertebrates, the medicinal leech is considered to be an interesting and appropriate model to study neuroimmune mechanisms. Indeed, this non-vertebrate animal can restore normal function of its central nervous system (CNS) after injury. Microglia accumulation at the damage site has been shown to be required for axon sprouting and for efficient regeneration. We characterized HmC1q as a novel chemotactic factor for leech microglial cell recruitment. In mammals, a C1q-binding protein (C1qBP alias gC1qR), which interacts with the globular head of C1q, has been reported to participate in C1q-mediated chemotaxis of blood immune cells. In this study, we evaluated the chemotactic activities of a recombinant form of HmC1q and its interaction with a newly characterized leech C1qBP that acts as its potential ligand. Methods Recombinant HmC1q (rHmC1q) was produced in the yeast Pichia pastoris. Chemotaxis assays were performed to investigate rHmC1q-dependent microglia migration. The involvement of a C1qBP-related molecule in this chemotaxis mechanism was assessed by flow cytometry and with affinity purification experiments. The cellular localization of C1qBP mRNA and protein in leech was investigated using immunohistochemistry and in situ hybridization techniques. Results rHmC1q-stimulated microglia migrate in a dose-dependent manner. This rHmC1q-induced chemotaxis was reduced when cells were preincubated with either anti-HmC1q or anti-human C1qBP antibodies. A C1qBP-related molecule was characterized in leech microglia. Conclusions A previous study showed that recruitment of microglia is observed after HmC1q release at the cut end of axons. Here, we demonstrate that rHmC1q-dependent chemotaxis might be driven via a HmC1q-binding protein located on the microglial cell surface. Taken together, these results highlight the importance of the interaction between C1q and C1qBP in microglial activation leading to nerve repair in the medicinal leech. PMID:22356764

  1. Autophagy inhibitors.

    PubMed

    Pasquier, Benoit

    2016-03-01

    Autophagy is a lysosome-dependent mechanism of intracellular degradation. The cellular and molecular mechanisms underlying this process are highly complex and involve multiple proteins, including the kinases ULK1 and Vps34. The main function of autophagy is the maintenance of cell survival when modifications occur in the cellular environment. During the past decade, extensive studies have greatly improved our knowledge and autophagy has exploded as a research field. This process is now widely implicated in pathophysiological processes such as cancer, metabolic, and neurodegenerative disorders, making it an attractive target for drug discovery. In this review, we will summarize the different types of inhibitors that affect the autophagy machinery and provide some potential therapeutic perspectives.

  2. Overview of GCOM-C1/SGLI science

    NASA Astrophysics Data System (ADS)

    Honda, Yoshiaki; Kajiwara, Koji; Sharma, Ram; Ono, Akiko; Imaoka, Kenji; Murakami, Hiroshi; Hori, Masahiro; Ono, Yusaku; Rostand, Dim

    2012-11-01

    For monitoring of global environmental change, the Japan Aerospace Exploration Agency (JAXA) has made a new plan of Global Change Observation Mission (GCOM). SGLI (Second Generation GLI) onboard GCOM-C (Climate) satellite, which is one of this mission, provides an optical sensor from Near-UV to TIR. Characteristic specifications of SGLI are as follows; 1) 250m resolutions over land and area along the shore, 2) Three directional polarization observation (red and NIR), and 3) 500m resolutions temperature over land and area along shore. These characteristics are useful in many fields of social benefits. In addition, 51 products will be made by mainly 35 principal investigators. We introduce the overview of GCOM-C1/SGLI science.

  3. Plasma enhanced C1 chemistry for green technology

    NASA Astrophysics Data System (ADS)

    Nozaki, Tomohiro

    2013-09-01

    Plasma catalysis is one of the innovative next generation green technologies that meet the needs for energy and materials conservation as well as environmental protection. Non-thermal plasma uniquely generates reactive species independently of reaction temperature, and these species are used to initiate chemical reactions at unexpectedly lower temperatures than normal thermochemical reactions. Non-thermal plasma thus broadens the operation window of existing chemical conversion processes, and ultimately allows modification of the process parameters to minimize energy and material consumption. We have been specifically focusing on dielectric barrier discharge (DBD) as one of the viable non-thermal plasma sources for practical fuel reforming. In the presentation, room temperature one-step conversion of methane to methanol and hydrogen using a miniaturized DBD reactor (microplasma reactor) is highlighted. The practical impact of plasma technology on existing C1-chemistry is introduced, and then unique characteristics of plasma fuel reforming such as non-equilibrium product distribution is discussed.

  4. C1,1 regularity for degenerate elliptic obstacle problems

    NASA Astrophysics Data System (ADS)

    Daskalopoulos, Panagiota; Feehan, Paul M. N.

    2016-03-01

    The Heston stochastic volatility process is a degenerate diffusion process where the degeneracy in the diffusion coefficient is proportional to the square root of the distance to the boundary of the half-plane. The generator of this process with killing, called the elliptic Heston operator, is a second-order, degenerate-elliptic partial differential operator, where the degeneracy in the operator symbol is proportional to the distance to the boundary of the half-plane. In mathematical finance, solutions to the obstacle problem for the elliptic Heston operator correspond to value functions for perpetual American-style options on the underlying asset. With the aid of weighted Sobolev spaces and weighted Hölder spaces, we establish the optimal C 1 , 1 regularity (up to the boundary of the half-plane) for solutions to obstacle problems for the elliptic Heston operator when the obstacle functions are sufficiently smooth.

  5. A Selection of Recent Advances in C1 Chemistry.

    PubMed

    Mesters, Carl

    2016-06-07

    This review presents a selection of recent publications related to the chemistry and catalysis of C1 molecules, including methane, methanol, carbon monoxide, and carbon dioxide. These molecules play an important role in the current supply of energy and chemicals and will likely become even more relevant because of the need to decarbonize fuels (shift from coal to natural gas) in line with CO2 capture and use to mitigate global warming, as well as a gradual shift on the supply side from crude oil to natural gas. This review includes both recent industrial developments, such as the huge increase in methanol-to-olefins-capacity build in China and the demonstration of oxidative coupling of methane, and scientific developments in these chemistries facilitated by improved capabilities in, for example, analytical tools and computational modeling.

  6. Bejel: acquirable only in childhood?

    PubMed

    Rothschild, Bruce M; Rothschild, Christine; Naples, Virginia; Billard, Michel; Panero, Barbara

    2006-10-01

    Bejel clearly has a long history in the Middle East and the Sudan, but was it transmitted to Europe? As the major manifestation of bejel is presence of periosteal reaction in 20-40% of afflicted populations, absence of significant population frequency of periosteal reaction in Europe would exclude that diagnosis. Examination of skeletal populations from continental Europe revealed no significant periosteal reaction at the time of and immediately subsequent to the Crusades. Thus, there is no evidence for bejel in Europe, in spite of clear contact (the mechanism of bejel transmission in children) between warring groups, at least during the Crusades. This supports the hypothesis that bejel is a childhood-acquired disease and apparently cannot be contracted in adulthood.

  7. 75 FR 53861 - Airworthiness Directives; Robert E. Rust, Jr. Model DeHavilland DH.C1 Chipmunk 21, DH.C1 Chipmunk...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-02

    ...-025-AD; Amendment 39-16426; AD 2010-18-01] RIN 2120-AA64 Airworthiness Directives; Robert E. Rust, Jr... adopting a new airworthiness directive (AD) for all Robert E. Rust, Jr. Models DeHavilland DH.C1 Chipmunk... Robert E. Rust, Jr. Models DeHavilland DH.C1 Chipmunk 21, DH.C1 Chipmunk 22, and DH.C1 Chipmunk...

  8. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  9. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  10. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  11. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  12. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  13. Acquired haemophilia in recipients of depot thioxanthenes.

    PubMed

    Stewart, A J; Manson, L M; Dasani, H; Beddall, A; Collins, P; Shima, M; Ludlam, C A

    2000-11-01

    We present two cases in which the occurrence of acquired haemophilia is associated with the use of depot preparations of the thioxanthenes zuclopenthixol and flupenthixol. These drugs have not previously been implicated in the aetiology of acquired haemophilia.

  14. Acquiring Evolving Technologies: Web Services Standards

    DTIC Science & Technology

    2016-06-30

    2006 Carnegie Mellon University Acquiring Evolving Technologies : Web Services Standards Harry L. Levinson Software Engineering Institute Carnegie...Acquiring Evolving Technologies : Web Services Standards 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 2 Acquiring Evolving Technologies : Web Services Standards © 2006 Carnegie Mellon University Acquiring

  15. Targeting Atp6v1c1 Prevents Inflammation and Bone Erosion Caused by Periodontitis and Reveals Its Critical Function in Osteoimmunology.

    PubMed

    Li, Sheng; Hao, Liang; Wang, Lin; Lu, Yun; Li, Qian; Zhu, Zheng; Shao, Jian-Zhong; Chen, Wei

    2015-01-01

    Periodontal disease (Periodontitis) is a serious disease that affects a majority of adult Americans and is associated with other systemic diseases, including diabetes, rheumatoid arthritis, and other inflammatory diseases. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this pervasive and destructive disease. In this study, we utilized novel adeno-associated virus (AAV)-mediated Atp6v1c1 knockdown gene therapy to treat bone erosion and inflammatory caused by periodontitis in mouse model. Atp6v1c1 is a subunit of the V-ATPase complex and regulator of the assembly of the V0 and V1 domains of the V-ATPase complex. We demonstrated previously that Atp6v1c1 has an essential function in osteoclast mediated bone resorption. We hypothesized that Atp6v1c1 may be an ideal target to prevent the bone erosion and inflammation caused by periodontitis. To test the hypothesis, we employed AAV RNAi knockdown of Atp6v1c1 gene expression to prevent bone erosion and gingival inflammation simultaneously. We found that lesion-specific injection of AAV-shRNA-Atp6v1c1 into the periodontal disease lesions protected against bone erosion (>85%) and gingival inflammation caused by P. gingivalis W50 infection. AAV-mediated Atp6v1c1 knockdown dramatically reduced osteoclast numbers and inhibited the infiltration of dendritic cells and macrophages in the bacteria-induced inflammatory lesions in periodontitis. Silencing of Atp6v1c1 expression also prevented the expressions of osteoclast-related genes and pro-inflammatory cytokine genes. Our data suggests that AAV-shRNA-Atp6v1c1 treatment can significantly attenuate the bone erosion and inflammation caused by periodontitis, indicating the dual function of AAV-shRNA-Atp6v1c1 as an inhibitor of bone erosion mediated by osteoclasts, and as an inhibitor of inflammation through down-regulation of pro

  16. Catalytic routes to fuels from C1 and oxygenate molecules.

    PubMed

    Wang, Shuai; Agirrezabal-Telleria, Iker; Bhan, Aditya; Simonetti, Dante; Takanabe, Kazuhiro; Iglesia, Enrique

    2017-03-16

    This account illustrates concepts in chemical kinetics underpinned by the formalism of transition state theory using catalytic processes that enable the synthesis of molecules suitable as fuels from C1 and oxygenate reactants. Such feedstocks provide an essential bridge towards a carbon-free energy future, but their volatility and low energy density require the formation of new C-C bonds and the removal of oxygen. These transformations are described here through recent advances in our understanding of the mechanisms and site requirements in catalysis by surfaces, with emphasis on enabling concepts that tackle ubiquitous reactivity and selectivity challenges. The hurdles in forming the first C-C bond from C1 molecules are illustrated by the oxidative coupling of methane, in which surface O-atoms form OH radicals from O2 and H2O molecules. These gaseous OH species act as strong H-abstractors and activate C-H bonds with earlier transition states than oxide surfaces, thus rendering activation rates less sensitive to the weaker C-H bonds in larger alkane products than in CH4 reactants. Anhydrous carbonylation of dimethyl ether forms a single C-C bond on protons residing within inorganic voids that preferentially stabilize the kinetically-relevant transition state through van der Waals interactions that compensate for the weak CO nucleophile. Similar solvation effects, but by intrapore liquids instead of inorganic hosts, also become evident as alkenes condense within MCM-41 channels containing isolated Ni(2+) active sites during dimerization reactions. Intrapore liquids preferentially stabilize transition states for C-C bond formation and product desorption, leading to unprecedented reactivity and site stability at sub-ambient temperatures and to 1-alkene dimer selectivities previously achieved only on organometallic systems with co-catalysts or activators. C1 homologation selectively forms C4 and C7 chains with a specific backbone (isobutane, triptane) on solid acids

  17. Corticomotoneuronal function and hyperexcitability in acquired neuromyotonia.

    PubMed

    Vucic, Steve; Cheah, Benjamin C; Yiannikas, Con; Vincent, Angela; Kiernan, Matthew C

    2010-09-01

    Acquired neuromyotonia encompasses a group of inflammatory disorders characterized by symptoms reflecting peripheral nerve hyperexcitability, which may be clinically confused in the early stages with amyotrophic lateral sclerosis. Despite a clear peripheral nerve focus, it remains unclear whether the ectopic activity in acquired neuromyotonia receives a central contribution. To clarify whether cortical hyperexcitability contributes to development of clinical features of acquired neuromyotonia, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical hyperexcitability in acquired neuromyotonia, and whether this technique could differentiate acquired neuromyotonia from amyotrophic lateral sclerosis. Cortical excitability studies were undertaken in 18 patients with acquired neuromyotonia and 104 patients with amyotrophic lateral sclerosis, with results compared to 62 normal controls. Short-interval intracortical inhibition in patients with acquired neuromyotonia was significantly different when compared to patients with amyotrophic lateral sclerosis (averaged short interval intracortical inhibition acquired neuromyotonia 11.3 +/- 1.9%; amyotrophic lateral sclerosis 2.6 +/- 0.9%, P < 0.001). In addition, the motor evoked potential amplitudes (acquired neuromyotonia 21.0 +/- 3.1%; amyotrophic lateral sclerosis 38.1 +/- 2.2%, P < 0.0001), intracortical facilitation (acquired neuromyotonia -0.9 +/- 1.3%; amyotrophic lateral sclerosis -2.3 +/- 0.6%, P < 0.0001), resting motor thresholds (acquired neuromyotonia 62.2 +/- 1.6%; amyotrophic lateral sclerosis 57.2 +/- 0.9%, P < 0.05) and cortical silent period durations (acquired neuromyotonia 212.8 +/- 6.9 ms; amyotrophic lateral sclerosis 181.1 +/- 4.3 ms, P < 0.0001) were significantly different between patients with acquired neuromyotonia and amyotrophic lateral sclerosis. Threshold tracking transcranial magnetic stimulation established corticomotoneuronal integrity

  18. Forkhead Box C1 Regulates Human Primary Keratinocyte Terminal Differentiation

    PubMed Central

    Deng, Liehua; Yang, Hengwen; Zhu, Leqing; Wang, Xiao; Edwards, Michael G.; Richers, Brittany; Leung, Donald Y. M.

    2016-01-01

    The epidermis serves as a critical protective barrier between the internal and external environment of the human body. Its remarkable barrier function is established through the keratinocyte (KC) terminal differentiation program. The transcription factors specifically regulating terminal differentiation remain largely unknown. Using a RNA-sequencing (RNA-seq) profiling approach, we found that forkhead box c 1 (FOXC1) was significantly up-regulated in human normal primary KC during the course of differentiation. This observation was validated in human normal primary KC from several different donors and human skin biopsies. Silencing FOXC1 in human normal primary KC undergoing differentiation led to significant down-regulation of late terminal differentiation genes markers including epidermal differentiation complex genes, keratinization genes, sphingolipid/ceramide metabolic process genes and epidermal specific cell-cell adhesion genes. We further demonstrated that FOXC1 works down-stream of ZNF750 and KLF4, and upstream of GRHL3. Thus, this study defines FOXC1 as a regulator specific for KC terminal differentiation and establishes its potential position in the genetic regulatory network. PMID:27907090

  19. Near-ultraviolet spectroscopy of Comet Austin (1989c1)

    NASA Technical Reports Server (NTRS)

    Valk, Jacobus H.; O'Dell, C. R.; Cochran, Anita L.; Cochran, William D.; Opal, Chet B. S.; Barker, Edwin S.

    1992-01-01

    Comet Austin (1989c1) was observed post-perihelion at a heliocentric distance near 1.25 AU. The wavelength range was from the atmospheric cutoff at 3000 to 4000 A. The coma spectra were calibrated into flux units and the contaminating sky spectrum and solar scattered light continuum were subtracted, leaving an ultraviolet spectrum of about 1.5-A resolution and excellent signal-to-noise ratio. The spectrum is dominated by emissions from OH, NH, CH, C3, and CN, some of the weaker emissions of which are seen here for the first time. More bands of CO(2+) were found than in any previous investigation and several intensity anomalies were noted; H2CO, OH(+), NCN, N(2+), and CN(+) may be present. Several emission features well above the noise level remain unidentified. The relative intensities of the OH and CN bands agree with the predictions of resonance fluorescence when one considers the potential effects of contamination by other molecules. The effects of the ozone absorption spectrum are not fully removed by the data-reduction process, although this does not affect these results.

  20. Associative Learning Through Acquired Salience

    PubMed Central

    Treviño, Mario

    2016-01-01

    Most associative learning studies describe the salience of stimuli as a fixed learning-rate parameter. Presumptive saliency signals, however, have also been linked to motivational and attentional processes. An interesting possibility, therefore, is that discriminative stimuli could also acquire salience as they become powerful predictors of outcomes. To explore this idea, we first characterized and extracted the learning curves from mice trained with discriminative images offering varying degrees of structural similarity. Next, we fitted a linear model of associative learning coupled to a series of mathematical representations for stimulus salience. We found that the best prediction, from the set of tested models, was one in which the visual salience depended on stimulus similarity and a non-linear function of the associative strength. Therefore, these analytic results support the idea that the net salience of a stimulus depends both on the items' effective salience and the motivational state of the subject that learns about it. Moreover, this dual salience model can explain why learning about a stimulus not only depends on the effective salience during acquisition but also on the specific learning trajectory that was used to reach this state. Our mathematical description could be instrumental for understanding aberrant salience acquisition under stressful situations and in neuropsychiatric disorders like schizophrenia, obsessive-compulsive disorder, and addiction. PMID:26793078

  1. Inherited or acquired metabolic disorders.

    PubMed

    Eichler, Florian; Ratai, Eva; Carroll, Jason J; Masdeu, Joseph C

    2016-01-01

    This chapter starts with a description of imaging of inherited metabolic disorders, followed by a discussion on imaging of acquired toxic-metabolic disorders of the adult brain. Neuroimaging is crucial for the diagnosis and management of a number of inherited metabolic disorders. Among these, inherited white-matter disorders commonly affect both the nervous system and endocrine organs. Magnetic resonance imaging (MRI) has enabled new classifications of these disorders that have greatly enhanced both our diagnostic ability and our understanding of these complex disorders. Beyond the classic leukodystrophies, we are increasingly recognizing new hereditary leukoencephalopathies such as the hypomyelinating disorders. Conventional imaging can be unrevealing in some metabolic disorders, but proton magnetic resonance spectroscopy (MRS) may be able to directly visualize the metabolic abnormality in certain disorders. Hence, neuroimaging can enhance our understanding of pathogenesis, even in the absence of a pathologic specimen. This review aims to present pathognomonic brain MRI lesion patterns, the diagnostic capacity of proton MRS, and information from clinical and laboratory testing that can aid diagnosis. We demonstrate that applying an advanced neuroimaging approach enhances current diagnostics and management. Additional information on inherited and metabolic disorders of the brain can be found in Chapter 63 in the second volume of this series.

  2. Angioedema Related to Angiotensin-Converting Enzyme Inhibitors: Attack Severity, Treatment, and Hospital Admission in a Prospective Multicenter Study.

    PubMed

    Javaud, Nicolas; Achamlal, Jallal; Reuter, Paul-George; Lapostolle, Frédéric; Lekouara, Akim; Youssef, Mustapha; Hamza, Lilia; Karami, Ahmed; Adnet, Frédéric; Fain, Olivier

    2015-11-01

    The number of cases of acquired angioedema related to angiotensin converting enzyme inhibitors induced (ACEI-AAE) is on the increase, with a potential concomitant increase in life-threatening attacks of laryngeal edema. Our objective was to determine the main characteristics of ACEI-AAE attacks and, in doing so, the factors associated with likelihood of hospital admission from the emergency department (ED) after a visit for an attack.A prospective, multicenter, observational study (April 2012-December 2014) was conducted in EDs of 4 French hospitals in collaboration with emergency services (SAMU 93) and a reference center for bradykinin-mediated angioedema. For each patient presenting with an attack, emergency physicians collected demographic and clinical presentation data, treatments, and clinical course. They recorded time intervals from symptom onset to ED arrival and to treatment decision, from ED arrival to specific treatment with plasma-derived C1-inhibitor (C1-INH) or icatibant, and from specific treatment to onset of symptom relief. Attacks requiring hospital admission were compared with those not requiring admission.Sixty-two eligible patients with ACEI-AAE (56% men, median age 63 years) were included. Symptom relief occurred significantly earlier in patients receiving specific treatment than in untreated patients (0.5 [0.5-1.0] versus 3.9 [2.5-7.0] hours; P < 0.0001). Even though icatibant was injected more promptly than plasma-derived C1-INH, there, however, was no significant difference in median time to onset of symptom relief between the 2 drugs (0.5 [0.5-1.3] versus 0.5 [0.4-1.0] hours for C1-INH and icatibant, respectively, P = 0.49). Of the 62 patients, 27 (44%) were admitted to hospital from the ED. In multivariate analysis, laryngeal involvement and progressive swelling at ED arrival were independently associated with admission (Odds ratio [95% confidence interval] = 6.2 [1.3-28.2] and 5.9 [1.3-26.5], respectively). A favorable course

  3. Human C1qRp is identical with CD93 and the mNI-11 antigen but does not bind C1q.

    PubMed

    McGreal, Eamon P; Ikewaki, Nobunao; Akatsu, Hiroyasu; Morgan, B Paul; Gasque, Philippe

    2002-05-15

    It has been suggested that the human C1qRp is a receptor for the complement component C1q; however, there is no direct evidence for an interaction between C1q and C1qRp. In this study, we demonstrate that C1q does not show enhanced binding to C1qRp-transfected cells compared with control cells. Furthermore, a soluble recombinant C1qRp-Fc chimera failed to interact with immobilized C1q. The proposed role of C1qRp in the phagocytic response in vivo is also unsupported in that we demonstrate that this molecule is not expressed by macrophages in a variety of human tissues and the predominant site of expression is on endothelial cells. Studies on the rodent homolog of C1qRp, known as AA4, have suggested that this molecule may function as an intercellular adhesion molecule. Here we show that C1qRp is the Ag recognized by several previously described mAbs, mNI-11 and two anti-CD93 Abs (clones X2 and VIMD2b). Interestingly, mNI-11 (Fab') has been shown to promote monocyte-monocyte and monocyte-endothelial cell adhesive interactions. We produced a recombinant C1qRp-Fc chimera containing the C-type lectin-like domain of C1qRp and found specific binding to vascular endothelial cells in sections of inflamed human tonsil, indicating the presence of a C1qRp ligand at this site. This interaction was Ca(2+) independent and was not blocked by our anti-C1qRp mAb BIIG-4, but was blocked by the proadhesive mAb mNI-11. Collectively, these data indicate that C1qRp is not a receptor for C1q, and they support the emerging role of C1qRp (here renamed CD93) in functions relevant to intercellular adhesion.

  4. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND... Statements of Smaller Reporting Companies § 210.8-06 Real estate operations acquired or to be acquired....

  5. Acquired immune deficiency syndrome: review.

    PubMed

    Scully, C; Cawson, R A; Porter, S R

    1986-07-19

    Acquired immunodeficiency syndrome (AIDS) is reviewed for dental practitioners, with an emphasis on oral findings; the clinical course, diagnosis, reporting, treatment, prognosis, transmission, and epidemiology are also covered. HIV infection has an incubation period that may be associated with glandular fever, a prodrome called AIDS-Related Complex (ARC) characterized by lymphadenopathy, low fever, weight loss, night sweats, diarrhea, oral candidosis, nonproductive cough and recurrent infections. AIDS is characterized by opportunistic infections. Over 50% present with pneumocystis carinii pneumonia, 21% with Kaposi's sarcoma, and 6% have both. The AIDS virus causes direct neurological symptoms in some cases. Oral candidosis (thrush) in a young male without a local cause such as xerostomia or immune suppression is strongly suggestive of AIDS. Other oral manifestations are severe herpes simplex, varicella-zoster, Epstein-Barr virus, cytomegalovirus, venereal warts, aphthous ulceration, mycobacterial oral ulcers, oral histoplasmosis, sinusitis and osteomyelitis of the jaw. Hairy leukoplakia, usually seen on the lateral border of the tongue, is probably caused by Epstein-Barr virus. Kaposi's sarcoma, an endothelial cell tumor, is characteristic of AIDS, and in 50% of patients is oral or perioral. Cervical lymph node enlargement will be seen in those with ARC as well as AIDS. No guidelines have been issued by the Department of Health and Social Security for dental surgeons in the UK for reporting AIDS cases. Although HIV virions have been isolated from saliva, there are no known incidents of transmission via saliva. HIV is less likely to be transmitted by needle stick injuries than, for example hepatitis B (25% risk), especially if the blood is from a carrier rather than a full blown AIDS case.

  6. Clinicopathological associations of acquired erythroblastopenia

    PubMed Central

    Gunes, Gursel; Malkan, Umit Yavuz; Yasar, Hatime Arzu; Eliacik, Eylem; Haznedaroglu, Ibrahim Celalettin; Demiroglu, Haluk; Sayinalp, Nilgun; Aksu, Salih; Etgul, Sezgin; Aslan, Tuncay; Goker, Hakan; Ozcebe, Osman Ilhami; Buyukasik, Yahya

    2015-01-01

    Introduction: Acquired erythroblastopenia (AE) is a rare clinical situation. It is characterized by the reduction of erythroid precursors in the bone marrow together with the low reticulocyte counts in the peripheral blood. Background: Main secondary causes of AE are drugs, Parvovirus B19 and other infectious reasons, lymphoid and myeloid neoplasia, autoimmune diseases, thymoma and pregnancy. The aim of this study is to assess the frequencies and clinical associations of AE via analyzing 12340 bone marrow samples in a retrospective manner. Material and method: Bone marrow aspirations which were obtained from patients who applied to Hacettepe University Hematology Clinic between 2002 and 2013, were analyzed retrospectively. Results: Thirty four erythroblastopenia cases were found. Patients ranged in age from 16 to 80 years with a median of 38 years. Fifteen patients were men (44%) and nineteen were women (56%). In these patients, detected causes of erythroblastopenia were MDS, idiopathic pure red cell aplasia (PRCA), parvovirus infection, post chemotherapy aplasia, plasma proliferative diseases, copper deficiency due to secondary amyloidosis, fever of unknown origin, hemophagocytic syndrome, enteric fever and legionella pneumonia. We found that between those reasons the most common causes of erythroblastopenia are MDS (17.7%) and idiopathic PRCA (17.7%). Discussion: As a result, erythroblastopenia in the bone marrow may be an early sign of MDS. In those AE cases possibility of being MDS must be kept in mind as it can be mistaken for PRCA. Conclusion: To conclude, in adults MDS without excess blast is one of the most common causes of erythroblastopenia in clinical practice and in case of erythroblastopenia the presence of MDS should be investigated. PMID:26885236

  7. Necroptosis in Niemann–Pick disease, type C1: a potential therapeutic target

    PubMed Central

    Cougnoux, A; Cluzeau, C; Mitra, S; Li, R; Williams, I; Burkert, K; Xu, X; Wassif, C A; Zheng, W; Porter, F D

    2016-01-01

    Niemann–Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention. PMID:26986514

  8. Fabrication of dye-sensitized solar cells using chlorophylls c1 and c2 and their oxidized forms c1' and c2' from Undaria pinnatifida (Wakame)

    NASA Astrophysics Data System (ADS)

    Wang, Xiao-Feng; Zhan, Cong-Hong; Maoka, Takashi; Wada, Yuji; Koyama, Yasushi

    2007-10-01

    Two different types of chlorophyll c ( c1 and c2) and their oxidized forms ( c1' and c2') were isolated from a brown seaweed, Undaria pinnatifida, and their structures were determined by mass spectrometry and 1H NMR spectroscopy. The order of conversion efficiencies in titania-based solar cells using these chlorophyll sensitizers, i.e., c2(4.6%)>c1(3.4%)>c2'(2.6%)≧c1'(2.5%), were explained in terms of a more extended conjugated system and the resultant higher electron densities in Chl c2 than Chl c1 as well as the different configurations and electron densities of the vinyl carboxyl group in Chls c2' and c1'.

  9. The production and secretion of complement component C1q by human mast cells.

    PubMed

    van Schaarenburg, Rosanne A; Suurmond, Jolien; Habets, Kim L L; Brouwer, Mieke C; Wouters, Diana; Kurreeman, Fina A S; Huizinga, Tom W J; Toes, René E M; Trouw, Leendert A

    2016-10-01

    C1q is the initiation molecule of the classical pathway of the complement system and is produced by macrophages and immature dendritic cells. As mast cells share the same myeloid progenitor cells, we have studied whether also mast cells can produce and secrete C1q. Mast cells were generated in vitro from CD34+ progenitor cells from buffy coats or cord blood. Fully differentiated mast cells were shown by both RNA sequencing and qPCR to express C1QA, C1QB and C1QC. C1q produced by mast cells has a similar molecular make-up as serum C1q. Reconstituting C1q depleted serum with mast cell supernatant in haemolytic assays, indicated that C1q secreted by mast cells is functionally active. The level of C1q in supernatants produced under basal conditions was considerably enhanced upon stimulation with LPS, dexamethasone in combination with IFN- γ or via FcεRI triggering. Mast cells in human tissues stained positive for C1q in both healthy and in inflamed tissue. Moreover, mast cells in healthy and diseased skin appear to be the predominant C1q positive cells. Together, our data reveal that mast cells are able to produce and secrete functional active C1q and indicate mast cells as a local source of C1q in human tissue.

  10. Cryptosporidiosis in the acquired immune deficiency syndrome.

    PubMed

    Cooper, D A; Wodak, A; Marriot, D J; Harkness, J L; Ralston, M; Hill, A; Penny, R

    1984-10-01

    Cryptosporidiosis was found in a patient with the acquired immune deficiency syndrome. The microbiological and morphological features of this newly recognized opportunistic infection are distinctive and diagnostic.

  11. Inhibitors of Kallikrein in Human Plasma

    PubMed Central

    McConnell, David J.

    1972-01-01

    Human plasma was fractionated by ammonium sulfate precipitation, DEAE-cellulose chromatography, and Sephadex G-200 gel filtration to determine which method would give the greatest number of clearly separable kallikrein inhibitory peaks. With G-200 gel filtration three peaks could be separated which were demonstrated to contain α2-macroglobulin, C1̄ inactivator, and α1-antitrypsin. No other kallikrein inhibitors could be identified. The fractions containing C1̄ inactivator and α2-macroglobulin appeared to be more effective against kallikrein than that containing α1-antitrypsin. A patient with hereditary angioneurotic edema was shown to have an abnormal C1̄ inactivator protein capable of interfering with kallikrein's biologic, but not its esterolytic activity. Heat-treated human plasma, a commonly used source of kininogen for experiments with kallikrein, was shown to have kallikrein inhibitory activity. PMID:4113391

  12. Immunoadsorption for pregnancy-associated severe acquired hemophilia.

    PubMed

    Zeitler, Heike; Ulrich-Merzenich, Gudrun; Marquardt, Natascha; Oldenburg, Johannes; Goldmann, Georg

    2014-02-01

    Postpartum hemorrhage is a common cause of maternal mortality. Acquired hemophilia (AH) is a rare, life-threatening bleeding disorder induced by autoantibodies against coagulation factors (inhibitors). We report about eight patients with postpartum AH (out of 82). Seven AH patients with severe bleeding complications were treated by the "Modified Bonn-Malmö Protocol (MBMP)" which consists of inhibitor elimination via immunoadsorption (IA) in combination with immunosuppression and high-dose Factor VIII substitution. One patient was treated only by immunosuppression. Seven out of eight patients with severe AH and mean inhibitor titers (IT) of 118 BU/mL were referred to our center. They were severe cases with a median delay of diagnosis of 30.5 days (range 7-278 days). After a median of 3 IA sessions (range 3-5 days), no inhibitor was detectable. The factor substitution was discontinued after a median of 13 IA sessions (range 8-24 days) and IA was terminated after a median of 15 sessions (range 9-27 days). One less severe affected patient (IT: 2.1 BU/mL) received prednisolone (1.5 mg/kg BW) for 120 days. Complete remission was achieved in all patients with a median follow-up of 100 months (range 56-126 m). The delayed diagnosis of pregnancy-associated AH leads to a high bleeding risk with bleeding associated complications. Immunoadsorption offers an important treatment option in severe AH, enabling a fast reconstitution of the blood coagulation with a reduced time for the Factor VIII substitution and for immunosuppressive treatment. In cases of postpartum bleeding the diagnosis of AH should be routinely considered.

  13. Human diploid fibroblasts have receptors for the globular domain of C1Q

    SciTech Connect

    Bordin, S.; Page, R.C.

    1986-03-01

    The authors showed that mass cultures of fibroblasts grown from gingival explants in DB medium with 10% human serum are enriched in a phenotype that binds C1q with an affinity much higher than the rest of the population. Because of potential biologic importance of C1q receptors, the authors studied whether the interaction between C1q and this phenotype was mediated by the globular or collagenous domains of the molecule. Globular fragments were prepared by digesting C1q with collagenase, and collagenous fragments obtained after pepsin treatment. C1q binding on cells in suspension was determined by reaction with /sup 125/I-C1q as reported. Competition experiments were performed under conditions in which intact /sup 125/I-C1q binding saturated all available receptors. The results showed that collagenous fragments inhibited 20% of the /sup 125/I-C1q binding to high affinity receptors, whereas inhibition by globular fragments was 70%. Unlabeled intact C1q and collagen type 1 were used as controls, and inhibited 92% and 17% of C1q binding, respectively. These studies show that C1q interacts with the fibroblast phenotype expressing high affinity receptors through its globular domain. The authors suggest that at sites of trauma, native C1 may bind to the surface of these cells via the globular domain of C1q, and that this unique phenotype may play an important role in tissue repair.

  14. Acquiring and Managing Electronic Journals. ERIC Digest.

    ERIC Educational Resources Information Center

    Curtis, Donnelyn; Yue, Paoshan

    Electronic journals are both a blessing and a curse for libraries. To be meaningful in the current information environment--to meet users' ever-increasing demands--libraries must acquire as many appropriate full text resources as possible, as quickly as possible, and make them easy to use. This Digest provides tips for acquiring and providing…

  15. Acquired idiopathic generalized anhidrosis: case report.

    PubMed

    Brantley, Elise I; Mutasim, Diya F; Heaton, Charles

    2011-01-01

    We report a case of acquired idiopathic generalized anhidrosis (AIGA) in a 56-year-old white woman. Acquired idiopathic generalized anhidrosis is an exceedingly rare group of heterogeneous disorders that has been almost exclusively reported in young Japanese males. Our case is unique in that AlGA may be underrecognized in this patient population.

  16. 26 CFR 1.860C-1 - Taxation of holders of residual interests.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 9 2010-04-01 2010-04-01 false Taxation of holders of residual interests. 1.860C-1 Section 1.860C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Real Estate Investment Trusts § 1.860C-1 Taxation of...

  17. 26 CFR 301.6230(c)-1 - Claim arising out of erroneous computation, etc.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Claim arising out of erroneous computation, etc. 301.6230(c)-1 Section 301.6230(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE....6230(c)-1 Claim arising out of erroneous computation, etc. (a) In general. A claim for refund...

  18. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter...

  19. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter...

  20. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter...

  1. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter of section 673... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF...

  2. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter of... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF...

  3. 17 CFR 270.23c-1 - Repurchase of securities by closed-end companies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... closed-end companies. 270.23c-1 Section 270.23c-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.23c-1 Repurchase of securities by closed-end companies. (a) A registered closed-end company may purchase for cash...

  4. 26 CFR 1.674(c)-1 - Excepted powers exercisable only by independent trustees.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... trustees. 1.674(c)-1 Section 1.674(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... § 1.674(c)-1 Excepted powers exercisable only by independent trustees. Section 674(c) provides an exception to the general rule of section 674(a) for certain powers that are exercisable by...

  5. 26 CFR 1.674(c)-1 - Excepted powers exercisable only by independent trustees.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... trustees. 1.674(c)-1 Section 1.674(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.674(c)-1 Excepted powers exercisable only by independent trustees. Section 674(c) provides an exception to the general rule of section 674(a) for certain powers that are exercisable...

  6. Acquired factor VIII deficiency associated with a novel primary immunodeficiency suggestive of autosomal recessive hyper IgE syndrome.

    PubMed

    Ozgur, Tuba Turul; Asal, Gulten Turkkan; Gurgey, Aytemiz; Tezcan, Ilhan; Ersoy, Fugen; Sanal, Ozden

    2007-05-01

    Primary immunodeficiency diseases (PID) are associated with various autoimmune complications and several manifestations of autoimmunity can be seen in the disorders of T cells, B cells, phagocytes, and complement components. Acquired hemophilia is a rare entity in childhood. Although autoantibodies may develop in various forms of PID, Factor VIII (FVIII) inhibitors have not been described before. Herein, we present a case of acquired hemophilia resulting from FVIII inhibitors who had underlying undefined PID features suggestive of autosomal recessive hyper IgE syndrome. Our patient responded to corticosteroid treatment rather well and quickly, with an increased FVIII level and decreased FVIII inhibitors. However, FVIII inhibitor reappeared 7 months later, and disappeared spontaneously 4 months ago. Long-term and close follow-up is needed to observe the long-term prognosis in this child.

  7. The soluble recombinant form of a binding protein/receptor for the globular domain of C1q (gC1qR) enhances blood coagulation.

    PubMed

    Peerschke, E I; Jesty, J; Reid, K B; Ghebrehiwet, B

    1998-01-01

    The gC1qR is a ubiquitously expressed, 33 kDa cellular protein which recognizes the globular domains of C1q. Recent evidence suggests that the gC1qR also serves as the Zn(++)-dependent endothelial cell binding site for factor XII and high-molecular-weight kininogen, and activates intrinsic coagulation and kinin pathways in purified systems. In addition, activated lymphocytes have been reported to release soluble gC1qR. Thus, the present study investigated the procoagulant potential of soluble gC1qR in human plasma using the recombinant protein (rgC1qR). rgC1qR supported a dose-dependent shortening of extrinsic coagulation using the prothrombin time in the presence of diluted (1/50-1/500) thromboplastin. Maximum enhancement of the prothrombin time resulted in shortening of the clotting time from 78.8 +/- 0.4 s to 68.5 +/- 0.6 s (mean +/- SD, n = 8) in the presence of 50 micrograms/ml (1.5 mumol/l) rgC1qR. rgC1qR also enhanced the intrinsic pathway of coagulation evaluated in the absence of activators of the contact system, as demonstrated by a shortening of the plasma recalcification time from 348 +/- 66 s to 140 +/- 23 s (n = 4). rgC1qR, however, had no effect on intrinsic coagulation in the presence of undiluted kaolin or ellagic acid, and under these conditions failed to shorten the activated partial thromboplastin time of factor VIII or factor-IX-deficient plasma. rgC1qR further failed to affect thrombin and factor Xa generation assayed using chromogenic substrates, and did not enhance thrombin-induced conversion of fibrinogen to fibrin. Interestingly, the procoagulant activity of the rgC1qR was measurable in either factor-XII- or factor-XI-deficient plasma, suggesting that it was not exclusively focused on the contact system of coagulation. Although the mechanism of action of gC1qR on blood coagulation remains obscure, the data suggest a potential role for this protein in hemostatic and thrombotic events.

  8. Optical Spectral Observations of a Flickering White-light Kernel in a C1 Solar Flare

    NASA Astrophysics Data System (ADS)

    Kowalski, Adam F.; Cauzzi, Gianna; Fletcher, Lyndsay

    2015-01-01

    We analyze optical spectra of a two-ribbon, long-duration C1.1 flare that occurred on 2011 August 18 within AR 11271 (SOL2011-08-18T15:15). The impulsive phase of the flare was observed with a comprehensive set of space-borne and ground-based instruments, which provide a range of unique diagnostics of the lower flaring atmosphere. Here we report the detection of enhanced continuum emission, observed in low-resolution spectra from 3600 Å to 4550 Å acquired with the Horizontal Spectrograph at the Dunn Solar Telescope. A small, <=0.''5 (1015 cm2) penumbral/umbral kernel brightens repeatedly in the optical continuum and chromospheric emission lines, similar to the temporal characteristics of the hard X-ray variation as detected by the Gamma-ray Burst Monitor on the Fermi spacecraft. Radiative-hydrodynamic flare models that employ a nonthermal electron beam energy flux high enough to produce the optical contrast in our flare spectra would predict a large Balmer jump in emission, indicative of hydrogen recombination radiation from the upper flare chromosphere. However, we find no evidence of such a Balmer jump in the bluemost spectral region of the continuum excess. Just redward of the expected Balmer jump, we find evidence of a "blue continuum bump" in the excess emission which may be indicative of the merging of the higher order Balmer lines. The large number of observational constraints provides a springboard for modeling the blue/optical emission for this particular flare with radiative-hydrodynamic codes, which are necessary to understand the opacity effects for the continuum and emission line radiation at these wavelengths.

  9. OPTICAL SPECTRAL OBSERVATIONS OF A FLICKERING WHITE-LIGHT KERNEL IN A C1 SOLAR FLARE

    SciTech Connect

    Kowalski, Adam F.; Cauzzi, Gianna; Fletcher, Lyndsay

    2015-01-10

    We analyze optical spectra of a two-ribbon, long-duration C1.1 flare that occurred on 2011 August 18 within AR 11271 (SOL2011-08-18T15:15). The impulsive phase of the flare was observed with a comprehensive set of space-borne and ground-based instruments, which provide a range of unique diagnostics of the lower flaring atmosphere. Here we report the detection of enhanced continuum emission, observed in low-resolution spectra from 3600 Å to 4550 Å acquired with the Horizontal Spectrograph at the Dunn Solar Telescope. A small, ≤0.''5 (10{sup 15} cm{sup 2}) penumbral/umbral kernel brightens repeatedly in the optical continuum and chromospheric emission lines, similar to the temporal characteristics of the hard X-ray variation as detected by the Gamma-ray Burst Monitor on the Fermi spacecraft. Radiative-hydrodynamic flare models that employ a nonthermal electron beam energy flux high enough to produce the optical contrast in our flare spectra would predict a large Balmer jump in emission, indicative of hydrogen recombination radiation from the upper flare chromosphere. However, we find no evidence of such a Balmer jump in the bluemost spectral region of the continuum excess. Just redward of the expected Balmer jump, we find evidence of a ''blue continuum bump'' in the excess emission which may be indicative of the merging of the higher order Balmer lines. The large number of observational constraints provides a springboard for modeling the blue/optical emission for this particular flare with radiative-hydrodynamic codes, which are necessary to understand the opacity effects for the continuum and emission line radiation at these wavelengths.

  10. Acquired resistance to BRAF inhibition in BRAFV600E mutant gliomas

    PubMed Central

    Yao, Tsun-Wen; Zhang, Jie; Prados, Michael; Weiss, William A.; James, C. David; Nicolaides, Theodore

    2017-01-01

    Activating mutation of BRAF is a common finding in pediatric gliomas. As many as 14% of high grade and up to 66% of certain subtypes of low grade pediatric glioma have the BRAFV600E mutation. Small molecule inhibitors that selectively target BRAFV600E are FDA approved for melanoma and have shown significant efficacy in treating BRAFV600E glioma in pre-clinical trials. Despite showing initial anti-tumor activity, acquired drug resistance significantly limits the benefit from being treated with BRAFV600E inhibitors. Here, we have identified molecular responses to BRAFV600E inhibitor treatment in human glioma models that have substantial clinical implications. Specifically, we show that BRAFV600E inhibitor resistant cells upregulate pro-survival mediators such as Wnt, and additionally increase receptor tyrosine kinase activity, including EGFR and Axl, promoting resistance to BRAFV600E inhibition. Our results suggest strategies to circumvent acquired resistance to BRAFV600E inhibitor therapy, and thereby improve outcomes for patients with BRAFV600E gliomas. PMID:27611946

  11. Proton pump inhibitors

    MedlinePlus

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This ...

  12. Silencing of atp6v1c1 prevents breast cancer growth and bone metastasis.

    PubMed

    Feng, Shengmei; Zhu, Guochun; McConnell, Matthew; Deng, Lianfu; Zhao, Qiang; Wu, Mengrui; Zhou, Qi; Wang, Jinshen; Qi, Jin; Li, Yi-Ping; Chen, Wei

    2013-01-01

    Previous studies have shown that Atp6v1c1, a regulator of the assembly of the V0 and V1 domains of the V-ATPase complex, is up-regulated in metastatic oral tumors. Despite these studies, the function of Atp6v1c1 in tumor growth and metastasis is still unknown. Atp6v1c1's expression in metastatic oral squamous cell carcinoma indicates that Atp6v1c1 has an important function in cancer growth and metastasis. We hypothesized that elevated expression of Atp6v1c1 is essential to cancer growth and metastasis and that Atp6v1c1 promotes cancer growth and metastasis through activation of V-ATPase activity. To test this hypothesis, a Lentivirus-mediated RNAi knockdown approach was used to study the function of Atp6v1c1 in mouse 4T1 mammary tumor cell proliferation and migration in vitro and cancer growth and metastasis in vivo. Our data revealed that silencing of Atp6v1c1 in 4T1 cancer cells inhibited lysosomal acidification and severely impaired 4T1 cell growth, migration, and invasion through Matrigel in vitro. We also show that Atp6v1c1 knockdown with Lenti-c1s3, a lentivirus targeting Atp6v1c1 for shRNA mediated knockdown, can significantly inhibit 4T1 xenograft tumor growth, metastasis, and osteolytic lesions in vivo. Our study demonstrates that Atp6v1c1 may promote breast cancer growth and bone metastasis through regulation of lysosomal V-ATPase activity, indicating that Atp6v1c1 may be a viable target for breast cancer therapy and silencing of Atp6v1c1 may be an innovative therapeutic approach for the treatment and prevention of breast cancer growth and metastasis.

  13. Suppression of Methylation-Mediated Transcriptional Gene Silencing by βC1-SAHH Protein Interaction during Geminivirus-Betasatellite Infection

    PubMed Central

    Raja, Priya; Li, Sizhun; Wolf, Jamie N.; Shen, Qingtang; Bisaro, David M.; Zhou, Xueping

    2011-01-01

    DNA methylation is a fundamental epigenetic modification that regulates gene expression and represses endogenous transposons and invading DNA viruses. As a counter-defense, the geminiviruses encode proteins that inhibit methylation and transcriptional gene silencing (TGS). Some geminiviruses have acquired a betasatellite called DNA β. This study presents evidence that suppression of methylation-mediated TGS by the sole betasatellite-encoded protein, βC1, is crucial to the association of Tomato yellow leaf curl China virus (TYLCCNV) with its betasatellite (TYLCCNB). We show that TYLCCNB complements Beet curly top virus (BCTV) L2- mutants deficient for methylation inhibition and TGS suppression, and that cytosine methylation levels in BCTV and TYLCCNV genomes, as well as the host genome, are substantially reduced by TYLCCNB or βC1 expression. We also demonstrate that while TYLCCNB or βC1 expression can reverse TGS, TYLCCNV by itself is ineffective. Thus its AC2/AL2 protein, known to have suppression activity in other geminiviruses, is likely a natural mutant in this respect. A yeast two-hybrid screen of candidate proteins, followed by bimolecular fluorescence complementation analysis, revealed that βC1 interacts with S-adenosyl homocysteine hydrolase (SAHH), a methyl cycle enzyme required for TGS. We further demonstrate that βC1 protein inhibits SAHH activity in vitro. That βC1 and other geminivirus proteins target the methyl cycle suggests that limiting its product, S-adenosyl methionine, may be a common viral strategy for methylation interference. We propose that inhibition of methylation and TGS by βC1 stabilizes geminivirus/betasatellite complexes. PMID:22028660

  14. Suppression of methylation-mediated transcriptional gene silencing by βC1-SAHH protein interaction during geminivirus-betasatellite infection.

    PubMed

    Yang, Xiuling; Xie, Yan; Raja, Priya; Li, Sizhun; Wolf, Jamie N; Shen, Qingtang; Bisaro, David M; Zhou, Xueping

    2011-10-01

    DNA methylation is a fundamental epigenetic modification that regulates gene expression and represses endogenous transposons and invading DNA viruses. As a counter-defense, the geminiviruses encode proteins that inhibit methylation and transcriptional gene silencing (TGS). Some geminiviruses have acquired a betasatellite called DNA β. This study presents evidence that suppression of methylation-mediated TGS by the sole betasatellite-encoded protein, βC1, is crucial to the association of Tomato yellow leaf curl China virus (TYLCCNV) with its betasatellite (TYLCCNB). We show that TYLCCNB complements Beet curly top virus (BCTV) L2⁻ mutants deficient for methylation inhibition and TGS suppression, and that cytosine methylation levels in BCTV and TYLCCNV genomes, as well as the host genome, are substantially reduced by TYLCCNB or βC1 expression. We also demonstrate that while TYLCCNB or βC1 expression can reverse TGS, TYLCCNV by itself is ineffective. Thus its AC2/AL2 protein, known to have suppression activity in other geminiviruses, is likely a natural mutant in this respect. A yeast two-hybrid screen of candidate proteins, followed by bimolecular fluorescence complementation analysis, revealed that βC1 interacts with S-adenosyl homocysteine hydrolase (SAHH), a methyl cycle enzyme required for TGS. We further demonstrate that βC1 protein inhibits SAHH activity in vitro. That βC1 and other geminivirus proteins target the methyl cycle suggests that limiting its product, S-adenosyl methionine, may be a common viral strategy for methylation interference. We propose that inhibition of methylation and TGS by βC1 stabilizes geminivirus/betasatellite complexes.

  15. Systemic Therapy In Acquired Haemophilia – A Single Institute Experience

    PubMed Central

    Prantik, Das; Gary, Benson

    2016-01-01

    A cornerstone of the management of Acquired Haemophilia A (AHA) involves inhibitor eradication. First line immunosuppressive agents are usually steroids, either alone or in combination with cyclophosphamide. We present the use of Rituximab, cyclophosphamide, vincristine and prednisolone (RCVP) combination as immunosuppressant in AHA in a small cohort of patients in order to control their symptoms and eradicate inhibitors. This was a retrospective analysis of all AHA patients treated at the Northern Ireland Haemophilia centre over a six year period. During this time, a total of six patients were newly diagnosed with AHA. Four of these patients failed to respond conventional therapy of steroids and cyclophosphamide, they were however successfully treated with RCVP/ RCV. All patients achieved complete remission with this regimen after 1 to 2 cycles of treatment. Remission has been maintained for an extended time period (range 33-69 months). As AHA is related to immune modulation and, in some cases, underlying malignancy we decided to use this regime as it is effective in either condition. From our experience, we demonstrate that RCVP combination is a promising treatment in patients with AHA who fail to respond to steroids alone or who have been on pre-existing immunosuppression. PMID:27698522

  16. Identification of the srtC1 Transcription Start Site and Catalytically Essential Residues Required for Actinomyces oris T14V SrtC1 Activity

    DTIC Science & Technology

    2011-07-27

    al., 1999, 2002; Frankel et al., 2007), Cys 193 in SrtC1 from Streptococcus pneumoniae (Manzano et al., 2008) and Cys 219 in SrtC1 from Group B...Sortase mediated pilus fiber biogenesis in Streptococcus pneumoniae . Structure 16: 1838 1848. Manzano C, Izore T, Job V, Di Guilmi AM & Dessen A... Streptococcus (Cozzi et al., 2011) are critical for each of their corresponding sortase activities. When two other residues (Leu263 and Thr265) in this

  17. Application of polymethacrylate resin as stationary phase in liquid chromatography with UV detection for C1-C7 aliphatic monocarboxylic acids and C1-C7 aliphatic monoamines.

    PubMed

    Ohta, Kazutoku; Towata, Atsuya; Ohashi, Masayoshi; Takeuchi, Toyohide

    2004-06-11

    The application of unfunctionized polymethacrylate resin (TSKgel G3000PWXL) as a stationary phase in liquid chromatography with UV detection for C1-C7 aliphatic monocarboxylic acids (formic acid, acetic acid, propionic acid, butyric acid, isovaleric acid, valeric acid, 3,3-dimethylbutyric acid, 4-methylvaleric acid, hexanoic acid, 2-methylhexanoic acid, 5-methylhexanoic acid and heptanoic acid) and C1-C7 aliphatic monoamines (methylamine, ethylamine, propylamine, isobutylamine, butylamine, isoamylamine, amylamine, 1,3-dimethylbutylamine, hexylamine, 2-heptylamine and heptylamine) was carried out. Using dilute sulfuric acid as the eluent, the TSKgel G3000PWXL, resin acted as an advanced stationary phase for these C1-C7 carboxylic acids. Excellent simultaneous separation and symmetrical peaks for these C1-C7 carboxylic acids were achieved on a TSKgel G3000PWXL column (150 mm x 6 mm i.d.) in 60 min with 0.25 mM sulfuric acid containing 1 mM 2-methylheptanoic acid at pH 3.3 as the eluent. Using dilute sodium hydroxide as the eluent, the TSKgel G3000PWXL resin also behaved as an advanced stationary phase for these C1-C7 amines. Excellent simultaneous separation and good peaks for these C1-C7 amines were achieved on the TSKgel G3000PWXL column in 60 min with 10 mM sodium hydroxide containing 0.5 mM 1-methylheptylamine at pH 11.9 as the eluent.

  18. Biodegradation and adsorption of C1- and C2-phenanthrenes and C1- and C2-dibenzothiophenes in the presence of clay minerals: effect on forensic diagnostic ratios.

    PubMed

    Ugochukwu, Uzochukwu C; Head, Ian M; Manning, David A C

    2014-07-01

    The impact of modified montmorillonites on adsorption and biodegradation of crude oil C1-phenanthrenes, C1-dibenzothiophenes, C2-phenanthrenes and C2-dibenzothiophenes was investigated in aqueous clay/oil microcosm experiments with a hydrocarbon degrading microorganism community. Consequently, the effect on C1-dibenzothiophenes/C1-phenanthrenes, C2-dibenzothiophenes/C2-phenanthrenes, 2+3-methyldibenzothiophene/4-methyldibenzothiophene and 1-methyldibenzothiophene/4-methyldibenzothiophene ratios commonly used as diagnostic ratios for oil forensic studies was evaluated. The clay mineral samples were treated to produce acid activated montmorillonite, organomontmorillonite and homoionic montmorillonite which were used in this study. The different clay minerals (modified and unmodified) showed varied degrees of biodegradation and adsorption of the C1-phenanthrenes, C1-dibenzothiophenes, C2-phenanthrenes and C2-dibenzothiophenes. The study indicated that as opposed to biodegradation, adsorption has no effect on the diagnostic ratios. Among the diagnostic ratios reviewed, only C2-dibenzothiophenes/C2-phenanthrenes ratio was neither affected by adsorption nor biodegradation making this ratio very useful in forensic studies of oil spills and oil-oil correlation.

  19. A case of acquired hemophilia A diagnosed after percutaneous endoscopic gastrostomy.

    PubMed

    Okamura, Takuma; Komatsu, Michiharu; Ito, Akihiro; Ito, Tetsuya; Suga, Tomoaki; Arakura, Norikazu; Sakai, Hitoshi; Tanaka, Eiji

    2015-10-01

    A 65-year-old male with no personal or familial history of bleeding disorders underwent percutaneous endoscopic gastrostomy (PEG) for neurogenic dysphagia due to subarachnoid hemorrhage. On postoperative day 6, continuous oozing of venous blood was observed at the stoma. Prothrombin time was within normal range, but activated partial thromboplastin time was prolonged. Cross-mixing test results indicated the existence of an inhibitor, and laboratory findings revealed decreased factor VIII activity and high levels of factor VIII inhibitor. The patient was diagnosed as having acquired hemophilia A, for which steroid monotherapy was effective. Acquired hemophilia A is a rare but potentially fatal disease. Clinicians should be aware of this condition in patients presenting with sudden hemorrhage after PEG or other endoscopic treatments, even in those with no apparent history of bleeding.

  20. Serum C1q as a novel biomarker of sarcopenia in older adults.

    PubMed

    Watanabe, Shinya; Sato, Koji; Hasegawa, Natsuki; Kurihara, Toshiyuki; Matsutani, Kenji; Sanada, Kiyoshi; Hamaoka, Takafumi; Fujita, Satoshi; Iemitsu, Motoyuki

    2015-03-01

    Aging-induced elevation in C1q secretion activates the Wnt signaling pathway in muscles, leading to the development of muscle fibrosis. However, the association between serum C1q level and muscle mass and strength remains unclear in humans. The aim of the study was to elucidate whether serum C1q level is associated with aging- and resistance training-induced changes in muscle mass and strength. First, in a cross-sectional study, we investigated the association between serum C1q level and muscle mass and strength in 131 healthy subjects, aged 20-81 yr. Second, in an intervention study, we examined the association between the effects of serum C1q level and muscle mass and strength on 12 wk resistance training in 11 healthy older adults (60-81 yr). In the cross-sectional study, serum C1q level increased with aging and was negatively correlated with muscle mass and strength. Furthermore, 12 wk resistance training in older adults reduced the age-associated elevation in serum C1q levels. The training effect of serum C1q level significantly correlated with the change in the cross-sectional area of the thigh (r = -0.703; P < 0.01). Serum C1q level may reflect loss of muscle mass; therefore, C1q may be a novel biomarker of sarcopenia.

  1. Charge density influences C1 domain ligand affinity and membrane interactions

    PubMed Central

    Lewin, Nancy E.; Kedei, Noemi; Hill, Colin S.; Selezneva, Julia S.; Valle, Christopher J.; Woo, Wonhee; Gorshkova, Inna; Blumberg, Peter M.

    2014-01-01

    The C1 domain, which represents the recognition motif on protein kinase C for the lipophilic second messenger diacylglycerol and its ultrapotent analog the phorbol esters, has emerged as a promising therapeutic target for cancer and other indications. Potential target selectivity is markedly enhanced both because binding reflects ternary complex formation between ligand, the C1 domain, and phospholipid, and because binding drives membrane insertion of the C1 domain, permitting aspects of the C1 domain surface outside the binding site per se to influence binding energetics. Here, focusing on charged residues identified in atypical C1 domains which contribute to their loss of ligand binding activity, we show that increasing charge along the rim of the binding cleft of the protein kinase C δ C1b domain raises the requirement for anionic phospholipids. Correspondingly, it shifts the selectivity of C1 domain translocation to the plasma membrane, which is more negatively charged than internal membranes. This change in localization is most pronounced in the case of more hydrophilic ligands, which provide weaker membrane stabilization than do the more hydrophobic ligands, and thus contributes an element to the structure activity relations for C1 domain ligands. Co-expressing pairs of C1 containing constructs with differing charges each expressing a distinct fluorescent tag provided a powerful tool to demonstrate the effect of increasing charge in the C1 domain. PMID:24777910

  2. Functional characterization of βC1 gene of Cotton leaf curl Multan betasatellite.

    PubMed

    Tiwari, Neha; Sharma, P K; Malathi, V G

    2013-02-01

    Whitefly-transmitted Begomoviruses having circular single stranded DNA genome cause severe leaf curl diseases in the tropical and subtropical region. The majority of Old World monopartite begomoviruses with DNA A component is associated with a satellite DNA of 1.3 kb length referred to as betasatellites. The presence of betasatellite is required to express typical symptoms in the primary hosts. Increased symptom expression in betasatellite's presence is attributed to a 13-15 kDa βC1 protein encoded by the βC1 gene on complementary sense strand. The exact mechanism by which the βC1 protein contributes to the symptoms' severity and helper viral DNA's accumulation is not yet understood. Here, we studied the βC1 protein of Cotton leaf curl Multan betasatellite, associated with mono and bipartite begomoviruses. The βC1 protein was expressed in prokaryotic system as 6XHis-βC1 fusion protein and recombinant protein showed size- and sequence-specific DNA binding activity. The host proteins which may interact with βC1 were identified by binding βC1 recombinant protein with heptapeptide in phage display library. The βC1-interacting host proteins predicted belong to metabolic and defense pathways, indicating that βC1 protein has a pivotal role in viral pathogenicity.

  3. XPB Induces C1D Expression to Counteract UV-Induced Apoptosis

    PubMed Central

    Li, Guang; Liu, Juhong; Abu-Asab, Mones; Masabumi, Shibuya; Maru, Yoshiro

    2010-01-01

    Although C1D has been shown to be involved in DNA double-strand breaks repair, how C1D expression was induced and the mechanism(s) by which C1D facilitates DNA repair in mammalian cells remain poorly understood. We and others have previously shown that expression of XPB protein efficiently compensated the UV-irradiation sensitive phenotype of 27-1 cells which lacks functional XPB. To further explore XPB-regulated genes that could be involved in UV-induced DNA repair, Differential Display analysis of mRNA level from CHO-9, 27-1 and 27-1 complemented with wild-type XPB were performed and C1D gene was identified as one of the major genes whose expression was significantly up-regulated by restoring XPB function. We found that XPB is essential to induce C1D transcription after UV-irradiation. The increase of C1D expression effectively compensates the UV-induced proteolysis of C1D and thus maintains cellular C1D level to cope with DNA damage inflicted by UV-irradiation. We further showed that although insufficient to rescue 27-1 cells from UV-induced apoptosis by itself, C1D facilitates XPB DNA repair through direct interaction with XPB. Our findings provided direct evidence that C1D is associated with DNA repair complex and may promote repair of UV-induced DNA damage. PMID:20530579

  4. The effects of fluoride on cell migration, cell proliferation, and cell metabolism in GH4C1 pituitary tumour cells.

    PubMed

    Mendoza-Schulz, A; Solano-Agama, C; Arreola-Mendoza, L; Reyes-Márquez, B; Barbier, O; Del Razo, L M; Mendoza-Garrido, M E

    2009-10-28

    The consumption of drinking water rich in fluoride has toxic effects on the central nervous system. In cell biology research, fluoride is currently used as a phosphatase inhibitor. The aim of the present study was to evaluate the effect of fluoride on different physiological processes in GH4C1 pituitary tumour cells. We used a range of different fluoride concentrations, from levels below normal human serum concentrations (0.23 and 1.2 micromol/L) to those observed in chronically exposed persons (10.7 micromol/L) and above (107 and 1072 micromol/L). Treatment of 10.7 micromol/L fluoride resulted in a discrete induction of DNA synthesis, without a change in cell number. Cell migration, a behaviour stimulated by growth factors, was increased in cells treated with 2.4 micromol/L. At this fluoride concentration, changes in phosphorylation status of both cytoskeletal and cytosolic protein fractions, as well as in actin cytoskeletal arrangements were observed. The GH4C1 fluoride treated cells had significantly less cellular protein than control cells, suggesting an effect of fluoride on hormone secretion and protein synthesis in this endocrine cell. The bioreduction of MTT was significantly increased with a wide range of fluoride concentrations. With the highest fluoride concentration, 1072 micromol/L, all of the analysed parameters were significantly reduced, suggesting that this dose is highly toxic in GH4C1 cells. Our results show that biologically relevant concentrations of fluoride are capable of increasing cell migration in tumour cells, suggesting that exposure to fluoride could stimulate tumour invasion.

  5. Occurrence and Antioxidant Activity of C1 Degradation Products in Cocoa

    PubMed Central

    De Taeye, Cédric; Kankolongo Cibaka, Marie-Lucie; Collin, Sonia

    2017-01-01

    Procyanidin C1 is by far the main flavan-3-ol trimer in cocoa. Like other flavan-3-ols, however, it suffers a lot during heat treatments such as roasting. RP-HPLC-HRMS/MS(ESI(−))analysis applied to an aqueous model medium containing commercial procyanidin C1 proved that epimerization is the main reaction involved in its degradation (accounting for 62% of degradation products). In addition to depolymerization, cocoa procyanidin C1 also proved sensitive to oxidation, yielding once- and twice-oxidized dimers. No chemical oligomer involving the native trimer was found in either model medium or cocoa, while two C1 isomers were retrieved. C1 degradation products exhibited antioxidant activity (monitored by RP-HPLC-Online TEAC) close to that of C1 (when expressed in µM TE/mg·kg−1). PMID:28264525

  6. The C1q complement family of synaptic organizers: not just complementary.

    PubMed

    Yuzaki, Michisuke

    2017-02-17

    Molecules that regulate formation, differentiation, and maintenance of synapses are called synaptic organizers. Recently, various 'C1q family' proteins have been shown to be released from neurons, and serve as a new class of synaptic organizers. Cbln1 and C1ql1 proteins regulate the formation and maintenance of parallel fiber-Purkinje cell and climbing fiber-Purkinje cell synapses, respectively, in the cerebellum. Cbln1 also modulates the function of postsynaptic delta2 glutamate receptors to regulate synaptic plasticity. C1ql2 and C1ql3, released from mossy fibers, determine the synaptic localization of postsynaptic kainate receptors in the hippocampus. C1ql3 also regulates the formation of synapses between the basolateral amygdala and the prefrontal cortex. These findings indicate the diverse functions of C1q family proteins in various brain regions.

  7. Regulation of ClC-1 and KATP channels in action potential-firing fast-twitch muscle fibers.

    PubMed

    Pedersen, Thomas Holm; de Paoli, Frank Vincenzo; de Paoli, Frank Vinzenco; Flatman, John A; Nielsen, Ole Baekgaard

    2009-10-01

    Action potential (AP) excitation requires a transient dominance of depolarizing membrane currents over the repolarizing membrane currents that stabilize the resting membrane potential. Such stabilizing currents, in turn, depend on passive membrane conductance (G(m)), which in skeletal muscle fibers covers membrane conductances for K(+) (G(K)) and Cl(-) (G(Cl)). Myotonic disorders and studies with metabolically poisoned muscle have revealed capacities of G(K) and G(Cl) to inversely interfere with muscle excitability. However, whether regulation of G(K) and G(Cl) occur in AP-firing muscle under normal physiological conditions is unknown. This study establishes a technique that allows the determination of G(Cl) and G(K) with a temporal resolution of seconds in AP-firing muscle fibers. With this approach, we have identified and quantified a biphasic regulation of G(m) in active fast-twitch extensor digitorum longus fibers of the rat. Thus, at the onset of AP firing, a reduction in G(Cl) of approximately 70% caused G(m) to decline by approximately 55% in a manner that is well described by a single exponential function characterized by a time constant of approximately 200 APs (phase 1). When stimulation was continued beyond approximately 1,800 APs, synchronized elevations in G(K) ( approximately 14-fold) and G(Cl) ( approximately 3-fold) caused G(m) to rise sigmoidally to approximately 400% of its level before AP firing (phase 2). Phase 2 was often associated with a failure to excite APs. When AP firing was ceased during phase 2, G(m) recovered to its level before AP firing in approximately 1 min. Experiments with glibenclamide (K(ATP) channel inhibitor) and 9-anthracene carboxylic acid (ClC-1 Cl(-) channel inhibitor) revealed that the decreased G(m) during phase 1 reflected ClC-1 channel inhibition, whereas the massively elevated G(m) during phase 2 reflected synchronized openings of ClC-1 and K(ATP) channels. In conclusion, G(Cl) and G(K) are acutely regulated in AP

  8. 29 CFR 2550.404c-1 - ERISA section 404(c) plans.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 9 2014-07-01 2014-07-01 false ERISA section 404(c) plans. 2550.404c-1 Section 2550.404c-1... REGULATIONS FOR FIDUCIARY RESPONSIBILITY § 2550.404c-1 ERISA section 404(c) plans. (a) In general. (1) Section 404(c) of the Employee Retirement Income Security Act of 1974 (ERISA or the Act) provides that if...

  9. 29 CFR 2550.404c-1 - ERISA section 404(c) plans.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 9 2011-07-01 2011-07-01 false ERISA section 404(c) plans. 2550.404c-1 Section 2550.404c-1... REGULATIONS FOR FIDUCIARY RESPONSIBILITY § 2550.404c-1 ERISA section 404(c) plans. (a) In general. (1) Section 404(c) of the Employee Retirement Income Security Act of 1974 (ERISA or the Act) provides that if...

  10. Antimicrobial activities and membrane-active mechanism of CPF-C1 against multidrug-resistant bacteria, a novel antimicrobial peptide derived from skin secretions of the tetraploid frog Xenopus clivii.

    PubMed

    Xie, Junqiu; Gou, Yuanmei; Zhao, Qian; Wang, Kairong; Yang, Xiongli; Yan, Jiexi; Zhang, Wei; Zhang, Bangzhi; Ma, Chi; Wang, Rui

    2014-11-01

    Hospital-acquired infections caused by multidrug-resistant bacteria pose significant challenges for treatment, which necessitate the development of new antibiotics. Antimicrobial peptides are considered potential alternatives to conventional antibiotics. The skin of Anurans (frogs and toads) amphibians is an extraordinarily rich source of antimicrobial peptides. CPF-C1 is a typical cationic antimicrobial peptide that was originally isolated from the tetraploid frog Xenopus clivii. Our results showed that CPF-C1 has potent antimicrobial activity against both sensitive and multidrug-resistant bacteria. It disrupted the outer and inner membranes of bacterial cells. CPF-C1 induced both propidium iodide uptake into the bacterial cell and the leakage of calcein from large liposome vesicles, which suggests a mode of action that involves membrane disturbance. Scanning electron microscopy and transmission electron microscopy verified the morphologic changes of CPF-C1-treated bacterial cells and large liposome vesicles. The membrane-dependent mode of action signifies that the CPF-C1 peptide functions freely and without regard to conventional resistant mechanisms. Additionally, it is difficult for bacteria to develop resistance against CPF-C1 under this action mode. Other studies indicated that CPF-C1 had low cytotoxicity against mammalian cell. In conclusion, considering the increase in multidrug-resistant bacterial infections, CPF-C1 may offer a new strategy that can be considered a potential therapeutic agent for the treatment of diseases caused by multidrug-resistant bacteria.

  11. Inhibition of the activation of Hageman factor (factor XII) by complement subcomponent C1q.

    PubMed

    Rehmus, E H; Greene, B M; Everson, B A; Ratnoff, O D

    1987-08-01

    Hageman factor (HF, Factor XII) is activated by glass, collagen, and ellagic acid, and initiates blood coagulation via the intrinsic pathway. C1q inhibits collagen-induced platelet aggregation and adherence of platelets to glass, effects attributable to the collagen-like region of C1q. We examined the actions of C1q on HF activation. Incubation of C1q with HF before addition of HF-deficient plasma extended the activated partial thromboplastin time. Similarly, when glass tubes were coated with C1q before testing, the partial thromboplastin time of normal plasma was increased. C1q reduced the activation of HF by ellagic acid, as measured by the release of p-nitroaniline from the synthetic substrate H-D-prolyl-L-phenylalanyl-L-arginine-p-nitroanilide dihydrochloride, an effect inhibited by monoclonal anti-human C1q murine IgG and by digestion of C1q by collagenase. Thus, C1q inhibits activation of HF in vitro in clot-promoting and amidolytic assays and suggests a regulatory mechanism for the inhibition of coagulation.

  12. Inhibition of the activation of Hageman factor (factor XII) by complement subcomponent C1q.

    PubMed Central

    Rehmus, E H; Greene, B M; Everson, B A; Ratnoff, O D

    1987-01-01

    Hageman factor (HF, Factor XII) is activated by glass, collagen, and ellagic acid, and initiates blood coagulation via the intrinsic pathway. C1q inhibits collagen-induced platelet aggregation and adherence of platelets to glass, effects attributable to the collagen-like region of C1q. We examined the actions of C1q on HF activation. Incubation of C1q with HF before addition of HF-deficient plasma extended the activated partial thromboplastin time. Similarly, when glass tubes were coated with C1q before testing, the partial thromboplastin time of normal plasma was increased. C1q reduced the activation of HF by ellagic acid, as measured by the release of p-nitroaniline from the synthetic substrate H-D-prolyl-L-phenylalanyl-L-arginine-p-nitroanilide dihydrochloride, an effect inhibited by monoclonal anti-human C1q murine IgG and by digestion of C1q by collagenase. Thus, C1q inhibits activation of HF in vitro in clot-promoting and amidolytic assays and suggests a regulatory mechanism for the inhibition of coagulation. PMID:3038961

  13. Engineering Botulinum Neurotoxin C1 as a Molecular Vehicle for Intra-Neuronal Drug Delivery.

    PubMed

    Vazquez-Cintron, Edwin J; Beske, Phillip H; Tenezaca, Luis; Tran, Bao Q; Oyler, Jonathan M; Glotfelty, Elliot J; Angeles, Christopher A; Syngkon, Aurelia; Mukherjee, Jean; Kalb, Suzanne R; Band, Philip A; McNutt, Patrick M; Shoemaker, Charles B; Ichtchenko, Konstantin

    2017-02-21

    Botulinum neurotoxin (BoNT) binds to and internalizes its light chain into presynaptic compartments with exquisite specificity. While the native toxin is extremely lethal, bioengineering of BoNT has the potential to eliminate toxicity without disrupting neuron-specific targeting, thereby creating a molecular vehicle capable of delivering therapeutic cargo into the neuronal cytosol. Building upon previous work, we have developed an atoxic derivative (ad) of BoNT/C1 through rationally designed amino acid substitutions in the metalloprotease domain of wild type (wt) BoNT/C1. To test if BoNT/C1 ad retains neuron-specific targeting without concomitant toxic host responses, we evaluated the localization, activity, and toxicity of BoNT/C1 ad in vitro and in vivo. In neuronal cultures, BoNT/C1 ad light chain is rapidly internalized into presynaptic compartments, but does not cleave SNARE proteins nor impair spontaneous neurotransmitter release. In mice, systemic administration resulted in the specific co-localization of BoNT/C1 ad with diaphragmatic motor nerve terminals. The mouse LD50 of BoNT/C1 ad is 5 mg/kg, with transient neurological symptoms emerging at sub-lethal doses. Given the low toxicity and highly specific neuron-targeting properties of BoNT/C1 ad, these data suggest that BoNT/C1 ad can be useful as a molecular vehicle for drug delivery to the neuronal cytoplasm.

  14. Engineering Botulinum Neurotoxin C1 as a Molecular Vehicle for Intra-Neuronal Drug Delivery

    PubMed Central

    Vazquez-Cintron, Edwin J.; Beske, Phillip H.; Tenezaca, Luis; Tran, Bao Q.; Oyler, Jonathan M.; Glotfelty, Elliot J.; Angeles, Christopher A.; Syngkon, Aurelia; Mukherjee, Jean; Kalb, Suzanne R.; Band, Philip A.; McNutt, Patrick M.; Shoemaker, Charles B.; Ichtchenko, Konstantin

    2017-01-01

    Botulinum neurotoxin (BoNT) binds to and internalizes its light chain into presynaptic compartments with exquisite specificity. While the native toxin is extremely lethal, bioengineering of BoNT has the potential to eliminate toxicity without disrupting neuron-specific targeting, thereby creating a molecular vehicle capable of delivering therapeutic cargo into the neuronal cytosol. Building upon previous work, we have developed an atoxic derivative (ad) of BoNT/C1 through rationally designed amino acid substitutions in the metalloprotease domain of wild type (wt) BoNT/C1. To test if BoNT/C1 ad retains neuron-specific targeting without concomitant toxic host responses, we evaluated the localization, activity, and toxicity of BoNT/C1 ad in vitro and in vivo. In neuronal cultures, BoNT/C1 ad light chain is rapidly internalized into presynaptic compartments, but does not cleave SNARE proteins nor impair spontaneous neurotransmitter release. In mice, systemic administration resulted in the specific co-localization of BoNT/C1 ad with diaphragmatic motor nerve terminals. The mouse LD50 of BoNT/C1 ad is 5 mg/kg, with transient neurological symptoms emerging at sub-lethal doses. Given the low toxicity and highly specific neuron-targeting properties of BoNT/C1 ad, these data suggest that BoNT/C1 ad can be useful as a molecular vehicle for drug delivery to the neuronal cytoplasm. PMID:28220863

  15. Anti-C1q Autoantibodies, Novel Tests, and Clinical Consequences

    PubMed Central

    Mahler, Michael; van Schaarenburg, Rosanne A.; Trouw, Leendert A.

    2013-01-01

    Although anti-C1q autoantibodies have been described more than four decades ago a constant stream of papers describing clinical associations or functional consequences highlights that anti-C1q antibodies are still hot and happening. By far the largest set of studies focus on anti-C1q antibodies is systemic lupus erythematosus (SLE). In SLE anti-C1q antibodies associate with involvement of lupus nephritis in such a way that in the absence of anti-C1q antibodies it is unlikely that a flare in nephritis will occur. Anti-C1q antibodies occur in several autoimmune conditions but also in healthy individuals. Although considerable progress has been made in the understanding of how anti-C1q antibodies may contribute to tissue injury there is still a lot to learn about the processes involved in the breaking of tolerance to this protein. There has been considerable improvement in the assays employed to test for the presence of anti-C1q antibodies. Hopefully with these new and standardized assays at hand larger clinical association studies will be conducted with independent replication. Such large-scale studies will reveal the true value of clinical testing for anti-C1q autoantibodies in several clinical conditions. PMID:23717311

  16. [Hospital-acquired urinary tract infections].

    PubMed

    Adukauskiene, Dalia; Cicinskaite, Ilona; Vitkauskiene, Astra; Macas, Andrius; Tamosiūnas, Ramūnas; Kinderyte, Aida

    2006-01-01

    Urinary tract infections are responsible for 40-60% of all hospital-acquired infections. Increased age of patients and comorbid diseases render hospitalized patients more susceptible to infection. Almost 80% of hospital-acquired urinary tract infections are associated with urinary catheters, and only 5-10% of urinary infections are caused by invasive manipulations in the urogenital tract. Pathogens of hospital-acquired urinary tract infections are frequently multi-resistant, and antibiotic therapy can only be successful when the complicating factors are eliminated or urodynamic function is restored. For treatment of complicated hospital-acquired urinary tract infections, the antibiotics must exhibit adequate pharmacodynamic and pharmacokinetic properties: high renal clearance of unmetabolized form with good antimicrobial activity in both acidic and alkaline urine. For selection of empirical treatment of hospital-acquired urinary tract infections, it is necessary to evaluate localization of infection, its severity, possible isolates, and the most frequent pathogens in the department where patient is treated. The best choice for the starting the antimicrobial therapy is the cheapest narrow-spectrum effective antibiotic in the treatment of urinary tract infection until microbiological evaluation of pathogens will be received. Adequate management of urinary tract infections lowers the rate of complications, requirements for antibacterial treatment, selection of multi-resistant isolates and is cost effective.

  17. Systemic reduction of rice blast by inhibitors of antioxidant enzymes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Systemic acquired disease resistance (SAR) of plants may result from an oxidative burst in their tissues caused by both increased production of ROS and decreased antioxidant activity, in particular, enzymatic. Here we tested whether the exogenous inhibitors of superoxide dismutase (SOD) and catalase...

  18. Functional C1q is present in the skin mucus of Siberian sturgeon (Acipenser baerii).

    PubMed

    Fan, Chunxin; Wang, Jian; Zhang, Xuguang; Song, Jiakun

    2015-01-01

    The skin mucus of fish acts as the first line of self-protection against pathogens in the aquatic environment and comprises a number of innate immune components. However, the presence of the critical classical complement component C1q, which links the innate and adaptive immune systems of mammalians, has not been explored in a primitive actinopterygian fish. In this study, we report that C1q is present in the skin mucus of the Siberian sturgeon (Acipenser baerii). The skin mucus was able to inhibit the growth of Escherichia coli. The bacteriostatic activity of the skin mucus was reduced by heating and by pre-incubation with EDTA or mouse anti-human C1q antibody. We also detected C1q protein in skin mucus using the western blot procedure and isolated a cDNA that encodes the Siberian sturgeon C1qC, which had 44.7-51.4% identity with C1qCs in teleosts and tetrapods. A phylogenetic analysis revealed that Siberian sturgeon C1qC lies at the root of the actinopterygian branch and is separate from the tetrapod branch. The C1qC transcript was expressed in many tissues as well as in skin. Our data indicate that C1q is present in the skin mucus of the Siberian sturgeon to protect against water-borne bacteria, and the C1qC found in the sturgeon may represent the primitive form of teleost and tetrapod C1qCs.

  19. Spinolaminar Line Test as a Screening Tool for C1 Stenosis

    PubMed Central

    Oshima, Yasushi; Kelly, Michael P.; Song, Kwang-Sup; Park, Moon Soo; Chuntarapas, Tapanut; Vo, Katie D.; Yeom, Jin S.; Takeshita, Katsushi; Riew, K. Daniel

    2015-01-01

    Study Design Retrospective cohort. Objective To clarify the sensitivity of C3–C2 spinolaminar line test as a screening tool for the stenosis of C1 space available for the cord (SAC). Methods Spine clinic records from April 2005 to August 2011 were reviewed. The C1 SAC was measured on lateral radiographs, and the relative positions between a C1 posterior arch and the C3–C2 spinolaminar line were examined and considered “positive” when the C1 ring lay ventral to the line. Computed tomography (CT) scans and magnetic resonance imaging (MRI) were utilized to measure precise diameters of C1 and C2 SAC and to check the existence of spinal cord compression. Results Four hundred eighty-seven patients were included in this study. There were 246 men and 241 women, with an average age of 53 years (range: 18 to 86). The mean SAC at C1 on radiographs was 21.2 mm (range: 13.5 to 28.2). Twenty-one patients (4.3%) were positive for the spinolaminar line test; all of these patients had C1 SAC of 19.4 mm or less. Eight patients (1.6%) had C1 SAC smaller than C2 on CT examination; all of these patients had a positive spinolaminar test, with high sensitivity (100%) and specificity (97%). MRI analysis revealed that two of the eight patients with a smaller C1 SAC had spinal cord compression at the C1 level. Conclusion Although spinal cord compression at the level of atlas without instability is a rare condition, the spinolaminar line can be used as a screening of C1 stenosis. PMID:27190740

  20. Inhibitors of Pyruvate Carboxylase

    PubMed Central

    Zeczycki, Tonya N.; Maurice, Martin St.; Attwood, Paul V.

    2010-01-01

    This review aims to discuss the varied types of inhibitors of biotin-dependent carboxylases, with an emphasis on the inhibitors of pyruvate carboxylase. Some of these inhibitors are physiologically relevant, in that they provide ways of regulating the cellular activities of the enzymes e.g. aspartate and prohibitin inhibition of pyruvate carboxylase. Most of the inhibitors that will be discussed have been used to probe various aspects of the structure and function of these enzymes. They target particular parts of the structure e.g. avidin – biotin, FTP – ATP binding site, oxamate – pyruvate binding site, phosphonoacetate – binding site of the putative carboxyphosphate intermediate. PMID:22180764

  1. Enhanced synaptic connectivity and epilepsy in C1q knockout mice.

    PubMed

    Chu, Yunxiang; Jin, Xiaoming; Parada, Isabel; Pesic, Alexei; Stevens, Beth; Barres, Ben; Prince, David A

    2010-04-27

    Excessive CNS synapses are eliminated during development to establish mature patterns of neuronal connectivity. A complement cascade protein, C1q, is involved in this process. Mice deficient in C1q fail to refine retinogeniculate connections resulting in excessive retinal innervation of lateral geniculate neurons. We hypothesized that C1q knockout (KO) mice would exhibit defects in neocortical synapse elimination resulting in enhanced excitatory synaptic connectivity and epileptiform activity. We recorded spontaneous and evoked field potential activity in neocortical slices and obtained video-EEG recordings from implanted C1q KO and wild-type (WT) mice. We also used laser scanning photostimulation of caged glutamate and whole cell recordings to map excitatory and inhibitory synaptic connectivity. Spontaneous and evoked epileptiform field potentials occurred at multiple sites in neocortical slices from C1q KO, but not WT mice. Laser mapping experiments in C1q KO slices showed that the proportion of glutamate uncaging sites from which excitatory postsynaptic currents (EPSCs) could be evoked ("hotspot ratio") increased significantly in layer IV and layer V, although EPSC amplitudes were unaltered. Density of axonal boutons was significantly increased in layer V pyramidal neurons of C1q KO mice. Implanted KO mice had frequent behavioral seizures consisting of behavioral arrest associated with bihemispheric spikes and slow wave activity lasting from 5 to 30 s. Results indicate that epileptogenesis in C1q KO mice is related to a genetically determined failure to prune excessive excitatory synapses during development.

  2. 26 CFR 1.641(c)-1 - Electing small business trust.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Electing small business trust. 1.641(c)-1...) INCOME TAX (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.641(c)-1 Electing small business trust. (a) In general. An electing small business trust (ESBT) within the meaning of section...

  3. Relevance of anti-C1q autoantibodies to lupus nephritis.

    PubMed

    Tsirogianni, Alexandra; Pipi, Elena; Soufleros, Kostantinos

    2009-09-01

    The first component of the classical pathway of the complement system (C1q) is considered to have a crucial role in the clearance of immune complexes (ICs) as well as in the removal of waste material originating from apoptotic cells. A prolonged exposure of C1q epitopes to the immune system could eventually lead to an autoimmune response against itself. Although autoantibodies against C1q are found in several diseases, their clinical interest originates from their strong association to active lupus nephritis (LN). Several studies indicate that anti-C1q autoantibodies could serve as a reliable serologic marker in the assessment of LN activity compared to other immunological tests. Additionally, it was suggested that anti-C1q autoantibodies could play a role in LN pathogenesis. Their potential pathogenic actions likely depend on genetic background, titers, Ig classes and subclasses, and specific epitopes of anti-C1q autoantibodies as well as C1q availability and allocation. It is still unclear which different types of anti-C1q autoantibodies dominate in each case and if their upregulation is pathogenic, an epiphenomenon of aberrant tissue damage, or compensatory to an uncontrolled immune response.

  4. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  5. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  6. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  7. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  8. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  9. 26 CFR 1.280C-1 - Disallowance of certain deductions for wage or salary expenses.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... salary expenses. 1.280C-1 Section 1.280C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Disallowance of certain deductions for wage or salary expenses. If an employer elects to claim the targeted... reduce its deduction for wage or salary expenses paid or incurred in the year the credit is earned by...

  10. 26 CFR 1.280C-1 - Disallowance of certain deductions for wage or salary expenses.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... salary expenses. 1.280C-1 Section 1.280C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... certain deductions for wage or salary expenses. If an employer elects to claim the targeted jobs credit... deduction for wage or salary expenses paid or incurred in the year the credit is earned by the...

  11. 26 CFR 1.280C-1 - Disallowance of certain deductions for wage or salary expenses.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... salary expenses. 1.280C-1 Section 1.280C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Disallowance of certain deductions for wage or salary expenses. If an employer elects to claim the targeted... reduce its deduction for wage or salary expenses paid or incurred in the year the credit is earned by...

  12. 26 CFR 1.280C-1 - Disallowance of certain deductions for wage or salary expenses.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... salary expenses. 1.280C-1 Section 1.280C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Disallowance of certain deductions for wage or salary expenses. If an employer elects to claim the targeted... reduce its deduction for wage or salary expenses paid or incurred in the year the credit is earned by...

  13. 26 CFR 1.280C-1 - Disallowance of certain deductions for wage or salary expenses.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... salary expenses. 1.280C-1 Section 1.280C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Disallowance of certain deductions for wage or salary expenses. If an employer elects to claim the targeted... reduce its deduction for wage or salary expenses paid or incurred in the year the credit is earned by...

  14. 26 CFR 301.6104(c)-1 - Disclosure of certain information to State officers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Disclosure of certain information to State officers. 301.6104(c)-1 Section 301.6104(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE...) of this section, the Internal Revenue Service will notify the Attorney General and the principal...

  15. Generalized van der Waals Hamiltonian: periodic orbits and C1 nonintegrability.

    PubMed

    Guirao, Juan L G; Llibre, Jaume; Vera, Juan A

    2012-03-01

    The aim of this paper is to study the periodic orbits of the generalized van der Waals Hamiltonian system. The tool for studying such periodic orbits is the averaging theory. Moreover, for this Hamiltonian system we provide information on its C(1) nonintegrability, i.e., on the existence of a second first integral of class C(1).

  16. 26 CFR 1.512(c)-1 - Special rules applicable to partnerships; in general.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Special rules applicable to partnerships; in general. 1.512(c)-1 Section 1.512(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of...

  17. 26 CFR 31.3406(c)-1 - Notified payee underreporting of reportable interest or dividend payments.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Notified payee underreporting of reportable interest or dividend payments. 31.3406(c)-1 Section 31.3406(c)-1 Internal Revenue INTERNAL REVENUE SERVICE...)(2)) made with respect to an account of a payee if the Internal Revenue Service or a broker...

  18. 26 CFR 1.641(c)-1 - Electing small business trust.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Electing small business trust. 1.641(c)-1... small business trust. (a) In general. An electing small business trust (ESBT) within the meaning of... meaning of section 642(c)(1). The limitations of section 681, regarding unrelated business income,...

  19. 26 CFR 1.641(c)-1 - Electing small business trust.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Electing small business trust. 1.641(c)-1... small business trust. (a) In general. An electing small business trust (ESBT) within the meaning of... meaning of section 642(c)(1). The limitations of section 681, regarding unrelated business income,...

  20. Cost of hospital-acquired infection.

    PubMed

    Hassan, Mahmud; Tuckman, Howard P; Patrick, Robert H; Kountz, David S; Kohn, Jennifer L

    2010-01-01

    The authors assessed the costs of hospital-acquired infections using rigorous econometric methods on publicly available data, controlling for the interdependency of length of stay and the incidence of hospital acquired infection, and estimated the cost shares of different payers. They developed a system of equations involving length of stay, incidence of infection, and the total hospital care cost to be estimated using simultaneous equations system. The main data came from the State of New Jersey UB 92 for 2004, complimented with data from the Annual Survey of Hospitals by the American Hospital Association and the Medicare Cost Report of 2004. The authors estimated that an incidence of hospital acquired infection increases the hospital care cost of a patient by $10,375 and it increases the length of stay by 3.30 days, and that a disproportionately higher portion of the cost is attributable to Medicare. They conclude that reliable cost estimates of hospital-acquired infections can be made using publicly available data. Their estimate shows a much larger aggregate cost of $16.6 billion as opposed to $5 billion reported by the Centers for Disease Control and Prevention but much less than $29 billion as reported elsewhere in the literature.

  1. 7 CFR 989.17 - Acquire.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 8 2012-01-01 2012-01-01 false Acquire. 989.17 Section 989.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN...

  2. How Did Light Acquire a Velocity?

    ERIC Educational Resources Information Center

    Lauginie, Pierre

    2013-01-01

    We discuss how light acquired a velocity through history, from the ancient Greeks to the early modern era. Combining abstract debates, models of light, practical needs, planned research and chance, this history illustrates several key points that should be brought out in science education.

  3. Sexually acquired Salmonella Typhi urinary tract infection.

    PubMed

    Wielding, Sally; Scott, Gordon

    2016-05-01

    We report a case of isolated urinary Salmonella enterica serotype Typhi in an HIV-positive man who has sex with men. He was clinically well and blood and stool cultures were negative, indicating that this may have been a sexually acquired urinary tract infection.

  4. Acquired nasal deformities in fighter pilots.

    PubMed

    Schreinemakers, Joyce R C; van Amerongen, Pieter; Kon, Moshe

    2010-07-01

    Fighter pilots may develop slowly progressive deformities of their noses during their flying careers. The spectrum of deformities that may be acquired ranges from soft tissue to osseous changes. The main cause is the varying pressure exerted by the oxygen mask on the skin and bony pyramid of the nose during flying.

  5. 7 CFR 989.17 - Acquire.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 8 2013-01-01 2013-01-01 false Acquire. 989.17 Section 989.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN...

  6. 7 CFR 989.17 - Acquire.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Acquire. 989.17 Section 989.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN...

  7. 7 CFR 989.17 - Acquire.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 8 2014-01-01 2014-01-01 false Acquire. 989.17 Section 989.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN...

  8. 7 CFR 989.17 - Acquire.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 8 2011-01-01 2011-01-01 false Acquire. 989.17 Section 989.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN...

  9. Eye Movement Correlates of Acquired Central Dyslexia

    ERIC Educational Resources Information Center

    Schattka, Kerstin I.; Radach, Ralph; Huber, Walter

    2010-01-01

    Based on recent progress in theory and measurement techniques, the analysis of eye movements has become one of the major methodological tools in experimental reading research. Our work uses this approach to advance the understanding of impaired information processing in acquired central dyslexia of stroke patients with aphasia. Up to now there has…

  10. Group Treatment in Acquired Brain Injury Rehabilitation

    ERIC Educational Resources Information Center

    Bertisch, Hilary; Rath, Joseph F.; Langenbahn, Donna M.; Sherr, Rose Lynn; Diller, Leonard

    2011-01-01

    The current article describes critical issues in adapting traditional group-treatment methods for working with individuals with reduced cognitive capacity secondary to acquired brain injury. Using the classification system based on functional ability developed at the NYU Rusk Institute of Rehabilitation Medicine (RIRM), we delineate the cognitive…

  11. Acquiring a Second Language for School.

    ERIC Educational Resources Information Center

    Collier, Virginia P.

    1995-01-01

    This report offers a conceptual model for use with language minority children who are entering a new school when they must acquire the language of the majority student population. The model has four development components or processes: sociocultural, linguistic, academic, and cognitive. These four components are described in detail. Research is…

  12. Acquired immunodeficiency syndrome with subacute sclerosing panencephalitis.

    PubMed

    Gowda, Vykuntaraju K N; Sukanya, V; Shivananda

    2012-11-01

    A 7-year-old boy with acquired immunodeficiency syndrome, receiving antiretroviral drugs for 2 years, presented with a recent onset of myoclonic jerks and cognitive deterioration. On examination, he manifested myoclonic jerks once every 10-15 seconds. His electroencephalogram indicated periodic complexes, and his cerebrospinal fluid tested positive for measles antibodies.

  13. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.

    PubMed

    Tan, Li; Wang, Jun; Tanizaki, Junko; Huang, Zhifeng; Aref, Amir R; Rusan, Maria; Zhu, Su-Jie; Zhang, Yiyun; Ercan, Dalia; Liao, Rachel G; Capelletti, Marzia; Zhou, Wenjun; Hur, Wooyoung; Kim, NamDoo; Sim, Taebo; Gaudet, Suzanne; Barbie, David A; Yeh, Jing-Ruey Joanna; Yun, Cai-Hong; Hammerman, Peter S; Mohammadi, Moosa; Jänne, Pasi A; Gray, Nathanael S

    2014-11-11

    The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.

  14. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

    PubMed Central

    Tan, Li; Wang, Jun; Tanizaki, Junko; Huang, Zhifeng; Aref, Amir R.; Rusan, Maria; Zhu, Su-Jie; Zhang, Yiyun; Ercan, Dalia; Liao, Rachel G.; Capelletti, Marzia; Zhou, Wenjun; Hur, Wooyoung; Kim, NamDoo; Sim, Taebo; Gaudet, Suzanne; Barbie, David A.; Yeh, Jing-Ruey Joanna; Yun, Cai-Hong; Hammerman, Peter S.; Mohammadi, Moosa; Jänne, Pasi A.; Gray, Nathanael S.

    2014-01-01

    The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a “DFG-out” covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket. PMID:25349422

  15. C2 laminar screw and C1-2 transarticular screw combined with C1 laminar hooks for atlantoaxial instability with unilateral vertebral artery injury.

    PubMed

    Guo, Qunfeng; Liu, Jun; Ni, Bin; Lu, Xuhua; Zhou, Fengjin

    2011-09-01

    Transarticular screw fixation (TASF) is technically demanding, with high risk of vertebral artery (VA) injury. How to manage intraoperative VA injury and choose optimal alternative fixation becomes a concern of spinal surgeons. In this study, the management strategy for a patient with suspected intraoperative VA injury was analyzed. A 53-year-old woman developed type II odontoid fracture and brain stem injury due to a motor vehicle accident 3 months earlier. After conservative treatments, the brain stem injury improved, but with residual ocular motility defect in the right eye. The odontoid fracture did not achieve fusion with displacement and absorption of fracture fragments. After admission, atlantoaxial fixation using bilateral C1-2 transarticular screws (TASs) combined with C1 laminar hooks was planed. The first TAS was inserted successfully. Unfortunately, suspected VA injury developed during tapping the tract for the second TAS. Considering the previous brain stem injury and that directly inserting the screw to tamponade the hemorrhage might cause VA stenosis or occlusion, we blocked the screw trajectory with bone wax. C2 laminar screw was implanted instead of intended TAS on the injured side. The management strategy for suspected VA injury should depend on intraoperative circumstances and be tailored to patients. Blocking screw trajectory with bone wax is a useful method to stop bleeding. Atlantoaxial fixation using C2 laminar screw and C1-2 TAS combined with C1 laminar hooks is an ideal alternative procedure.

  16. Separation and conductimetric detection of C1-C7 aliphatic monocarboxylic acids and C1-C7 aliphatic monoamines on unfunctionized polymethacrylate resin columns.

    PubMed

    Ohta, Kazutoku; Towata, Atsuya; Ohashi, Masayoshi; Takeuchi, Toyohide

    2004-06-11

    The application of unfunctionized polymethacrylate resin (TSKgel G3000PWXL) as a stationary phase in liquid chromatography with conductimetric detection for C1-C7 aliphatic monocarboxylic acids (formic acid, acetic acid, propionic acid, butyric acid, isovaleric acid, valeric acid, 3,3-dimethylbutyric acid, 4-methylvaleric acid, hexanoic acid, 2-methylhexanoic acid, 5-methylhexanoic acid and heptanoic acid) and C1-C7 aliphatic monoamines (methylamine, ethylamine, propylamine, isobutylamine, butylamine, isoamylamine, amylamine, 1,3-dimethylbutylamine, hexylamine, 2-heptylamine and heptylamine) was attempted with C8 aliphatic monocarboxylic acids (2-propylvaleric acid, 2-ethylhexanoic acid, 2-methylheptanoic acid and octanoic acid) and C8 aliphatic monoamines (1,5-dimethylhexylamine, 2-ethylhexylamine, 1-methylheptylamine and octylamine) as eluents, respectively. Using 1 mM 2-methylheptanoic acid at pH 4.0 as the eluent, excellent separation and relatively high sensitive detection for these C1-C7 carboxylic acids were achieved on a TSKgel G3000PWXL column (150 mm x 6 mm i.d.) in 60 min. Using 2 mM octylamine at pH 11.0 as the eluent, excellent separation and relatively high sensitive detection for these C1-C7 amines were also achieved on the TSKgel G3000PWXL column in 60 min.

  17. Novel corrosion inhibitor technology

    SciTech Connect

    Van de Ven, P.; Fritz, P.; Pellet, R.

    1999-11-01

    A novel, patented corrosion inhibitor technology has been identified for use in heat transfer applications such as automotive and heavy-duty coolant. The new technology is based on a low-toxic, virtually depletion-free carboxylic acid corrosion inhibitor package that performs equally well in mono ethylene glycol and in less toxic propylene glycol coolants. An aqueous inhibitor concentrate is available to provide corrosion protection where freezing protection is not an issue. In the present paper, this inhibitor package is evaluated in the different base fluids: mono ethylene glycol, mono propylene glycol and water. Results are obtained in both standardized and specific corrosion tests as well as in selected field trials. These results indicate that the inhibitor package remains effective and retains the benefits previously identified in automotive engine coolant applications: excellent corrosion protection under localized conditions, general corrosion conditions as well as at high temperature.

  18. Assessment of the relative contribution of different protease inhibitors to the inhibition of plasmin in vivo.

    PubMed

    Levi, M; Roem, D; Kamp, A M; de Boer, J P; Hack, C E; ten Cate, J W

    1993-02-01

    It has been shown that the most important inhibitor of plasmin is alpha 2-antiplasmin, however, other protease inhibitors are able to inhibit this proteolytic enzyme as well. The contribution of the various protease inhibitors to the inhibition of plasmin in vivo has never been quantitatively assessed. To assess the relative contribution of the different protease inhibitors on the inhibition of plasmin we developed a series of sensitive immunoassays for the detection of complexes between plasmin and the protease inhibitors alpha 2-antiplasmin, alpha 2-macroglobulin, antithrombin III, alpha 1-antitrypsin and C1-inhibitor, utilizing monoclonal antibodies that are specifically directed against complexed protease inhibitors and a monoclonal antibody against plasmin. It was confirmed that alpha 2-antiplasmin is the most important inhibitor of plasmin in vivo, however, complexes of plasmin with alpha 2-macroglobulin, antithrombin III, alpha 1-antitrypsin- and C1-inhibitor were also detected. Particularly during activation of fibrinolysis complexes between plasmin and inhibitors other than alpha 2-antiplasmin were detected. It was observed that during different situations the inhibition profile of plasmin was not constant e.g. in patients with diffuse intravascular coagulation plasma levels of plasmin-alpha 1-antitrypsin and plasmin-C1-inhibitor were increased whereas in plasma from patients who were treated with thrombolytic agents complexes of plasmin with alpha 2-macroglobulin and with antithrombin III were significantly elevated. In conclusion, we confirmed the important role of alpha 2-antiplasmin in the inhibition of plasmin, however, in situations in which fibrinolysis is activated other protease inhibitors also account for the inhibition of plasmin in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. A PP2C-1 Allele Underlying a Quantitative Trait Locus Enhances Soybean 100-Seed Weight.

    PubMed

    Lu, Xiang; Xiong, Qing; Cheng, Tong; Li, Qing-Tian; Liu, Xin-Lei; Bi, Ying-Dong; Li, Wei; Zhang, Wan-Ke; Ma, Biao; Lai, Yong-Cai; Du, Wei-Guang; Man, Wei-Qun; Chen, Shou-Yi; Zhang, Jin-Song

    2017-03-28

    Cultivated soybeans may lose some useful genetic locus during domestication. Introgression of genes from wild soybeans may broaden the genetic background and improve soybean agronomic traits. Here, through whole-genome sequencing of an RIL population derived from a cross between a wild soybean ZYD7 and a cultivated soybean HN44, and mapping of QTLs for seed weight, we discover that a phosphatase 2C-1 (PP2C-1) allele from wild soybean ZYD7 contributes to the increase of seed weight/size in transgenic plants. The PP2C-1 may achieve this function by enhancing cell size of integument and activating a subset of seed trait-related genes. The PP2C-1 was further found to associate with a transcription factor GmBZR1 and facilitate accumulation of dephosphorylated GmBZR1. In contrast, a PP2C-2 allele with variations of a few amino acids at N-terminus does not exhibit this function. Moreover, the GmBZR1 can promote seed weight/size in transgenic plants. Through analysis of cultivated soybean accessions, we find that 40% of the examined accessions do not have the PP2C-1 allele, suggesting that these accessions can be improved through introduction of the PP2C-1 allele. Our study identifies an elite allele PP2C-1, which can enhance seed weight/size. Manipulation of the allele by molecule-assisted breeding may increase production in soybean and other legumes/crops.

  20. Amplitude analysis of the χc 1→η π+π- decays

    NASA Astrophysics Data System (ADS)

    Ablikim, M.; Achasov, M. N.; Ahmed, S.; Ai, X. C.; Albayrak, O.; Albrecht, M.; Ambrose, D. J.; Amoroso, A.; An, F. F.; An, Q.; Bai, J. Z.; Bakina, O.; Baldini Ferroli, R.; Ban, Y.; Bennett, D. W.; Bennett, J. V.; Berger, N.; Bertani, M.; Bettoni, D.; Bian, J. M.; Bianchi, F.; Boger, E.; Boyko, I.; Briere, R. A.; Cai, H.; Cai, X.; Cakir, O.; Calcaterra, A.; Cao, G. F.; Cetin, S. A.; Chai, J.; Chang, J. F.; Chelkov, G.; Chen, G.; Chen, H. S.; Chen, J. C.; Chen, M. L.; Chen, S.; Chen, S. J.; Chen, X.; Chen, X. R.; Chen, Y. B.; Cheng, H. P.; Chu, X. K.; Cibinetto, G.; Dai, H. L.; Dai, J. P.; Dbeyssi, A.; Dedovich, D.; Deng, Z. Y.; Denig, A.; Denysenko, I.; Destefanis, M.; de Mori, F.; Ding, Y.; Dong, C.; Dong, J.; Dong, L. Y.; Dong, M. Y.; Dou, Z. L.; Du, S. X.; Duan, P. F.; Fan, J. Z.; Fang, J.; Fang, S. S.; Fang, X.; Fang, Y.; Farinelli, R.; Fava, L.; Feldbauer, F.; Felici, G.; Feng, C. Q.; Fioravanti, E.; Fritsch, M.; Fu, C. D.; Gao, Q.; Gao, X. L.; Gao, Y.; Gao, Z.; Garzia, I.; Goetzen, K.; Gong, L.; Gong, W. X.; Gradl, W.; Greco, M.; Gu, M. H.; Gu, Y. T.; Guan, Y. H.; Guo, A. Q.; Guo, L. B.; Guo, R. P.; Guo, Y.; Guo, Y. P.; Haddadi, Z.; Hafner, A.; Han, S.; Hao, X. Q.; Harris, F. A.; He, K. L.; Heinsius, F. H.; Held, T.; Heng, Y. K.; Holtmann, T.; Hou, Z. L.; Hu, C.; Hu, H. M.; Hu, J. F.; Hu, T.; Hu, Y.; Huang, G. S.; Huang, J. S.; Huang, X. T.; Huang, X. Z.; Huang, Y.; Huang, Z. L.; Hussain, T.; Ikegami Andersson, W.; Ji, Q.; Ji, Q. P.; Ji, X. B.; Ji, X. L.; Jiang, L. W.; Jiang, X. S.; Jiang, X. Y.; Jiao, J. B.; Jiao, Z.; Jin, D. P.; Jin, S.; Johansson, T.; Julin, A.; Kalantar-Nayestanaki, N.; Kang, X. L.; Kang, X. S.; Kavatsyuk, M.; Ke, B. C.; Kiese, P.; Kliemt, R.; Kloss, B.; Kolcu, O. B.; Kopf, B.; Kornicer, M.; Kupsc, A.; Kühn, W.; Lange, J. S.; Lara, M.; Larin, P.; Leithoff, H.; Leng, C.; Li, C.; Li, Cheng; Li, D. M.; Li, F.; Li, F. Y.; Li, G.; Li, H. B.; Li, H. J.; Li, J. C.; Li, Jin; Li, K.; Li, K.; Li, Lei; Li, P. R.; Li, Q. Y.; Li, T.; Li, W. D.; Li, W. G.; Li, X. L.; Li, X. N.; Li, X. Q.; Li, Y. B.; Li, Z. B.; Liang, H.; Liang, Y. F.; Liang, Y. T.; Liao, G. R.; Lin, D. X.; Liu, B.; Liu, B. J.; Liu, C. X.; Liu, D.; Liu, F. H.; Liu, Fang; Liu, Feng; Liu, H. B.; Liu, H. H.; Liu, H. H.; Liu, H. M.; Liu, J.; Liu, J. B.; Liu, J. P.; Liu, J. Y.; Liu, K.; Liu, K. Y.; Liu, L. D.; Liu, P. L.; Liu, Q.; Liu, S. B.; Liu, X.; Liu, Y. B.; Liu, Y. Y.; Liu, Z. A.; Liu, Zhiqing; Loehner, H.; Long, Y. F.; Lou, X. C.; Lu, H. J.; Lu, J. G.; Lu, Y.; Lu, Y. P.; Luo, C. L.; Luo, M. X.; Luo, T.; Luo, X. L.; Lyu, X. R.; Ma, F. C.; Ma, H. L.; Ma, L. L.; Ma, M. M.; Ma, Q. M.; Ma, T.; Ma, X. N.; Ma, X. Y.; Ma, Y. M.; Maas, F. E.; Maggiora, M.; Malik, Q. A.; Mao, Y. J.; Mao, Z. P.; Marcello, S.; Messchendorp, J. G.; Mezzadri, G.; Min, J.; Min, T. J.; Mitchell, R. E.; Mo, X. H.; Mo, Y. J.; Morales Morales, C.; Muchnoi, N. Yu.; Muramatsu, H.; Musiol, P.; Nefedov, Y.; Nerling, F.; Nikolaev, I. B.; Ning, Z.; Nisar, S.; Niu, S. L.; Niu, X. Y.; Olsen, S. L.; Ouyang, Q.; Pacetti, S.; Pan, Y.; Patteri, P.; Pelizaeus, M.; Peng, H. P.; Peters, K.; Pettersson, J.; Ping, J. L.; Ping, R. G.; Poling, R.; Prasad, V.; Qi, H. R.; Qi, M.; Qian, S.; Qiao, C. F.; Qin, L. Q.; Qin, N.; Qin, X. S.; Qin, Z. H.; Qiu, J. F.; Rashid, K. H.; Redmer, C. F.; Ripka, M.; Rong, G.; Rosner, Ch.; Ruan, X. D.; Sarantsev, A.; Savrié, M.; Schnier, C.; Schoenning, K.; Schumann, S.; Shan, W.; Shao, M.; Shen, C. P.; Shen, P. X.; Shen, X. Y.; Sheng, H. Y.; Shi, M.; Song, W. M.; Song, X. Y.; Sosio, S.; Spataro, S.; Sun, G. X.; Sun, J. F.; Sun, S. S.; Sun, X. H.; Sun, Y. J.; Sun, Y. Z.; Sun, Z. J.; Sun, Z. T.; Tang, C. J.; Tang, X.; Tapan, I.; Thorndike, E. H.; Tiemens, M.; Uman, I.; Varner, G. S.; Wang, B.; Wang, B. L.; Wang, D.; Wang, D. Y.; Wang, K.; Wang, L. L.; Wang, L. S.; Wang, M.; Wang, P.; Wang, P. L.; Wang, W.; Wang, W. P.; Wang, X. F.; Wang, Y.; Wang, Y. D.; Wang, Y. F.; Wang, Y. Q.; Wang, Z.; Wang, Z. G.; Wang, Z. H.; Wang, Z. Y.; Wang, Z. Y.; Weber, T.; Wei, D. H.; Weidenkaff, P.; Wen, S. P.; Wiedner, U.; Wolke, M.; Wu, L. H.; Wu, L. J.; Wu, Z.; Xia, L.; Xia, L. G.; Xia, Y.; Xiao, D.; Xiao, H.; Xiao, Z. J.; Xie, Y. G.; Xiu, Q. L.; Xu, G. F.; Xu, J. J.; Xu, L.; Xu, Q. J.; Xu, Q. N.; Xu, X. P.; Yan, L.; Yan, W. B.; Yan, W. C.; Yan, Y. H.; Yang, H. J.; Yang, H. X.; Yang, L.; Yang, Y. X.; Ye, M.; Ye, M. H.; Yin, J. H.; You, Z. Y.; Yu, B. X.; Yu, C. X.; Yu, J. S.; Yuan, C. Z.; Yuan, W. L.; Yuan, Y.; Yuncu, A.; Zafar, A. A.; Zallo, A.; Zeng, Y.; Zeng, Z.; Zhang, B. X.; Zhang, B. Y.; Zhang, C.; Zhang, C. C.; Zhang, D. H.; Zhang, H. H.; Zhang, H. Y.; Zhang, J.; Zhang, J. J.; Zhang, J. L.; Zhang, J. Q.; Zhang, J. W.; Zhang, J. Y.; Zhang, J. Z.; Zhang, K.; Zhang, L.; Zhang, S. Q.; Zhang, X. Y.; Zhang, Y.; Zhang, Y.; Zhang, Y. H.; Zhang, Y. N.; Zhang, Y. T.; Zhang, Yu; Zhang, Z. H.; Zhang, Z. P.; Zhang, Z. Y.; Zhao, G.; Zhao, J. W.; Zhao, J. Y.; Zhao, J. Z.; Zhao, Lei; Zhao, Ling; Zhao, M. G.; Zhao, Q.; Zhao, Q. W.; Zhao, S. J.; Zhao, T. C.; Zhao, Y. B.; Zhao, Z. G.; Zhemchugov, A.; Zheng, B.; Zheng, J. P.; Zheng, W. J.; Zheng, Y. H.; Zhong, B.; Zhou, L.; Zhou, X.; Zhou, X. K.; Zhou, X. R.; Zhou, X. Y.; Zhu, K.; Zhu, K. J.; Zhu, S.; Zhu, S. H.; Zhu, X. L.; Zhu, Y. C.; Zhu, Y. S.; Zhu, Z. A.; Zhuang, J.; Zotti, L.; Zou, B. S.; Zou, J. H.; Besiii Collaboration

    2017-02-01

    Using 448.0 ×1 06 ψ (3686 ) events collected with the BESIII detector, an amplitude analysis is performed for ψ (3686 )→γ χc 1 , χc 1→η π+π- decays. The most dominant two-body structure observed is a0(980 )±π∓ ; a0(980 )±→η π± . The a0(980 ) line shape is modeled using a dispersion relation, and a significant nonzero a0(980 ) coupling to the η'π channel is measured. We observe χc 1→a2(1700 )π production for the first time, with a significance larger than 17 σ . The production of mesons with exotic quantum numbers, JP C=1-+ , is investigated, and upper limits for the branching fractions χc 1→π1(1400 )±π∓ , χc 1→π1(1600 )±π∓ , and χc 1→π1(2015 )±π∓ , with subsequent π1(X )±→η π± decay, are determined.

  1. Atomic resolution model of the antibody Fc interaction with the complement C1q component.

    PubMed

    Schneider, Sebastian; Zacharias, Martin

    2012-05-01

    The globular C1q heterotrimer is a subunit of the C1 complement factor. Binding of the C1q subunit to the constant (Fc) part of antibody molecules is a first step and key event of complement activation. Although three-dimensional structures of C1q and antibody Fc subunits have been determined experimentally no atomic resolution structure of the C1q-Fc complex is known so far. Based on systematic protein-protein docking searches and Molecular Dynamics simulations a structural model of the C1q-IgG1-Fc-binding geometry has been obtained. The structural model is compatible with available experimental data on the interaction between the two partner proteins. It predicts a binding geometry that involves mainly the B-subunit of the C1q-trimer and both subunits of the IgG1-Fc-dimer with small conformational adjustments with respect to the unbound partners to achieve high surface complementarity. In addition to several charge-charge and polar contacts in the rim region of the interface it also involves nonpolar contacts between the two proteins and is compatible with the carbohydrate moiety of the Fc subunit. The model for the complex structure provides a working model for rationalizing available biochemical data on this important interaction and can form the basis for the design of Fc variants with a greater capacity to activate the complement system for example on binding to cancer cells or other target structures.

  2. Dimension spectrum of asymptotically additive potentials for C1 average conformal repellers

    NASA Astrophysics Data System (ADS)

    Cao, Yongluo

    2013-09-01

    In this paper, the dimension spectrum of asymptotically additive potentials for C1 average conformal repellers is considered. First, we give dimension estimates of arbitrary subsets for C1 average conformal repellers and we also consider the pointwise dimension of invariant measures. Furthermore, we consider the dimension spectrum of asymptotically additive potentials and its properties. As applications, we give an affirmative answer to the problem posed by Olsen (2003 J. Math. Pures Appl. 82 1591-649) for general types of level sets and obtain the dimension spectrum of weak Gibbs measures for continuous potentials on C1 average conformal repellers.

  3. [Acquired paraneoplastic hypertrichosis lanuginosa associated with scleroderma].

    PubMed

    Valda Rodriguez, L; Torrico Velasco, J; Zeballos Vasconcellos, R

    1990-01-01

    Acquired hypertrichosis lanuginosa is universally recognized as an individual disease and seldom reported as a genuine paraneoplastic manifestation. We report the case of a 30-year old woman with acquired hypertrichosis lanuginosa. Due to the finding of a cervical lymph node metastasis, she was investigated for an internal neoplasm, but the original tumour could not be found by the usual methods. A bronchogenic carcinoma was discovered at autopsy. Beside hypertrichosis, this patient had other disorders not described in the literature as associated with that disease, viz.: progressive systemic scleroderma, fissured and hyperpigmented tongue, thrombocytopenia, galactorrhoea, axillary and pubic alopecia and overcurvature of toe nails. A review of similar cases in the literature provided clinical arguments in favour of the hormonal origin of this paraneoplastic hypertrichosis.

  4. Acquired portosystemic collaterals: anatomy and imaging.

    PubMed

    Leite, Andréa Farias de Melo; Mota, Américo; Chagas-Neto, Francisco Abaeté; Teixeira, Sara Reis; Elias Junior, Jorge; Muglia, Valdair Francisco

    2016-01-01

    Portosystemic shunts are enlarged vessels that form collateral pathological pathways between the splanchnic circulation and the systemic circulation. Although their causes are multifactorial, portosystemic shunts all have one mechanism in common-increased portal venous pressure, which diverts the blood flow from the gastrointestinal tract to the systemic circulation. Congenital and acquired collateral pathways have both been described in the literature. The aim of this pictorial essay was to discuss the distinct anatomic and imaging features of portosystemic shunts, as well as to provide a robust method of differentiating between acquired portosystemic shunts and similar pathologies, through the use of illustrations and schematic drawings. Imaging of portosystemic shunts provides subclinical markers of increased portal venous pressure. Therefore, radiologists play a crucial role in the identification of portosystemic shunts. Early detection of portosystemic shunts can allow ample time to perform endovascular shunt operations, which can relieve portal hypertension and prevent acute or chronic complications in at-risk patient populations.

  5. Clinical laboratory data: acquire, analyze, communicate, liberate.

    PubMed

    Azzazy, Hassan M E; Elbehery, Ali H A

    2015-01-01

    The availability of portable healthcare devices, which can acquire and transmit medical data to remote experts would dramatically affect healthcare in areas with poor infrastructure. Smartphones, which feature touchscreen computer capabilities and sophisticated cameras, have become widely available with over billion units shipped in 2013. In the clinical laboratory, smartphones have recently brought the capabilities of key instruments such as spectrophotometers, fluorescence analyzers and microscopes into the palm of the hand. Several research groups have developed sensitive and low-cost smartphone-based diagnostic assay prototypes for testing cholesterol, albumin, vitamin D, tumor markers, and the detection of infectious agents. This review covers the use of smartphones to acquire, analyze, communicate, and liberate clinical laboratory data. Smartphones promise to dramatically improve the quality and quantity of healthcare offered in resource-limited areas.

  6. Subcortical infarction resulting in acquired stuttering.

    PubMed

    Ciabarra, A M; Elkind, M S; Roberts, J K; Marshall, R S

    2000-10-01

    Stuttering is an uncommon presentation of acute stroke. Reported cases have often been associated with left sided cortical lesions, aphasia, and difficulties with other non-linguistic tests of rhythmic motor control. Three patients with subcortical lesions resulting in stuttering are discussed. In one patient the ability to perform time estimations with a computerised repetitive time estimation task was characterised. One patient had a pontine infarct with clinical evidence of cerebellar dysfunction. A second patient had a left basal ganglionic infarct and a disruption of timing estimation. A third patient had a left subcortical infarct and a mild aphasia. These findings expand the reported distribution of infarction that can result in acquired stuttering. Subcortical mechanisms of speech control and timing may contribute to the pathophysiology of acquired stuttering.

  7. Recognising and managing community-acquired pneumonia.

    PubMed

    Gibson, Vanessa

    2015-11-18

    Pneumonia remains a significant cause of morbidity and mortality in the UK and yet the seriousness of the disease is underestimated. Pneumonia can be life-threatening because the delicate tissues of the alveoli and pulmonary capillaries are susceptible to damage from the inflammatory response. This damage leads to consolidation that prevents the diffusion of oxygen and carbon dioxide, and this in turn can lead to respiratory failure. This article summarises guidance on the diagnosis and management of community-acquired pneumonia, and also includes information on the prevention of pneumonia. This information should be valuable to nurses working in a variety of clinical areas since patients with community-acquired pneumonia are encountered in primary, intermediate, secondary and critical care.

  8. Acquired versus familial demyelinative neuropathies in children.

    PubMed

    Miller, R G; Gutmann, L; Lewis, R A; Sumner, A J

    1985-01-01

    The electrophysiologic differences between chronic acquired demyelinative neuropathy and the demyelinative form of Charcot-Marie-Tooth disease have recently been reported. The present report extends these observations to include the genetically determined demyelinating neuropathies seen in metachromatic leukodystrophy, Krabbe's leukodystrophy, and Cockayne's syndrome. The electrophysiologic features of metachromatic leukodystrophy (five patients), Krabbe's (four patients), and Cockayne's syndrome (three patients) were all similar. There was uniform slowing of conduction (both in different nerves and in different nerve segments), and conduction block was not seen. These findings are consistent with a uniform degree of demyelination in multiple nerves and throughout the entire length of individual axons. Thus, uniform slowing of nerve conduction constitutes strong evidence for a familial demyelinative neuropathy, as opposed to the multifocal slowing seen in acute and chronic acquired demyelinative neuropathy.

  9. Acquired portosystemic collaterals: anatomy and imaging*

    PubMed Central

    Leite, Andréa Farias de Melo; Mota Jr., Américo; Chagas-Neto, Francisco Abaeté; Teixeira, Sara Reis; Elias Junior, Jorge; Muglia, Valdair Francisco

    2016-01-01

    Portosystemic shunts are enlarged vessels that form collateral pathological pathways between the splanchnic circulation and the systemic circulation. Although their causes are multifactorial, portosystemic shunts all have one mechanism in common-increased portal venous pressure, which diverts the blood flow from the gastrointestinal tract to the systemic circulation. Congenital and acquired collateral pathways have both been described in the literature. The aim of this pictorial essay was to discuss the distinct anatomic and imaging features of portosystemic shunts, as well as to provide a robust method of differentiating between acquired portosystemic shunts and similar pathologies, through the use of illustrations and schematic drawings. Imaging of portosystemic shunts provides subclinical markers of increased portal venous pressure. Therefore, radiologists play a crucial role in the identification of portosystemic shunts. Early detection of portosystemic shunts can allow ample time to perform endovascular shunt operations, which can relieve portal hypertension and prevent acute or chronic complications in at-risk patient populations. PMID:27777479

  10. The urological management of the patient with acquired immunodeficiency syndrome.

    PubMed

    Heyns, Chris F; Fisher, Megan

    2005-04-01

    In people infected with the human immunodeficiency virus (HIV) both the CD4 T-cell count and the viral load are used to monitor disease progression to acquired immunodeficiency syndrome (AIDS). CD4 counts of <500/mm(3) are associated with opportunistic infections and certain malignancies, so-called 'AIDS-defining' conditions. Highly active antiretroviral therapy, using combinations of reverse transcriptase inhibitors and/or protease inhibitors, can improve considerably the prognosis of people who are HIV-positive, but such therapy is not yet widely available in many developing countries. People with AIDS are predisposed to urinary tract infection (UTI) by uncommon bacteria and pathogens, e.g. fungi, parasites and viruses, which may affect any urogenital organ; treatment should be culture-specific and long-term, because there is a tendency to recurrence, infection with multiple organisms and resistant isolates. Voiding dysfunction in patients with AIDS is usually a result of neurological complications caused by opportunistic infections, and has a poor prognosis. Of patients with AIDS, 30-50% develop a cancer, especially Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL). KS may involve any urogenital organ, but is usually part of systemic disease. Small lesions on the external genitalia can be treated with laser, cryotherapy or surgical excision, larger lesions with radiotherapy, and disseminated or visceral KS with multidrug chemotherapy. NHL may involve the kidneys, testes and retroperitoneal lymph nodes, thus obstructing the ureters, which may require ureteric stenting or percutaneous nephrostomy. NHL can be treated with radiotherapy and combination chemotherapy. Urolithiasis in patients with AIDS may be caused by indinavir, a protease inhibitor, but the more common types of stones may also occur. Fluid-electrolyte and acid-base disturbances are common in patients with advanced AIDS, secondary to vomiting, diarrhoea, malnutrition or septicaemia. HIV

  11. Acquired resistance of Mycobacterium tuberculosis to bedaquiline.

    PubMed

    Andries, Koen; Villellas, Cristina; Coeck, Nele; Thys, Kim; Gevers, Tom; Vranckx, Luc; Lounis, Nacer; de Jong, Bouke C; Koul, Anil

    2014-01-01

    Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multi-drug resistant tuberculosis in decades. In vitro resistance to BDQ was previously shown to be due to target-based mutations. Here we report that non-target based resistance to BDQ, and cross-resistance to clofazimine (CFZ), is due to mutations in Rv0678, a transcriptional repressor of the genes encoding the MmpS5-MmpL5 efflux pump. Efflux-based resistance was identified in paired isolates from patients treated with BDQ, as well as in mice, in which it was confirmed to decrease bactericidal efficacy. The efflux inhibitors verapamil and reserpine decreased the minimum inhibitory concentrations of BDQ and CFZ in vitro, but verapamil failed to increase the bactericidal effect of BDQ in mice and was unable to reverse efflux-based resistance in vivo. Cross-resistance between BDQ and CFZ may have important clinical implications.

  12. CRYSTALLINE SOYBEAN TRYPSIN INHIBITOR

    PubMed Central

    Kunitz, M.

    1947-01-01

    A study has been made of the general properties of crystalline soybean trypsin inhibitor. The soy inhibitor is a stable protein of the globulin type of a molecular weight of about 24,000. Its isoelectric point is at pH 4.5. It inhibits the proteolytic action approximately of an equal weight of crystalline trypsin by combining with trypsin to form a stable compound. Chymotrypsin is only slightly inhibited by soy inhibitor. The reaction between chymotrypsin and the soy inhibitor consists in the formation of a reversibly dissociable compound. The inhibitor has no effect on pepsin. The inhibiting action of the soybean inhibitor is associated with the native state of the protein molecule. Denaturation of the soy protein by heat or acid or alkali brings about a proportional decrease in its inhibiting action on trypsin. Reversal of denaturation results in a proportional gain in the inhibiting activity. Crystalline soy protein when denatured is readily digestible by pepsin, and less readily by chymotrypsin and by trypsin. Methods are given for measuring trypsin and inhibitor activity and also protein concentration with the aid of spectrophotometric density measurements at 280 mµ. PMID:19873496

  13. Brucella abortus Infection Acquired in Microbiology Laboratories

    PubMed Central

    Fiori, Pier Luigi; Mastrandrea, Scilla; Rappelli, Paola; Cappuccinelli, Piero

    2000-01-01

    We report an outbreak of laboratory-acquired Brucella abortus infection originating in the accidental breakage of a centrifuge tube. A total of 12 laboratory workers were infected (attack rate of 31%), with an incubation time ranging from 6 weeks to 5 months. Antibody titers were evaluated weekly in all personnel exposed, allowing the diagnosis of the infection in most cases before the onset of clinical symptoms, so that specific therapy could be administrated. PMID:10790142

  14. Acquiring Secure Systems Through Information Economics

    DTIC Science & Technology

    2015-05-01

    Introduction “For all future weapons systems that DoD will acquire or procure, DoD will mandate specific cybersecurity standards for weapons...systems to meet. Acquisition and procurement policy and practice will be updated to promote effective cybersecurity throughout a system’s life cycle...physical damage or injury Motivating Contractor Efforts - Contractors have different priorities than the DOD when it comes to cybersecurity - Classic

  15. Earth Knowledge Acquired by Middle School Students

    NASA Technical Reports Server (NTRS)

    Ride, Sally

    2008-01-01

    Earth Knowledge Acquired by Middle School Students (EarthKAM), an education activity, allows middle school students to program a digital camera on board the International Space Station to photograph a variety of geographical targets for study in the classroom. Photos are made available on the web for viewing and study by participating schools around the world. Educators use the images for projects involving Earth Science, geography, physics, and social science.

  16. Acquired Antibiotic Resistance Genes: An Overview

    PubMed Central

    van Hoek, Angela H. A. M.; Mevius, Dik; Guerra, Beatriz; Mullany, Peter; Roberts, Adam Paul; Aarts, Henk J. M.

    2011-01-01

    In this review an overview is given on antibiotic resistance (AR) mechanisms with special attentions to the AR genes described so far preceded by a short introduction on the discovery and mode of action of the different classes of antibiotics. As this review is only dealing with acquired resistance, attention is also paid to mobile genetic elements such as plasmids, transposons, and integrons, which are associated with AR genes, and involved in the dispersal of antimicrobial determinants between different bacteria. PMID:22046172

  17. Acquired ciliary circumscribed grey hair (ACCG).

    PubMed

    Romero, A G; Calatayud, J C

    2001-12-01

    Grey-haired areas usually occur due to aging or inheritance. A case is described of abrupt occurrence of a focal circumscribed grey-hair in the eyebrow region (a single hair) in a 27-year-old woman. The phenomenon was named acquired ciliary circumscribed grey-hair (ACCG). Qualitative and semiquantitative findings were obtained by microanalytical studies. In addition to morphological differences from control hair, the ACCG hair showed a high percentage of sulfur (99.8%) and absence of oligoelements.

  18. Rare presentation of spontaneous acquired diaphragmatic hernia.

    PubMed

    Gupta, Shweta; Bali, Roseleen Kaur; Das, Kamanasish; Sisodia, Anula; Dewan, R K; Singla, Rupak

    2011-01-01

    Spontaneous acquired diaphragmatic hernia without any apparent history of trauma is a very rare condition and is very difficult to diagnose. We present a case of a 21-year-old male who presented with abdominal pain for one month and four episodes of vomiting for one day. Clinical suspicion, chest radiography with nasogastric tube in situ and computed tomography (CT) confirmed the diagnosis. The diaphragmatic defect was repaired surgically. The patient had an uneventful post-operative recovery.

  19. The pathophysiology of acquired premature ejaculation.

    PubMed

    McMahon, Chris G; Jannini, Emmanuele A; Serefoglu, Ege C; Hellstrom, Wayne J G

    2016-08-01

    The second Ad Hoc International Society for Sexual Medicine (ISSM) Committee for the Definition of Premature Ejaculation defined acquired premature ejaculation (PE) as a male sexual dysfunction characterized by a the development of a clinically significant and bothersome reduction in ejaculation latency time in men with previous normal ejaculatory experiences, often to about 3 minutes or less, the inability to delay ejaculation on all or nearly all vaginal penetrations, and the presence of negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy. The literature contains a diverse range of biological and psychological etiological theories. Acquired PE is commonly due to sexual performance anxiety, psychological or relationship problems, erectile dysfunction (ED), and occasionally prostatitis and hyperthyroidism, consistent with the predominant organic etiology of acquired PE, men with this complaint are usually older, have a higher mean BMI and a greater incidence of comorbid disease including hypertension, sexual desire disorder, diabetes mellitus, chronic prostatitis, and ED compared to lifelong, variable and subjective PE.

  20. The pathophysiology of acquired premature ejaculation

    PubMed Central

    Jannini, Emmanuele A.; Serefoglu, Ege C.; Hellstrom, Wayne J. G.

    2016-01-01

    The second Ad Hoc International Society for Sexual Medicine (ISSM) Committee for the Definition of Premature Ejaculation defined acquired premature ejaculation (PE) as a male sexual dysfunction characterized by a the development of a clinically significant and bothersome reduction in ejaculation latency time in men with previous normal ejaculatory experiences, often to about 3 minutes or less, the inability to delay ejaculation on all or nearly all vaginal penetrations, and the presence of negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy. The literature contains a diverse range of biological and psychological etiological theories. Acquired PE is commonly due to sexual performance anxiety, psychological or relationship problems, erectile dysfunction (ED), and occasionally prostatitis and hyperthyroidism, consistent with the predominant organic etiology of acquired PE, men with this complaint are usually older, have a higher mean BMI and a greater incidence of comorbid disease including hypertension, sexual desire disorder, diabetes mellitus, chronic prostatitis, and ED compared to lifelong, variable and subjective PE. PMID:27652216

  1. (+)-Rimocidin Synthetic Studies: Construction of the C(1-27) Aglycone Skeleton

    PubMed Central

    Smith, Amos B.; Foley, Megan A.; Dong, Shuzhi; Orbin, Alia

    2010-01-01

    Assembly of the C(1-27) macrocyclic skeleton of rimocidinolide, the aglycone of (+)-rimocidin (1), has been achieved in convergent fashion. Key features of the synthetic strategy entail application of multicomponent Type 1 Anion Relay Chemistry (ARC), in conjunction with the SN2/SN2' reaction manifolds of vinyl epoxides, both employing 2-susbtituted-1,3-dithianes to construct the C(1-19) carbon backbone. Yamaguchi union of a C(20-27) vinyl borate ester, possessing the all trans triene, with an advanced C(1-19) vinyl iodide followed by macrocyclization via Suzuki-Miyaura cross-coupling completed construction of the C(1-27) rimocidinolide skeleton. PMID:19621880

  2. Observation of the h(c)(1P) Using e+ e- collisions above the DD threshold.

    PubMed

    Pedlar, T K; Cronin-Hennessy, D; Hietala, J; Dobbs, S; Metreveli, Z; Seth, K K; Tomaradze, A; Xiao, T; Martin, L; Powell, A; Wilkinson, G; Mendez, H; Ge, J Y; Miller, D H; Shipsey, I P J; Xin, B; Adams, G S; Hu, D; Moziak, B; Napolitano, J; Ecklund, K M; Insler, J; Muramatsu, H; Park, C S; Pearson, L J; Thorndike, E H; Ricciardi, S; Thomas, C; Artuso, M; Blusk, S; Mountain, R; Skwarnicki, T; Stone, S; Zhang, L M; Bonvicini, G; Cinabro, D; Lincoln, A; Smith, M J; Zhou, P; Zhu, J; Naik, P; Rademacker, J; Asner, D M; Edwards, K W; Randrianarivony, K; Tatishvili, G; Briere, R A; Vogel, H; Onyisi, P U E; Rosner, J L; Alexander, J P; Cassel, D G; Das, S; Ehrlich, R; Gibbons, L; Gray, S W; Hartill, D L; Heltsley, B K; Kreinick, D L; Kuznetsov, V E; Patterson, J R; Peterson, D; Riley, D; Ryd, A; Sadoff, A J; Shi, X; Sun, W M; Yelton, J; Rubin, P; Lowrey, N; Mehrabyan, S; Selen, M; Wiss, J; Libby, J; Kornicer, M; Mitchell, R E; Shepherd, M R; Tarbert, C M; Besson, D

    2011-07-22

    Using 586  pb(-1) of e+ e- collision data at E(c.m.) = 4170  MeV, produced at the Cornell Electron Storage Ring collider and collected with the CLEO-c detector, we observe the process e+ e- → π+ π- h(c)(1P). We measure its cross section to be 15.6±2.3±1.9±3.0  pb, where the third error is due to the external uncertainty on the branching fraction of ψ(2S) → π0 h(c)(1P), which we use for normalization. We also find evidence for e+ e- → ηh(c)(1P) at 4170 MeV at the 3σ level and see hints of a rise in the e+ e- → π+ π- h(c)(1P) cross section at 4260 MeV.

  3. Retro-odontoid cystic mass treated by laminectomy and C1-C2 fixation.

    PubMed

    Lin, Dasheng; Ding, Zhenqi; Guo, Yanjie; Lian, Kejian

    2014-11-01

    Retro-odontoid cysts associated with chronic atlantoaxial subluxation are extremely rare. This article describes a case of retro-odontoid cystic mass associated with chronic atlantoaxial subluxation and its management with posterior C1 and partial C2 laminectomy and C1-C2 pedicle screw fixation without resection of the retro-odontoid cyst. A 64-year-old woman experienced a sudden onset of neck pain, hand and foot paresthesia. Atlantoaxial instability associated with a retro-odontoid cystic mass was found in the imaging. The patient underwent posterior C1 and partial C2 laminectomy and C1-C2 pedicle screws fixation without resection of the retro-odontoid cyst. During the 24 months followup period, the cyst disappeared completely and the patient remained symptom free and returned to independent daily living. These findings suggest that posterior laminectomy and fixation without resection of the retro-odontoid cyst is relatively simple and safe and the results are satisfactory.

  4. Development of the Advanced Technology Microwave Sounder (ATMS) for NPOESS C1

    NASA Astrophysics Data System (ADS)

    Brann, C.; Kunkee, D.

    2008-12-01

    The National Polar-orbiting Operational Environmental Satellite System's Advanced Technology Microwave Sounder (ATMS) is planned for flight on the first NPOESS mission (C1) in 2013. The C1 ATMS will be the second instrument of the ATMS series and will provide along with the companion Cross-track Infrared Sounder (CrIS), atmospheric temperature and moisture profiles for NPOESS. The first flight of the ATMS is scheduled in 2010 on the NPOESS Preparatory Project (NPP) satellite, which is an early instrument risk reduction component of the NPOESS mission. This poster will focus on the development of the ATMS for C1 including aspects of the sensor calibration, antenna beam and RF characteristics and scanning. New design aspects of the C1 ATMS, required primarily by parts obsolescence, will also be addressed in this poster.

  5. 26 CFR 1.1244(c)-1 - Section 1244 stock defined.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... under section 1244(c)(1)(C). Payments for the parking of automobiles ordinarily do not constitute rents... means the entire amount received as an annuity under an annuity, endowment, or life insurance...

  6. 26 CFR 1.412(c)(1)-1 - Determinations to be made under funding method-terms defined.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...-terms defined. 1.412(c)(1)-1 Section 1.412(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT... Plans, Etc. § 1.412(c)(1)-1 Determinations to be made under funding method—terms defined. (a) Actuarial... bargained plans, see § 1.412(c)(1)-2; for principles applicable to funding methods in general,...

  7. 48 CFR 1845.502-70 - Contractor-acquired property.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor-acquired... Possession of Contractors 1845.502-70 Contractor-acquired property. All contractor-acquired property must be... contractor-acquired. (2) Submission of DD Form 1419, DOD Industrial Plant Requisition, or equivalent...

  8. 17 CFR 240.15c1-8 - Sales at the market.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a...

  9. 17 CFR 240.15c1-8 - Sales at the market.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a...

  10. 26 CFR 1.1244(c)-1 - Section 1244 stock defined.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 11 2012-04-01 2012-04-01 false Section 1244 stock defined. 1.1244(c)-1 Section....1244(c)-1 Section 1244 stock defined. (a) In general. For purposes of §§ 1.1244(a)-1 to 1.1244(e)-1, inclusive: (1) The term pre-November 1978 stock means stock issued after June 30, 1958, and on or...

  11. Minimum variance and variance of outgoing quality limit MDS-1(c1, c2) plans

    NASA Astrophysics Data System (ADS)

    Raju, C.; Vidya, R.

    2016-06-01

    In this article, the outgoing quality (OQ) and total inspection (TI) of multiple deferred state sampling plans MDS-1(c1,c2) are studied. It is assumed that the inspection is rejection rectification. Procedures for designing MDS-1(c1,c2) sampling plans with minimum variance of OQ and TI are developed. A procedure for obtaining a plan for a designated upper limit for the variance of the OQ (VOQL) is outlined.

  12. Characterization of the membrane-targeting C1 domain in Pasteurella multocida toxin.

    PubMed

    Kamitani, Shigeki; Kitadokoro, Kengo; Miyazawa, Masayuki; Toshima, Hirono; Fukui, Aya; Abe, Hiroyuki; Miyake, Masami; Horiguchi, Yasuhiko

    2010-08-13

    Pasteurella multocida toxin (PMT) is a virulence factor responsible for the pathogenesis of some forms of pasteurellosis. The toxin activates G(q)- and G(12/13)-dependent pathways through the deamidation of a glutamine residue in the alpha-subunit of heterotrimeric GTPases. We recently reported the crystal structure of the C terminus (residues 575-1285) of PMT (C-PMT), which is composed of three domains (C1, C2, and C3), and that the C1 domain is involved in the localization of C-PMT to the plasma membrane, and the C3 domain possesses a cysteine protease-like catalytic triad. In this study, we analyzed the membrane-targeting function of the C1 domain in detail. The C1 domain consists of seven helices of which the first four (residues 590-670), showing structural similarity to the N terminus of Clostridium difficile toxin B, were found to be involved in the recruitment of C-PMT to the plasma membrane. C-PMT lacking these helices (C-PMT DeltaC1(4H)) neither localized to the plasma membrane nor stimulated the G(q/12/13)-dependent signaling pathways. When the membrane-targeting property was complemented by a peptide tag with an N-myristoylation motif, C-PMT DeltaC1(4H) recovered the PMT activity. Direct binding between the C1 domain and liposomes containing phospholipids was evidenced by surface plasmon resonance analyses. These results indicate that the C1 domain of C-PMT functions as a targeting signal for the plasma membrane.

  13. 17 CFR 240.15c1-8 - Sales at the market.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a...

  14. 17 CFR 240.15c1-8 - Sales at the market.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a...

  15. 17 CFR 240.15c1-8 - Sales at the market.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a...

  16. Induction of autophagy counteracts the anticancer effect of cisplatin in human esophageal cancer cells with acquired drug resistance.

    PubMed

    Yu, Le; Gu, Chunping; Zhong, Desheng; Shi, Lili; Kong, Yi; Zhou, Zhitao; Liu, Shuwen

    2014-12-01

    Cisplatin-based chemotherapy frequently resulted in acquired resistance. The underpinning mechanism of such resistance remains obscure especially in relation to autophagic response. This study thus investigated the role of autophagy in the anticancer activity of cisplatin in human esophageal cancer cells with acquired cisplatin resistance. In response to cisplatin treatment, EC109 cells exhibited substantial apoptosis and senescence whereas cisplatin-resistant EC109/CDDP cells exhibited resistance. In this respect, cisplatin increased ERK phosphorylation whose inhibition by MEK inhibitor significantly attenuated the cytotoxic and cytostatic effect of cisplatin. Notably, cisplatin preferentially induces autophagy in EC109/CDDP cells but not in EC109 cells. Moreover, the induction of autophagy was accompanied by the suppression of mTORC1 activity. Abolition of autophagy by pharmacological inhibitors or knockdown of ATG5/7 re-sensitized EC109/CDDP cells. Co-administration of an autophagy inhibitor chloroquine and cisplatin significantly suppressed tumor growth whereas cisplatin monotherapy failed to elicit anticancer activity in nude mice xenografted with EC109/CDDP cells. To conclude, our data implicate autophagic response as a key mechanism of acquired resistance to cisplatin, suggesting that autophagy is a novel target to improve therapy efficiency of cisplatin toward human esophageal cancers with acquired resistance.

  17. Two human homeobox genes, c1 and c8: structure analysis and expression in embryonic development

    SciTech Connect

    Simeone, A.; Mavilio, F.; Acampora, D.; Giampaolo, A.; Faiella, A.; Zappavigna, V.; D'Esposito, M.; Pannese, M.; Russo, G.; Boncinelli, E.; Peschle, C.

    1987-07-01

    Two human cDNA clones (HHO.c1.95 and HHO.c8.5111) containing a homeobox region have been characterized, and the respective genomic regions have been partially analyzed. Expression of the corresponding genes, termed c1 and c8, was evaluated in different organs and body parts during human embryonic/fetal development. HHO.c1.95 apparently encodes a 217-amino acid protein containing a class I homeodomain that shares 60 out of 61 amino acid residues with the Antennapedia homeodomain of Drosophila melanogaster. HHO.c8.5111 encodes a 153-amino acid protein containing a homeodomains identical to that of the frog AC1 gene. Clones HHO.c1 and HHO.c8 detect by blot-hybridization one and two specific polyadenylylated transcripts, respectively. These are differentially expressed in spinal cord, backbone rudiments, limb buds (or limbs), heart, and skin of human embryos and early fetuses in the 5- to 9-week postfertilization period, thus suggesting that the c1 and c8 genes play a key role in a variety of developmental processes. Together, the results of the embryonic/fetal expression of c1 and c8 and those of two previously analyzed genes (c10 and c13) indicate a coherent pattern of expression of these genes in early human ontogeny.

  18. The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

    PubMed Central

    Gao, Wei; Kim, Jin-Yong; Anderson, Jeffrey R.; Akopian, Tatos; Hong, Seungpyo; Jin, Ying-Yu; Kandror, Olga; Kim, Jong-Woo; Lee, In-Ae; Lee, Sun-Young; McAlpine, James B.; Mulugeta, Surafel; Sunoqrot, Suhair; Wang, Yuehong; Yang, Seung-Hwan; Yoon, Tae-Mi; Goldberg, Alfred L.; Pauli, Guido F.; Cho, Sanghyun

    2014-01-01

    Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development. PMID:25421483

  19. Complement Protein C1q Forms a Complex with Cytotoxic Prion Protein Oligomers

    PubMed Central

    Erlich, Paul; Dumestre-Pérard, Chantal; Ling, Wai Li; Lemaire-Vieille, Catherine; Schoehn, Guy; Arlaud, Gérard J.; Thielens, Nicole M.; Gagnon, Jean; Cesbron, Jean-Yves

    2010-01-01

    A growing number of studies have investigated the interaction between C1q and PrP, but the oligomeric form of PrP involved in this interaction remains to be determined. Aggregation of recombinant full-length murine PrP in the presence of 100 mm NaCl allowed us to isolate three different types of oligomers by size-exclusion chromatography. In contrast to PrP monomers and fibrils, these oligomers activate the classical complement pathway, the smallest species containing 8–15 PrP protomers being the most efficient. We used Thioflavine T fluorescence to monitor PrP aggregation and showed that, when added to the reaction, C1q has a cooperative effect on PrP aggregation and leads to the formation of C1q-PrP complexes. In these complexes, C1q interacts through its globular domains preferentially with the smallest oligomers, as shown by electron microscopy, and retains the ability to activate the classical complement pathway. Using two cell lines, we also provide evidence that C1q inhibits the cytotoxicity induced by the smallest PrP oligomers. The cooperative interaction between C1q and PrP could represent an early step in the disease, where it prevents elimination of the prion seed, leading to further aggregation. PMID:20410306

  20. Post-transplant development of C1q-positive HLA antibodies and kidney graft survival.

    PubMed

    Piazza, Antonina; Poggi, Elvira; Ozzella, Giuseppina; Adorno, Domenico

    2013-01-01

    The development of de novo human leukocyte antigen (HLA) donor specific antibodies (DSA), detected by both cytotoxic or solid phase assays, was considered the major risk factor for allograft failure in kidney transplantation. However, it was shown that not all patients with persistent production of DSA suffered loss of their grafts. Modified Luminex-Single Antigen assays, able to identify C1q-fixing antibodies, represent a new strategy in assessing the clinical relevance of detected DSA. This study demonstrated that C1q-fixing capability of de novo DSA is a clinically relevant marker of worse outcome and inferior graft survival in kidney transplantation. In fact, our findings evidenced a very low graft survival only in the patients who developed DSA able to fix C1q during post-transplant course, while patients producing C1q-negative DSA had good graft survival, which was comparable to that found in our previous study for DSA-negative patients. Moreover, anti-HLA class II antibodies had a higher incidence than anti-HLA class I, and the ability to fix C1q was significantly more frequent among anti-DQ DSA than anti-DR DSA. Monitoring of de novo C1q-DSA production represents a useful, non-invasive tool for risk stratification and prediction of graft outcome in kidney transplantation.

  1. High resolution catalogue of emission lines in the spectra of comet C/2002 C1 Ikeya-Zhang

    NASA Astrophysics Data System (ADS)

    Capria, M. T.; Cremonese, G.; de Sanctis, M. C.; Buzzoni, A.

    2003-04-01

    The comet C/2002 C1 Ikeya-Zhang was observed at the Telescopio Nazionale Galileo in Canary Islands with the echelle spectrograph SARG during the night 19-20 of April 2002. One echelle spectrum composed by 55 orders covering the spectral range from 462 to 792 nm with R=57000 was acquired. The observations were performed in the frame of a program aimed to collect, catalogue and identify cometary emission lines in the optical part of the spectral range. In this range many important lines of daughters molecules and ions can be found; most of these lines were detected many times with low resolution spectroscopy, but the cataloguing with high resolution spectroscopy was done until now for few comets, and many lines still remain unidentified. We present here a first version of our catalogue, in which the line identification, based on wavelength coincidence only, is made using as starting line lists the ones compiled by Brown et al. [1] and Cochran and Cochran [2]. The O(1S) and O(1D) metastable lines are also clearly visible in our spectra and well separated from the other cometary and telluric lines, so we present also a preliminary estimate of the ratio of the green and red lines. [1] M.E. Brown et al. (1996) AJ, 112. [2] A. Cochran and D. Cochran (2002) Icarus, 157.

  2. 1-Nitropyrene (1-NP) induces apoptosis and apparently a non-apoptotic programmed cell death (paraptosis) in Hepa1c1c7 cells

    SciTech Connect

    Asare, Nana Landvik, Nina E.; Lagadic-Gossmann, Dominique; Rissel, Mary; Tekpli, Xavier; Ask, Kjetil; Lag, Marit; Holme, Jorn A.

    2008-07-15

    Mechanistic studies of nitro-PAHs (polycyclic aromatic hydrocarbons) of interest might help elucidate which chemical characteristics are most important in eliciting toxic effects. 1-Nitropyrene (1-NP) is the predominant nitrated PAH emitted in diesel exhaust. 1-NP-exposed Hepa1c1c7 cells exhibited marked changes in cellular morphology, decreased proliferation and different forms of cell death. A dramatic increase in cytoplasmic vacuolization was observed already after 6 h of exposure and the cells started to round up at 12 h. The rate of cell proliferation was markedly reduced at 24 h and apoptotic as well as propidium iodide (PI)-positive cells appeared. Electron microscopic examination revealed that the vacuolization was partly due to mitochondria swelling. The caspase inhibitor Z-VAD-FMK inhibited only the apoptotic cell death and Nec-1 (an inhibitor of necroptosis) exhibited no inhibitory effects on either cell death or vacuolization. In contrast, cycloheximide markedly reduced both the number of apoptotic and PI-positive cells as well as the cytoplasmic vacuolization, suggesting that 1-NP induced paraptotic cell death. All the MAPKs; ERK1/2, p38 and JNK, appear to be involved in the death process since marked activation was observed upon 1-NP exposure, and their inhibitors partly reduced the induced cell death. The ERK1/2 inhibitor PD 98057 completely blocked the induced vacuolization, whereas the other MAPKs inhibitors only had minor effects on this process. These findings suggest that 1-NP may cause apoptosis and paraptosis. In contrast, the corresponding amine (1-aminopyrene) elicited only minor apoptotic and necrotic cell death, and cells with characteristics typical of paraptosis were absent.

  3. Acquired prosopagnosia without word recognition deficits.

    PubMed

    Susilo, Tirta; Wright, Victoria; Tree, Jeremy J; Duchaine, Bradley

    2015-01-01

    It has long been suggested that face recognition relies on specialized mechanisms that are not involved in visual recognition of other object categories, including those that require expert, fine-grained discrimination at the exemplar level such as written words. But according to the recently proposed many-to-many theory of object recognition (MTMT), visual recognition of faces and words are carried out by common mechanisms [Behrmann, M., & Plaut, D. C. ( 2013 ). Distributed circuits, not circumscribed centers, mediate visual recognition. Trends in Cognitive Sciences, 17, 210-219]. MTMT acknowledges that face and word recognition are lateralized, but posits that the mechanisms that predominantly carry out face recognition still contribute to word recognition and vice versa. MTMT makes a key prediction, namely that acquired prosopagnosics should exhibit some measure of word recognition deficits. We tested this prediction by assessing written word recognition in five acquired prosopagnosic patients. Four patients had lesions limited to the right hemisphere while one had bilateral lesions with more pronounced lesions in the right hemisphere. The patients completed a total of seven word recognition tasks: two lexical decision tasks and five reading aloud tasks totalling more than 1200 trials. The performances of the four older patients (3 female, age range 50-64 years) were compared to those of 12 older controls (8 female, age range 56-66 years), while the performances of the younger prosopagnosic (male, 31 years) were compared to those of 14 younger controls (9 female, age range 20-33 years). We analysed all results at the single-patient level using Crawford's t-test. Across seven tasks, four prosopagnosics performed as quickly and accurately as controls. Our results demonstrate that acquired prosopagnosia can exist without word recognition deficits. These findings are inconsistent with a key prediction of MTMT. They instead support the hypothesis that face

  4. Group theoretical study of nonstrange and strange mixed symmetric baryon states [N{sub c}-1,1] in the 1/N{sub c} expansion

    SciTech Connect

    Matagne, N.; Stancu, Fl.

    2010-06-01

    Using group theory arguments we extend and complete our previous work by deriving all SU(6) exact wave functions associated with the spectrum of mixed symmetric baryon states [N{sub c}-1,1] in the 1/N{sub c} expansion. The extension to SU(6) enables us to study the mass spectra of both strange and nonstrange baryons, while previous work was restricted to nonstrange baryons described by SU(4). The wave functions are specially written in a form to allow a comparison with the approximate, customarily used wave functions, where the system is separated into a ground state core and an excited quark. We show that the matrix elements of the flavor operator calculated with the exact wave functions acquire the same asymptotic form at large N{sub c}, irrespective of the spin-flavor multiplet contained in [N{sub c}-1,1], while with the approximate wave function one cannot obtain a similar behavior. The isoscalar factors of the permutation group of N{sub c} particles derived here can be used in any problem where a given fermion system is described by the partition [N{sub c}-1,1], and one fermion has to be separated from the rest.

  5. C1-c2 pedicle screw fixation for treatment of old odontoid fractures.

    PubMed

    Qi, Lei; Li, Mu; Zhang, Shuai; Si, Haipeng; Xue, Jingsong

    2015-02-01

    Nonunion and C1-C2 instability of odontoid fractures usually result from delayed diagnosis and inappropriate treatment. However, the available treatment options for odontoid fractures remain controversial. The authors evaluated the effectiveness of internal screw fixation via the C1 and C2 pedicle in cases of old odontoid fractures. This retrospective study included 21 patients with old odontoid fractures (13 men and 8 women; mean age, 46.5 years; range, 24-69 years). Internal screw fixation via the C1 and C2 pedicle was performed in all patients. Fracture reduction and C1-C2 fusion were assessed with imaging. The neck pain visual analog scale score and cervical spinal cord functional Japanese Orthopaedic Association score (for those who had cervical spinal cord injury) were used to evaluate the effectiveness of treatment. Postoperative complications were recorded. Postoperative imaging showed that the C1-C2 dislocation was satisfactorily repositioned in all patients. Bone fusion was observed 1 year after surgery in all patients. No loosening or breaking of internal fixation occurred. The preoperative neck pain visual analog scale score was 5.9±1.5 and improved significantly to 1.8±0.8 after surgery (P<.001). The Japanese Orthopaedic Association score in patients with cervical spinal injury (n=14) was 9.2±1.9 and also significantly improved to 13.8±1.9 at the last follow-up examination (P<.001), with an average improvement rate of 61.0%. No iatrogenic vertebral artery injury or severe spinal cord injury occurred. Screw fixation via the C1 and C2 pedicle was found to be an effective and safe surgical approach for the treatment of old odontoid fractures with C1-C2 dislocation or instability.

  6. ClC-1 chloride channels: state-of-the-art research and future challenges

    PubMed Central

    Imbrici, Paola; Altamura, Concetta; Pessia, Mauro; Mantegazza, Renato; Desaphy, Jean-François; Camerino, Diana Conte

    2015-01-01

    The voltage-dependent ClC-1 chloride channel belongs to the CLC channel/transporter family. It is a homodimer comprising two individual pores which can operate independently or simultaneously according to two gating modes, the fast and the slow gate of the channel. ClC-1 is preferentially expressed in the skeletal muscle fibers where the presence of an efficient Cl- homeostasis is crucial for the correct membrane repolarization and propagation of action potential. As a consequence, mutations in the CLCN1 gene cause dominant and recessive forms of myotonia congenita (MC), a rare skeletal muscle channelopathy caused by abnormal membrane excitation, and clinically characterized by muscle stiffness and various degrees of transitory weakness. Elucidation of the mechanistic link between the genetic defects and the disease pathogenesis is still incomplete and, at this time, there is no specific treatment for MC. Still controversial is the subcellular localization pattern of ClC-1 channels in skeletal muscle as well as its modulation by some intracellular factors. The expression of ClC-1 in other tissues such as in brain and heart and the possible assembly of ClC-1/ClC-2 heterodimers further expand the physiological properties of ClC-1 and its involvement in diseases. A recent de novo CLCN1 truncation mutation in a patient with generalized epilepsy indeed postulates an unexpected role of this channel in the control of neuronal network excitability. This review summarizes the most relevant and state-of-the-art research on ClC-1 chloride channels physiology and associated diseases. PMID:25964741

  7. The orexinergic neurons receive synaptic input from C1 cells in rats

    PubMed Central

    Bochorishvili, Genrieta; Nguyen, Thanh; Coates, Melissa B.; Viar, Kenneth E.; Stornetta, Ruth L.; Guyenet, Patrice G.

    2014-01-01

    The C1 cells, located in the rostral ventrolateral medulla (RVLM), are activated by pain, hypoxia, hypoglycemia, infection and hypotension and elicit cardiorespiratory stimulation, adrenaline and ACTH release, and arousal. The orexin neurons contribute to the autonomic responses to acute psychological stress. Here, using an anatomical approach, we consider whether the orexin neurons could also be contributing to the autonomic effects elicited by C1 neuron activation. Phenylethanolamine N-methyl transferase-immunoreactive (PNMT-ir) axons were detected amongst orexin-ir somata and close appositions between PNMT-ir axonal varicosities and orexin-ir profiles were observed. The existence of synapses between PNMT-ir boutons labeled with diaminobenzidine and orexinergic neurons labeled with immunogold was confirmed by electron microscopy. We labeled RVLM neurons with a lentiviral vector that expresses the fusion protein ChR2-mCherry under the control of the catecholaminergic neuron-selective promoter PRSx8 and obtained light and ultrastructural evidence that these neurons innervate the orexin cells. Using a Cre-dependent adeno-associated vector and TH-Cre rats we confirmed that the projection from RVLM catecholaminergic neurons to the orexinergic neurons originates predominantly from PNMT-ir catecholaminergic (i.e. C1 cells). The C1 neurons were found to establish predominantly asymmetric synapses with orexin-ir cell bodies or dendrites. These synapses were packed with small clear vesicles and also contained dense core vesicles. In summary, the orexin neurons are among the hypothalamic neurons contacted and presumably excited by the C1 cells. The C1-orexin neuronal connection is probably one of several suprabulbar pathways through which the C1 neurons activate breathing and the circulation, raise blood glucose and facilitate arousal from sleep. PMID:24984694

  8. Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis.

    PubMed

    Mayerl, Steffen; Müller, Julia; Bauer, Reinhard; Richert, Sarah; Kassmann, Celia M; Darras, Veerle M; Buder, Katrin; Boelen, Anita; Visser, Theo J; Heuer, Heike

    2014-05-01

    Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS.

  9. Alanine mutagenesis of the primary antigenic escape residue cluster, c1, of apical membrane antigen 1.

    PubMed

    Dutta, Sheetij; Dlugosz, Lisa S; Clayton, Joshua W; Pool, Christopher D; Haynes, J David; Gasser, Robert A; Batchelor, Adrian H

    2010-02-01

    Antibodies against apical membrane antigen 1 (AMA1) inhibit invasion of Plasmodium merozoites into red cells, and a large number of single nucleotide polymorphisms on AMA1 allow the parasite to escape inhibitory antibodies. The availability of a crystal structure makes it possible to test protein engineering strategies to develop a monovalent broadly reactive vaccine. Previously, we showed that a linear stretch of polymorphic residues (amino acids 187 to 207), localized within the C1 cluster on domain 1, conferred the highest level of escape from inhibitory antibodies, and these were termed antigenic escape residues (AER). Here we test the hypothesis that immunodampening the C1 AER will divert the immune system toward more conserved regions. We substituted seven C1 AER of the FVO strain Plasmodium falciparum AMA1 with alanine residues (ALA). The resulting ALA protein was less immunogenic than the native protein in rabbits. Anti-ALA antibodies contained a higher proportion of cross-reactive domain 2 and domain 3 antibodies and had higher avidity than anti-FVO. No overall enhancement of cross-reactive inhibitory activity was observed when anti-FVO and anti-ALA sera were compared for their ability to inhibit invasion. Alanine mutations at the C1 AER had shifted the immune response toward cross-strain-reactive epitopes that were noninhibitory, refuting the hypothesis but confirming the importance of the C1 cluster as an inhibitory epitope. We further demonstrate that naturally occurring polymorphisms that fall within the C1 cluster can predict escape from cross-strain invasion inhibition, reinforcing the importance of the C1 cluster genotype for antigenic categorization and allelic shift analyses in future phase 2b trials.

  10. ClC-1 chloride channels: state-of-the-art research and future challenges.

    PubMed

    Imbrici, Paola; Altamura, Concetta; Pessia, Mauro; Mantegazza, Renato; Desaphy, Jean-François; Camerino, Diana Conte

    2015-01-01

    The voltage-dependent ClC-1 chloride channel belongs to the CLC channel/transporter family. It is a homodimer comprising two individual pores which can operate independently or simultaneously according to two gating modes, the fast and the slow gate of the channel. ClC-1 is preferentially expressed in the skeletal muscle fibers where the presence of an efficient Cl(-) homeostasis is crucial for the correct membrane repolarization and propagation of action potential. As a consequence, mutations in the CLCN1 gene cause dominant and recessive forms of myotonia congenita (MC), a rare skeletal muscle channelopathy caused by abnormal membrane excitation, and clinically characterized by muscle stiffness and various degrees of transitory weakness. Elucidation of the mechanistic link between the genetic defects and the disease pathogenesis is still incomplete and, at this time, there is no specific treatment for MC. Still controversial is the subcellular localization pattern of ClC-1 channels in skeletal muscle as well as its modulation by some intracellular factors. The expression of ClC-1 in other tissues such as in brain and heart and the possible assembly of ClC-1/ClC-2 heterodimers further expand the physiological properties of ClC-1 and its involvement in diseases. A recent de novo CLCN1 truncation mutation in a patient with generalized epilepsy indeed postulates an unexpected role of this channel in the control of neuronal network excitability. This review summarizes the most relevant and state-of-the-art research on ClC-1 chloride channels physiology and associated diseases.

  11. [Iris heterochromia in acquired Horner's syndrome].

    PubMed

    Beynat, J; Soichot, P; Bidot, S; Dugas, B; Creuzot-Garcher, C; Bron, A

    2007-09-01

    Horner's syndrome (HS) is related to an interruption of the oculosympathetic nerve pathway. The classic clinical findings associated with this condition are ptosis, miosis, and enophthalmos. Heterochromia is typically described in congenital HS, but it is an uncommon finding in acquired HS. We report a case of post-traumatic HS associated with heterochromia. A literature review indicates that this type of heterochromia may be related to a reduction in the number of iris melanocytes. This mechanism may be the same in the physiological iris color modifications in adulthood.

  12. [Acquired immunodeficiency syndrome in pediatric patients].

    PubMed

    Molina Moguel, J L; Ruiz Illezcas, R; Forsbach Sánchez, S; Carreño Alvarez, S; Picco Díaz, I

    1990-12-01

    The object of this study was to determine how many of the patients treated at the Pediatric Odontology Clinic, a branch of the Maxillo-Facial Surgery Service at the Veinte de Noviembre Regional Hospital, ISSSTE, are VIH-positive of show serious manifestations of Acquired Immuno-Deficiency Syndrome (AIDS). For such purpose, 100 pediatric patients suffering from different systemic or local diseases were evaluated, the most common being hematological alterations. Results evidenced the presence of VIH in the blood of five of the pediatric subjects, all suffering from Hemophilia.

  13. Origins of species: acquired genomes and individuality

    NASA Technical Reports Server (NTRS)

    Margulis, L.

    1993-01-01

    Entire genomes with their accompanying protein synthetic systems are transferred throughout the biosphere primarily as bacteria and protists which become symbionts as they irreversibly integrate into pre-existing organisms to form more complex individuals. Individualization is stabilized by simultaneous transmission of once-separate heterologous genetic systems. The origin of new species is hypothesized to correlate with the acquisition, integration and subsequent inheritance of such acquired microbial genomes. These processes were recognized by Mereschkovsky ("Symbiogenesis" in Russian, 1909) and by Wallin ("Symbionticism", see p. 181, this issue).

  14. Common acquired causes of thrombosis in children.

    PubMed

    Tolbert, Jaszianne; Carpenter, Shannon L

    2013-08-01

    Compared to adults, venous thromboembolism in the pediatric population is a rare event. Cancer, cardiac disease, antiphospholipid antibodies, and indwelling catheters are established risk factors for thromboembolism in children. We examined the literature related to thrombophilia in children, childhood cancer and thrombosis, cardiac disease and thrombosis, and antiphospholipid antibody syndrome in children. Citations in identified articles yielded additional articles for review. We found that studies of acquired thrombophilia in children are limited. Current treatment for thromboembolism in children is based on adult data therefore optimal treatment in this population remains unclear.

  15. Acquired Congenital Malalignment of the Great Toenails

    PubMed Central

    Decker, Ashley; Scher, Richard K.; Avarbock, Andrew

    2016-01-01

    Congenital malalignment is the lateral deviation of the nail plate along the longitudinal axis due to the lateral rotation of the nail matrix. The nail plate grows out in ridges caused by repeated microtrauma to the nail. Common complications include onychomycosis, Pseudomonas infection and acute or chronic paronychia. Treatment options range from conservative management to surgical options including realignment and nail matrixectomy. Congenital malalignment usually presents in infancy or childhood, but we present two cases of acquired malalignment occurring in the teenage years. PMID:27171597

  16. C1q complement component and -antibodies reflect SLE activity and kidney involvement.

    PubMed

    Horák, P; Hermanová, Z; Zadrazil, J; Ciferská, H; Ordeltová, M; Kusá, L; Zurek, M; Tichý, T

    2006-07-01

    The role of the complement system in the pathogenesis of systemic diseases is very ambivalent. In systemic lupus erythematosus (SLE), many abnormalities in the activation of the complement system have been reported. The most important antibodies formed against the complement system in SLE are the ones associated with the C1q component. The aim of this study was to assess separately the anti-C1q antibodies and C1q component in the serum from 65 patients with SLE, then in individuals with (n=33) and without (n=32) lupus nephritis and with active (n=36) and nonactive (n=29) form of the disease (European Consensus Lupus Activity Measurement, ECLAM>3, ECLAMC1q antibodies were measured by the Enzyme-Linked Immunosorbent Assay (ELISA) test, while radial immunodiffusion according to Mancini was used to measure the C1q complement component. The mean serum levels were 90.89+/-13 IU/ml for anti-C1q antibodies and 145+/-52 mg/l for C1q. The significant difference in C1q antibodies levels was found between individuals with and without lupus nephritis (117.5+/-52 IU/ml vs. 28.2+/-12.2 IU/ml, p=0.0001) and between those with active and nonactive SLE (154.6+/-115 IU/ml vs. 50.6+/-73, p=0.001). C1q complement component was statistically lower in patients with lupus nephritis (144+/-30 mg/l vs. 175+/-50 mg/ml, p=0.002) and in active patients (138+/-40 mg/l vs. 202+/-20 mg/l, p=0.001). If the two parameters are measured together, they seem to have a mirror-like pattern of serum concentration, and they are potential markers of SLE activity and of the presence of lupus nephritis.

  17. Variation in complement protein C1q is not a major contributor to cognitive impairment in Parkinson’s disease

    PubMed Central

    Carbutt, Sophia; Duff, Jennifer; Yarnall, Alison; Burn, David J.; Hudson, Gavin

    2015-01-01

    Traditional dogma regarding the brain as an immune exempt organ has changed in recent years. New research has highlighted the role of the classical complement cascade in both synaptic elimination and function, driven largely by the role of the pathway initiating protein C1q. Given the links between C1q and cognitive function we assessed the genetic variability of the C1q encoding genes: C1QA, C1QB and C1QC between PD patients and matched controls. Despite a strong link between C1Q/cognitive decline and PD/cognitive decline we were unable to find a link between common C1Q variation and PD. We conclude that common C1Q-A/B/C genetic variation is unlikely to contribute to cognitive decline or the missing heritability in PD. PMID:25817358

  18. Simulation of XPS C1s spectra of organic monolayers by quantum chemical methods.

    PubMed

    Giesbers, Marcel; Marcelis, Antonius T M; Zuilhof, Han

    2013-04-16

    Several simple methods are presented and evaluated to simulate the X-ray photoelectron spectra (XPS) of organic monolayers and polymeric layers by density functional theory (DFT) and second-order Møller-Plesset theory (MP2) in combination with a series of basis sets. The simulated carbon (C1s) XPS spectra as obtained via B3LYP/6-311G(d,p) or M11/6-311G(d,p) calculations are in good agreement (average mean error <0.3 eV) with the experimental spectra, and good estimates of C1s spectra can be obtained via E(C1s)(exp) = 0.9698EC1s(theory) + 20.34 (in eV) (B3LYP/6-311G(d,p)). As a result, the simulated C1s XPS spectra can elucidate the binding energies of the different carbon species within an organic layer and, in this way, greatly aid the assignment of complicated C1s XPS spectra. The paper gives a wide range of examples, including haloalkanes, esters, (thio-)ethers, leaving groups, clickable functionalities, and bioactive moieties.

  19. C1q deficiency: identification of a novel missense mutation and treatment with fresh frozen plasma.

    PubMed

    Topaloglu, Rezan; Taskiran, Ekim Z; Tan, Cagman; Erman, Baran; Ozaltin, Fatih; Sanal, Ozden

    2012-07-01

    A Turkish patient with C1q deficiency presented with a lupus-like disease, and a new missense mutation at A chain is presented. To characterize the genetic defect, all exons of the genes for the A, B, and C chains of C1q were sequenced in the patient. This revealed a missense mutation in the collagen-like domain of the A chain, p.Gly31 Arg. No other sequence variants, including the common silent mutations, were found in the three chains. Exon 1 of the C1q A chain was sequenced in 105 samples from healthy controls for this particular mutation. None of these carried the mutation. The C1q-deficient patient was treated with fresh frozen plasma infusions. Our findings showed that Turkish patients may have different mutations than the previously described common mutation, and once again, not only nonsense mutations but also missense mutations cause hereditary C1q deficiency. Regular fresh frozen plasma infusions to the patient have been clinically and therapeutically successful.

  20. The semaphorin 7A receptor Plexin C1 is lost during melanoma metastasis.

    PubMed

    Lazova, Rossitza; Gould Rothberg, Bonnie E; Rimm, David; Scott, Glynis

    2009-04-01

    The transformation of normal melanocytes, or melanocyte stem cells, to melanoma, is a complex process involving multiple mechanisms. Loss of tumor suppressor proteins, which function as brakes on cell growth, migration, or cell survival, was recognized early on as an important mechanism for initiation and progression of melanoma. Semaphorins and their cognate receptors, Plexins and neuropilins, are involved in neuronal pathfinding, immune function, and tumor progression through effects on blood vessel growth and cell migration. Semaphorin 7A (Sema7A) is a membrane-linked semaphorin that is expressed by human keratinocytes, and we have shown that Sema7A binds to human melanocytes through beta1-integrins and the Plexin C1 receptor. Functional studies showed that Sema7A stimulates cytoskeletal reorganization in human melanocytes, resulting in adhesion and dendrite formation. Downstream targets of Plexin C1 signaling in human melanocytes include cofilin and LIM kinase II, both of which are critical mediators of cell adhesion and migration. In this report, we analyzed the expression of Plexin C1 using immunohistochemistry on sections of primary and matched metastatic lesions from 19 subjects and in a large melanoma tumor microarray. Our data show a significant loss of Plexin C1 in metastatic melanoma compared with primary melanoma, suggesting the possibility that the Plexin C1 receptor is a tumor suppressor protein for melanoma.

  1. Protein phosphatase AP2C1 negatively regulates basal resistance and defense responses to Pseudomonas syringae.

    PubMed

    Shubchynskyy, Volodymyr; Boniecka, Justyna; Schweighofer, Alois; Simulis, Justinas; Kvederaviciute, Kotryna; Stumpe, Michael; Mauch, Felix; Balazadeh, Salma; Mueller-Roeber, Bernd; Boutrot, Freddy; Zipfel, Cyril; Meskiene, Irute

    2017-01-06

    Mitogen-activated protein kinases (MAPKs) mediate plant immune responses to pathogenic bacteria. However, less is known about the cell autonomous negative regulatory mechanism controlling basal plant immunity. We report the biological role of Arabidopsis thaliana MAPK phosphatase AP2C1 as a negative regulator of plant basal resistance and defense responses to Pseudomonas syringae AP2C2, a closely related MAPK phosphatase, also negatively controls plant resistance. Loss of AP2C1 leads to enhanced pathogen-induced MAPK activities, increased callose deposition in response to pathogen-associated molecular patterns or to P. syringae pv. tomato (Pto) DC3000, and enhanced resistance to bacterial infection with Pto. We also reveal the impact of AP2C1 on the global transcriptional reprogramming of transcription factors during Pto infection. Importantly, ap2c1 plants show salicylic acid-independent transcriptional reprogramming of several defense genes and enhanced ethylene production in response to Pto This study pinpoints the specificity of MAPK regulation by the different MAPK phosphatases AP2C1 and MKP1, which control the same MAPK substrates, nevertheless leading to different downstream events. We suggest that precise and specific control of defined MAPKs by MAPK phosphatases during plant challenge with pathogenic bacteria can strongly influence plant resistance.

  2. The C1 area of rostral ventrolateral medulla: a central site integrating autonomic responses to hemorrhage.

    PubMed

    Reis, D J; Ruggiero, D A; Morrison, S F

    1989-12-01

    Activation of the sympathetic neurons and release of adrenomedullary catecholamines are the principal early reflex responses to hemorrhage. These are initiated by arterial baro- and chemoreceptors, from other cardiopulmonary receptors, and by intracerebral receptors responding to ischemia. A principal gateway for integrating the autonomic responses are a small collection of neurons in a region of the rostral ventrolateral medulla (RVL), containing a cluster of neurons of the C1 adrenergic cell group, the C1 area. Neurons in the C1 area of RVL project exclusively to autonomic nuclei of the spinal cord, are tonically active, and fire with a rhythm linked to the cardiac cycle. They are essential for maintaining resting discharge of sympathetic nerves and, consequently, arterial pressure (AP) and heart rate. They also are critical for reflex changes in AP in the baro- and chemoreceptor, somato-sympathetic (pain), and cerebral ischemic reflexes. Neurons of the C1 area are under tonic excitatory and inhibitory control by pathways from other autonomic centers. They are controlled by a range of neurotransmitters including, gamma aminobutyric acid (GABA), acetylcholine, catecholamines, enkephalin, and several neuropeptides. They also serve as a site of action for the hypotensive actions of several clinically important neurotransmitters. The C1-area of RVL may play a critical role in the autonomic responses to hemorrhage and may be an important target for drugs seeking to treat hemorrhagic shock.

  3. Evidence of Real-Space Transfer in Buried-Channel GexC1-x Devices

    NASA Astrophysics Data System (ADS)

    Liu, En-Shao; Kelly, David; Donnelly, Joseph; Tutuc, Emanuel; Banerjee, Sanjay

    2008-03-01

    We present experimental evidence of real-space transfer (RST) in buried-channel GexC1-x p-type metal-oxide-semiconductor field effect transistors (MOSFET) containing a Si cap layer. The output characteristics of these devices reveal a negative differential resistance (NDR) below 150K, at the onset of the saturation regime. This observation indicates a charge transfer from GexC1-x layer into the Si cap at sufficiently large drain bias values. The lower hole mobility of the Si cap with respect to the GexC1-x, translates into a drain current reduction, hence the observed NDR. Our low-field, temperature-dependent mobility measurements indeed reveal a higher effective carrier mobility in the buried-channel GexC1-x layer with respect to a Si-reference sample, which suggests that the observed NDR is caused by RST of holes from the GexC1-x into the Si layer.

  4. Acquired and congenital coronary artery abnormalities.

    PubMed

    Young, Ming-Lon; McLeary, Michael; Chan, Kak-Chen

    2017-01-01

    Sudden unexpected cardiac deaths in approximately 20% of young athletes are due to acquired or congenital coronary artery abnormalities. Kawasaki disease is the leading cause for acquired coronary artery abnormalities, which can cause late coronary artery sequelae including aneurysms, stenosis, and thrombosis, leading to myocardial ischaemia and ventricular fibrillation. Patients with anomalous left coronary artery from the pulmonary artery can develop adequate collateral circulation from the right coronary artery in the newborn period, which remains asymptomatic only to manifest in adulthood with myocardial ischaemia, ventricular arrhythmias, and sudden death. Anomalous origin of coronary artery from the opposite sinus occurs in 0.7% of the young general population aged between 11 and 15 years. If the anomalous coronary artery courses between the pulmonary artery and the aorta, sudden cardiac death may occur during or shortly after vigorous exercise, especially in patients where the anomalous left coronary artery originates from the right sinus of Valsalva. Symptomatic patients with evidence of ischaemia should have surgical correction. No treatment is needed for asymptomatic patients with an anomalous right coronary artery from the left sinus of Valsalva. At present, there is no consensus regarding how to manage asymptomatic patients with anomalous left coronary artery from the right sinus of Valsalva and interarterial course. Myocardial bridging is commonly observed in cardiac catheterisation and it rarely causes exercise-induced coronary syndrome or cardiac death. In symptomatic patients, refractory or β-blocker treatment and surgical un-bridging may be considered.

  5. Software for Acquiring Image Data for PIV

    NASA Technical Reports Server (NTRS)

    Wernet, Mark P.; Cheung, H. M.; Kressler, Brian

    2003-01-01

    PIV Acquisition (PIVACQ) is a computer program for acquisition of data for particle-image velocimetry (PIV). In the PIV system for which PIVACQ was developed, small particles entrained in a flow are illuminated with a sheet of light from a pulsed laser. The illuminated region is monitored by a charge-coupled-device camera that operates in conjunction with a data-acquisition system that includes a frame grabber and a counter-timer board, both installed in a single computer. The camera operates in "frame-straddle" mode where a pair of images can be obtained closely spaced in time (on the order of microseconds). The frame grabber acquires image data from the camera and stores the data in the computer memory. The counter/timer board triggers the camera and synchronizes the pulsing of the laser with acquisition of data from the camera. PIVPROC coordinates all of these functions and provides a graphical user interface, through which the user can control the PIV data-acquisition system. PIVACQ enables the user to acquire a sequence of single-exposure images, display the images, process the images, and then save the images to the computer hard drive. PIVACQ works in conjunction with the PIVPROC program which processes the images of particles into the velocity field in the illuminated plane.

  6. [HIV infection and acquired immunodeficiency syndrome].

    PubMed

    Takamatsu, J

    1997-05-01

    On June 4, 1981, MMWR published a report about Pneumocystis carinii pneumonia in homosexual men in Los Angeles. This was the first published report. A years later, this disease was named acquired immunodeficiency syndrome (AIDS). In the following year, Montangier et al in France discovered the causative agent, which they called lymphadenopathy virus (LAV), now known as human immunodeficiency virus (HIV). In 1985, solid-phase enzymeimmunoassay for the detection of the antibody to HIV was developed. Since then, other new techniques for the identification of HIV infection have been become available. These include more sensitive methods (for example; polymerase chain reaction techniques). Although these techniques facilitate early and definite diagnosis of infection, these tests may fail to detect the antibody in sera during window period of infection or overdiagnose infection in sera contaminated with genes not related to HIV. Although preventing blood exposure is the primary means of preventing occupationally acquired human immunodeficiency virus (HIV) infection, appropriate post-exposure management is an important element of workplace safety. Information suggesting that zidovudine (ZDV) postexposure prophylaxis (PEP) may reduce the risk for HIV transmission after occupational exposure to HIV infected blood prompted a Public Health Service (PHS) interagency working group, with expert consultation, and recommendations on PEP and management of occupational exposure to HIV in relation to these findings were discussed.

  7. Treatment of community-acquired pneumonia.

    PubMed

    Lee, Young R; Houngue, Coovi; Hall, Ronald G

    2015-01-01

    Community-acquired pneumonia is the sixth leading cause of death in the USA. Adherence to the 2007 Infectious Diseases Society of America/American Thoracic Society community-acquired pneumonia guidelines has been associated with improved clinical outcomes. However, choice between guideline-recommended treatments is at the discretion of the prescribing clinician. This review is intended to discuss the characteristics of these treatment options including dosing frequency, dose adjustment for renal/hepatic dysfunction, serious/common adverse events, drug interactions, lung penetration, pharmacokinetic-pharmacodynamic target and effect of obesity to help guide antimicrobial selection. An increasing portion of patients are receiving expanded empiric coverage for methicillin-resistant Staphylococcus aureus as recommended by the American Thoracic Society and Infectious Diseases Society of America for healthcare-associated pneumonia. However, this expanded coverage may not be achieving the desired improvements in clinical outcomes. We expect this increasingly diverse spectrum of patients with pneumonia to eventually result in the merger of these two guidelines to include all patients with pneumonia.

  8. Clinicopathological correlation of acquired hyperpigmentary disorders.

    PubMed

    Patel, Anisha B; Kubba, Raj; Kubba, Asha

    2013-01-01

    Acquired pigmentary disorders are group of heterogenous entities that share single, most significant, clinical feature, that is, dyspigmentation. Asians and Indians, in particular, are mostly affected. Although the classic morphologies and common treatment options of these conditions have been reviewed in the global dermatology literature, the value of histpathological evaluation has not been thoroughly explored. The importance of accurate diagnosis is emphasized here as the underlying diseases have varying etiologies that need to be addressed in order to effectively treat the dyspigmentation. In this review, we describe and discuss the utility of histology in the diagnostic work of hyperpigmentary disorders, and how, in many cases, it can lead to targeted and more effective therapy. We focus on the most common acquired pigmentary disorders seen in Indian patients as well as a few uncommon diseases with distinctive histological traits. Facial melanoses, including mimickers of melasma, are thoroughly explored. These diseases include lichen planus pigmentosus, discoid lupus erythematosus, drug-induced melanoses, hyperpigmentation due to exogenous substances, acanthosis nigricans, and macular amyloidosis.

  9. The Acquired Immunodeficiency Syndrome: current status.

    PubMed Central

    Quagliarello, V.

    1982-01-01

    A recently recognized syndrome of acquired immunodeficiency (Acquired Immunodeficiency Syndrome-AIDS) has arisen since June 1981. It has received international attention. The clinical spectrum consists of repeated opportunistic infections, rare malignancies, and autoimmune phenomena, occurring in previously healthy adults with no history of an immunologic disorder. The population subset at risk for this syndrome appears to be predominantly homosexual American males and intravenous drug abusers with rare cases being reported in heterosexuals, hemophiliacs, and foreign patients, especially Haitians. The immunologic aberrancy in all patients described appears limited to T-lymphocyte hyporesponsiveness and imbalance of T-helper and suppressor cells. This disordered immunoregulation is a consistent finding in all reported cases and appears to predispose to the opportunistic infections and malignancies which have been associated with a 40 percent mortality. The underlying factor responsible for the immunoregulatory defect is unknown but possible etiologies include a transmissible infectious agent, drug use, chronic antigen stimulation, and spermatozoa exposure. Treatment of the associated infections and malignancies has been a frustrating endeavor as many patients respond incompletely or relapse soon after successful treatment course. Preventive measures, including patient education, physician awareness, and immunomodulating agents, are discussed. PMID:6134399

  10. Acquired factor VIII deficiency after consuming the dried gallbladder of a cobra, Naja naja

    PubMed Central

    Kim, Hyun Ju; Lee, Won Sik; Lee, Young Jin; Jun, Hyun Soo; Seo, Su-Kil

    2010-01-01

    Acquired factor VIII deficiency is very rare, often fatal. It is associated with pregnancy, autoimmune diseases, malignancy, and drugs, although no underlying cause is found in 50%. A 49-year-old male was referred with right shoulder bruising. The coagulation test showed a prolonged activated partial thromboplastin time. The factor VIII level was less than 1%, and the factor VIII inhibitor antibody titer was 246 Bethesda units/mL. The findings were compatible with acquired factor VIII deficiency. He had consumed the dried gallbladder of a cobra, Naja naja, for two weeks, it contained venom. After the initial treatment with factor VIII, he did not take supplemental coagulation factor VIII. The patient was readmitted with left forearm swelling. He lost consciousness suddenly and brain computed tomography (CT) revealed a subdural hematoma. Despite administering recombinant factor VII, his bleeding was not controlled and he died. PMID:21120211

  11. Update on HIV-1 acquired and transmitted drug resistance in Africa.

    PubMed

    Ssemwanga, Deogratius; Lihana, Raphael W; Ugoji, Chinenye; Abimiku, Alash'le; Nkengasong, John; Dakum, Patrick; Ndembi, Nicaise

    2015-01-01

    The last ten years have witnessed a significant scale-up and access to antiretroviral therapy in Africa, which has improved patient quality of life and survival. One major challenge associated with increased access to antiretroviral therapy is the development of antiretroviral resistance due to inconsistent drug supply and/or poor patient adherence. We review the current state of both acquired and transmitted drug resistance in Africa over the past ten years (2001-2011) to identify drug resistance associated with the different drug regimens used on the continent and to help guide affordable strategies for drug resistance surveillance. A total of 161 references (153 articles, six reports and two conference abstracts) were reviewed. Antiretroviral resistance data was available for 40 of 53 African countries. A total of 5,541 adult patients from 99 studies in Africa were included in this analysis. The pooled prevalence of drug resistance mutations in Africa was 10.6%, and Central Africa had the highest prevalence of 54.9%. The highest prevalence of nucleoside reverse transcriptase inhibitor mutations was in the west (55.3%) and central (54.8%) areas; nonnucleoside reverse transcriptase inhibitor mutations were highest in East Africa (57.0%) and protease inhibitors mutations highest in Southern Africa (16.3%). The major nucleoside reverse transcriptase inhibitor mutation in all four African regions was M184V. Major nonnucleoside reverse transcriptase inhibitor as well as protease inhibitor mutations varied by region. The prevalence of drug resistance has remained low in several African countries although the emergence of drug resistance mutations varied across countries. Continued surveillance of antiretroviral therapy resistance remains crucial in gauging the effectiveness of country antiretroviral therapy programs and strategizing on effective and affordable strategies for successful treatment.

  12. Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance

    PubMed Central

    Hugo, Willy; Shi, Hubing; Sun, Lu; Piva, Marco; Song, ChunYing; Kong, Xiangju; Moriceau, Gatien; Hong, Aayoung; Dahlman, Kimberly B.; Johnson, Douglas B.; Sosman, Jeffrey A.; Ribas, Antoni; Lo, Roger S.

    2015-01-01

    SUMMARY Clinically acquired resistance to MAPK inhibitor (MAPKi) therapies for melanoma cannot be fully explained by genomic mechanisms and may be accompanied by co-evolution of intra-tumoral immunity. We sought to discover non-genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative, transcriptomic-methylomic analysis of patient-matched melanoma tumors biopsied before therapy and during disease progression. Transcriptomic alterations across resistant tumors were highly recurrent, in contrast to mutations, and were frequently correlated with differential methylation of tumor cell-intrinsic CpG sites. We identified in the tumor cell compartment supra-physiologic c-MET up-expression, infra-physiologic LEF1 down-expression, and YAP1 signature enrichment as drivers of acquired resistance. Importantly, high intra-tumoral cytolytic T-cell inflammation prior to MAPKi therapy preceded CD8 T-cell deficiency/exhaustion and loss of antigen-presentation in half of disease-progressive melanomas, suggesting cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy. Thus, melanoma acquires MAPKi-resistance with highly dynamic and recurrent non-genomic alterations and co-evolving intra-tumoral immunity. PMID:26359985

  13. Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.

    PubMed

    Hugo, Willy; Shi, Hubing; Sun, Lu; Piva, Marco; Song, Chunying; Kong, Xiangju; Moriceau, Gatien; Hong, Aayoung; Dahlman, Kimberly B; Johnson, Douglas B; Sosman, Jeffrey A; Ribas, Antoni; Lo, Roger S

    2015-09-10

    Clinically acquired resistance to MAPK inhibitor (MAPKi) therapies for melanoma cannot be fully explained by genomic mechanisms and may be accompanied by co-evolution of intra-tumoral immunity. We sought to discover non-genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative, transcriptomic-methylomic analysis of patient-matched melanoma tumors biopsied before therapy and during disease progression. Transcriptomic alterations across resistant tumors were highly recurrent, in contrast to mutations, and were frequently correlated with differential methylation of tumor cell-intrinsic CpG sites. We identified in the tumor cell compartment supra-physiologic c-MET up-expression, infra-physiologic LEF1 down-expression and YAP1 signature enrichment as drivers of acquired resistance. Importantly, high intra-tumoral cytolytic T cell inflammation prior to MAPKi therapy preceded CD8 T cell deficiency/exhaustion and loss of antigen presentation in half of disease-progressive melanomas, suggesting cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy. Thus, melanoma acquires MAPKi resistance with highly dynamic and recurrent non-genomic alterations and co-evolving intra-tumoral immunity.

  14. Unnatural C-1 homologues of pancratistatin — Synthesis and promising biological activities

    PubMed Central

    Vshyvenko, Sergey; Scattolon, Jon; Hudlicky, Tomas; Romero, Anntherese E.; Kornienko, Alexander; Ma, Dennis; Tuffley, Ian; Pandey, Siyaram

    2016-01-01

    Several C-1 homologues of pancratistatin and 7-deoxypancratistatin were synthesized by a phenanthrene–phenathridone oxidative recyclization strategy. The key steps involved the enzymatic dihydroxylation of bromobenzene, addition of an aryl alane to an epoxyaziridine, an intramolecular aziridine opening on silica gel in solid phase, and the above-mentioned recylization strategy. Experimental and spectral data are reported for all new compounds. All synthesized C-1 homologues of pancratistatin and 7-deoxypancratistatin were evaluated for antiproliferative activity in a panel of human cancer cell lines. As expected, the 7-hydroxy compounds were found to be more potent and the activity of the C-1 benzoxymethyl analogue exceeded that of narciclasine, which was used as a positive control. PMID:28017970

  15. SGLT2 inhibitors.

    PubMed

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM.

  16. Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury

    PubMed Central

    Wang, Feng; Zhang, Guangyuan; Lu, Zeyuan; Geurts, Aron M; Usa, Kristie; Jacob, Howard J; Cowley, Allen W; Wang, Niansong; Liang, Mingyu

    2015-01-01

    Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1+/− rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1+/− rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1+/− rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury. PMID:26108065

  17. Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury

    PubMed Central

    Galvan, Manuel D.; Luchetti, Sabina; Burgos, Adrian M.; Nguyen, Hal X.; Hooshmand, Mitra J.; Anderson, Aileen J.; Hamers, Frank P.T.

    2009-01-01

    Although studies have suggested a role for the complement system in the pathophysiology of spinal cord injury (SCI), that role remains poorly defined. Additionally, the relative contribution of individual complement pathways in SCI is unknown. Our initial studies revealed that systemic complement activation was strongly influenced by genetic background and gender. Thus, to investigate the role of the classical complement pathway in contusion-induced SCI, male C1q knockout (KO) and wildtype (WT) mice on a complement sufficient background (BUB) received a mild-moderate T9 contusion injury with the Infinite Horizon (IH) impactor. BUB C1q KO mice exhibited greater locomotor recovery in comparison to BUB WT mice (p < 0.05). Improved recovery observed in BUB C1q KO mice was also associated with decreased threshold for withdrawal from a mild stimulus using von Frey filament testing. Surprisingly, quantification of microglia/macrophages (F4/80) by FACS analysis showed that BUB C1q KO mice exhibited a significantly greater percentage of macrophages in the spinal cord compared to BUB WT mice 3 days post injury (p < 0.05). However, this increased macrophage response appeared to be transient as stereological assessment of spinal cord tissue obtained 28 days post injury revealed no difference in F4/80 positive cells between groups. Stereological assessment of spinal cord tissue showed that BUB C1q KO mice had reduced lesion volume and an increase in tissue sparing in comparison to BUB WT mice (p < 0.05). Taken together, these data suggest that initiation of the classical complement pathway via C1q is detrimental to recovery after SCI. PMID:19091977

  18. Endovascular Treatment of a Vertebral Artery Pseudoaneurysm Following Posterior C1-C2 Transarticular Screw Fixation

    SciTech Connect

    Mendez, Jose C. Gonzalez-Llanos, Francisco

    2005-01-15

    We present a case of vertebral artery pseudoaneurysm after a posterior C1-C2 transarticular screw fixation procedure that was effectively treated with endovascular coil occlusion. Vertebral artery pseudoaneurysm complicating posterior C1-C2 transarticular fixation is extremely rare, with only one previous case having been reported previously. Endovascular occlusion is better achieved in the subacute phase of the pseudoaneurysm, when the wall of the pseudoaneurysm has matured and stabilized. Further follow-up angiographies are mandatory in order to confirm that there is no recurrence of the lesion.

  19. Solar gases in meteorites - The origin of chondrites and C1 carbonaceous chondrites

    NASA Technical Reports Server (NTRS)

    Heymann, D.

    1978-01-01

    Evidence suggesting that chondritic meteorites broke off from parent bodies in earth-crossing orbits is considered. It is suggested that ordinary chondrites have an asteroidal origin, and the possibility that C1 chondrites have a cometary origin is examined. Indications of heavy shock and reheating among L and H chondrites provides support for an asteroidal origin, while the Apollo and Amor objects are too small to be unfragmented asteroids, as proposed in the Anders theory of the origin of gas-rich meteorites. Events associated with the megaregolith are discussed in the framework of the proposed cometary origin of C1 chondrites.

  20. C1q binding to Dengue Virus inhibits infection of THP-1 and cellular inflammatory responses

    PubMed Central

    Douradinha, Bruno; McBurney, Sean P.; de Melo, Klecia M. Soares; Smith, Amanda P.; Krishna, Neel K.; Barratt-Boyes, Simon M.; Evans, Jared D.; Nascimento, Eduardo J. M.; Marques, Ernesto T. A

    2014-01-01

    Summary Dengue virus infection elicits a spectrum of clinical presentations ranging from asymptomatic to severe disease. The mechanisms leading to severe dengue are not known, however it has been reported that the complement system is hyper-activated in severe dengue. Screening of complement proteins demonstrated that C1q, a pattern recognition molecule, can bind directly to Dengue Virus Envelope protein and to whole Dengue Virus serotype 2. Incubation of Dengue Virus serotype 2 with C1q prior to infection of THP-1 cells led to decreased virus infectivity and modulation of mRNA expression of immunoregulatory molecules suggesting reduced inflammatory responses. PMID:24246304

  1. Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.

    PubMed

    Kim, S-M; Kim, H; Yun, M R; Kang, H N; Pyo, K-H; Park, H J; Lee, J M; Choi, H M; Ellinghaus, P; Ocker, M; Paik, S; Kim, H R; Cho, B C

    2016-07-18

    Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50<250 nm). Clones of FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine-cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent

  2. Loss of Cellular Sialidases Does Not Affect the Sialylation Status of the Prion Protein but Increases the Amounts of Its Proteolytic Fragment C1

    PubMed Central

    Katorcha, Elizaveta; Klimova, Nina; Makarava, Natallia; Savtchenko, Regina; Pan, Xuefang; Annunziata, Ida; Takahashi, Kohta; Miyagi, Taeko; Pshezhetsky, Alexey V.; d’Azzo, Alessandra; Baskakov, Ilia V.

    2015-01-01

    The central molecular event underlying prion diseases involves conformational change of the cellular form of the prion protein (PrPC), which is a sialoglycoprotein, into the disease-associated, transmissible form denoted PrPSc. Recent studies revealed a correlation between the sialylation status of PrPSc and incubation time to disease and introduced a new hypothesis that progression of prion diseases could be controlled or reversed by altering the sialylation level of PrPC. Of the four known mammalian sialidases, the enzymes that cleave off sialic acid residues, only NEU1, NEU3 and NEU4 are expressed in the brain. To test whether cellular sialidases control the steady-state sialylation level of PrPC and to identify the putative sialidase responsible for desialylating PrPC, we analyzed brain-derived PrPC from knockout mice deficient in Neu1, Neu3, Neu4, or from Neu3/Neu4 double knockouts. Surprisingly, no differences in the sialylation of PrPC or its proteolytic product C1 were noticed in any of the knockout mice tested as compared to the age-matched controls. However, significantly higher amounts of the C1 fragment relative to full-length PrPC were detected in the brains of Neu1 knockout mice as compared to WT mice or to the other knockout mice. Additional experiments revealed that in neuroblastoma cell line the sialylation pattern of C1 could be changed by an inhibitor of sialylatransferases. In summary, this study suggests that targeting cellular sialidases is apparently not the correct strategy for altering the sialylation levels of PrPC, whereas modulating the activity of sialylatransferases might offer a more promising approach. Our findings also suggest that catabolism of PrPC involves its α-cleavage followed by desialylation of the resulting C1 fragments by NEU1 and consequent fast degradation of the desialylated products. PMID:26569607

  3. Cholinesterase inhibitors from botanicals

    PubMed Central

    Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P.; Ahmed, K. K. Mueen

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

  4. ACECARD. Acquire CoOmmodities Easily Card

    SciTech Connect

    Soler, E.E.

    1996-09-01

    Acquire Commodities Easily Card (AceCard) provides an automated end-user method to distribute company credit card charges to internal charge numbers. AceCard will allow cardholders to record card purchases in an on-line order log, enter multiple account distributions per order that can be posted to the General Ledger, track orders, and receipt information, and provide a variety of cardholder and administrative reports. Please note: Customers must contact Ed Soler (423)-576-6151, Lockheed Martin Energy Systems, for help with the installation of the package. The fee for this installation help will be coordinated by the customer and Lockheed Martin and is in addition to cost of the package from ESTSC. Customers should contact Sandy Presley (423)-576-4708 for user help.

  5. Acquire CoOmmodities Easily Card

    SciTech Connect

    Soler, E. E.

    1998-05-29

    Acquire Commodities Easily Card (AceCard) provides an automated end-user method to distribute company credit card charges to internal charge numbers. AceCard will allow cardholders to record card purchases in an on-line order log, enter multiple account distributions per order that can be posted to the General Ledger, track orders, and receipt information, and provide a variety of cardholder and administrative reports. Please note: Customers must contact Ed Soler (423)-576-6151, Lockheed Martin Energy Systems, for help with the installation of the package. The fee for this installation help will be coordinated by the customer and Lockheed Martin and is in addition to cost of the package from ESTSC. Customers should contact Sandy Presley (423)-576-4708 for user help.

  6. Innate and acquired bacteriophage-mediated immunity

    PubMed Central

    Barr, Jeremy J.; Youle, Merry; Rohwer, Forest

    2013-01-01

    We recently described a novel, non-host-derived, phage-mediated immunity active at mucosal surfaces, the main site of pathogen entry in metazoans. In that work, we showed that phage T4 adheres to mucus glycoproteins via immunoglobulin-like domains displayed on its capsid. This adherence positions the phage in mucus surfaces where they are more likely to encounter and kill bacteria, thereby benefiting both the phage and its metazoan host. We presented this phage-metazoan symbiosis based on an exclusively lytic model of phage infection. Here we extend our bacteriophage adherence to mucus (BAM) model to consider the undoubtedly more complex dynamics in vivo. We hypothesize how mucus-adherent phages, both lytic and temperate, might impact the commensal microbiota as well as protect the metazoan epithelium from bacterial invasion. We suggest that BAM may provide both an innate and an acquired antimicrobial immunity. PMID:24228227

  7. Acquired immunodeficiency syndrome and health care professionals.

    PubMed

    Menon, V; Bharucha, K

    1994-01-01

    As health care professionals, we face a grave risk of acquiring HIV infection in the course of our work. But how many of us really know the precautions to be applied in the hospital set up in dealing with HIV infected patients? A knowledge, attitude and practice (KAP) study was conducted in Pune hospitals to assess the current status. Among the results 65% servants had not heard of AIDS, 85% nursing staff did not apply the Universal Safety Precautions (USP) approach, 13.5% resident thought that the HIV was not transmitted by blood, 30% consultants would avoid contact with an HIV positive patient. This study has shown that definite lacunae exist in knowledge specific to the particular population in question. A proposal for an education programme which is target specific and one of constant renewal is sought.

  8. Signal regulators of systemic acquired resistance

    PubMed Central

    Gao, Qing-Ming; Zhu, Shifeng; Kachroo, Pradeep; Kachroo, Aardra

    2015-01-01

    Salicylic acid (SA) is an important phytohormone that plays a vital role in a number of physiological responses, including plant defense. The last two decades have witnessed a number of breakthroughs related to biosynthesis, transport, perception and signaling mediated by SA. These findings demonstrate that SA plays a crictical role in both local and systemic defense responses. Systemic acquired resistance (SAR) is one such SA-dependent response. SAR is a long distance signaling mechanism that provides broad spectrum and long-lasting resistance to secondary infections throughout the plant. This unique feature makes SAR a highly desirable trait in crop production. This review summarizes the recent advances in the role of SA in SAR and discusses its relationship to other SAR inducers. PMID:25918514

  9. Treatment of the acquired von Willebrand syndrome.

    PubMed

    Budde, Ulrich; Scheppenheim, Sonja; Dittmer, Rita

    2015-12-01

    Acquired von Willebrand syndrome (aVWS) accounts for 22% of patients with abnormal von Willebrand factor. Most patients with known pathophysiological mechanisms suffer from cardiovascular, myeloproliferative and lymphoproliferative disorders. Less frequent associations are of autoimmune origin, due to hyperfibrinolysis, adsorption to tumor cells, reduced synthesis and prolonged circulation. The mechanisms leading to aVWS is hitherto not known in patients with liver and kidney diseases, drug use, glycogen storage disease, virus infections and at least 18 other disease entities. Diagnosis is complicated by the battery of tests needed, and their inherent rather low sensitivity and specificity for aVWS. Thus, even in acute bleeding situations it may take days until a firm diagnosis is settled and specific therapies can be initiated. The main aim is to shed more light onto this, compared with inherited von Willebrand disease, rare disease which affects at least 2-3% of the older population.

  10. Intensive care unit-acquired weakness.

    PubMed

    Horn, J; Hermans, G

    2017-01-01

    When critically ill, a severe weakness of the limbs and respiratory muscles often develops with a prolonged stay in the intensive care unit (ICU), a condition vaguely termed intensive care unit-acquired weakness (ICUAW). Many of these patients have serious nerve and muscle injury. This syndrome is most often seen in surviving critically ill patients with sepsis or extensive inflammatory response which results in increased duration of mechanical ventilation and hospital length of stay. Patients with ICUAW often do not fully recover and the disability will seriously impact on their quality of life. In this chapter we discuss the current knowledge on the pathophysiology and risk factors of ICUAW. Tools to diagnose ICUAW, how to separate ICUAW from other disorders, and which possible treatment strategies can be employed are also described. ICUAW is finally receiving the attention it deserves and the expectation is that it can be better understood and prevented.

  11. Severe acquired anaemia in Africa: new concepts.

    PubMed

    van Hensbroek, Michael B; Jonker, Femkje; Bates, Imelda

    2011-09-01

    Severe anaemia is common in Africa. It has a high mortality and particularly affects young children and pregnant women. Recent research provides new insights into the mechanisms and causes of severe acquired anaemia and overturns accepted dogma. Deficiencies of vitamin B12 and vitamin A, but not of iron or folic acid, are associated with severe anaemia. Bacterial infections and, in very young children, hookworm infections are also common in severe anaemia. Irrespective of the aetiology, the mechanism causing severe anaemia is often red cell production failure. Severe anaemia in Africa is therefore a complex multi-factorial syndrome, which, even in an individual patient, is unlikely to be amenable to a single intervention. Policies and practices concerning anaemia diagnosis, treatment and prevention need to be substantially revised if we are to make a significant impact on the huge burden of severe anaemia in Africa.

  12. Acquiring case adaptation knowledge: A hybrid approach

    SciTech Connect

    Leake, D.B.; Kinley, A.; Wilson, D.

    1996-12-31

    The ability of case-based reasoning (CBR) systems to apply cases to novel situations depends on their case adaptation knowledge. However, endowing CBR systems with adequate adaptation knowledge has proven to be a very difficult task. This paper describes a hybrid method for performing case adaptation, using a combination of rule-based and case-based reasoning. It shows how this approach provides a framework for acquiring flexible adaptation knowledge from experiences with autonomous adaptation and suggests its potential as a basis for acquisition of adaptation knowledge from interactive user guidance. It also presents initial experimental results examining the benefits of the approach and comparing the relative contributions of case learning and adaptation learning to reasoning performance.

  13. Acquired immunodeficiency syndrome: Ga-67 citrate imaging

    SciTech Connect

    Woolfenden, J.M.; Carrasquillo, J.A.; Larson, S.M.; Simmons, J.T.; Masur, H.; Smith, P.D.; Shelhamer, J.H.; Ognibene, F.P.

    1987-02-01

    All gallium-67 citrate scans obtained in patients with acquired immunodeficiency syndrome (AIDS) at the Clinical Center, National Institutes of Health (Bethesda, Md.) were retrospectively analyzed and correlated with the results of bronchoscopy, chest radiography, and endoscopy. There were 164 scans of 95 patients. Twenty scans were from patients with Pneumocystis carinii pneumonia; 19 were abnormal, for a sensitivity of 95%. Ga-67 uptake tended to be less in patients receiving therapy for P. carinii pneumonia. Chest radiographs were normal at least initially in three patients with abnormal scans and P. carinii pneumonia. Unusually prominent colonic activity was associated with infection in some patients. No lesions of Kaposi sarcoma showed tracer uptake. Gallium scanning is useful for detecting P. carinii pneumonia and other opportunistic infections in patients with AIDS, but it is not useful for localizing Kaposi sarcoma.

  14. Guidelines for prevention of hospital acquired infections

    PubMed Central

    Mehta, Yatin; Gupta, Abhinav; Todi, Subhash; Myatra, SN; Samaddar, D. P.; Patil, Vijaya; Bhattacharya, Pradip Kumar; Ramasubban, Suresh

    2014-01-01

    These guidelines, written for clinicians, contains evidence-based recommendations for the prevention of hospital acquired infections Hospital acquired infections are a major cause of mortality and morbidity and provide challenge to clinicians. Measures of infection control include identifying patients at risk of nosocomial infections, observing hand hygiene, following standard precautions to reduce transmission and strategies to reduce VAP, CR-BSI, CAUTI. Environmental factors and architectural lay out also need to be emphasized upon. Infection prevention in special subsets of patients - burns patients, include identifying sources of organism, identification of organisms, isolation if required, antibiotic prophylaxis to be used selectively, early removal of necrotic tissue, prevention of tetanus, early nutrition and surveillance. Immunodeficient and Transplant recipients are at a higher risk of opportunistic infections. The post tranplant timetable is divided into three time periods for determining risk of infections. Room ventilation, cleaning and decontamination, protective clothing with care regarding food requires special consideration. Monitoring and Surveillance are prioritized depending upon the needs. Designated infection control teams should supervise the process and help in collection and compilation of data. Antibiotic Stewardship Recommendations include constituting a team, close coordination between teams, audit, formulary restriction, de-escalation, optimizing dosing, active use of information technology among other measure. The recommendations in these guidelines are intended to support, and not replace, good clinical judgment. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments. PMID:24701065

  15. Community-Acquired Pneumonia in Latin America.

    PubMed

    Iannella, Hernán A; Luna, Carlos M

    2016-12-01

    Community-acquired pneumonia (CAP) is associated with significant morbidity and mortality in Latin America and the Caribbean (LAC) region. Poverty, socioeconomic factors, and malnutrition influence the incidence and outcome of CAP in LAC. In LAC, Streptococcus pneumoniae is the most frequent microorganism responsible for CAP, (incidence: 24-78%); the incidence of atypical microorganisms is similar to other regions of the world. Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is a growing problem in the LAC region, with the Caribbean being the second most affected area worldwide after Sub-Saharan Africa. Pneumococcal pneumonia remains the most common cause of CAP in HIV-infected patients, but Pneumocystis jirovecii and tuberculosis (TB) are also common in this population. The heterogeneity of the health care systems and social inequity between different countries in LAC, and even between different settings inside the same country, is a difficult issue. TB, including multidrug-resistant TB, is several times more common in South American and Central American countries compared with North America. Furthermore, hantaviruses circulating in the Americas (new world hantaviruses) generate a severe respiratory disease called hantavirus pulmonary syndrome, with an associated mortality as high as 50%. More than 30 hantaviruses have been reported in the Western Hemisphere, with more frequent cases registered in the southern cone (Argentina, Chile, Uruguay, Paraguay, Bolivia, and Brazil). Respiratory viruses (particularly influenza) remain an important cause of morbidity and mortality, particularly in the elderly. Low rates of vaccination (against influenza as well as pneumococcus) may heighten the risk of these infections in low- and middle-income countries.

  16. An amphioxus gC1q protein binds human IgG and initiates the classical pathway: Implications for a C1q-mediated complement system in the basal chordate.

    PubMed

    Gao, Zhan; Li, Mengyang; Ma, Jie; Zhang, Shicui

    2014-12-01

    The origin of the classical complement pathway remains open during chordate evolution. A C1q-like member, BjC1q, was identified in the basal chordate amphioxus. It is predominantly expressed in the hepatic caecum, hindgut, and notochord, and is significantly upregulated following challenge with bacteria or lipoteichoic acid and LPS. Recombinant BjC1q and its globular head domain specifically interact with lipoteichoic acid and LPS, but BjC1q displays little lectin activity. Moreover, rBjC1q can assemble to form the high molecular weight oligomers necessary for binding to proteases C1r/C1s and for complement activation, and binds human C1r/C1s/mannan-binding lectin-associated serine protease-2 as well as amphioxus serine proteases involved in the cleavage of C4/C2, and C3 activation. Importantly, rBjC1q binds with human IgG as well as an amphioxus Ig domain containing protein, resulting in the activation of the classical complement pathway. This is the first report showing that a C1q-like protein in invertebrates is able to initiate classical pathway, raising the possibility that amphioxus possesses a C1q-mediated complement system. It also suggests a new scenario for the emergence of the classical complement pathway, in contrast to the proposal that the lectin pathway evolved into the classical pathway.

  17. Augmented HR Repair Mediates Acquired Temozolomide Resistance in Glioblastoma.

    PubMed

    Gil Del Alcazar, Carlos Rodrigo; Todorova, Pavlina Krasimirova; Habib, Amyn A; Mukherjee, Bipasha; Burma, Sandeep

    2016-10-01

    Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults and is universally fatal. The DNA alkylating agent temozolomide is part of the standard-of-care for GBM. However, these tumors eventually develop therapy-driven resistance and inevitably recur. While loss of mismatch repair (MMR) and re-expression of MGMT have been shown to underlie chemoresistance in a fraction of GBMs, resistance mechanisms operating in the remaining GBMs are not well understood. To better understand the molecular basis for therapy-driven temozolomide resistance, mice bearing orthotopic GBM xenografts were subjected to protracted temozolomide treatment, and cell lines were generated from the primary (untreated) and recurrent (temozolomide-treated) tumors. As expected, the cells derived from primary tumors were sensitive to temozolomide, whereas the cells from the recurrent tumors were significantly resistant to the drug. Importantly, the acquired resistance to temozolomide in the recurrent lines was not driven by re-expression of MGMT or loss of MMR but was due to accelerated repair of temozolomide-induced DNA double-strand breaks (DSB). Temozolomide induces DNA replication-associated DSBs that are primarily repaired by the homologous recombination (HR) pathway. Augmented HR appears to underpin temozolomide resistance in the recurrent lines, as these cells were cross-resistant to other agents that induced replication-associated DSBs, exhibited faster resolution of damage-induced Rad51 foci, and displayed higher levels of sister chromatid exchanges (SCE). Furthermore, in light of recent studies demonstrating that CDK1 and CDK2 promote HR, it was found that CDK1/2 inhibitors countered the heightened HR in recurrent tumors and sensitized these therapy-resistant tumor cells to temozolomide.

  18. Orthogonal polynomial Schauder bases in C[-1,1] with optimal growth of degrees

    SciTech Connect

    Skopina, M A

    2001-04-30

    For each {epsilon}>0 an orthogonal Schauder basis of algebraic polynomials P{sub n} in C[-1,1] is constructed such that the degrees of the polynomials have the estimate n(1+{epsilon}). This growth rate is the lowest possible.

  19. Compartment C1, engine room. View down compionway of top of ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Compartment C-1, engine room. View down compionway of top of engine cylinder heads; note slots in frame at left of photograph, slots hold steel bars which form a protective grating above the engines during battle. (081) - USS Olympia, Penn's Landing, 211 South Columbus Boulevard, Philadelphia, Philadelphia County, PA

  20. 29 CFR Appendix B to Subpart C of... - Figures C-1 through C-16

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Figures C-1 through C-16 B Appendix B to Subpart C of Part 1928 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) OCCUPATIONAL SAFETY AND HEALTH STANDARDS FOR AGRICULTURE Roll-Over Protective Structures Pt. 1928, Subpt. C, App....

  1. C1 anterior arch preservation in transnasal odontoidectomy using three-dimensional endoscope: A case report

    PubMed Central

    Zenga, Francesco; Marengo, Nicola; Pacca, Paolo; Pecorari, Giancarlo; Ducati, Alessandro

    2015-01-01

    Background: The transoral ventral corridor is the most common approach used to reach the craniovertebral junction (CVJ). Over the last decade, many case reports have demonstrated the transnasal corridor to the odontoid peg represents a practicable route to remove the tip of the odontoid process. The biomechanical consequences of the traditional odontoidectomy led to the necessity of a cervical spine stabilization. Preserving the inferior portion of the C1 anterior arch should prevent instability. Case Description: This is the first report in which the technique to remove the tip of the odontoid while preserving the C1 anterior arch is described by means of a three-dimensional (3D) endoscope. A 53-year-old man underwent a transnasal 3D endoscopic approach because of a complex CVJ malformation. The upper-medial portion of the C1 anterior arch was removed preserving its continuity, and the odontoidectomy was performed. After surgery, a dynamic X-ray scan showed no difference in CVJ motility in comparison with the preoperative one. Conclusions: The stereoscopic perception augmented the precision of the surgical gesture in the deep field. The importance of a 3D view relates to the depth of field, which a two-dimensional endoscopy cannot provide. This affects the preservation of the C1 anterior arch because of the presence of critical structures that are exposed to potential damage if not displayed. PMID:26759737

  2. Cleanup Verification Package for the 118-C-1, 105-C Solid Waste Burial Ground

    SciTech Connect

    M. J. Appel and J. M. Capron

    2007-07-25

    This cleanup verification package documents completion of remedial action for the 118-C-1, 105-C Solid Waste Burial Ground. This waste site was the primary burial ground for general wastes from the operation of the 105-C Reactor and received process tubes, aluminum fuel spacers, control rods, reactor hardware, spent nuclear fuel and soft wastes.

  3. 40 CFR Appendix C-1 to Subpart E... - Required Provisions-Consulting Engineering Agreements

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Engineering Agreements C Appendix C-1 to Subpart E of Part 35 Protection of Environment ENVIRONMENTAL... Provisions—Consulting Engineering Agreements 1. General 2. Responsibility of the Engineer 3. Scope of Work 4... drawings, designs, specifications, reports, and incidental engineering work or materials...

  4. 40 CFR Appendix C-1 to Subpart E... - Required Provisions-Consulting Engineering Agreements

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Engineering Agreements C Appendix C-1 to Subpart E of Part 35 Protection of Environment ENVIRONMENTAL... Provisions—Consulting Engineering Agreements 1. General 2. Responsibility of the Engineer 3. Scope of Work 4... drawings, designs, specifications, reports, and incidental engineering work or materials...

  5. A South American Prehistoric Mitogenome: Context, Continuity, and the Origin of Haplogroup C1d

    PubMed Central

    Sans, Mónica; Figueiro, Gonzalo; Hughes, Cris E.; Lindo, John; Hidalgo, Pedro C.; Malhi, Ripan S.

    2015-01-01

    Based on mitochondrial DNA (mtDNA), it has been estimated that at least 15 founder haplogroups peopled the Americas. Subhaplogroup C1d3 was defined based on the mitogenome of a living individual from Uruguay that carried a lineage previously identified in hypervariable region I sequences from ancient and modern Uruguayan individuals. When complete mitogenomes were studied, additional substitutions were found in the coding region of the mitochondrial genome. Using a complete ancient mitogenome and three modern mitogenomes, we aim to clarify the ancestral state of subhaplogroup C1d3 and to better understand the peopling of the region of the Río de la Plata basin, as well as of the builders of the mounds from which the ancient individuals were recovered. The ancient mitogenome, belonging to a female dated to 1,610±46 years before present, was identical to the mitogenome of one of the modern individuals. All individuals share the mutations defining subhaplogroup C1d3. We estimated an age of 8,974 (5,748–12,261) years for the most recent common ancestor of C1d3, in agreement with the initial peopling of the geographic region. No individuals belonging to the defined lineage were found outside of Uruguay, which raises questions regarding the mobility of the prehistoric inhabitants of the country. Moreover, the present study shows the continuity of Native lineages over at least 6,000 years. PMID:26509686

  6. Spirastrellolide E: Synthesis of an advanced C(1)-C(24) southern hemisphere

    PubMed Central

    Sokolsky, Alexander; Wang, Xiaozhao; Smith, Amos B.

    2014-01-01

    The synthesis of a C(1)-C(24) advanced southern hemisphere fragment towards the total synthesis of spirastrellolide E has been achieved. Highlights of the route include a highly convergent Type I Anion Relay Chemistry (ARC) tactic for fragment assembly, in conjunction with a directed, regioselective gold-catalyzed alkyne functionalization to generate the central unsaturated [6,6]-spiroketal. PMID:26097261

  7. 4. PROPOSED C1 ASSEMBLY AND TESTING FACILITIES FOR THE ORDINANCE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. PROPOSED C-1 ASSEMBLY AND TESTING FACILITIES FOR THE ORDINANCE GUIDED MISSILE CENTER AT REDSTONE ARSENAL, NEAR THE SOUTH END OF MADKIN MOUNTAIN. OCTOBER 1950, HANNES LUEHRSEN COLLECTION, MSFC MASTER PLANNING OFFICE. - Marshall Space Flight Center, East Test Area, Dodd Road, Huntsville, Madison County, AL

  8. Tomographic correlation for Magerl's technique in C1-C2 arthrodesis in children

    PubMed Central

    Chiaramonti, Bárbara Camargo; Kim, So Yeon; Marchese, Luiz Roberto Delboni; Letaif, Olavo Biraghi; Marcon, Raphael Martus; Cristante, Alexandre Fogaça

    2013-01-01

    OBJECTIVE: To analyze through tomographic studies, the morphology and dimensions of the C1-C2 vertebrae in pediatric patients, to evaluate the possibility of application of Magerl's technique in these patients, and to contribute with data for the usage of the technique in safety. METHOD: Forty normal cervical tomographies, from patients at an age range of 24-120 months of age and from both genders, were retrospectively analyzed. Data was statistically analyzed to obtain mean value and variations of each measurement: length from the C2's pedicle to C1's lateral mass, thickness of the pedicle of C2, the attack angle of the screw at the C2 isthmus with the horizontal axis and the distance from the odontoid to the anterior arch of C1. RESULTS: The mean values obtained were: length right 30.86 mm, left 31.47 mm; thickness right 5.28 mm, left 5.26 mm; attack angle right 46.250 , left 44.500 ; distance from odontoid to anterior arch of C1 2,17 mm. CONCLUSION: The Magerl technique, after tomographic study, seems to be a viable option to be used in pediatric patients. Level of Evidence IV, Case Series. PMID:24453677

  9. 26 CFR 1.512(c)-1 - Special rules applicable to partnerships; in general.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Special rules applicable to partnerships; in... Exempt Organizations § 1.512(c)-1 Special rules applicable to partnerships; in general. In the event an organization to which section 511 applies is a member of a partnership regularly engaged in a trade or...

  10. 26 CFR 1.512(c)-1 - Special rules applicable to partnerships; in general.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Special rules applicable to partnerships; in... Exempt Organizations § 1.512(c)-1 Special rules applicable to partnerships; in general. In the event an organization to which section 511 applies is a member of a partnership regularly engaged in a trade or...

  11. 26 CFR 1.512(c)-1 - Special rules applicable to partnerships; in general.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 7 2012-04-01 2012-04-01 false Special rules applicable to partnerships; in... Exempt Organizations § 1.512(c)-1 Special rules applicable to partnerships; in general. In the event an organization to which section 511 applies is a member of a partnership regularly engaged in a trade or...

  12. 26 CFR 1.512(c)-1 - Special rules applicable to partnerships; in general.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Special rules applicable to partnerships; in... Exempt Organizations § 1.512(c)-1 Special rules applicable to partnerships; in general. In the event an organization to which section 511 applies is a member of a partnership regularly engaged in a trade or...

  13. Fluorographane (C1H(x)F(1-x-δ))n: synthesis and properties.

    PubMed

    Sofer, Zdeněk; Šimek, Petr; Mazánek, Vlastimil; Šembera, Filip; Janoušek, Zbyněk; Pumera, Martin

    2015-04-04

    Fluorographane (C1HxF1-x-δ)n was obtained from graphene by hydrogenation via the Birch reaction with consequent fluorination of the resulting graphane. Fluorographane exhibits fast heterogeneous electron transfer rates and hydrophobicity, which increase with increasing fluorination.

  14. 26 CFR 31.3306(c)-1 - Employment; services performed before 1955.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Federal Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) § 31.3306(c)-1... which they were performed. (b) The tax applies with respect to remuneration paid by an employer...

  15. 17 CFR 240.15c1-2 - Fraud and misrepresentation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Fraud and misrepresentation... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-2 Fraud and... any act, practice, or course of business which operates or would operate as a fraud or deceit upon...

  16. 17 CFR 240.15c1-2 - Fraud and misrepresentation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Fraud and misrepresentation... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-2 Fraud and... any act, practice, or course of business which operates or would operate as a fraud or deceit upon...

  17. 17 CFR 240.15c1-2 - Fraud and misrepresentation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Fraud and misrepresentation... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-2 Fraud and... any act, practice, or course of business which operates or would operate as a fraud or deceit upon...

  18. 26 CFR 1.404(c)-1 - Certain negotiated plans; effect of section 404(c).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Certain negotiated plans; effect of section 404.... § 1.404(c)-1 Certain negotiated plans; effect of section 404(c). (a) Section 404(a) does not apply to... include a trust established under a plan of an employer, or group of employers, who are in...

  19. βC1 of chili leaf curl betasatellite is a pathogenicity determinant

    PubMed Central

    2011-01-01

    Background Cotton leaf curl disease in the Indian subcontinent is associated with several distinct begomoviruses that interact with a disease-specific DNA satellite named Cotton leaf curl Multan betasatellite (CLCuMB). However, we have recently reported that Chili leaf curl betasatellite (ChLCB) is also occasionally found associated with the disease in Pakistan. The question as to whether ChLCB contributes to the development of disease symptoms such as leaf curling and enations remain to be answered. We have previously shown that the expression of βC1 of CLCuMB develops all symptoms of cotton leaf curl disease in Nicotiana benthamiana when expressed from PVX vector. Findings The role of ChLCB in the induction of typical disease symptoms was studied by its expression from PVX vector in N. benthamiana. The expression of βC1 from PVX vector developed severe leaf curl symptoms and leaf-like enations that resemble the phenotype induced by βC1 of CLCuMB. Conclusions The results presented here show that the expression of βC1 of ChLCB from PVX vector exhibit phenotype typical of cotton leaf curl and therefore ChLCB may contribute to the disease symptoms. PMID:22067326

  20. View to starboard, starboard engine room, compartment C1; salt water ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View to starboard, starboard engine room, compartment C-1; salt water circulating pipe at center. Note annunciator to right of pipe and engine room telegraph at left center. Gage at left top center is a vacuum gage. (060) - USS Olympia, Penn's Landing, 211 South Columbus Boulevard, Philadelphia, Philadelphia County, PA

  1. χc 1 and χc 2 production at e+e- colliders

    NASA Astrophysics Data System (ADS)

    CzyŻ, Henryk; Kühn, Johann H.; Tracz, Szymon

    2016-08-01

    Direct, resonant production of the charmonium states χc 1 and χc 2 in electron-positron annihilation is investigated. Depending on details of the model, a sizeable variation of the prediction for the production cross section is anticipated. It is demonstrated that resonant production could be observed under favorable circumstances.

  2. [Reduction of chlorates by acinetobacter thermotoleranticus C-1 in the presence of chromate ions].

    PubMed

    Smirnova, G F; Podgorskiĭ, V S; Muchnik, F V

    2010-01-01

    The rate of chlorate reduction by A. thermotoleranticus C-1 reached 59.6-63.7 mg/l an hour and did not practically depend on chlorate concentration in a broad range. Chlorate and chromate being jointly present in the medium, the rate of chlorate-reduction depended on chromate concentration and remained at the same level when content of chromate reached 5 mg/l. Under CrO4(2-) of 10.0 mg/l the reduction of chlorate by A. thermotoleranticus became inconsiderably slower. The increase of CrO4(2-) content to 20.0-30.0 mg/l decreased the chlorate reduction rate from 63.7 to 18.3-5.8 mg/l an hour, and availability of 50.0 mg/l of chromate was the inhibiting concentration for chlorate destruction and led to irreversible loss of the capacity ofA. thermotoleranticus C-1 to reduce chlorate. The reduction of chromate proceeded simultaneously with that of chlorate. The rate of chromate reduction by A. thermotoleranticus C-1 under their content in the medium of 3-20 mg/l was 0.5-0.37 mg/l an hour and decreased considerably with the increase of concentration of chromate-ions. Availability of chlorate had no effect on reduction of chromate by A. thermotoleranticus C-1.

  3. View forward, starboard engine room, compartment C1; note RPM indicator ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View forward, starboard engine room, compartment C-1; note RPM indicator at top right of photograph, bilge drain manifold at lower right; worm gear at left is probably part of a hydraulic reversing gear. (057) - USS Olympia, Penn's Landing, 211 South Columbus Boulevard, Philadelphia, Philadelphia County, PA

  4. 26 CFR 31.3302(c)-1 - Limit on total credits.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Limit on total credits. 31.3302(c)-1 Section 31... credits. (a) In general. Paragraph (b) of this section relates to the limitation on the aggregate of the credits allowable under section 3302 (a) and (b). Paragraph (c) of this section relates to...

  5. 26 CFR 31.3302(c)-1 - Limit on total credits.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 15 2014-04-01 2014-04-01 false Limit on total credits. 31.3302(c)-1 Section 31... credits. (a) In general. Paragraph (b) of this section relates to the limitation on the aggregate of the credits allowable under section 3302 (a) and (b). Paragraph (c) of this section relates to...

  6. 26 CFR 31.3302(c)-1 - Limit on total credits.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Limit on total credits. 31.3302(c)-1 Section 31... credits. (a) In general. Paragraph (b) of this section relates to the limitation on the aggregate of the credits allowable under section 3302 (a) and (b). Paragraph (c) of this section relates to...

  7. An Evaluation of Title I Model C1: The Special Regression Model.

    ERIC Educational Resources Information Center

    Mandeville, Garrett K.

    The RMC Research Corporation evaluation model C1--the special regression model (SRM)--was evaluated through a series of computer simulations and compared with an alternative model, the norm referenced model (NRM). Using local data and national norm data to determine reasonable values for sample size and pretest posttest correlation parameters, the…

  8. 17 CFR 240.15c1-2 - Fraud and misrepresentation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Fraud and misrepresentation... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-2 Fraud and... any act, practice, or course of business which operates or would operate as a fraud or deceit upon...

  9. 17 CFR 240.15c1-2 - Fraud and misrepresentation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Fraud and misrepresentation... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-2 Fraud and... any act, practice, or course of business which operates or would operate as a fraud or deceit upon...

  10. Retro-odontoid cystic mass treated by laminectomy and C1-C2 fixation

    PubMed Central

    Lin, Dasheng; Ding, Zhenqi; Guo, Yanjie; Lian, Kejian

    2014-01-01

    Retro-odontoid cysts associated with chronic atlantoaxial subluxation are extremely rare. This article describes a case of retro-odontoid cystic mass associated with chronic atlantoaxial subluxation and its management with posterior C1 and partial C2 laminectomy and C1-C2 pedicle screw fixation without resection of the retro-odontoid cyst. A 64-year-old woman experienced a sudden onset of neck pain, hand and foot paresthesia. Atlantoaxial instability associated with a retro-odontoid cystic mass was found in the imaging. The patient underwent posterior C1 and partial C2 laminectomy and C1-C2 pedicle screws fixation without resection of the retro-odontoid cyst. During the 24 months followup period, the cyst disappeared completely and the patient remained symptom free and returned to independent daily living. These findings suggest that posterior laminectomy and fixation without resection of the retro-odontoid cyst is relatively simple and safe and the results are satisfactory. PMID:25404777

  11. C1-continuous Virtual Element Method for Poisson-Kirchhoff plate problem

    SciTech Connect

    Gyrya, Vitaliy; Mourad, Hashem Mohamed

    2016-09-20

    We present a family of C1-continuous high-order Virtual Element Methods for Poisson-Kirchho plate bending problem. The convergence of the methods is tested on a variety of meshes including rectangular, quadrilateral, and meshes obtained by edge removal (i.e. highly irregular meshes). The convergence rates are presented for all of these tests.

  12. 26 CFR 1.412(c)(1)-1 - Determinations to be made under funding method-terms defined.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...-terms defined. 1.412(c)(1)-1 Section 1.412(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.412(c)(1)-1 Determinations to be made under funding method—terms defined. (a... collectively bargained plans, see § 1.412(c)(1)-2; for principles applicable to funding methods in......

  13. 40 CFR Table C-1 to Subpart C of... - Test Concentration Ranges, Number of Measurements Required, and Maximum Discrepancy Specification

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Measurements Required, and Maximum Discrepancy Specification C Table C-1 to Subpart C of Part 53 Protection of... Reference Methods Pt. 53, Subpt. C, Table C-1 Table C-1 to Subpart C of Part 53—Test Concentration Ranges... 0.25 to 0.35 2 2 .03 Total 7 8 Effective Date Note: At 75 FR 35601, June 22, 2010, table C-1...

  14. Probing the Paracoccus denitrificans cytochrome c1 / c552 interaction by mutagenesis and fast kinetics†

    PubMed Central

    Janzon, Julia; Yuan, Quan; Malatesta, Francesco; Hellwig, Petra; Ludwig, Bernd; Durham, Bill; Millett, Francis

    2008-01-01

    Electron transfer (ET) between Paracoccus denitrificans cytochrome c1 and cytochrome c552 was studied using the soluble redox fragments cyt c1CF and cyt c552F. A new ruthenium cyt c552F derivative labeled at C23 (Ruz-23-c552F) was designed to measure rapid electron transfer with cyt c1CF in the physiological direction using flash photolysis. The bimolecular rate constant k12 decreased rapidly with ionic strength above 40 mM, consistent with a diffusional process guided by long-range electrostatic interactions between the two proteins. However, a new kinetic phase was detected below 35 mM ionic strength with the ruthenium photoexcitation technique in which k12 became very rapid (3 × 109 M−1s−1) and nearly independent of ionic strength, suggesting that the reaction became so fast that it was controlled by short-range diffusion along the protein surfaces guided by hydrophobic interactions. These results are consistent with a two-step model for formation of the final encounter complex. No intracomplex electron transfer between Ruz-23-c552F and c1CF was observed even at the lowest ionic strength, indicating that the dissociation constant of the complex was greater than 30 µM. On the other hand, the ruthenium-labeled yeast cytochrome c derivative Ruz-39-Cc formed a tight 1:1 complex with cyt c1CF at ionic strengths below 60 mM with an intracomplex electron transfer rate constant of 50,000 s−1. A group of cyt c1CF variants in the presumed docking site were generated based on information from the yeast cyt bc1/cyt c co-crystal structure. Kinetic analysis of cyt c1CF mutants located near the heme crevice provided preliminary identification of the interaction site for cyt c552F, and suggest that formation of the encounter complex is guided primarily by the overall electrostatic surface potential rather than by defined ions. PMID:19006325

  15. The C1C2: A framework for simultaneous model selection and assessment

    PubMed Central

    Eklund, Martin; Spjuth, Ola; Wikberg, Jarl ES

    2008-01-01

    Background There has been recent concern regarding the inability of predictive modeling approaches to generalize to new data. Some of the problems can be attributed to improper methods for model selection and assessment. Here, we have addressed this issue by introducing a novel and general framework, the C1C2, for simultaneous model selection and assessment. The framework relies on a partitioning of the data in order to separate model choice from model assessment in terms of used data. Since the number of conceivable models in general is vast, it was also of interest to investigate the employment of two automatic search methods, a genetic algorithm and a brute-force method, for model choice. As a demonstration, the C1C2 was applied to simulated and real-world datasets. A penalized linear model was assumed to reasonably approximate the true relation between the dependent and independent variables, thus reducing the model choice problem to a matter of variable selection and choice of penalizing parameter. We also studied the impact of assuming prior knowledge about the number of relevant variables on model choice and generalization error estimates. The results obtained with the C1C2 were compared to those obtained by employing repeated K-fold cross-validation for choosing and assessing a model. Results The C1C2 framework performed well at finding the true model in terms of choosing the correct variable subset and producing reasonable choices for the penalizing parameter, even in situations when the independent variables were highly correlated and when the number of observations was less than the number of variables. The C1C2 framework was also found to give accurate estimates of the generalization error. Prior information about the number of important independent variables improved the variable subset choice but reduced the accuracy of generalization error estimates. Using the genetic algorithm worsened the model choice but not the generalization error estimates

  16. Preschoolers Acquire General Knowledge by Sharing in Pretense

    ERIC Educational Resources Information Center

    Sutherland, Shelbie L.; Friedman, Ori

    2012-01-01

    Children acquire general knowledge about many kinds of things, but there are few known means by which this knowledge is acquired. In this article, it is proposed that children acquire generic knowledge by sharing in pretend play. In Experiment 1, twenty-two 3- to 4-year-olds watched pretense in which a puppet represented a "nerp" (an unfamiliar…

  17. 19 CFR 148.38 - Sale of articles acquired abroad.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 2 2013-04-01 2013-04-01 false Sale of articles acquired abroad. 148.38 Section... § 148.38 Sale of articles acquired abroad. An article brought in under the $800 or $1,600 exemption for articles acquired abroad for personal or household use and subsequently sold is not dutiable or subject...

  18. 19 CFR 148.38 - Sale of articles acquired abroad.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 2 2010-04-01 2010-04-01 false Sale of articles acquired abroad. 148.38 Section... § 148.38 Sale of articles acquired abroad. An article brought in under the $800 or $1,600 exemption for articles acquired abroad for personal or household use and subsequently sold is not dutiable or subject...

  19. 19 CFR 148.38 - Sale of articles acquired abroad.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 2 2011-04-01 2011-04-01 false Sale of articles acquired abroad. 148.38 Section... § 148.38 Sale of articles acquired abroad. An article brought in under the $800 or $1,600 exemption for articles acquired abroad for personal or household use and subsequently sold is not dutiable or subject...

  20. 19 CFR 148.38 - Sale of articles acquired abroad.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 2 2012-04-01 2012-04-01 false Sale of articles acquired abroad. 148.38 Section... § 148.38 Sale of articles acquired abroad. An article brought in under the $800 or $1,600 exemption for articles acquired abroad for personal or household use and subsequently sold is not dutiable or subject...