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Sample records for cell deficient patients

  1. Clinical experience in T cell deficient patients

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    Cole Theresa S

    2010-05-01

    Full Text Available Abstract T cell disorders have been poorly understood until recently. Lack of knowledge of underlying molecular mechanisms together with incomplete data on long term outcome have made it difficult to assess prognosis and give the most effective treatment. Rapid progress in defining molecular defects, improved supportive care and much improved results from hematopoietic stem cell transplantation (HSCT now mean that curative treatment is possible for many patients. However, this depends on prompt recognition, accurate diagnosis and careful treatment planning. This review will discuss recent progress in our clinical and molecular understanding of a variety of disorders including: severe combined immunodeficiency, specific T cell immunodeficiencies, signaling defects, DNA repair defects, immune-osseous dysplasias, thymic disorders and abnormalities of apoptosis. There is still much to discover in this area and some conditions which are as yet very poorly understood. However, with increased knowledge about how these disorders can present and the particular problems each group may face it is hoped that these patients can be recognized early and managed appropriately, so providing them with the best possible outcome.

  2. Deficient leukemia inhibitory factor signaling in muscle precursor cells from patients with type 2 diabetes

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    Broholm, Christa; Brandt, Claus; Schultz, Ninna S;

    2012-01-01

    The cytokine leukemia-inhibitory factor (LIF) is expressed by skeletal muscle and induces proliferation of muscle precursor cells, an important feature of skeletal muscle maintenance and repair. We hypothesized that muscle precursor cells from patients with type 2 diabetes had a deficient response...... to LIF. The mRNA and protein expressions of LIF and its receptor (LIFR) were measured in skeletal muscle biopsies from healthy individuals and patients with type 2 diabetes by use of qPCR and Western blot. LIF signaling and response were studied following administration of recombinant LIF and si......RNA knockdown of suppressor of cytokine signaling (SOCS)3 in myoblast cultures established from healthy individuals and patients with type 2 diabetes. Myoblast proliferation rate was assessed by bromodeoxyuridine incorporation. LIF and LIFR proteins were increased in both muscle tissue and cultured myoblasts...

  3. Osteoporosis and Vitamin D Deficiency in Patients with Sickle Cell Disease

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    Zeynep Ozdemir

    2016-07-01

    Full Text Available Aim: Bone disorders such as osteopenia or osteoporosis are the most common clinical manifestations seen in sickle cell disease (SCD with a high of morbidity. There are many reasons, including vitamin D deficiency for the appearance of bone problems. In the present study we aimed to evaluate osteopathy in patients with SCD using bone mineral densitometry (BMD and biochemical indices. Material and Method: 61 patients (29 female, 32 male were included in the study. The age, gender, and biochemical parameters with BMD were evaluated using dual energy X-ray absorptiometry from lumbar vertebrae. According to Z scores, [-2] was considered as osteoporosis. Multivariate analysis was performed to determine the factors influencing BMD. Results: There were a total of 61 SCD patients. The average age was 21.06±5.06 (15-27 years and the mean BMI was 19.15±2.98 kg/m2. 23 patients were osteopenic (11 female, 12 male (37.7% and 26 were osteoporotic (12 female, 13 male (44.3%. Twelve patients (6 female and 6 male (18% had normal Z scores. Vitamin D was found severely deficient (

  4. Expansion of inflammatory innate lymphoid cells in patients with common variable immune deficiency

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    Cols, Montserrat; Rahman, Adeeb; Maglione, Paul J.; Garcia-Carmona, Yolanda; Simchoni, Noa; Ko, Huai-Bin M.; Radigan, Lin; Cerutti, Andrea; Blankenship, Derek; Pascual, Virginia; Cunningham-Rundles, Charlotte

    2016-01-01

    Background Common variable immunodeficiency (CVID) is an antibody deficiency treated with immunoglobulin; however, patients can have noninfectious inflammatory conditions that lead to heightened morbidity and mortality. Objectives Modular analyses of RNA transcripts in whole blood previously identified an upregulation of many interferon-responsive genes. In this study we sought the cell populations leading to this signature. Methods Lymphoid cells were measured in peripheral blood of 55 patients with CVID (31 with and 24 without inflammatory/autoimmune complications) by using mass cytometry and flow cytometry. Surface markers, cytokines, and transcriptional characteristics of sorted innate lymphoid cells (ILCs) were defined by using quantitative PCR. Gastrointestinal and lung biopsy specimens of subjects with inflammatory disease were stained to seek ILCs in tissues. Results The linage-negative, CD127+, CD161+ lymphoid population containing T-box transcription factor, retinoic acid–related orphan receptor (ROR) γt, IFN-γ, IL-17A, and IL-22, all hallmarks of type 3 innate lymphoid cells, were expanded in the blood of patients with CVID with inflammatory conditions (mean, 3.7% of PBMCs). ILCs contained detectable amounts of the transcription factors inhibitor of DNA binding 2, T-box transcription factor, and RORγt and increased mRNA transcripts for IL-23 receptor (IL-23R) and IL-26, demonstrating inflammatory potential. In gastrointestinal and lung biopsy tissues of patients with CVID, numerous IFN-γ+RORγt+CD3− cells were identified, suggesting a role in these mucosal inflammatory states. Conclusions An expansion of this highly inflammatory ILC population is a characteristic of patients with CVID with inflammatory disease; ILCs and the interferon signature are markers for the uncontrolled inflammatory state in these patients. PMID:26542033

  5. Mechanistic Models Predict Efficacy of CCR5-Deficient Stem Cell Transplants in HIV Patient Populations.

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    Hosseini, I; Gabhann, F Mac

    2016-02-01

    Combination antiretroviral therapy (cART) effectively suppresses viral load in HIV-infected individuals, but it is not a cure. Bone marrow transplants using HIV-resistant stem cells have renewed hope that cure is achievable but key questions remain e.g., what percentage of stem cells must be HIV-resistant to achieve cure?. As few patients have undergone transplants, we built a mechanistic model of HIV/AIDS to approach this problem. The model includes major players of infection, reproduces the complete course of the disease, and simulates crucial components of clinical treatments, such as cART, irradiation, host recovery, gene augmentation, and donor chimerism. Using clinical data from 172 cART-naïve HIV-infected individuals, we created virtual populations to predict performance of CCR5-deficient stem-cell therapies and explore interpatient variability. We validated our model against a published clinical study of CCR5-modified T-cell therapy. Our model predicted that donor chimerism must exceed 75% to achieve 90% probability of cure across patient populations.

  6. B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients

    NARCIS (Netherlands)

    I. Brigida (Immacolata); A.V. Sauer (Aisha); F. Ferrua (Francesca); S. Giannelli (Stefania); S. Scaramuzza (Samantha); V. Pistoia (Valentina); M.C. Castiello (Maria Carmina); B.H. Barendregt (Barbara); M.P. Cicalese (Maria Pia); F. Casiraghi (Federica); C. Brombin (Chiara); J. Puck (Jennifer); K. Muller (Karin); L.D. Notarangelo (Luigi Daniele); D. Montin (Davide); J.M. van Montfrans (Joris); M.G. Roncarolo (Maria Grazia); E. Traggiai (Elisabetta); J.J.M. van Dongen (Jacques); M. van der Burg (Mirjam); A. Aiuti (Alessandro)

    2014-01-01

    textabstractBackground Adenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) g

  7. Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies

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    2016-08-15

    SCID; Omenn's Syndrome; Reticular Dysgenesis; Wiskott-Aldrich Syndrome; Bare Lymphocyte Syndrome; Common Variable Immunodeficiency; Chronic Granulomatous Disease; CD40 Ligand Deficiency; Hyper IgM Syndrome; X-linked Lymphoproliferative Disease; Hemophagocytic Lymphohistiocytosis; Griscelli Syndrome; Chediak-Higashi Syndrome; Langerhan's Cell Histiocytosis

  8. The kinetics of early T and B cell immune recovery after bone marrow transplantation in RAG-2-deficient SCID patients.

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    Atar Lev

    Full Text Available The kinetics of T and B cell immune recovery after bone marrow transplantation (BMT is affected by many pre- and post-transplant factors. Because of the profoundly depleted baseline T and B cell immunity in recombination activating gene 2 (RAG-2-deficient severe combined immunodeficiency (SCID patients, some of these factors are eliminated, and the immune recovery after BMT can then be clearly assessed. This process was followed in ten SCID patients in parallel to their associated transplant-related complications. Early peripheral presence of T and B cells was observed in 8 and 4 patients, respectively. The latter correlated with pre-transplant conditioning therapy. Cells from these patients carried mainly signal joint DNA episomes, indicative of newly derived B and T cells. They were present before the normalization of the T cell receptor (TCR and the B cell receptor (BCR repertoire. Early presentation of the ordered TCR gene rearrangements after BMT occurred simultaneously, but this pattern was heterogeneous over time, suggesting different and individual thymic recovery processes. Our findings early after transplant could suggest the long-term patients' clinical outcome. Early peripheral presence of newly produced B and T lymphocytes from their production and maturation sites after BMT suggests donor stem cell origin rather than peripheral expansion, and is indicative of successful outcome. Peripheral detection of TCR excision circles and kappa-deleting recombination excision circles in RAG-2-deficient SCID post-BMT are early markers of T and B cell reconstitution, and can be used to monitor outcome and tailor specific therapy for patients undergoing BMT.

  9. Protein degradation in a LAMP-2-deficient B-lymphoblastoid cell line from a patient with Danon disease.

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    Sánchez-Lanzas, Raul; Alvarez-Castelao, Beatriz; Bermejo, Teresa; Ayuso, Teresa; Tuñón, Teresa; Castaño, José G

    2016-08-01

    Danon disease, a condition characterized by cardiomyopathy, myopathy, and intellectual disability, is caused by mutations in the LAMP-2 gene. Lamp-2A protein, generated by alternative splicing from the Lamp-2 pre-mRNA, is reported to be the lysosomal membrane receptor essential for the chaperone-mediated autophagic pathway (CMA) aimed to selective protein targeting and translocation into the lysosomal lumen for degradation. To study the relevance of Lamp-2 in protein degradation, a lymphoblastoid cell line was obtained by EBV transformation of B-cells from a Danon patient. The derived cell line showed no significant expression of Lamp-2 protein. The steady-state mRNA and protein levels of alpha-synuclein, IΚBα, Rcan1, and glyceraldehyde-3-phosphate dehydrogenase, four proteins reported to be selective substrates of the CMA pathway, were similar in control and Lamp-2-deficient cells. Inhibition of protein synthesis showed that the half-life of alpha-synuclein, IΚBα, and Rcan1 was similar in control and Lamp-2-deficient cells, and its degradation prevented by proteasome inhibitors. Both in control and Lamp-2-deficient cells, induction of CMA and macroautophagy by serum and aminoacid starvation of cells for 8h produced a similar decrease in IΚBα and Rcan1 protein levels and was prevented by the addition of lysosome and autophagy inhibitors. In conclusion, the results presented here showed that Lamp-2 deficiency in human lymphoblastoid cells did not modify the steady-state levels or the degradation of several protein substrates reported as selective substrates of the CMA pathway.

  10. Deficiency of pulmonary Valpha24 Vbeta11 natural killer T cells in corticosteroid-naïve sarcoidosis patients.

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    Korosec, Peter; Rijavec, Matija; Silar, Mira; Kern, Izidor; Kosnik, Mitja; Osolnik, Katarina

    2010-04-01

    Invariant natural killer T (NKT) cells might contribute to the amplified and prolonged T-cell immune response that characterizes sarcoidosis. Therefore, we want to investigate the frequency and distribution of pulmonary invariant NKT cells in corticosteroid-naïve patients with sarcoidosis. We used multi-parameter flow cytometry with antibodies against CD3, CD4, CD8, CD14, CD19, CD45, CD16/56, TCR Valpha24, and TCR Vbeta11, on bronchoalveolar lavage fluid (BALF), to examine the frequency and distribution of pulmonary invariant NKT cells in 47 newly diagnosed sarcoidosis patients and in 8 control subjects. The frequencies of BALF Valpha24 Vbeta11 invariant NKT cells were significantly lower in patients with sarcoidosis in comparison to control subjects. Moreover, lower invariant NKT cell frequencies in patients with sarcoidosis significantly correlated with exaggerated BALF lymphocytosis and CD4 T cell responses. This study demonstrated a pulmonary deficiency in the frequency of a subset of T cells with immunoregulatory function in patients with sarcoidosis.

  11. A targetable fluorescent sensor reveals that copper-deficient SCO1 and SCO2 patient cells prioritize mitochondrial copper homeostasis.

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    Dodani, Sheel C; Leary, Scot C; Cobine, Paul A; Winge, Dennis R; Chang, Christopher J

    2011-06-08

    We present the design, synthesis, spectroscopy, and biological applications of Mitochondrial Coppersensor-1 (Mito-CS1), a new type of targetable fluorescent sensor for imaging exchangeable mitochondrial copper pools in living cells. Mito-CS1 is a bifunctional reporter that combines a Cu(+)-responsive fluorescent platform with a mitochondrial-targeting triphenylphosphonium moiety for localizing the probe to this organelle. Molecular imaging with Mito-CS1 establishes that this new chemical tool can detect changes in labile mitochondrial Cu(+) in a model HEK 293T cell line as well as in human fibroblasts. Moreover, we utilized Mito-CS1 in a combined imaging and biochemical study in fibroblasts derived from patients with mutations in the two synthesis of cytochrome c oxidase 1 and 2 proteins (SCO1 and SCO2), each of which is required for assembly and metalation of functionally active cytochrome c oxidase (COX). Interestingly, we observe that although defects in these mitochondrial metallochaperones lead to a global copper deficiency at the whole cell level, total copper and exchangeable mitochondrial Cu(+) pools in SCO1 and SCO2 patient fibroblasts are largely unaltered relative to wild-type controls. Our findings reveal that the cell maintains copper homeostasis in mitochondria even in situations of copper deficiency and mitochondrial metallochaperone malfunction, illustrating the importance of regulating copper stores in this energy-producing organelle.

  12. Correction of deficient CD34+ cells from peripheral blood after mobilization in a patient with congenital erythropoietic porphyria.

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    Mazurier, F; Géronimi, F; Lamrissi-Garcia, I; Morel, C; Richard, E; Ged, C; Fontanellas, A; Moreau-Gaudry, F; Morey, M; de Verneuil, H

    2001-03-01

    Congenital erythropoietic porphyria (CEP) is an inherited disease due to a deficiency in the uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme pathway. It is characterized by accumulation of uroporphyrin I in the bone marrow, peripheral blood, and other organs. The onset of most cases occurs in infancy and the main symptoms are cutaneous photosensitivity and hemolysis. For severe transfusion-dependent cases, when allogeneic cell transplantation cannot be performed, autografting of genetically modified primitive/stem cells is the only alternative. In the present study, efficient mobilization of peripheral blood primitive CD34(+) cells was performed on a young adult CEP patient. Retroviral transduction of this cell population with the therapeutic human UROS (hUS) gene resulted in both enzymatic and metabolic correction of CD34(+)-derived cells, as demonstrated by the increase in UROS activity and by a 53% drop in porphyrin accumulation. A 10-24% gene transfer efficiency was achieved in the most primitive cells, as demonstrated by the expression of enhanced green fluorescent protein (EGFP) in long-term culture-initiating cells (LTC-IC). Furthermore, gene expression remained stable during in vitro erythroid differentiation. Therefore, these results are promising for the future treatment of CEP patients by gene therapy.

  13. Correction of glucocerebrosidase deficiency after retroviral-mediated gene transfer into hematopoietic progenitor cells from patients with Gaucher disease

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    Fink, J.K.; Correll, P.H.; Perry, L.K.; Brady, R.O.; Karlsson, S. (National Institutes of Health, Bethesda, MD (USA))

    1990-03-01

    Retroviral gene transfer has been used successfully to correct the glucocerebrosidase (GCase) deficiency in primary hematopoietic cells from patients with Gaucher disease. For this model of somatic gene therapy, the authors developed a high-titer, amphotropic retroviral vector designated NTG in which the human GCase gene was driven by the mutant polyoma virus enhancer/herpesvirus thymidine kinase gene (tk) promoter (Py{sup +}/Htk). NTG normalized GCase activity in transduced Gaucher fibroblasts and efficiently infected human monocytic and erythroleukemic cell lines. RNA blot-hybridization (Northern blot) analysis of these hemaptopoietic cell lines showed unexpectedly high-level expression from the Moloney murine leukemia virus long terminal repeat (Mo-MLV LTR) and levels of Py{sup +}/Htk enhancer/promoter-initiated human GCase RNA that approximated endogenous GCase RNA levels. Furthermore, NTG efficiently infected human hematopoietic progenitor cells. Detection of the provirus in approximately one-third of NTG-infected progenitor colonies that had not been selected in G418-containing medium indicates that relative resistance to G418 underestimated the actual gene transfer efficiency. Northern blot analysis of NTG-infected, progenitor-derived cells showed expression from both the Mo-MLV LTR and the Py{sup +}/Htk enhancer/promoter. NTG-transduced hematopoietic progenitor cells from patients with Gaucher disease generated progeny in which GCase activity has been normalized.

  14. High Production of IL-18 by Dendritic Cells Induced by Sera from Patients with Primary Antibody Deficiency

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    Maryam Nourizadeh

    2007-06-01

    Full Text Available Predominantly antibody deficiencies are a category of primary immunodeficiency diseases, whichconsist of several rare disorders such as common variable immunodeficiency (CVID and X-linked agammaglobulinemia (XLA. We evaluated the effects of CVID and XLA patients’ sera as a source of microenviromental factors on maturation and function of monocyte-derived DCs.Blood was collected from 10 CVID and 5 XLA patients before immunoglobulin replacementtherapy and also from 8 healthy volunteers in order to obtain necessary sera for this study. Monocyte derived DCs were generated from blood cells obtained from healthy volunteers in the presence of GM-CSF, IL-4 and 10% serum concentrations from cases and controls. Immature DCs were incubated with monocyte conditioned medium (MCM and TNF-α in order to generate mature DCs. Interleukin 18 (IL-18 production by CD40L-activated mature DCs was measured after 24 hours of culture in vitro.IL-18 production by DCs generated in the presence of CVID and XLA patients’ sera were6.75±2.59 and 7.08±1.75 ng/ml, respectively, which were significantly higher than normal serumconditioned DCs (3.55±0.68 ng/ml.These results suggest that the sera of patients with predominantly antibody deficiencies maycontain soluble factor(s that can induce a significant increase in IL-18 production by DCs.

  15. Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations

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    Casarin Alberto

    2012-04-01

    Full Text Available Abstract Background Mutations in SCO2 cause cytochrome c oxidase deficiency (COX and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients’ cells. Bezafibrate (BZF, an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene. Methods We have investigated the effect of BZF and copper in cells with SCO2 mutations using spectrophotometric methods to analyse respiratory chain activities and a luciferase assay to measure ATP production.. Results Individual mitochondrial enzymes displayed different responses to BZF. COX activity increased by about 40% above basal levels (both in controls and patients, with SCO2 cells reaching 75-80% COX activity compared to untreated controls. The increase in COX was paralleled by an increase in ATP production. The effect was dose-dependent: it was negligible with 100 μM BZF, and peaked at 400 μM BZF. Higher BZF concentrations were associated with a relative decline of COX activity, indicating that the therapeutic range of this drug is very narrow. Combined treatment with 100 μM CuCl2 and 200 μM BZF (which are only marginally effective when administered individually achieved complete rescue of COX activity in SCO2 cells. Conclusions These data are crucial to design therapeutic trials for this otherwise fatal disorder. The additive effect of copper and BZF will allow to employ lower doses of each drug and to reduce their potential toxic effects. The exact mechanism of action of BZF remains to be determined.

  16. Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34+ cells isolated from Artemis or RAG1-deficient patients.

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    Lagresle-Peyrou, Chantal; Benjelloun, Fatine; Hue, Christophe; Andre-Schmutz, Isabelle; Bonhomme, Delphine; Forveille, Monique; Beldjord, Kheira; Hacein-Bey-Abina, Salima; De Villartay, Jean-Pierre; Charneau, Pierre; Durandy, Anne; Fischer, Alain; Cavazzana-Calvo, Marina

    2008-02-01

    Severe combined immunodeficiency (SCID) caused by mutation of the recombination-activating gene 1 (RAG1) or Artemis gene lead to the absence of B- and T-cell differentiation. The only curative treatment is allogeneic bone marrow (BM) transplantation, which displays a high survival rate when an HLA compatible donor is available but has a poorer prognosis when the donor is partially compatible. Consequently, gene therapy may be a promising alternative strategy for these diseases. Here, we report that lentiviral gene-corrected BM CD34(+) cells (isolated from Artemis- or RAG1-deficient patients) sustain human B-cell differentiation following injection into non-obese diabetic/SCID (NOD-SCID) mice previously infused with anti-interleukin-2 receptor beta chain monoclonal antibody. In most of the mice BM, engrafted with Artemis-transduced cells, human B-cell differentiation occurred until the mature stage. The B cells were functional as human immunoglobulin M (IgM) was present in the serum. Following injection with RAG1-transduced cells, human engraftment occurred in vivo but B-cell differentiation until the mature stage was less frequent. However, when it occurred, it was always associated with human IgM production. This overall approach represents a useful tool for evaluating gene transfer efficiency in human SCID forms affecting B-cell development (such as Artemis deficiency) and for testing new vectors for improving in vivo RAG1 complementation.

  17. Generation of a bile salt export pump deficiency model using patient-specific induced pluripotent stem cell-derived hepatocyte-like cells

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    Imagawa, Kazuo; Takayama, Kazuo; Isoyama, Shigemi; Tanikawa, Ken; Shinkai, Masato; Harada, Kazuo; Tachibana, Masashi; Sakurai, Fuminori; Noguchi, Emiko; Hirata, Kazumasa; Kage, Masayoshi; Kawabata, Kenji; Sumazaki, Ryo; Mizuguchi, Hiroyuki

    2017-01-01

    Bile salt export pump (BSEP) plays an important role in hepatic secretion of bile acids and its deficiency results in severe cholestasis and liver failure. Mutation of the ABCB11 gene encoding BSEP induces BSEP deficiency and progressive familial intrahepatic cholestasis type 2 (PFIC2). Because liver transplantation remains standard treatment for PFIC2, the development of a novel therapeutic option is desired. However, a well reproducible model, which is essential for the new drug development for PFIC2, has not been established. Therefore, we attempted to establish a PFIC2 model by using iPSC technology. Human iPSCs were generated from patients with BSEP-deficiency (BD-iPSC), and were differentiated into hepatocyte-like cells (HLCs). In the BD-iPSC derived HLCs (BD-HLCs), BSEP was not expressed on the cell surface and the biliary excretion capacity was significantly impaired. We also identified a novel mutation in the 5′-untranslated region of the ABCB11 gene that led to aberrant RNA splicing in BD-HLCs. Furthermore, to evaluate the drug efficacy, BD-HLCs were treated with 4-phenylbutyrate (4PBA). The membrane BSEP expression level and the biliary excretion capacity in BD-HLCs were rescued by 4PBA treatment. In summary, we succeeded in establishing a PFIC2 model, which may be useful for its pathophysiological analysis and drug development. PMID:28150711

  18. Generation of a bile salt export pump deficiency model using patient-specific induced pluripotent stem cell-derived hepatocyte-like cells.

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    Imagawa, Kazuo; Takayama, Kazuo; Isoyama, Shigemi; Tanikawa, Ken; Shinkai, Masato; Harada, Kazuo; Tachibana, Masashi; Sakurai, Fuminori; Noguchi, Emiko; Hirata, Kazumasa; Kage, Masayoshi; Kawabata, Kenji; Sumazaki, Ryo; Mizuguchi, Hiroyuki

    2017-02-02

    Bile salt export pump (BSEP) plays an important role in hepatic secretion of bile acids and its deficiency results in severe cholestasis and liver failure. Mutation of the ABCB11 gene encoding BSEP induces BSEP deficiency and progressive familial intrahepatic cholestasis type 2 (PFIC2). Because liver transplantation remains standard treatment for PFIC2, the development of a novel therapeutic option is desired. However, a well reproducible model, which is essential for the new drug development for PFIC2, has not been established. Therefore, we attempted to establish a PFIC2 model by using iPSC technology. Human iPSCs were generated from patients with BSEP-deficiency (BD-iPSC), and were differentiated into hepatocyte-like cells (HLCs). In the BD-iPSC derived HLCs (BD-HLCs), BSEP was not expressed on the cell surface and the biliary excretion capacity was significantly impaired. We also identified a novel mutation in the 5'-untranslated region of the ABCB11 gene that led to aberrant RNA splicing in BD-HLCs. Furthermore, to evaluate the drug efficacy, BD-HLCs were treated with 4-phenylbutyrate (4PBA). The membrane BSEP expression level and the biliary excretion capacity in BD-HLCs were rescued by 4PBA treatment. In summary, we succeeded in establishing a PFIC2 model, which may be useful for its pathophysiological analysis and drug development.

  19. Altered development of NKT cells, γδ T cells, CD8 T cells and NK cells in a PLZF deficient patient.

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    Maggie Eidson

    Full Text Available In mice, the transcription factor, PLZF, controls the development of effector functions in invariant NKT cells and a subset of NKT cell-like, γδ T cells. Here, we show that in human lymphocytes, in addition to invariant NKT cells, PLZF was also expressed in a large percentage of CD8+ and CD4+ T cells. Furthermore, PLZF was also found to be expressed in all γδ T cells and in all NK cells. Importantly, we show that in a donor lacking functional PLZF, all of these various lymphocyte populations were altered. Therefore, in contrast to mice, PLZF appears to control the development and/or function of a wide variety of human lymphocytes that represent more than 10% of the total PBMCs. Interestingly, the PLZF-expressing CD8+ T cell population was found to be expanded in the peripheral blood of patients with metastatic melanoma but was greatly diminished in patients with autoimmune disease.

  20. Generation of a High Number of Healthy Erythroid Cells from Gene-Edited Pyruvate Kinase Deficiency Patient-Specific Induced Pluripotent Stem Cells.

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    Garate, Zita; Quintana-Bustamante, Oscar; Crane, Ana M; Olivier, Emmanuel; Poirot, Laurent; Galetto, Roman; Kosinski, Penelope; Hill, Collin; Kung, Charles; Agirre, Xabi; Orman, Israel; Cerrato, Laura; Alberquilla, Omaira; Rodriguez-Fornes, Fatima; Fusaki, Noemi; Garcia-Sanchez, Felix; Maia, Tabita M; Ribeiro, Maria L; Sevilla, Julian; Prosper, Felipe; Jin, Shengfang; Mountford, Joanne; Guenechea, Guillermo; Gouble, Agnes; Bueren, Juan A; Davis, Brian R; Segovia, Jose C

    2015-12-08

    Pyruvate kinase deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene. Erythrocytes from PKD patients show an energetic imbalance causing chronic non-spherocytic hemolytic anemia, as pyruvate kinase defects impair ATP production in erythrocytes. We generated PKD induced pluripotent stem cells (PKDiPSCs) from peripheral blood mononuclear cells (PB-MNCs) of PKD patients by non-integrative Sendai viral vectors. PKDiPSCs were gene edited to integrate a partial codon-optimized R-type pyruvate kinase cDNA in the second intron of the PKLR gene by TALEN-mediated homologous recombination (HR). Notably, we found allele specificity of HR led by the presence of a single-nucleotide polymorphism. High numbers of erythroid cells derived from gene-edited PKDiPSCs showed correction of the energetic imbalance, providing an approach to correct metabolic erythroid diseases and demonstrating the practicality of this approach to generate the large cell numbers required for comprehensive biochemical and metabolic erythroid analyses.

  1. Generation of a High Number of Healthy Erythroid Cells from Gene-Edited Pyruvate Kinase Deficiency Patient-Specific Induced Pluripotent Stem Cells

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    Garate, Zita; Quintana-Bustamante, Oscar; Crane, Ana M.; Olivier, Emmanuel; Poirot, Laurent; Galetto, Roman; Kosinski, Penelope; Hill, Collin; Kung, Charles; Agirre, Xabi; Orman, Israel; Cerrato, Laura; Alberquilla, Omaira; Rodriguez-Fornes, Fatima; Fusaki, Noemi; Garcia-Sanchez, Felix; Maia, Tabita M.; Ribeiro, Maria L.; Sevilla, Julian; Prosper, Felipe; Jin, Shengfang; Mountford, Joanne; Guenechea, Guillermo; Gouble, Agnes; Bueren, Juan A.; Davis, Brian R.; Segovia, Jose C.

    2015-01-01

    Summary Pyruvate kinase deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene. Erythrocytes from PKD patients show an energetic imbalance causing chronic non-spherocytic hemolytic anemia, as pyruvate kinase defects impair ATP production in erythrocytes. We generated PKD induced pluripotent stem cells (PKDiPSCs) from peripheral blood mononuclear cells (PB-MNCs) of PKD patients by non-integrative Sendai viral vectors. PKDiPSCs were gene edited to integrate a partial codon-optimized R-type pyruvate kinase cDNA in the second intron of the PKLR gene by TALEN-mediated homologous recombination (HR). Notably, we found allele specificity of HR led by the presence of a single-nucleotide polymorphism. High numbers of erythroid cells derived from gene-edited PKDiPSCs showed correction of the energetic imbalance, providing an approach to correct metabolic erythroid diseases and demonstrating the practicality of this approach to generate the large cell numbers required for comprehensive biochemical and metabolic erythroid analyses. PMID:26549847

  2. Generation of a High Number of Healthy Erythroid Cells from Gene-Edited Pyruvate Kinase Deficiency Patient-Specific Induced Pluripotent Stem Cells

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    Zita Garate

    2015-12-01

    Full Text Available Pyruvate kinase deficiency (PKD is a rare erythroid metabolic disease caused by mutations in the PKLR gene. Erythrocytes from PKD patients show an energetic imbalance causing chronic non-spherocytic hemolytic anemia, as pyruvate kinase defects impair ATP production in erythrocytes. We generated PKD induced pluripotent stem cells (PKDiPSCs from peripheral blood mononuclear cells (PB-MNCs of PKD patients by non-integrative Sendai viral vectors. PKDiPSCs were gene edited to integrate a partial codon-optimized R-type pyruvate kinase cDNA in the second intron of the PKLR gene by TALEN-mediated homologous recombination (HR. Notably, we found allele specificity of HR led by the presence of a single-nucleotide polymorphism. High numbers of erythroid cells derived from gene-edited PKDiPSCs showed correction of the energetic imbalance, providing an approach to correct metabolic erythroid diseases and demonstrating the practicality of this approach to generate the large cell numbers required for comprehensive biochemical and metabolic erythroid analyses.

  3. Generalized verrucosis in a patient with GATA2 deficiency.

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    West, E S; Kingsbery, M Y; Mintz, E M; Hsu, A P; Holland, S M; Rady, P L; Tyring, S K; Grossman, M E

    2014-05-01

    Generalized verrucosis is a characteristic of several genetic and immunodeficiency disorders including epidermodysplasia verruciformis; warts, hypogammaglobulinaemia, infections and myelokathexis (WHIM) syndrome; warts, immunodeficiency, lymphoedema and anogenital dysplasia (WILD) syndrome; severe combined immune deficiency and HIV, among others. In recent years, it has been consistently recognized in patients with GATA2 deficiency, a novel immunodeficiency syndrome characterized by monocytopenia, B-cell and natural killer-cell lymphopenia, and a tendency to develop myeloid leukaemias and disseminated mycobacterial, human papillomavirus (HPV) and opportunistic fungal infections. Mutations in GATA2 cause haploinsufficiency and track in families as an autosomal dominant immunodeficiency. GATA2 is a transcription factor involved in early haematopoietic differentiation and lymphatic and vascular development. We describe a case of generalized verrucosis with HPV type 57 presenting in a young man with GATA2 deficiency. GATA2 deficiency is a novel dominant immunodeficiency that is often recognized later in life and should be considered in the differential diagnosis of patients with generalized verrucosis.

  4. Augmented cell death with Bloom syndrome helicase deficiency.

    Science.gov (United States)

    Kaneko, Hideo; Fukao, Toshiyuki; Kasahara, Kimiko; Yamada, Taketo; Kondo, Naomi

    2011-01-01

    Bloom syndrome (BS) is a rare autosomal genetic disorder characterized by lupus-like erythematous telangi-ectasias of the face, sun sensitivity, infertility, stunted growth, upper respiratory infection, and gastrointestinal infections commonly associated with decreased immuno-globulin levels. The syndrome is associated with immuno-deficiency of a generalized type, ranging from mild and essentially asympto-matic to severe. Chromosomal abnormalities are hallmarks of the disorder, and high frequencies of sister chromatid exchanges and quadriradial configurations in lymphocytes and fibroblasts are diagnostic features. BS is caused by mutations in BLM, a member of the RecQ helicase family. We determined whether BLM deficiency has any effects on cell growth and death in BLM-deficient cells and mice. BLM-deficient EB-virus-transformed cell lines from BS patients and embryonic fibroblasts from BLM-/- mice showed slower growth than wild-type cells. BLM-deficient cells showed abnormal p53 protein expression after irradiation. In BLM-/- mice, small body size, reduced number of fetal liver cells and increased cell death were observed. BLM deficiency causes the up-regulation of p53, double-strand break and apoptosis, which are likely observed in irradiated control cells. Slow cell growth and increased cell death may be one of the causes of the small body size associated with BS patients.

  5. Vitamin C deficiency in an anticoagulated patient.

    Science.gov (United States)

    Yousef, George M; Goebel, Lynne J

    2013-06-01

    A 64-year-old woman presented with a hemorrhagic perifollicular rash on her legs while taking warfarin. After biopsy, vitamin C deficiency was suggested as the diagnosis, which ascorbic acid assays later confirmed. Clinical resolution of the rash followed supplementation with vitamin C. Patients on a vitamin K limited diet may also be limiting their intake of vitamin C. Physicians should be aware of this possible correlation, and consider checking vitamin C levels in patients with a perifollicular hemorrhagic rash or other signs of vitamin C deficiency while on warfarin.

  6. Vitamin D deficiency in hemodialysis patients

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    Beena Bansal

    2012-01-01

    Full Text Available Background : Vitamin D [(25(OHD] deficiency and insufficiency is common in patients with chronic kidney disease (CKD. 25(OHD has been found to have beneficial effects on bone, cardiovascular and immune functions. There are little data about vitamin D levels in Indian patients on dialysis. This study was undertaken to determine the vitamin D status of Indian CKD patients on hemodialysis. Materials and Methods : We included 45 patients on maintenance hemodialysis coming to Medanta, Medicity, Gurgaon. 25(OHD levels were measured with radioimmunoassay (Diasorin method and parathyroid hormone (PTH was measured using electrochemiluminiscence immunoassay (ECLIA. Results : The mean age of patients was 55 ± 13 years. 32/45 (71% were males. 23/45 (51% were diabetics. The median duration of hemodialysis was 5.5 months (range 1-74 months. 33/45 (74% patients were on thrice weekly hemodialysis. The mean level of vitamin D was 10.14 ± 8.7 ng/ml. Majority of the patients [43/45 (95.5%] were either vitamin D deficient or had insufficient levels. 40/45 (88.9% were vitamin D deficient (levels <20 ng/ml; of these, 29/40 (64.4% had severe vitamin D deficiency (levels <10 ng/ml and 3/45 (6.7% had insufficient levels (20-30 ng/ml of vitamin D. Only 2/45 (4.4% patients had normal levels of vitamin D. 23/45 (51% of patients were receiving calcitriol. The mean levels of serum calcium, phosphorus, alkaline phosphatase, and albumin were 8.8 ± 0.64 mg/dl, 5.0 ± 0.7 mg/dl, 126 ± 10.3 IU/l and 3.6 ± 0.62 g/dl, respectively. PTH levels ranged from 37 to 1066 pg/ml, and the median was 195.8 pg/ml. There was a weak correlation between 25(OHD levels and weight, sex, hemoglobin, albumin, alkaline phosphatase, and presence of diabetes. There was, however, no correlation with duration of dialysis or PTH levels. Conclusion : Vitamin D deficiency and insufficiency are universal in our hemodialysis patients, with severe vitamin D deficiency in two-third of patients.

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

    Science.gov (United States)

    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.

  8. Caspase 12 in calnexin-deficient cells.

    Science.gov (United States)

    Groenendyk, Jody; Zuppini, Anna; Shore, Gordon; Opas, Michal; Bleackley, R Chris; Michalak, Marek

    2006-11-07

    We investigated a role for calnexin, caspase 12, and Bap31 in endoplasmic reticulum stress-induced apoptosis in calnexin-deficient mouse embryonic fibroblasts and a calnexin-deficient human T cell line (NKR). We showed that calnexin-deficient mouse embryonic fibroblasts are relatively resistant to endoplasmic reticulum stress-induced apoptosis. Western blot analysis demonstrated that both wild-type and calnexin-deficient cells contained a caspase 12 protein. Caspase 12 expression was slightly inhibited in calnexin-deficient cells, and the protein carried out specific cleavage in the presence of thapsigargin. Immunoprecipitation experiments revealed that in the endoplasmic reticulum, caspase 12 forms complexes with Bap31 and calnexin. Treatment of wild-type cells with thapsigargin induced apoptosis and cleavage of Bap31. However, in the absence of calnexin, there was no significant cleavage of Bap31. There was also a negligible processing of caspase 8 in these cells. This work indicates that calnexin may play a role in modulating the sensitivity of a cell to apoptosis induced by endoplasmic reticulum stress, in conjunction with caspase 12 and Bap31.

  9. SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID.

    Science.gov (United States)

    Schuetz, Catharina; Neven, Benedicte; Dvorak, Christopher C; Leroy, Sandrine; Ege, Markus J; Pannicke, Ulrich; Schwarz, Klaus; Schulz, Ansgar S; Hoenig, Manfred; Sparber-Sauer, Monika; Gatz, Susanne A; Denzer, Christian; Blanche, Stephane; Moshous, Despina; Picard, Capucine; Horn, Biljana N; de Villartay, Jean-Pierre; Cavazzana, Marina; Debatin, Klaus-Michael; Friedrich, Wilhelm; Fischer, Alain; Cowan, Morton J

    2014-01-09

    A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T(-)B(-)NK(+)SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T(-)B(-)NK(+)SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.

  10. Lack of nonfunctional B-cell receptor rearrangements in a patient with normal B cell numbers despite partial RAG1 deficiency and atypical SCID/Omenn syndrome

    DEFF Research Database (Denmark)

    Ohm-Laursen, Line; Nielsen, Christian; Fisker, Niels

    2008-01-01

    and the patient had eosinophilia. These presentations are consistent with atypical severe combined immunodeficiency (SCID)/Omenn Syndrome and the diagnosis was confirmed by demonstration of homozygosity for the R841W mutation in the catalytic core of RAG1. Comparison of the patient's immunoglobulin heavy chain...... chromosome 14. CONCLUSION: We hypothesize that the R841W mutation causes a malfunction of RAG1 that has differential outcome on V(D)J recombination in B and T cells, as the patient had normal B cell numbers but suffered severe alpha-beta T-cell immunodeficiency.......INTRODUCTION: A 2.5-month old boy presented with recurrent wheezing, protracted diarrhea, erythrodermia, and failure to thrive. METHODS AND RESULTS: Laboratory analysis showed lymphocytopenia with severely reduced T-cell numbers but normal numbers of B and NK cells. Serum IgE was increased...

  11. Nutritional Deficiency in Patients with Heart Failure

    Directory of Open Access Journals (Sweden)

    Edoardo Sciatti

    2016-07-01

    Full Text Available Heart failure (HF is the main cause of mortality and morbidity in Western countries. Although evidence-based treatments have substantially improved outcomes, prognosis remains poor with high costs for health care systems. In patients with HF, poor dietary behaviors are associated with unsatisfactory quality of life and adverse outcome. The HF guidelines have not recommended a specific nutritional strategy. Despite the role of micronutrient deficiency, it has been extensively studied, and data about the efficacy of supplementation therapy in HF are not supported by large randomized trials and there is limited evidence regarding the outcomes. The aim of the present review is to analyze the state-of-the-art of nutritional deficiencies in HF, focusing on the physiological role and the prognostic impact of micronutrient supplementation.

  12. Acquired hemoglobin variants and exposure to glucose-6-phosphate dehydrogenase deficient red blood cell units during exchange transfusion for sickle cell disease in a patient requiring antigen-matched blood.

    Science.gov (United States)

    Raciti, Patricia M; Francis, Richard O; Spitalnik, Patrice F; Schwartz, Joseph; Jhang, Jeffrey S

    2013-08-01

    Red blood cell exchange (RBCEx) is frequently used in the management of patients with sickle cell disease (SCD) and acute chest syndrome or stroke, or to maintain target hemoglobin S (HbS) levels. In these settings, RBCEx is a category I or II recommendation according to guidelines on the use of therapeutic apheresis published by the American Society for Apheresis. Matching donor red blood cells (RBCs) to recipient phenotypes (e.g., C, E, K-antigen negative) can decrease the risk of alloimmunization in patients with multi-transfused SCD. However, this may select for donors with a higher prevalence of RBC disorders for which screening is not performed. This report describes a patient with SCD treated with RBCEx using five units negative for C, E, K, Fya, Fyb (prospectively matched), four of which were from donors with hemoglobin variants and/or glucose-6-phosphate dehydrogenase (G6PD) deficiency. Pre-RBCEx HbS quantification by high performance liquid chromatography (HPLC) demonstrated 49.3% HbS and 2.8% hemoglobin C, presumably from transfusion of a hemoglobin C-containing RBC unit during a previous RBCEx. Post-RBCEx HPLC showed the appearance of hemoglobin G-Philadelphia. Two units were G6PD-deficient. The patient did well, but the consequences of transfusing RBC units that are G6PD-deficient and contain hemoglobin variants are unknown. Additional studies are needed to investigate effects on storage, in-vivo RBC recovery and survival, and physiological effects following transfusion of these units. Post-RBCEx HPLC can monitor RBCEx efficiency and detect the presence of abnormal transfused units.

  13. Phenotypic studies of natural killer cell subsets in human transporter associated with antigen processing deficiency.

    Directory of Open Access Journals (Sweden)

    Jacques Zimmer

    Full Text Available Peripheral blood natural killer (NK cells from patients with transporter associated with antigen processing (TAP deficiency are hyporesponsive. The mechanism of this defect is unknown, but the phenotype of TAP-deficient NK cells is almost normal. However, we noticed a high percentage of CD56(bright cells among total NK cells from two patients. We further investigated TAP-deficient NK cells in these patients and compared them to NK cells from two other TAP-deficient patients with no clinical symptoms and to individuals with chronic inflammatory diseases other than TAP deficiency (chronic lung diseases or vasculitis. Peripheral blood mononuclear cells isolated from venous blood were stained with fluorochrome-conjugated antibodies and the phenotype of NK cells was analyzed by flow cytometry. In addition, (51Chromium release assays were performed to assess the cytotoxic activity of NK cells. In the symptomatic patients, CD56(bright NK cells represented 28% and 45%, respectively, of all NK cells (higher than in healthy donors. The patients also displayed a higher percentage of CD56(dimCD16(- NK cells than controls. Interestingly, this unusual NK cell subtype distribution was not found in the two asymptomatic TAP-deficient cases, but was instead present in several of the other patients. Over-expression of the inhibitory receptor CD94/NKG2A by TAP-deficient NK cells was confirmed and extended to the inhibitory receptor ILT2 (CD85j. These inhibitory receptors were not involved in regulating the cytotoxicity of TAP-deficient NK cells. We conclude that expansion of the CD56(bright NK cell subtype in peripheral blood is not a hallmark of TAP deficiency, but can be found in other diseases as well. This might reflect a reaction of the immune system to pathologic conditions. It could be interesting to investigate the relative distribution of NK cell subsets in various respiratory and autoimmune diseases.

  14. A study of anemia in human immunodeficiency virus patients: Estimating the prevalence, analyzing the causative effect of nutritional deficiencies, and correlating the degree of severity with CD4 cell counts

    Directory of Open Access Journals (Sweden)

    Ajay Panwar

    2016-01-01

    Full Text Available Background: Anemia is a common complication of human immunodeficiency virus (HIV infection. The role of iron, Vitamin B12, and folate deficiencies, which are otherwise most common causes of anemia, is not well-established in HIV patients. Several studies in India have shown that severe immunodeficiency is associated with higher grade of anemia, but correlation of CD4 cell counts with severity of anemia is not well-documented. Aims: The aims of the present study were: To estimate the point prevalence of anemia in HIV patients, to analyze the causative role of iron, Vitamin B12, and folate deficiencies in anemic HIV patients, and correlating the degree of severity of anemia with CD4 cell counts. Materials and Methods: This study was a cross-sectional study. The study group enrolled 103 consecutive HIV patients attending medical emergency, medical outpatient department, medical wards, and anti-retroviral therapy (ART center at a tertiary care medical center in North India. Study participation consisted of a single visit during which relevant data, including medical history, current medications, CD4 T-lymphocyte count, complete hemogram with red blood cell indices, peripheral smear picture, iron studies, serum Vitamin B12, serum folate and bone marrow studies, were recorded on a case report form. Anemia was classified according to the World Health Organization criteria. Data analysis was carried out using Microsoft Excel and Statistical Package for the Social Sciences software. Results: 86.4% (89/103 patients were found to be anemic. There was no significant difference in prevalence of anemia in ART-naive patients from those who were on ART (P > 0.05. Pearson′s correlation had shown a highly significant positive correlation of hemoglobin and CD4 cell counts in male patients (r = 0.418 as well as female patients (r = 0.565. Normocytic normochromic was the most common type of anemia in males (46% as well as females (42%. Significant iron deficiency

  15. Secondary Carnitine Deficiency in Dialysis Patients: Shall We Supplement It?

    OpenAIRE

    Wanders, Ronald J. A.; Tim Ulinski; Stephanie E. Reuter; Asha Moudgil

    2016-01-01

    Carnitine, essential for fatty acid β-oxidation, is obtained from diet and through de novo biosynthesis. The organic cation/carnitine transporter 2 (OCTN2) facilitates carnitine cellular transport and kidney resorption. Carnitine depletion occurs in OCTN2-deficient patients, with serious clinical complications including cardiomyopathy, myopathy, and hypoketotic hypoglycaemia. Neonatal screening can detect OCTN2 deficiency. OCTN2-deficiency is also known as primary carnitine deficiency. Carnit...

  16. Three distinct cases of copper deficiency in hospitalized pediatric patients.

    Science.gov (United States)

    Dembinski, Karolina; Gargasz, Anne Elizabeth; Dabrow, Sharon; Rodriguez, Lisa

    2012-08-01

    Although copper deficiency is a rare occurrence in the developed world, attention should be given to the proper supplementation of minerals to at-risk pediatric patients. This study presents 3 distinct cases of copper deficiency in hospitalized patients aged 14 months, 6 years, and 12 years. Two patients had short bowel syndrome, requiring prolonged parenteral nutrition or complex intravenous fluid supplementation. The third patient was severely malnourished. Copper deficiency manifested in all of our patients as either microcytic anemia or pancytopenia with myelodysplastic syndrome. Copper deficiency is an important diagnosis to be considered in patients with prematurity, parenteral nutrition dependency, malabsorption, and/or those with malnutrition. More studies are needed to establish appropriate amounts of copper supplementation to replenish copper stores in deficient patients.

  17. Extrapulmonary Aspergillus infection in patients with CARD9 deficiency

    Science.gov (United States)

    Gazendam, Roel P.; Freeman, Alexandra F.; Hsu, Amy P.; Collar, Amanda L.; Sugui, Janyce A.; Drummond, Rebecca A.; Rongkavilit, Chokechai; Hoffman, Kevin; Henderson, Carolyn; Clark, Lily; Mezger, Markus; Swamydas, Muthulekha; Engeholm, Maik; Schüle, Rebecca; Neumayer, Bettina; Mikelis, Constantinos M.; Pittaluga, Stefania; Prasad, Vinod K.; Singh, Anurag; Milner, Joshua D.; Williams, Kelli W.; Lim, Jean K.; Kwon-Chung, Kyung J.; Holland, Steven M.; Hartl, Dominik; Kuijpers, Taco W.

    2016-01-01

    Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra-abdominal aspergillosis at age 25. Neither patient developed Aspergillus infection of the lungs. One patient had homozygous M1I CARD9 (caspase recruitment domain family member 9) mutation, while the other had homozygous Q295X CARD9 mutation; both patients lacked CARD9 protein expression. The patients had normal monocyte and Th17 cell numbers in peripheral blood, but their mononuclear cells exhibited impaired production of proinflammatory cytokines upon fungus-specific stimulation. Neutrophil phagocytosis, killing, and oxidative burst against Aspergillus fumigatus were intact, but neither patient accumulated neutrophils in infected tissue despite normal neutrophil numbers in peripheral blood. The neutrophil tissue accumulation defect was not caused by defective neutrophil-intrinsic chemotaxis, indicating that production of neutrophil chemoattractants in extrapulmonary tissue is impaired in CARD9 deficiency. Taken together, our results show that CARD9 deficiency is the first known inherited or acquired condition that predisposes to extrapulmonary Aspergillus infection with sparing of the lungs, associated with impaired neutrophil recruitment to the site of infection. PMID:27777981

  18. B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ.

    Science.gov (United States)

    Salzer, Elisabeth; Santos-Valente, Elisangela; Klaver, Stefanie; Ban, Sol A; Emminger, Wolfgang; Prengemann, Nina Kathrin; Garncarz, Wojciech; Müllauer, Leonhard; Kain, Renate; Boztug, Heidrun; Heitger, Andreas; Arbeiter, Klaus; Eitelberger, Franz; Seidel, Markus G; Holter, Wolfgang; Pollak, Arnold; Pickl, Winfried F; Förster-Waldl, Elisabeth; Boztug, Kaan

    2013-04-18

    Primary B-cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family suffering from recurrent infections and severe lupuslike autoimmunity. Immunophenotyping revealed progressive decrease of CD19(+) B cells, a defective class switch indicated by low numbers of IgM- and IgG-memory B cells, as well as increased numbers of CD21(low) B cells. Combined homozygosity mapping and exome sequencing identified a biallelic splice-site mutation in protein C kinase δ (PRKCD), causing the absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate was decreased, and mRNA levels of nuclear factor interleukin (IL)-6 and IL-6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B-cell deficiency with severe autoimmunity.

  19. Red cell pyruvate kinase deficiency in Southern Sardinia.

    Science.gov (United States)

    Perseu, L; Giagu, N; Satta, S; Sollaino, M C; Congiu, R; Galanello, R

    2010-12-15

    Pyruvate kinase (PK) deficiency is the most frequent red cell enzymatic defect responsible for hereditary non-spherocytic hemolytic anemia. The clinical picture is quite variable and the reasons of this variability have been only partially clarified. We report the clinical description and the extended molecular analysis in 3 PK deficient patients with clinical phenotype of variable severity. We studied the clinical and hematological aspects of 3 patients and analyzed the following genes: pyruvate kinase-R, glucose-6-phosphate-dehydrogenase, α-globin, uridindiphosphoglucuronil transferase and HFE. One patient (A) with a severe clinical picture resulted homozygote for exon 8 nt994A substitution, the other 2 (brothers) were compound heterozygotes for exon 8 nt994A and exon 11 nt1456T mutation. One of the two brothers with a more severe phenotype coinherited also had G6PD deficiency, while both had microcytosis due to the homozygosity for the non-deletional form of α-thalassemia ATG→ACG substitution at the initiation codon of the alpha2 globin gene. Our results suggest that extended molecular analysis is useful for studying how several interacting gene mutations contribute to the clinical variability of pyruvate kinase deficiency.

  20. Longer telomere length in COPD patients with α1-antitrypsin deficiency independent of lung function.

    Directory of Open Access Journals (Sweden)

    Aabida Saferali

    Full Text Available Oxidative stress is involved in the pathogenesis of airway obstruction in α1-antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in α1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 α1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from blood and DNA from lung tissue in a subset of 51 controls. We found that telomere length in the blood was significantly longer in α1-antitrypsin deficient COPD patients compared with control COPD patients (p = 1×10(-29. Telomere length was not related to lung function in α1-antitrypsin deficient patients (p = 0.3122 or in COPD controls (p = 0.1430. Although mean telomere length was significantly shorter in the blood when compared with the lungs (p = 0.0078, telomere length was correlated between the two tissue types (p = 0.0122. Our results indicate that telomere length is better preserved in α1-antitrypsin deficient COPD patients than in non-deficient patients. In addition, measurement of telomere length in the blood may be a suitable surrogate for measurement in the lung.

  1. Longer telomere length in COPD patients with α1-antitrypsin deficiency independent of lung function.

    Science.gov (United States)

    Saferali, Aabida; Lee, Jee; Sin, Don D; Rouhani, Farshid N; Brantly, Mark L; Sandford, Andrew J

    2014-01-01

    Oxidative stress is involved in the pathogenesis of airway obstruction in α1-antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in α1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 α1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from blood and DNA from lung tissue in a subset of 51 controls. We found that telomere length in the blood was significantly longer in α1-antitrypsin deficient COPD patients compared with control COPD patients (p = 1×10(-29)). Telomere length was not related to lung function in α1-antitrypsin deficient patients (p = 0.3122) or in COPD controls (p = 0.1430). Although mean telomere length was significantly shorter in the blood when compared with the lungs (p = 0.0078), telomere length was correlated between the two tissue types (p = 0.0122). Our results indicate that telomere length is better preserved in α1-antitrypsin deficient COPD patients than in non-deficient patients. In addition, measurement of telomere length in the blood may be a suitable surrogate for measurement in the lung.

  2. Essential fatty acid deficiency in patients with severe fat malabsorption

    DEFF Research Database (Denmark)

    Jeppesen, Palle B; Christensen, Michael Søberg; Høy, Carl-Erik;

    1997-01-01

    Essential fatty acid deficiency is commonly described in patients receiving parenteral nutrition, but the occurrence in patients with severe fat malabsorption not receiving parenteral nutrition is uncertain. One hundred twelve patients were grouped according to their degree of fat malabsorption...... proportion of patients with gastrointestinal diseases resulting in malabsorption of > 25-50% of dietary fat intake and not treated with parenteral nutrition have biochemical signs of essential fatty acid deficiency. The clinical effect of these changes are yet to be elucidated....

  3. Vitamin B12 deficiency and gastric histopathology in older patients

    Institute of Scientific and Technical Information of China (English)

    KR Dholakia; TS Dharmarajan; D Yadav; S Oiseth; EP Norkus; CS Pitchumoni

    2005-01-01

    AIM: To compare upper gastric endoscopic and histopathologic findings in older adults in the presence and absence of B12 deficiency.METHODS: A prospective analysis of upper gastric endoscopic and gastric histopathologic findings from 30 newly identified B12-deficient patients (11 males,19 females) and 16 controls with normal B12 status (6males, 10 females) was performed. For all subjects, the indication for upper endoscopy and gastric biopsy were unrelated to B12 status. A single pathologist, blinded to B12 status, processed and interpreted the biopsy samples. Endoscopic and histopathologic findings were correlated with age, gender, hematocrit (Hct), MCV and B12 status.RESULTS: The B12-deficient group had significantly lower mean serum B12 levels compared to the controls (P<0.00005) while their mean Hct, MCV and serum albumin levels were similar. Iron deficiency (ferritinbased) was present in 21% of B12-deficient patients and intrinsic factor antibodies were present in29% (5/17) of B12-deficient patients. The endoscopic findings revealed significantly different rates of gastritis and atrophy between the B12-deficient and control groups (P= 0.017).B12-deficient patients had significantly less superficial gastritis (62% vs 94%) and significantly more atrophic gastritis (28% vs 0%) as compared to the controls (P= 0.039). Intestinal metaplasia was similar in both groups. Helicobacter pyloriinfection rates were similar in the B12-deficient patients and controls (40% vs31%).CONCLUSION: Significantly different endoscopic findings and types of gastritis could often be observed in the presence and absence of B12 deficiency. Atrophy,based on endoscopy, and atrophic gastritis, based on histopathology, suggest the presence of B12 deficiency.Gastric histopathology is not influenced by the age,gender, Hct or MCV of the patients.

  4. Prevalence and hematological indicators of G6PD deficiency in malaria-infected patients

    Institute of Scientific and Technical Information of China (English)

    Manas Kotepui; Kwuntida Uthaisar; Bhukdee PhunPhuech; Nuoil Phiwklam

    2016-01-01

    Background:This study aimed to evaluate the prevalence and alteration of hematological parameters in malaria patients with a glucose-6-phosphate dehydrogenase (G6PD) deficiency,in the western region of Thailand,an endemic region for malaria.Methods:Data about patients with malaria hospitalized between 2013 and 2015 were collected.Clinical and sociodemographic characteristics such as age and gender,diagnosis on admission,and parasitological results were mined from medical records of the laboratory unit of the Phop Phra Hospital in Tak Province,Thailand.Venous blood samples were collected at the time of admission to hospital to determine G6PD deficiency by fluorescence spot test and detect malaria parasites by thick and thin film examination.Other data such as complete blood count and parasite density were also collected and analyzed.Results:Among the 245 malaria cases,28 (11.4 %) were diagnosed as Plasmodium falciparum infections and 217 cases (88.6 %) were diagnosed as P.vivax infections.Seventeen (6.9 %) patients had a G6PD deficiency and 228 (93.1%) patients did not have a G6PD deficiency.Prevalence of male patients with G6PD deficiency was higher than that of female patients (P < 0.05,OR =5.167).Among the patients with a G6PD deficiency,two (11.8 %) were infected with P.falciparum,while the remaining were infected with P.vivax.Malaria patients with a G6PD deficiency have higher monocyte counts (0.6 × 103/μL) than those without a G6PD deficiency (0.33 × 103/μL) (P< 0.05,OR=5.167).Univariate and multivariate analyses also confirmed that malaria patients with a G6PD deficiency have high monocyte counts.The association between G6PD status and monocyte counts was independent of age,gender,nationality,Plasmodium species,and parasite density (P < 0.005).Conclusion:This study showed a prevalence of G6PD deficiency in a malaria-endemic area.This study also supported the assertion that patients with G6PD-deficient red blood cells had no protection

  5. Oxidative stress induces mitochondrial fragmentation in frataxin-deficient cells

    Energy Technology Data Exchange (ETDEWEB)

    Lefevre, Sophie [Mitochondria, Metals and Oxidative Stress Laboratory, Institut Jacques Monod, CNRS-Universite Paris-Diderot, Sorbonne Paris Cite, 15 rue Helene Brion, 75205 Paris cedex 13 (France); ED515 UPMC, 4 place Jussieu 75005 Paris (France); Sliwa, Dominika [Mitochondria, Metals and Oxidative Stress Laboratory, Institut Jacques Monod, CNRS-Universite Paris-Diderot, Sorbonne Paris Cite, 15 rue Helene Brion, 75205 Paris cedex 13 (France); Rustin, Pierre [Inserm, U676, Physiopathology and Therapy of Mitochondrial Disease Laboratory, 75019 Paris (France); Universite Paris-Diderot, Faculte de Medecine Denis Diderot, IFR02 Paris (France); Camadro, Jean-Michel [Mitochondria, Metals and Oxidative Stress Laboratory, Institut Jacques Monod, CNRS-Universite Paris-Diderot, Sorbonne Paris Cite, 15 rue Helene Brion, 75205 Paris cedex 13 (France); Santos, Renata, E-mail: santos.renata@ijm.univ-paris-diderot.fr [Mitochondria, Metals and Oxidative Stress Laboratory, Institut Jacques Monod, CNRS-Universite Paris-Diderot, Sorbonne Paris Cite, 15 rue Helene Brion, 75205 Paris cedex 13 (France)

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Yeast frataxin-deficiency leads to increased proportion of fragmented mitochondria. Black-Right-Pointing-Pointer Oxidative stress induces complete mitochondrial fragmentation in {Delta}yfh1 cells. Black-Right-Pointing-Pointer Oxidative stress increases mitochondrial fragmentation in patient fibroblasts. Black-Right-Pointing-Pointer Inhibition of mitochondrial fission in {Delta}yfh1 induces oxidative stress resistance. -- Abstract: Friedreich ataxia (FA) is the most common recessive neurodegenerative disease. It is caused by deficiency in mitochondrial frataxin, which participates in iron-sulfur cluster assembly. Yeast cells lacking frataxin ({Delta}yfh1 mutant) showed an increased proportion of fragmented mitochondria compared to wild-type. In addition, oxidative stress induced complete fragmentation of mitochondria in {Delta}yfh1 cells. Genetically controlled inhibition of mitochondrial fission in these cells led to increased resistance to oxidative stress. Here we present evidence that in yeast frataxin-deficiency interferes with mitochondrial dynamics, which might therefore be relevant for the pathophysiology of FA.

  6. Purine nucleoside phosphorylase deficiency in two unrelated Saudi patients

    OpenAIRE

    Alangari, Abdullah; Al-Harbi, Abdullah; Al-Ghonaium, Abdulaziz; Santisteban, Ines; Hershfield, Michael

    2009-01-01

    Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive metabolic disorder that results in combined immunodeficiency, neurologic dysfunction and autoimmunity. PNP deficiency has never been reported from Saudi Arabia or in patients with an Arabic ethnic background. We report on two Saudi girls with PNP deficiency. Both showed severe lymphopenia and neurological involvement. Sequencing of the PNP gene of one girl revealed a novel missense mutation Pro146>Leu in exon 4 due...

  7. Serum zinc levels in patients with iron deficiency anemia and its association with symptoms of iron deficiency anemia.

    Science.gov (United States)

    Kelkitli, Engin; Ozturk, Nurinnisa; Aslan, Nevin Alayvaz; Kilic-Baygutalp, Nurcan; Bayraktutan, Zafer; Kurt, Nezahat; Bakan, Nuri; Bakan, Ebubekir

    2016-04-01

    Iron deficiency anemia (IDA) is a major public health problem especially in underdeveloped and developing countries. Zinc is the co-factor of several enzymes and plays a role in iron metabolism, so zinc deficiency is associated with IDA. In this study, it was aimed to investigate the relationship of symptoms of IDA and zinc deficiency in adult IDA patients. The study included 43 IDA patients and 43 healthy control subjects. All patients were asked to provide a detailed history and were subjected to a physical examination. The hematological parameters evaluated included hemoglobin (Hb); hematocrit (Ht); red blood cell (erythrocyte) count (RBC); and red cell indices mean corpuscular volume (MCV), mean corpuscular hemoglobin (МСН), mean corpuscular hemoglobin concentration (МСНС), and red cell distribution width (RDW). Anemia was defined according to the criteria defined by the World Health Organization (WHO). Serum zinc levels were measured in the flame unit of atomic absorption spectrophotometer. Symptoms attributed to iron deficiency or depletion, defined as fatigue, cardiopulmonary symptoms, mental manifestations, epithelial manifestations, and neuromuscular symptoms, were also recorded and categorized. Serum zinc levels were lower in anemic patients (103.51 ± 34.64 μ/dL) than in the control subjects (256.92 ± 88.54 μ/dL; zinc level zinc level > 100 μ/dL. When the serum zinc level was compared with pica, no statistically significant correlation was found (p = 0.742). Zinc is a trace element that functions in several processes in the body, and zinc deficiency aggravates IDA symptoms. Measurement of zinc levels and supplementation if necessary should be considered for IDA patients.

  8. Limbal Stem Cell Deficiency: Current Treatment Options and Emerging Therapies

    Directory of Open Access Journals (Sweden)

    Michel Haagdorens

    2016-01-01

    Full Text Available Severe ocular surface disease can result in limbal stem cell deficiency (LSCD, a condition leading to decreased visual acuity, photophobia, and ocular pain. To restore the ocular surface in advanced stem cell deficient corneas, an autologous or allogenic limbal stem cell transplantation is performed. In recent years, the risk of secondary LSCD due to removal of large limbal grafts has been significantly reduced by the optimization of cultivated limbal epithelial transplantation (CLET. Despite the great successes of CLET, there still is room for improvement as overall success rate is 70% and visual acuity often remains suboptimal after successful transplantation. Simple limbal epithelial transplantation reports higher success rates but has not been performed in as many patients yet. This review focuses on limbal epithelial stem cells and the pathophysiology of LSCD. State-of-the-art therapeutic management of LSCD is described, and new and evolving techniques in ocular surface regeneration are being discussed, in particular, advantages and disadvantages of alternative cell scaffolds and cell sources for cell based ocular surface reconstruction.

  9. Severe cutaneous human papilloma virus infection associated with Natural Killer cell deficiency following stem cell transplantation for severe combined immunodeficiency

    Science.gov (United States)

    Kamili, Qurat-ul-Ain; Seeborg, Filiz O; Saxena, Kapil; Nicholas, Sarah K; Banerjee, Pinaki P; Angelo, Laura S; Mace, Emily M; Forbes, Lisa R; Martinez, Caridad; Wright, Teresa S; Orange, Jordan S.; Hanson, Imelda Celine

    2016-01-01

    Capsule Summary The authors identify Natural Killer cell deficiency in post-transplant severe combined immunodeficiency patients who developed severe human papilloma virus infections as a long term complication. PMID:25159470

  10. Optic neuropathy in a patient with pyruvate dehydrogenase deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Small, Juan E. [Massachusetts General Hospital and Harvard Medical School, Department of Radiology, Boston, MA (United States); Gonzalez, Guido E. [Massachusetts Eye and Ear Infirmary and Harvard Medical School, Department of Radiology, Boston, MA (United States); Clinica Alemana de Santiago, Departmento de Imagenes, Santiago (Chile); Nagao, Karina E.; Walton, David S. [Massachusetts Eye and Ear Infirmary and Harvard Medical School, Department of Ophthalmology, Boston, MA (United States); Caruso, Paul A. [Massachusetts Eye and Ear Infirmary and Harvard Medical School, Department of Radiology, Boston, MA (United States)

    2009-10-15

    Pyruvate dehydrogenase (PDH) deficiency is a genetic disorder of mitochondrial metabolism. The clinical manifestations range from severe neonatal lactic acidosis to chronic neurodegeneration. Optic neuropathy is an uncommon clinical sequela and the imaging findings of optic neuropathy in these patients have not previously been described. We present a patient with PDH deficiency with bilateral decreased vision in whom MRI demonstrated bilateral optic neuropathy and chiasmopathy. (orig.)

  11. Diagnosis and treatment of iron deficiency in patients with heart failure: expert position paper from French cardiologists.

    Science.gov (United States)

    Cohen-Solal, Alain; Leclercq, Christophe; Mebazaa, Alexandre; De Groote, Pascal; Damy, Thibaud; Isnard, Richard; Galinier, Michel

    2014-10-01

    The prevalence of iron deficiency is high -even in the absence of anaemia- in patients with chronic heart failure (HF). Although iron deficiency is easily diagnosed with two biomarkers (serum ferritin and transferrin saturation), it is underdiagnosed in patients with HF. Iron is not only necessary for red blood cells, but also for cells in tissues with high-energy demands (heart, muscle, brain). Even before the onset of anaemia, HF patients with iron deficiency have decreased physical and cognitive performances and a poorer quality of life. Moreover, iron deficiency is a risk factor, independent of anaemia, of unfavourable outcome (death or heart transplantation) in patients with chronic HF. Several randomized controlled studies have shown improvement in exercise capacity, New York Heart Association functional class and quality of life after correction of iron deficiency. The results of these clinical trials, which are supported by European guidelines, suggest considering iron deficiency in HF as a possible therapeutic target.

  12. Iron deficiency anemia: online methods of patient education

    Directory of Open Access Journals (Sweden)

    Doiniţa Crişan

    2011-06-01

    Full Text Available The authors present some of the most important online patient education methods in English on iron deficiency anemia (easy-to-read articles, information leaflets, easy-to-understand fact sheets, newsletters, patient page, glossaries, frequently asked questions, quizzes, forums, blogs, and patient stories.

  13. Micronutrient deficiencies in patients with chronic atrophic autoimmune gastritis: A review

    Science.gov (United States)

    Cavalcoli, Federica; Zilli, Alessandra; Conte, Dario; Massironi, Sara

    2017-01-01

    Chronic atrophic autoimmune gastritis (CAAG) is an organ-specific autoimmune disease characterized by an immune response, which is directed towards the parietal cells and intrinsic factor of the gastric body and fundus and leads to hypochlorhydria, hypergastrinemia and inadequate production of the intrinsic factor. As a result, the stomach’s secretion of essential substances, such as hydrochloric acid and intrinsic factor, is reduced, leading to digestive impairments. The most common is vitamin B12 deficiency, which results in a megaloblastic anemia and iron malabsorption, leading to iron deficiency anemia. However, in the last years the deficiency of several other vitamins and micronutrients, such as vitamin C, vitamin D, folic acid and calcium, has been increasingly described in patients with CAAG. In addition the occurrence of multiple vitamin deficiencies may lead to severe hematological, neurological and skeletal manifestations in CAAG patients and highlights the importance of an integrated evaluation of these patients. Nevertheless, the nutritional deficiencies in CAAG are largely understudied. We have investigated the frequency and associated features of nutritional deficiencies in CAAG in order to focus on any deficit that may be clinically significant, but relatively easy to correct. This descriptive review updates and summarizes the literature on different nutrient deficiencies in CAAG in order to optimize the treatment and the follow-up of patients affected with CAAG. PMID:28216963

  14. Secondary Carnitine Deficiency in Dialysis Patients: Shall We Supplement It?

    Directory of Open Access Journals (Sweden)

    Ronald J.A. Wanders

    2016-07-01

    Full Text Available Carnitine, essential for fatty acid β-oxidation, is obtained from diet and through de novo biosynthesis. The organic cation/carnitine transporter 2 (OCTN2 facilitates carnitine cellular transport and kidney resorption. Carnitine depletion occurs in OCTN2-deficient patients, with serious clinical complications including cardiomyopathy, myopathy, and hypoketotic hypoglycaemia. Neonatal screening can detect OCTN2 deficiency. OCTN2-deficiency is also known as primary carnitine deficiency. Carnitine deficiency may result from fatty acid β-oxidation disorders, which are diagnosed via plasma acylcarnitine profiling, but also under other conditions including haemodialysis. Given the importance of the kidney in maintaining carnitine homeostasis, it is not unexpected that longterm haemodialysis treatment is associated with the development of secondary carnitine deficiency, characterised by low endogenous L-carnitine levels and accumulation of deleterious medium and long- chain acylcarnitines. These alterations in carnitine pool composition have been implicated in a number of dialysis-related disorders, including erythropoietin-resistant renal anaemia. The association between erythropoietin resistance and carnitine levels has been demonstrated, with the proportion of medium and long-chain acylcarnitines within the total plasma carnitine pool positively correlated with erythropoietin resistance. Recent research has demonstrated that carnitine supplementation results in a significant reduction in erythropoietin dose requirements in patients with erythropoietin-resistant anaemia. Few studies have been conducted assessing the treatment of carnitine deficiency and haemodialysisrelated cardiac complications, particularly in children. Thus, a study was recently conducted which showed that intravenous carnitine in children receiving haemodialysis significantly increased plasma carnitine.

  15. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans

    OpenAIRE

    Warnatz, Klaus; Salzer, Ulrich; Rizzi, Marta; Fischer, Beate; Gutenberger, Sylvia; Böhm, Joachim; Kienzler, Anne-Kathrin; Pan-Hammarström, Qiang; Hammarström, Lennart; Rakhmanov, Mirzokhid; Schlesier, Michael; Grimbacher, Bodo; Peter, Hans-Hartmut; Eibel, Hermann

    2009-01-01

    B-cell survival depends on signals induced by B-cell activating factor (BAFF) binding to its receptor (BAFF-R). In mice, mutations in BAFF or BAFF-R cause B-cell lymphopenia and antibody deficiency. Analyzing BAFF-R expression and BAFF-binding to B cells in common variable immunodeficiency (CVID) patients, we identified two siblings carrying a homozygous deletion in the BAFF-R gene. Removing most of the BAFF-R transmembrane part, the deletion precludes BAFF-R expression. Without BAFF-R, B-cel...

  16. Replication fork stability confers chemoresistance in BRCA-deficient cells

    DEFF Research Database (Denmark)

    Chaudhuri, Arnab Ray; Callen, Elsa; Ding, Xia;

    2016-01-01

    Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3....../4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11...... nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficient tumour cells that do not develop Brca2 reversion mutations...

  17. A Patient with G6PD Deficiency and Falciparum Malaria

    Directory of Open Access Journals (Sweden)

    Y Fagani

    2007-04-01

    Full Text Available A 20 year old male patient from Afghanistan with a history of G6PD deficiency and clinical manifestations of malaria referred to Bou-Ali Hospital in Tehran, capital of Iran. Giemsa stained thick blood films revealed an infection of Plasmodium falciparum with 33700 parasite/μL of blood. The patient was successfully treated according to malaria treatment guideline.

  18. HMG-CoA lyase (HL) gene: Cloning and characterization of the 5{prime} end of the mouse gene, gene targeting in ES cells, and demonstration of large deletions in three HL-deficient patients

    Energy Technology Data Exchange (ETDEWEB)

    Wang, S.; Robert, M.F.; Mitchell, G.A. [Hopital Sainte-Justine, Quebec (Canada)] [and others

    1994-09-01

    3-hydroxy-3-methylglutaryl CoA lyase (HL) is a mitochondrial matrix enzyme which catalyzes the last step of leucine catabolism and of ketogenesis. Autosomal recessive HL deficiency in humans results in episodes of hypoglycemia and coma. We are interested in the pathophysiology of HL deficiency as a model for both amino acid and fatty acid inborn errors. We have cloned the human and mouse HL genes. In order to analyze the 5{prime} nontranslated region of mouse HL gene, we cloned and sequenced a 1.8 kb fragment containing the 5{prime} extremity including exon 1 and about 1.6 kb of 5{prime} nontranslated sequence. The region surrounding exon 1 is CpG-rich (66.4%). Using the criteria of West, the Observed/Expected ratio for CpG dinucleotides is 0.7 ({ge}0.6 is consistent with a CpG island). We are carrying out primer extension and RNase protection experiments to determine the transcription initiation site. We constructed a gene targeting vector by introducing the neomycin resistance gene into exon 2 of a 7.5 kb genomic subclone of the mouse HL gene. Targeting was performed by electroporating 10 mg linearized vector into 10{sup 7} ES cells and selecting for 12 days with G418. 5/228 colonies (2.2%) had homologous recombination as shown by PCR screening and Southern analysis. We are microinjecting the 5 targeted clones into blastocysts to create an HL-deficient mouse. To date we have obtained two chimeras with contributions of 95% and 55% from 129, by coat color estimates. Three of 27 (11%) of the HL-deficient patients studied were suggested by genomic Southern analysis to be homozygous for large intragenic deletions. We confirmed this and defined the boundaries using exonic PCR.

  19. [The frequency and development of tissue iron deficiency in 6 iron deficiency anemia patients with plummer-vinson syndrome].

    Science.gov (United States)

    Uchida, T; Matsuno, M; Ide, M; Kawachi, Y

    1998-11-01

    The physical signs of tissue iron deficiency include smooth and red tongue, angular stomatitis, koilonychia, and pica. The incidence of these conditions is unknown in Japan. We evaluated the frequency and development of tissue iron deficiency in 353 patients with iron deficiency anemia. The frequency of tissue iron deficiency was 6.8%; papillary atrophy of the tongue, 5.4%; abnormal nails, 5.4%; angular stomatitis, 1.1%; Plummer-Vinson syndrome, 1.7%; and pica, 0.06%. These findings were compared with the date collected by Wintrobe and Beveridge. The development and incidence of tissue iron deficiency correlated significantly with the severity of iron deficiency anemia.

  20. Selenoprotein O deficiencies suppress chondrogenic differentiation of ATDC5 cells.

    Science.gov (United States)

    Yan, Jidong; Fei, Yao; Han, Yan; Lu, Shemin

    2016-10-01

    Selenoprotein O (Sel O) is a selenium-containing protein, but its function is still unclear. In the present study, we observed that the mRNA and protein expression levels of Sel O increased during chondrogenic induction of ATDC5 cells. The effects of Sel O on chondrocyte differentiation were then examined through shRNA-mediated gene silencing technique. The expression of Sel O was significantly suppressed at both mRNA and protein levels in a stable cell line transfected with a Sel O-specific target shRNA construct. Thereafter, we demonstrated that Sel O deficiencies suppress chondrogenic differentiation of ATDC5 cells. Sel O deficiencies inhibited expression of chondrogenic gene Sox9, Col II, and aggrecan. Sel O-deficient cells also accumulated a few cartilage glycosaminoglycans (GAGs) and decreased the activity of alkaline phosphatase (ALP). In addition, Sel O deficiencies inhibited chondrocyte proliferation through delayed cell cycle progression by suppression of cyclin D1 expression. Moreover, Sel O deficiencies induced chondrocyte death through cell apoptosis. In summary, we describe the expression patterns and the essential roles of Sel O in chondrocyte viability, proliferation, and chondrogenic differentiation. Additionally, Sel O deficiency-mediated impaired chondrogenesis may illustrate the mechanisms of Se deficiency in the pathophysiological process of the endemic osteoarthropathy.

  1. CD4CD8αα lymphocytes, a novel human regulatory T cell subset induced by colonic bacteria and deficient in patients with inflammatory bowel disease.

    Directory of Open Access Journals (Sweden)

    Guillaume Sarrabayrouse

    2014-04-01

    Full Text Available How the microbiota affects health and disease is a crucial question. In mice, gut Clostridium bacteria are potent inducers of colonic interleukin (IL-10-producing Foxp3 regulatory T cells (Treg, which play key roles in the prevention of colitis and in systemic immunity. In humans, although gut microbiota dysbiosis is associated with immune disorders, the underlying mechanism remains unknown. In contrast with mice, the contribution of Foxp3 Treg in colitis prevention has been questioned, suggesting that other compensatory regulatory cells or mechanisms may exist. Here we addressed the regulatory role of the CD4CD8 T cells whose presence had been reported in the intestinal mucosa and blood. Using colonic lamina propria lymphocytes (LPL and peripheral blood lymphocytes (PBL from healthy individuals, and those with colon cancer and irritable bowel disease (IBD, we demonstrated that CD4CD8αα (DP8α T lymphocytes expressed most of the regulatory markers and functions of Foxp3 Treg and secreted IL-10. Strikingly, DP8α LPL and PBL exhibited a highly skewed repertoire toward the recognition of Faecalibacterium prausnitzii, a major Clostridium species of the human gut microbiota, which is decreased in patients with IBD. Furthermore, the frequencies of DP8α PBL and colonic LPL were lower in patients with IBD than in healthy donors and in the healthy mucosa of patients with colon cancer, respectively. Moreover, PBL and LPL from most patients with active IBD failed to respond to F. prausnitzii in contrast to PBL and LPL from patients in remission and/or healthy donors. These data (i uncover a Clostridium-specific IL-10-secreting Treg subset present in the human colonic LP and blood, (ii identify F. prausnitzii as a major inducer of these Treg, (iii argue that these cells contribute to the control or prevention of colitis, opening new diagnostic and therapeutic strategies for IBD, and (iv provide new tools to address the systemic impact of both these Treg

  2. Deficiencies

    Data.gov (United States)

    U.S. Department of Health & Human Services — A list of all deficiencies currently listed on Nursing Home Compare, including the nursing home that received the deficiency, the associated inspection date,...

  3. Development of a human mitochondrial oligonucleotide microarray (h-MitoArray and gene expression analysis of fibroblast cell lines from 13 patients with isolated F1Fo ATP synthase deficiency

    Directory of Open Access Journals (Sweden)

    Hansíková Hana

    2008-01-01

    Full Text Available Abstract Background To strengthen research and differential diagnostics of mitochondrial disorders, we constructed and validated an oligonucleotide microarray (h-MitoArray allowing expression analysis of 1632 human genes involved in mitochondrial biology, cell cycle regulation, signal transduction and apoptosis. Using h-MitoArray we analyzed gene expression profiles in 9 control and 13 fibroblast cell lines from patients with F1Fo ATP synthase deficiency consisting of 2 patients with mt9205ΔTA microdeletion and a genetically heterogeneous group of 11 patients with not yet characterized nuclear defects. Analysing gene expression profiles, we attempted to classify patients into expected defect specific subgroups, and subsequently reveal group specific compensatory changes, identify potential phenotype causing pathways and define candidate disease causing genes. Results Molecular studies, in combination with unsupervised clustering methods, defined three subgroups of patient cell lines – M group with mtDNA mutation and N1 and N2 groups with nuclear defect. Comparison of expression profiles and functional annotation, gene enrichment and pathway analyses of differentially expressed genes revealed in the M group a transcription profile suggestive of synchronized suppression of mitochondrial biogenesis and G1/S arrest. The N1 group showed elevated expression of complex I and reduced expression of complexes III, V, and V-type ATP synthase subunit genes, reduced expression of genes involved in phosphorylation dependent signaling along MAPK, Jak-STAT, JNK, and p38 MAP kinase pathways, signs of activated apoptosis and oxidative stress resembling phenotype of premature senescent fibroblasts. No specific functionally meaningful changes, except of signs of activated apoptosis, were detected in the N2 group. Evaluation of individual gene expression profiles confirmed already known ATP6/ATP8 defect in patients from the M group and indicated several candidate

  4. Iron deficiency anemia in patients with inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    Goldberg ND

    2013-06-01

    Full Text Available Neil D Goldberg Emeritus Chief of Gastroenterology, University of Maryland St. Joseph Medical Center, Towson, MD, USA Abstract: Iron deficiency anemia is the most common form of anemia worldwide, caused by poor iron intake, chronic blood loss, or impaired absorption. Patients with inflammatory bowel disease (IBD are increasingly likely to have iron deficiency anemia, with an estimated prevalence of 36%–76%. Detection of iron deficiency is problematic as outward signs and symptoms are not always present. Iron deficiency can have a significant impact on a patient's quality of life, necessitating prompt management and treatment. Effective treatment includes identifying and treating the underlying cause and initiating iron replacement therapy with either oral or intravenous iron. Numerous formulations for oral iron are available, with ferrous fumarate, sulfate, and gluconate being the most commonly prescribed. Available intravenous formulations include iron dextran, iron sucrose, ferric gluconate, and ferumoxytol. Low-molecular weight iron dextran and iron sucrose have been shown to be safe, efficacious, and effective in a host of gastrointestinal disorders. Ferumoxytol is the newest US Food and Drug Administration-approved intravenous iron therapy, indicated for iron deficiency anemia in adults with chronic kidney disease. Ferumoxytol is also being investigated in Phase 3 studies for the treatment of iron deficiency anemia in patients without chronic kidney disease, including subgroups with IBD. A review of the efficacy and safety of iron replacement in IBD, therapeutic considerations, and recommendations for the practicing gastroenterologist are presented. Keywords: anemia, inflammatory bowel disease, intravenous iron, iron deficiency, oral iron, therapy

  5. Awareness of vitamin D deficiency among at-risk patients

    Directory of Open Access Journals (Sweden)

    Alemu Esubalew

    2012-01-01

    Full Text Available Abstract Background Vitamin D deficiency is a significant problem for a growing proportion of the UK population. Individuals with dark or covered skin are at particularly high risk due to ethno-cultural, environmental and genetic factors. We assessed the level of awareness of vitamin D deficiency among at-risk patients in order to identify groups most in need of education. Findings A cross-sectional survey using a piloted questionnaire was conducted among consecutive at-risk patients without a diagnosis of Vitamin D deficiency arriving at a large inner city general practice in the North West of England over a five day period. The survey was completed by 221 patients. The mean age was 35 years. 28% of them (n = 61 had never heard about vitamin D. Older patients (p = 0.003 were less likely to have heard about vitamin D. 54% of participants were unaware of the commonest symptoms of vitamin D deficiency. 34% did not expose their skin other than their face in the last one year, and 11% did not include vitamin D rich foods in their diet. Conclusion The majority of at-risk patients are aware of vitamin D; nevertheless, there is a significant lack of knowledge among older people, who have higher morbidity. A programme of targeted education of the at-risk population is recommended.

  6. Iron deficiency in Helicobacter pylori infected patients in Baghdad

    Directory of Open Access Journals (Sweden)

    Jenan A. Muhsin

    2011-12-01

    Full Text Available Objectives: Recent studies have suggested an association of Helicobacter pylori and iron deficiency (ID.Materials and methods: To examine an association between H.pylori infection and ID, blood sampling and a data collectionsurvey were performed in 78 H.pylori infected patients and 22 healthy subjects as control. Serum ferritin and ironwere measured by ELISA and direct enzymatic method techniques respectively.Results: The result showed that 24 of the patients (30.7% have serum ferritin and iron concentrations below the normalrange indicating iron deficiency, with no significantly difference between women and men. ID was more pronounced inpatients with stomach ulcer (58.3% than those without stomach ulcer (41.7% respectively.Conclusions: The conclusion was that H.pylori infection might have a role in iron deficiency and subsequently iron deficiencyanemia. J Microbiol Infect Dis 2011; 1(3:114-117

  7. [TREATMENT OF REFRACTORY RHINOSINUSITIS IN PATIENTS WITH IGE-DEFICIENCY].

    Science.gov (United States)

    Tsaryk, V V

    2014-12-01

    The most significant:clinical manifestation of isolated IgE-deficiency is chronic and recurrent sinopulmonary diseases. A few papers about treatment of IgE-deficiency, which shows the effect of intravenous immunoglobulin (IVIG) at a dose of 300-400 mg/kg was found. The results of such studies has level of evidence D. In our study we included IgE-deficient patients with refractory rhinosinusitis, which confirmed the diagnosis on the basis of at least two-fold examination with an interval of 1 month in the absence of obvious causes of secondary immunosuppression. In the study group included 82 patients (49 female, 34 male) aged 18 to 61, with the refractory rhinosinusitis combined with deficient IgE, total--33 (group 1) and partial--4 patients (group 2). In 22 patients (26.8%) immunoglobulin E deficiency combined with decreased serum concentrations of IgG sub-classes and other classes. The control group are 33 patients with refractory rhinosinusitis who refused IVIG. Immunoglobulinl intramuscularly administered at a dose of 0.3-0.4 ml/kg body weight for 3 days in a row 2-3 courses at intervals of 2-3 weeks. In the absence of clinical effect of said treatment for 2-3 months, we used IVIG at a dose of 200-400 mg/kg 1 month 1-3 courses with the consent of the patient. The clinical ohserved in 49 patients (87%), which was to reduce the number, severity and duration of exacerhations course rhinosinusitis. After IVIG were marked with significantly higher serum concentrations of total IgE in patients with total and partial deficiency compared with the results of intramuscular immunoglobulin. During treatment significantly increased serum concentration not only IgE (from 3.05 IU/ml ± 1.21 IU/ml to 12.5/IU/ml ± 1.86 IU/ml in total deficit; P rhinosinusitis deficient IgE. This clinical and immunological effects we regarded as the influence of small doses of immunoglobulin to Fc-receptors on B lymphocytes mediated by regulatory mechanism of antibody production (Bayry J. et al).

  8. Copper deficiency in patients with cystinosis with cysteamine toxicity

    DEFF Research Database (Denmark)

    Besouw, Martine T P; Schneider, Jerry; Janssen, Mirian C;

    2013-01-01

    To assess whether copper deficiency plays a role in the recently described cysteamine toxicity in patients with cystinosis, and to examine whether polymorphisms in copper transporters, lysyl oxidase, and/or type I procollagen genes could be responsible for the occurrence of cysteamine toxicity in...

  9. Neutropenia in Patients with Primary Antibody Deficiency Disorders

    Directory of Open Access Journals (Sweden)

    "Nima Rezaei

    2004-06-01

    Neutropenia may occur in any of the primary immunodeficiency disorders. Persistent or severe infections always pose a supposition, which deserves further evaluation for detecting an underlying immune deficiency syndrome and neutropenia, since a delay in diagnosis may result in a serious organ damage or even death of the patient.

  10. Iron deficiency in patients with idiopathic pulmonary arterial hypertension

    NARCIS (Netherlands)

    van Empel, Vanessa P M; Lee, Joy; Williams, Trevor J; Kaye, David M

    2014-01-01

    BACKGROUND: Iron deficiency has been reported to be highly prevalent in idiopathic pulmonary arterial hypertension (iPAH) patients, with the potential to influence cardiac performance, pulmonary artery pressures and the pulmonary vascular response to hypoxia. METHODS: Iron status was evaluated in 29

  11. Development and implementation of a novel assay for L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) in cell lysates: L-2-HGDH deficiency in 15 patients with L-2-hydroxyglutaric aciduria.

    Science.gov (United States)

    Kranendijk, M; Salomons, G S; Gibson, K M; Aktuglu-Zeybek, C; Bekri, S; Christensen, E; Clarke, J; Hahn, A; Korman, S H; Mejaski-Bosnjak, V; Superti-Furga, A; Vianey-Saban, C; van der Knaap, M S; Jakobs, C; Struys, E A

    2009-12-01

    L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by mutations in the gene encoding L-2-hydroxyglutarate dehydrogenase. An assay to evaluate L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) activity in fibroblast, lymphoblast and/or lymphocyte lysates has hitherto been unavailable. We developed an L-2-HGDH enzyme assay in cell lysates based on the conversion of stable-isotope-labelled L-2-hydroxyglutarate to 2-ketoglutarate, which is converted into L-glutamate in situ. The formation of stable isotope labelled L-glutamate is therefore a direct measure of L-2-HGDH activity, and this product is detected by liquid chromatography-tandem mass spectrometry. A deficiency of L-2-HGDH activity was detected in cell lysates from 15 out of 15 L-2-HGA patients. Therefore, this specific assay confirmed the diagnosis unambiguously affirming the relationship between molecular and biochemical observations. Residual activity was detected in cells derived from one L-2-HGA patient. The L-2-HGDH assay will be valuable for examining in vitro riboflavin/FAD therapy to rescue L-2-HGDH activity.

  12. Severe lactic acidosis due to thiamine deficiency in a patient with B-cell leukemia/lymphoma on total parenteral nutrition during high-dose methotrexate therapy.

    Science.gov (United States)

    Svahn, Johanna; Schiaffino, Maria Cristina; Caruso, Ubaldo; Calvillo, Michaela; Minniti, Giuseppe; Dufour, Carlo

    2003-12-01

    An 11-month-old girl with B-cell leukemia/lymphoma developed profound lethargy due to severe lactic acidosis during chemotherapy and total parenteral nutrition (TPN). Initial treatment with NaHCO3 was ineffective. Treatment with a vitamin cocktail (OH-cobalamin, pyridoxine, thiamine, riboflavine, biotin, carnitine) at pharmacologic doses rapidly improved the child's clinical and laboratory status. Lactic acidosis was caused by an impairment of pyruvate dehydrogenase complex, which was due to lack of its necessary cofactor thiamine in the TPN. This case report indicates that lactic acidosis may be a front-line diagnosis in patients on TPN with lethargy and outlines the need for monitoring thiamine supply in TPN.

  13. Vitamin D Deficiency in Patients with Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Suzan M. Attar

    2013-01-01

    Full Text Available Objectives: Hypovitaminosis D is common in the general population. Many studies that have been conducted to show the association between vitamin D deficiency and systemic lupus erythematosus (SLE reveal that deficiencies in vitamin D are common in this group of patients. Our aim was to study the relationship between 25(OHD and disease activity in patients with SLE.Methods: Retrospective cohort study of patients with SLE who were followed up at King Abdulaziz University Hospital, Jeddah, from January 2007 to November 2010. Demographic and clinical data were recorded and the 25(OHD levels of the patients were measured. Chi square tests, Student’s t-test, ANOVA and Pearson tests were used for data analysis. ANOVA test was followed by Bonferroni correction. A p-value <0.05 was considered significant.Results: Ninety-five patients with SLE were enrolled in the study. The levels of 25(OHD were significantly lower in patients with active SLE (n=41; 43% than in those with inactive disease (n=54; 57%; p=0.04. The mean (SD levels were 22.3 (14 nmol/L for patients with active disease against 25.0 (14 nmol/L for patients with inactive SLE. No correlation was detected between 25(OH D levels and disease activity score evaluated by SLEDAI-2K. By Pearson correlation, a significant negative correlation existed between 25(OH D and anti ds-DNA (r=-0.38; p<0.001; a positive correlation existed between 25(OHD levels and C4 (r=0.25; p=0.25. By chi square testing, azathioprine treatment (OR=3.5, low C4 (OR= 2.23, low C3 (OR=1.92, and active disease (OR=1.6 were associated with 25(OHD deficiency in SLE patients.Conclusion: Vitamin D deficiency is frequent in patients with SLE. Patients with SLE have a higher risk of developing 25(OHD deficiency in the presence of low serum C3 and C4 levels, and high anti-dsDNA levels.

  14. Prevalence of vitamin D deficiency in human immunodeficiency virus-infected patients

    Directory of Open Access Journals (Sweden)

    V Fridman

    2012-11-01

    Full Text Available Purpose of the study: Vitamin D deficiency in the adults could produce osteomalacia, secondary hyperparathyroidism with bone loss and increased risk of fractures. An increased prevalence of osteopenia, osteoporosis, decreased bone density, vitamin D deficiency and increased risk of fracture was found in HIV-positive patients. A study performed in Buenos Aires, Argentina that included non-HIV-infected adult patients showed 15% prevalence of vitamin D deficiency in winter and 0% prevalence in summer. There is no local data published of vitamin D deficiency in HIV-positive populations. The aim of the study is to determinate the prevalence of vitamin deficiency in our HIV-positive population receiving HAART. Methods: An observational, retrospective study was performed. We reviewed the clinical charts of the HIV-positive adult patients attending the infectious disease clinic. We collected data of vitamin D, parathormone and beta cross laps value; we recorded if the test was performed in winter or summer. We considered vitamin D deficiency if<10 ng/ml. We recorded age, sex, comorbidities (diabetes mellitus, renal failure, hepatic failure, HBV and/or HCV coinfection, menopause, malignancy and metabolic syndrome, months since HIV diagnosis, CD4 count, viral load and HAART. Summary of results: 60 patients were included, 49 (65% of whom were male. Mean age was 49.15 years. Mean time from diagnosis was 112 months. Mean CD4 count was 548 cells/mm3 and 6.6% presented CD4 <200; 83.3% had viral load <50 copies/mm3. All patients were on HAART; 50% received efavirenz, 65% received tenofovir and 11.6% recived atazanavir. Mean vitamin D value was 23.58 ng/ml (5–66.5 ng/ml. In winter, 15.3% of the patients had <10 ng/ml of vitamin D and mean value was 24.16 ng/ml (10–40 ng/ml. Although the mean value in summer was 25.8 ng/ml (11.6–66 ng/ml 10% of the patients had vitamin D deficiency. PTH value was abnormal in 31.6% of patients and beta cross laps was

  15. Prevalence of nutritional deficiency in patients with pulmonary tuberculosis

    Directory of Open Access Journals (Sweden)

    Silvana Gomes Nunes Piva

    2013-06-01

    Full Text Available OBJECTIVE: To determine the prevalence of nutritional deficiency among patients with pulmonary tuberculosis. METHODS: This was a cross-sectional study using data obtained from the Brazilian Case Registry Database and from the medical records of patients diagnosed with pulmonary tuberculosis (15-59 years of age residing in one of the municipalities that make up the 16th Regional Health District of the state of Bahia. We calculated the incidence, lethality, and mortality rates, as well as the prevalence of nutritional deficiency, as evaluated by body mass index. Demographic, social, clinical, and epidemiological data were collected. RESULTS: Of the 72 confirmed cases of tuberculosis, 59 (81.9% were in males, and 21 (29.2% of the patients were in the 40-49 year age bracket. The majority (85.3% described themselves as Mulatto or Black; 55.2% reported using alcohol; and approximately 90% were treated as outpatients. In the district and age bracket studied, the incidence of pulmonary tuberculosis was 30.6/100,000 population. Among the 72 patients, data regarding nutritional status was available for 34. Of those, 50% and 25%, respectively, presented nutritional deficiency at the beginning and at the end of treatment. No statistically significant differences were found between normal-weight and malnourished patients regarding the characteristics studied. CONCLUSIONS: The prevalence of nutritional deficiency was high among our sample of patients with pulmonary tuberculosis. This underscores the importance of nutritional follow-up for the assessment of tuberculosis treatment in the decision-making process regarding therapeutic interventions.

  16. RELATIONSHIP BETWEEN LIPID PEROXIDATION AND RED BLOOD CELL IMMUNE FUNCTION IN PATIENTS WITH SPLEEN DEFICIENCY%脾虚患者脂质过氧化和红细胞免疫功能关系

    Institute of Scientific and Technical Information of China (English)

    章梅; 邱根全; 夏天

    2001-01-01

    Objective:To explore the effect of lipid peroxidation on red blood cell immune function in patients with spleen deficiency.Method:By the methods of TBA and red blood cell-yeast mixed flower circle,the RBC-C3b receptor rate,malonyldialdehyde(MDA) of plasma and erythrocyte membrane in patients with spleen deficiency were determined respectively.Result:The red blood cell C3b receptor rate(RBC-C3bRR)and red blood cell immune compound(RBC-IC) were lowered,but the MDA content in plasma and erythrocyte membrane were increased respectively.The relative analysis suggested that there were relationship between the RBC-C3bRR and MAD content in plasma and erythrocyte membrane.Conclusion:The lipid peroxidation lesion of red blood cell membrane had a bad effect on RBC-C3bRR.%目的:探讨脾虚患者脂质过氧化对红细胞免疫功能的影响。方法:采用红细胞酵母菌混合花环法和硫代巴比妥酸(TBA)法检测脾虚患者红细胞膜C3b受体花环率(RBC-C3bRR)、血浆及红细胞膜丙二醛(MDA)水平。结果:脾虚患者RBC-C3bRR和红细胞膜免疫复合物花环率(RBC-ICR)明显降低,血浆MDA和红细胞膜MDA明显升高;RBC-C3bRR与血浆MDA、红细胞膜MDA呈负相关,其中红细胞膜MDA和RBC-C3bRR关系更为密切。结论:红细胞膜脂质过氧化损害对RBC-C3bRR有不利影响。

  17. Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.

    Science.gov (United States)

    Dobbs, Kerry; Domínguez Conde, Cecilia; Zhang, Shen-Ying; Parolini, Silvia; Audry, Magali; Chou, Janet; Haapaniemi, Emma; Keles, Sevgi; Bilic, Ivan; Okada, Satoshi; Massaad, Michel J; Rounioja, Samuli; Alwahadneh, Adel M; Serwas, Nina K; Capuder, Kelly; Çiftçi, Ergin; Felgentreff, Kerstin; Ohsumi, Toshiro K; Pedergnana, Vincent; Boisson, Bertrand; Haskoloğlu, Şule; Ensari, Arzu; Schuster, Michael; Moretta, Alessandro; Itan, Yuval; Patrizi, Ornella; Rozenberg, Flore; Lebon, Pierre; Saarela, Janna; Knip, Mikael; Petrovski, Slavé; Goldstein, David B; Parrott, Roberta E; Savas, Berna; Schambach, Axel; Tabellini, Giovanna; Bock, Christoph; Chatila, Talal A; Comeau, Anne Marie; Geha, Raif S; Abel, Laurent; Buckley, Rebecca H; İkincioğulları, Aydan; Al-Herz, Waleed; Helminen, Merja; Doğu, Figen; Casanova, Jean-Laurent; Boztuğ, Kaan; Notarangelo, Luigi D

    2015-06-18

    Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).

  18. Impression cytology and in vivo confocal microscopy in corneas with total limbal stem cell deficiency

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    Aline Lütz de Araújo

    2013-10-01

    Full Text Available PURPOSES: To describe corneal changes seen on in vivo confocal microscopy in patients with total limbal stem cell deficiency and to correlate them with cytological findings. METHODS: A prospective case series including 13 eyes (8 patients with total limbal deficiency was carried out. Stem cell deficiency was diagnosed clinically and by corneal impression cytology. Confocal images of the central cornea were taken with the Heidelberg Retina Tomograph II, Rostock Corneal Module (Heidelberg Engineering, Heidelberg, Germany. RESULTS: Impression cytology of the cornea revealed conjunctival epithelial cells and goblet cells in all cases. In vivo confocal microscopy showed disruption of normal layers of the corneal epithelium in all eyes. Confocal images showed cells with characteristics of conjunctival epithelium at the cornea in 76.9% of the total. These findings on confocal microscopy were compatible to limbal stem cell deficiency. Additionally, goblet cells, squamous metaplasia, inflammatory cells and dendritic cells were observed. The sub-basal nerve plexus was not identified in any of the corneas. Corneal neovessels were observed at the epithelium and stroma. All cases showed diffuse hyper-reflective images of the stroma corresponding to opacity of the tissue. CONCLUSIONS: Limbal stem cell deficiency had been confirmed by impression cytology in all cases, and 76.9% of the cases could also be diagnosed by in vivo confocal microscopy through the conjunctival epithelial cell visualization on the corneal surface. Frequent confocal microscopy findings were abnormal cells at the cornea (conjunctival epithelial, goblet and inflammatory cells, corneal neovessels and diffuse hyper-reflection of the stroma.

  19. Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency

    NARCIS (Netherlands)

    Diekman, E.F.; Koning, T.J. de; Verhoeven-Duif, N.M.; Rovers, M.M.; Hasselt, P.M. van

    2014-01-01

    IMPORTANCE The impact of betaine treatment on outcome in patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency is presently unclear. OBJECTIVE To investigate the effect of betaine treatment on development and survival in patients with severe MTHFR deficiency. DATA SOURCES MEDLI

  20. Survival and Psychomotor Development With Early Betaine Treatment in Patients With Severe Methylenetetrahydrofolate Reductase Deficiency

    NARCIS (Netherlands)

    Diekman, Eugene F.; de Koning, Tom J.; Verhoeven-Duif, Nanda M.; Rovers, Maroeska M.; van Hasselt, Peter M.

    2014-01-01

    IMPORTANCE The impact of betaine treatment on outcome in patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency is presently unclear. OBJECTIVE To investigate the effect of betaine treatment on development and survival in patients with severe MTHFR deficiency. DATA SOURCES MEDLI

  1. Premature awakening and underuse of neuromuscular monitoring in a registry of patients with butyrylcholinesterase deficiency

    DEFF Research Database (Denmark)

    Thomsen, J L; Nielsen, C V; Palmqvist, D F;

    2015-01-01

    BACKGROUND: Patients with butyrylcholinesterase (BChE) deficiency can experience prolonged paralysis after receiving suxamethonium or mivacurium. We hypothesized that patients suspected of BChE deficiency had a higher risk of being awakened while paralysed and having respiratory complications...

  2. Chromosomal replication incompatibility in Dam methyltransferase deficient Escherichia coli cells

    DEFF Research Database (Denmark)

    Freiesleben, Ulrik Von

    1996-01-01

    Dam methyltransferase deficient Escherichia coli cells containing minichromosomes were constructed. Free plasmid DNA could not be detected in these cells and the minichromosomes were found to be integrated in multiple copies in the origin of replication (oriC) region of the host chromosome...

  3. Depressed immune surveillance against cancer: role of deficient T cell: extracellular matrix interactions.

    Science.gov (United States)

    Górski, A; Castronovo, V; Stepień-Sopniewska, B; Grieb, P; Ryba, M; Mrowiec, T; Korczak-Kowalska, G; Wierzbicki, P; Matysiak, W; Dybowska, B

    1994-07-01

    Although T cells infiltrate malignant tumors, the local immune response is usually inefficient and tumors escape destruction. While extracellular matrix proteins strongly costimulate T cell responses in normal individuals, our studies indicate that peripheral blood T cells from cancer patients and tumor infiltrating cells respond poorly or are resistant to stimulative signals mediated by collagen I and IV and fibronectin. Moreover, the adhesive properties of cancer T cells are markedly depressed. Those functional deficiencies are paralleled by variable deficits in integrin and non-integrin T cell receptors for extracellular matrix. Immunotherapy with BCG causes a dramatic but transient increase in T cell: ECM interactions.

  4. Vena porta thrombosis in patient with inherited factor VII deficiency

    DEFF Research Database (Denmark)

    Klovaite, Jolanta; Friis-Hansen, Lennart Jan; Larsen, Fin S;

    2010-01-01

    with inherited FVII deficiency and chronic vena porta thrombosis. She presented at 32 weeks of gestation with spontaneously increased international normalized ratio, severe thrombocytopenia and very few unspecific symptoms. The extensive examination of the patient revealed cavernous transformation of the portal...... vein with well expressed portosystemic collaterals, heterozygosity for three common polymorphisms in FVII gene, associated with reduction in plasma FVII levels, and no other factors predisposing to thrombosis....

  5. Anesthetic Management of a Pediatric Patient with Arginase Deficiency

    Directory of Open Access Journals (Sweden)

    Abdulkadir Atım

    2011-09-01

    Full Text Available Arginase deficiency is an autosomal recessive disorder of the urea cycle in which a defect in conversion of arginine to urea and ornithine leads to hyperammonemia. Patients with urea cycle disorders may show increased protein catabolism due to inadequate intake of energy, protein and essential amino acids; infections, fever and surgery. A 12-year-old girl with arginase deficiency, ASA II who weighed 40 kg was scheduled for bilateral adductor, quadriceps and gastrocnemius tenotomies. She had mental retardation, spasticity and flexion posture of thelower limbs. Metabolic homeostasis was restored with appropriate diet. Successful anesthetic management allowed the patient to be discharged 48 hours after surgery. Increased levels of arginine and ammonia during or after surgery may lead to serious complications such as hypotension, cerebral edema, convulsions, hypothermia and spasticity. Thus special attention must be given to metabolic homeostasis and nutrition of the patients with arginase deficiency in the perioperative period. Primary goals should be to minimize stress levels by effective anxiolysis, provide an adequate amount of protein-free energy with proper fluid management and to obtain an effective preemptive and postoperative analgesia. In addition to a high level of knowledge, successful anesthesia requires professional communication among nursing staff, dietitians, pediatric metabolism specialist, surgeon and anesthesiologist.

  6. Deficiency in Homologous Recombination Renders Mammalian Cells More Sensitive to Proton Versus Photon Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Grosse, Nicole; Fontana, Andrea O. [Laboratory for Molecular Radiobiology, University Hospital Zurich, Zurich (Switzerland); Hug, Eugen B.; Lomax, Antony; Coray, Adolf [Center for Proton Therapy, Paul Scherrer Institute, Villigen (Switzerland); Augsburger, Marc [Laboratory for Molecular Radiobiology, University Hospital Zurich, Zurich (Switzerland); Paganetti, Harald [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Sartori, Alessandro A. [Institute of Molecular Cancer Research, University of Zurich, Zurich (Switzerland); Pruschy, Martin, E-mail: martin.pruschy@usz.ch [Laboratory for Molecular Radiobiology, University Hospital Zurich, Zurich (Switzerland)

    2014-01-01

    Purpose: To investigate the impact of the 2 major DNA repair machineries on cellular survival in response to irradiation with the 2 types of ionizing radiation. Methods and Materials: The DNA repair and cell survival endpoints in wild-type, homologous recombination (HR)-deficient, and nonhomologous end-joining-deficient cells were analyzed after irradiation with clinically relevant, low-linear energy transfer (LET) protons and 200-keV photons. Results: All cell lines were more sensitive to proton irradiation compared with photon irradiation, despite no differences in the induction of DNA breaks. Interestingly, HR-deficient cells and wild-type cells with small interfering RNA-down-regulated Rad51 were markedly hypersensitive to proton irradiation, resulting in an increased relative biological effectiveness in comparison with the relative biological effectiveness determined in wild-type cells. In contrast, lack of nonhomologous end-joining did not result in hypersensitivity toward proton irradiation. Repair kinetics of DNA damage in wild-type cells were equal after both types of irradiation, although proton irradiation resulted in more lethal chromosomal aberrations. Finally, repair kinetics in HR-deficient cells were significantly delayed after proton irradiation, with elevated amounts of residual γH2AX foci after irradiation. Conclusion: Our data indicate a differential quality of DNA damage by proton versus photon irradiation, with a specific requirement for homologous recombination for DNA repair and enhanced cell survival. This has potential relevance for clinical stratification of patients carrying mutations in the DNA damage response pathways.

  7. Pyridoxine deficiency in adult patients with status epilepticus.

    Science.gov (United States)

    Dave, Hina N; Eugene Ramsay, Richard; Khan, Fawad; Sabharwal, Vivek; Irland, Megan

    2015-11-01

    An 8-year-old girl treated at our facility for superrefractory status epilepticus was found to have a low pyridoxine level at 5 μg/L. After starting pyridoxine supplementation, improvement in the EEG for a 24-hour period was seen. We decided to look at the pyridoxine levels in adult patients admitted with status epilepticus. We reviewed the records on patients admitted to the neurological ICU for status epilepticus (SE). Eighty-one adult patients were identified with documented pyridoxine levels. For comparison purposes, we looked at pyridoxine levels in outpatients with epilepsy (n=132). Reported normal pyridoxine range is >10 ng/mL. All but six patients admitted for SE had low normal or undetectable pyridoxine levels. A selective pyridoxine deficiency was seen in 94% of patients with status epilepticus (compared to 39.4% in the outpatients) which leads us to believe that there is a relationship between status epilepticus and pyridoxine levels.

  8. Deficient natural killer cell function in preeclampsia

    Energy Technology Data Exchange (ETDEWEB)

    Alanen, A.; Lassila, O.

    1982-11-01

    Natural killer cell activity of peripheral blood lymphocytes was measured against K-562 target cells with a 4-hour /sup 51/Cr release assay in 15 primigravid women with preeclamptic symptoms. Nineteen primigravid women with an uncomplicated pregnancy and 18 nonpregnant women served as controls. The natural killer cell activity of preeclamptic women was observed to be significantly lower than that of both control groups. Natural killer cells in preeclamptic women responded normally to augmentation caused by interferon. These findings give further evidence for the participation of the maternal immune system in this pregnancy disorder.

  9. TAP-deficient human iPS cell-derived myeloid cell lines as unlimited cell source for dendritic cell-like antigen-presenting cells.

    Science.gov (United States)

    Haruta, M; Tomita, Y; Yuno, A; Matsumura, K; Ikeda, T; Takamatsu, K; Haga, E; Koba, C; Nishimura, Y; Senju, S

    2013-05-01

    We previously reported a method to generate dendritic cell (DC)-like antigen-presenting cells (APC) from human induced pluripotent stem (iPS) cells. However, the method is relatively complicated and laborious. In the current study, we attempted to establish a method through which we could obtain a large number of functional APC with a simple procedure. We transduced iPS cell-derived CD11b(+) myeloid cells with genes associated with proliferative or anti-senescence effects, enabling the cells to propagate for more than 4 months in a macrophage colony-stimulating factor (M-CSF)-dependent manner while retaining their capacity to differentiate into functional APC. We named these iPS cell-derived proliferating myeloid cells 'iPS-ML', and the iPS-ML-derived APC 'ML-DC'. In addition, we generated TAP2-deficient iPS cell clones by zinc finger nuclease-aided targeted gene disruption. TAP2-deficient iPS cells and iPS-ML avoided recognition by pre-activated allo-reactive CD8(+) T cells. TAP2-deficient ML-DC expressing exogenously introduced HLA-A2 genes stimulated HLA-A2-restricted MART-1-specific CD8(+) T cells obtained from HLA-A2-positive allogeneic donors, resulting in generation of MART-1-specific cytotoxic T lymphocyte (CTL) lines. TAP-deficient iPS-ML introduced with various HLA class I genes may serve as an unlimited source of APC for vaccination therapy. If administered into allogeneic patients, ML-DC with appropriate genetic modifications may survive long enough to stimulate antigen-specific CTL and, after that, be completely eliminated. Based on the present study, we propose an APC-producing system that is simple, safe and applicable to all patients irrespective of their HLA types.

  10. The immunophenotypic fingerprint of patients with primary antibody deficiencies is partially present in their asymptomatic first-degree relatives.

    Science.gov (United States)

    Bogaert, Delfien J A; De Bruyne, Marieke; Debacker, Veronique; Depuydt, Pauline; De Preter, Katleen; Bonroy, Carolien; Philippé, Jan; Bordon, Victoria; Lambrecht, Bart N; Kerre, Tessa; Cerutti, Andrea; Vermaelen, Karim Y; Haerynck, Filomeen; Dullaers, Melissa

    2017-01-01

    The etiology of primary antibody deficiencies is largely unknown. Beside rare monogenic forms, the majority of cases seem to have a more complex genetic basis. Whereas common variable immunodeficiency has been investigated in depth, there are only a few reports on milder primary antibody deficiencies such as idiopathic primary hypogammaglobulinemia and IgG subclass deficiency. We performed flow cytometric immunophenotyping in 33 patients with common variable immunodeficiency, 23 with idiopathic primary hypogammaglobulinemia and 21 with IgG subclass deficiency, as well as in 47 asymptomatic first-degree family members of patients and 101 unrelated healthy controls. All three groups of patients showed decreased memory B- and naïve T-cell subsets and decreased B-cell activating factor receptor expression. In contrast, circulating follicular helper T-cell frequency and expression of inducible T-cell co-stimulator and chemokine receptors were only significantly altered in patients with common variable immunodeficiency. Asymptomatic first-degree family members of patients demonstrated similar, albeit intermediate, alterations in naïve and memory B- and T-cell subsets. About 13% of asymptomatic relatives had an abnormal peripheral B-cell composition. Furthermore, asymptomatic relatives showed decreased levels of CD4(+) recent thymic emigrants and increased central memory T cells. Serum IgG and IgM levels were also significantly lower in asymptomatic relatives than in healthy controls. We conclude that, in our cohort, the immunophenotypic landscape of primary antibody deficiencies comprises a spectrum, in which some alterations are shared between all primary antibody deficiencies whereas others are only associated with common variable immunodeficiency. Importantly, asymptomatic first-degree family members of patients were found to have an intermediate phenotype for peripheral B- and T-cell subsets.

  11. Spectrum of mutations in Lebanese patients with phenylalanine hydroxylase deficiency.

    Science.gov (United States)

    Karam, Pascale E; Alhamra, Rasha Shahabeddeen; Nemer, Georges; Usta, Julnar

    2013-02-15

    Phenylketonuria is an autosomal recessive inborn error of metabolism resulting from phenylalanine hydroxylase deficiency. Genetic basis of phenylalanine hydroxylase deficiency has been reported in various European and Asian countries with few reports available in Arab populations of the Mediterranean region. This is the first pilot study describing phenotype and genotype of 23 Lebanese patients with phenylketonuria. 48% of the patients presented mainly with neurological signs at a mean age of 2 years 9 months, as newborn screening is not yet a nationwide policy. 56.5% of the patients had classical phenylketonuria. Thirteen different mutations were identified: splice site 52%, frameshift 31%, and missense 17% with no nonsense mutations. IVS10-11G>A was found mainly in Christians at high relative frequency whereas Muslims carried the G352fs and R261Q mutations. A rare splice mutation IVS7+1G>T, not described before, was identified in the homozygous state in one family with moderate phenylketonuria phenotype. Genotype-phenotype correlation using Guldberg arbitrary value method showed high consistency between predicted and observed phenotypes. Calculated homozygosity rate was 0.07 indicating the genetic heterogeneity in our patients. Our findings underline the admixture of different ethnicities and religions in Lebanon that might help tracing back the PAH gene flux history across the Mediterranean region.

  12. Glucose-6-phosphate dehydrogenase (G6PD-deficient epithelial cells are less tolerant to infection by Staphylococcus aureus.

    Directory of Open Access Journals (Sweden)

    Yi-Ting Hsieh

    Full Text Available Glucose-6-phosphate dehydrogenase (G6PD is a key enzyme in the pentose phosphate pathway and provides reducing energy to all cells by maintaining redox balance. The most common clinical manifestations in patients with G6PD deficiency are neonatal jaundice and acute hemolytic anemia. The effects of microbial infection in patients with G6PD deficiency primarily relate to the hemolytic anemia caused by Plasmodium or viral infections and the subsequent medication that is required. We are interested in studying the impact of bacterial infection in G6PD-deficient cells. G6PD knock down A549 lung carcinoma cells, together with the common pathogen Staphylococcus aureus, were employed in our cell infection model. Here, we demonstrate that a lower cell viability was observed among G6PD-deficient cells when compared to scramble controls upon bacterial infection using the MTT assay. A significant increase in the intracellular ROS was detected among S. aureus-infected G6PD-deficient cells by observing dichlorofluorescein (DCF intensity within cells under a fluorescence microscope and quantifying this signal using flow cytometry. The impairment of ROS removal is predicted to enhance apoptotic activity in G6PD-deficient cells, and this enhanced apoptosis was observed by annexin V/PI staining under a confocal fluorescence microscope and quantified by flow cytometry. A higher expression level of the intrinsic apoptotic initiator caspase-9, as well as the downstream effector caspase-3, was detected by Western blotting analysis of G6PD-deficient cells following bacterial infection. In conclusion, we propose that bacterial infection, perhaps the secreted S. aureus α-hemolysin in this case, promotes the accumulation of intracellular ROS in G6PD-deficient cells. This would trigger a stronger apoptotic activity through the intrinsic pathway thereby reducing cell viability when compared to wild type cells.

  13. Molecular analysis of mutations in a patient with purine nucleoside phosphorylase deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Aust, M.R.; Norby-Slycord, C.J.; Andrews, L.G.; Markert, M.L. (Duke Univ. Medical Center, Durham, NC (United States)); Barrett, M.J. (Sunnyside Hospital, Clackamas, OR (United States))

    1992-10-01

    Purine nucleoside phosphorylase (PNP) deficiency is an inherited autosomal recessive disorder resulting in severe combined immunodeficiency. The purpose of this study was to determine the molecular defects responsible for PNP deficiency in one such patient. The patient's PNP cDNA was amplified by PCR and sequenced. Point mutations leading to amino acid substitutions were found in both alleles. One point mutation led to a Ser-to-Gly substitution at amino acid 51 and was common to both alleles. In addition, an Asp-to-Gly substitution at amino acid 128 and an Arg-to-Pro substitution at amino acid 234 were found in the maternal and paternal alleles, respectively. In order to prove that these mutations were responsible for the disease state, each of the three mutations was constructed separately by site-directed mutagenesis of the normal PNP cDNA, and each was transiently expressed in COS cells. Lysates from cells transfected with the allele carrying the substitution at amino acid 51 retained both function and immunoreactivity. Lysates from cells transfected with PNP alleles carrying a substitution at either amino acid 128 or amino acid 234 contained immunoreactive material but had no detectable human PNP activity. In summary, molecular analysis of this patient identified point mutations within the PNP gene which are responsible for the enzyme deficiency. 52 refs., 5 figs.

  14. Serum paraoxonase 1 activity in patients with iron deficiency anemia

    Science.gov (United States)

    Gedikbasi, Asuman; Akalin, Nilgul; Gunaldi, Meral; Yilmaz, Deniz; Mert, Meral; Harmankaya, Ozlem; Soylu, Aliye; Karakaya, Pinar; Kumbasar, Abdulbaki

    2016-01-01

    Introduction In this study we aimed to detect paraoxonase 1 (PON-1) activity in iron deficiency anemia (IDA) and to compare it with healthy controls by observing the change after iron therapy. Material and methods In this study, 50 adult patients with IDA and 40 healthy subjects were enrolled. All patients were analyzed at the beginning and after treatment according to laboratory assessments. Results Mean paraoxonase and arylesterase activities in the iron deficiency anemia group were significantly lower than mean activities of the control group (102.4 ±19.2 U/l and 163.3 ±13.68 U/l, respectively and 157.3 ±26.4 U/l and 256.1 ±24.6 U/l, respectively; p = 0.0001 for both). Paraoxonase and arylesterase activities significantly increased after treatment for IDA (143.2 ±13.9 and 197.6 ±27.9 U/l, respectively, p = 0.0001). Mean activities after treatment with iron were significantly lower than mean activities in the control group (p = 0.002; p = 0.0001 respectively). Conclusions Paraoxonase and arylesterase activities in patients with IDA significantly increased after treatment with iron therapy. In adults IDA may also be one of the factors associated with increased risk of atherosclerosis. PMID:27478448

  15. Mutations in CHD7 in patients with CHARGE syndrome cause T-B + natural killer cell + severe combined immune deficiency and may cause Omenn-like syndrome.

    NARCIS (Netherlands)

    Gennery, A.R.; Slatter, M.A.; Rice, J.; Hoefsloot, L.H.; Barge, D.; McLean-Tooke, A.; Montgomery, T.; Goodship, J.A.; Burt, A.D.; Flood, T.J.; Abinun, M.; Cant, A.J.; Johnson, D.

    2008-01-01

    More than 11 genetic causes of severe combined immunodeficiency (SCID) have been identified, affecting development and/or function of T lymphocytes, and sometimes B lymphocytes and natural killer (NK) cells. Deletion of 22q11.2 is associated with immunodeficiency, although less than 1% of cases are

  16. Evaluation of erythrocyte and reticulocyte parameters as indicative of iron deficiency in patients with anemia of chronic disease

    Science.gov (United States)

    Torino, Ana Beatriz Barbosa; Gilberti, Maria de Fátima Pererira; da Costa, Edvilson; de Lima, Gisélia Aparecida Freire; Grotto, Helena Zerlotti Wolf

    2015-01-01

    Objective The aim of this study was to evaluate the effectiveness of mature red cell and reticulocyte parameters to identify three conditions: iron deficiency anemia, anemia of chronic disease, and anemia of chronic disease associated with absolute iron deficiency. Methods Peripheral blood cells from 117 adult patients with anemia were classified according to iron status, inflammation, and hemoglobinopathies as: iron deficiency anemia (n = 42), anemia of chronic disease (n = 28), anemia of chronic disease associated with iron deficiency anemia (n = 22), and heterozygous β-thalassemia (n = 25). The percentage of microcytic erythrocytes, hypochromic erythrocytes, and the levels of hemoglobin in both reticulocytes and mature red cells were determined. Receiver operating characteristic analysis was used to evaluate the accuracy of the parameters in differentiating anemia. Results There was no difference between the groups of iron deficiency and anemia of chronic disease associated with absolute iron deficiency for any of the parameters. The percentage of hypochromic erythrocytes was the best parameter to identify absolute iron deficiency in patients with anemia of chronic disease (area under curve = 0.785; 95% confidence interval: 0.661–0.909 with sensitivity of 72.7%, and specificity of 70.4%; cut-off value 1.8%). The formula microcytic erythrocyte count minus hypochromic erythrocyte count was very accurate to differentiate iron deficiency anemia from heterozygous β-thalassemia (area under curve = 0.977; 95% confidence interval: 0.950–1.005 with a sensitivity of 96.2%, and specificity of 92.7%; cut-off value 13.8). Conclusion The erythrocyte and reticulocyte indices are moderately good to identify absolute iron deficiency in patients with anemia of chronic disease. PMID:25818816

  17. Apoptosis and signalling in acid sphingomyelinase deficient cells

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    Sillence Dan J

    2001-11-01

    Full Text Available Abstract Background Recent evidence suggests that the activation of a non-specific lipid scramblase during apoptosis induces the flipping of sphingomyelin from the cell surface to the cytoplasmic leaftet of the plasma membrane. Inner leaflet sphingomyelin is then cleaved to ceramide by a neutral sphingomyelinase. The production of this non-membrane forming lipid induces blebbing of the plasma membrane to aid rapid engulfment by professional phagocytes. However contrary evidence suggests that cells which are deficient in acid sphingomyelinase are defective in apoptosis signalling. This data has been interpreted as support for the activation of acid sphingomyelinase as an early signal in apoptosis. Hypothesis An alternative explanation is put forward whereby the accumulation of intracellular sphingomyelin in sphingomyelinase deficient cells leads to the formation of intracellular rafts which lead to the sequestration of important signalling molecules that are normally present on the cell surface where they perform their function. Testing the hypothesis It is expected that the subcellular distribution of important signalling molecules is altered in acid sphingomyelinase deficient cells, leading to their sequestration in late endosomes / lysosomes. Other sphingolipid storage diseases such as Niemann-Pick type C which have normal acid sphingomyelinase activity would also be expected to show the same phenotype. Implications of the hypothesis If true the hypothesis would provide a mechanism for the pathology of the sphingolipid storage diseases at the cellular level and also have implications for the role of ceramide in apoptosis.

  18. Precautionary Measures for Successful Open Heart Surgery in G6PD Deficient Patient- A Case Report

    Science.gov (United States)

    2016-01-01

    Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is among the most common enzymatic disorders of red blood cells. Cardiac surgeries on this group of individuals are associated with an additional risk in terms of impaired oxygenation, prolonged ventilation and increased risk of haemolysis. These patients have a very low threshold for haemolysis due to oxidative stress. Many commonly used drugs also predispose the individual for haemolysis when they are subjected to surgery. Here we present a known case of G6PD deficient patient with symptoms of breathlessness for the last nine years who was taken for surgery with pre-planned precautionary measures to avoid unnecessary haemolysis. The echocardiography report revealed severe mixed mitral lesion and moderate tricuspid regurgitation. On general examination she had mild pallor and icterus. We planned for a thorough investigation to prepare her for mitral valve replacement and tricuspid annuloplasty. These groups of patients are at high risk of haemolysis during perioperative period and need prolonged mechanical ventilation and hospital stay due to impaired oxygen carrying capacity and oxidative stress due to deficient free radical scavenging system. The patient underwent mechanical mitral valve replacement and tricuspid annuloplasty under cardiopulmonary bypass with precautionary measures to prevent the risk of haemolysis and associated complications. She had an uneventful recovery. PMID:28208930

  19. Successful bone marrow transplantation in a patient with DNA ligase IV deficiency and bone marrow failure

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    Bechtold Astrid

    2007-01-01

    Full Text Available Abstract Background DNA Ligase IV deficiency syndrome is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA ligase IV gene (LIG4. The clinical phenotype shows overlap with a number of other rare syndromes, including Seckel syndrome, Nijmegen breakage syndrome, and Fanconi anemia. Thus the clinical diagnosis is often delayed and established by exclusion. Methods We describe a patient with pre- and postnatal growth retardation and dysmorphic facial features in whom the diagnoses of Seckel-, Dubowitz-, and Nijmegen breakage syndrome were variably considered. Cellular radiosensitivity in the absence of clinical manifestations of Ataxia telangiectasia lead to the diagnosis of DNA ligase IV (LIG4 deficiency syndrome, confirmed by compound heterozygous mutations in the LIG4 gene. At age 11, after a six year history of progressive bone marrow failure and increasing transfusion dependency the patient was treated with matched sibling donor hematopoetic stem cell transplantation (HSCT using a fludarabine-based conditioning regimen without irradiation. Results The post-transplantation course was uneventful with rapid engraftment leading to complete and stable chimerism. Now at age 16, the patient has gained weight and is in good clinical condition. Conclusion HSCT using mild conditioning without irradiation qualifies as treatment of choice in LIG4-deficient patients who have a matched sibling donor.

  20. Recollection deficiencies in patients with major depressive disorder.

    Science.gov (United States)

    Drakeford, Justine L; Edelstyn, Nicola M J; Oyebode, Femi; Srivastava, Shrikant; Calthorpe, William R; Mukherjee, Tirthankar

    2010-02-28

    Neuropsychological research suggests that recognition memory (RM) and recall memory are impaired in patients with a major depressive disorder or a dysphoric mood state. This study examines the proposal that abnormalities in recollection (a form of recall) result from a breakdown in frontal strategic memory processes involved in encoding and retrieval, and executive functions linked to reality monitoring, planning, problem-solving, reasoning and decision-making. We investigated two predictions arising from this theory. Firstly, patients diagnosed with a major depressive disorder (MDD) will display a dissociation between (deficient) recollection and (preserved) familiarity. Secondly, if recollection impairments are indicative of a breakdown in prefrontal strategic memory processes which are dependent, at least in part, on executive processes, then an explicit correlational approach predicts that recollection will be positively associated with the severity of executive dysfunction in MDD patients. The remember/know paradigm was used to investigate RM for words and neutral faces in 16 MDD patients and 16 healthy volunteers, matched for age, gender and estimates of premorbid IQ. Measures of executive function included working memory, reasoning and decision-making. Applying the Dual Process Signal Detection interpretation of the remember/know data, the MDD group displayed significant impairments in RM and recollection rates for both verbal and neutral facial memoranda. In contrast, familiarity-aware rates were preserved. There was no evidence of executive dysfunction in the patient group, and little evidence that recollection rates correlated with executive function. Furthermore, a single process signal detection approach suggested that the MDD patients displayed a reduction in sensitivity for RM and remember rates but not know responses. The criteria for detecting studied from unstudied items, and remembering from knowing, were the same in both patient and healthy

  1. Mechanism of testosterone deficiency in the transgenic sickle cell mouse.

    Science.gov (United States)

    Musicki, Biljana; Zhang, Yuxi; Chen, Haolin; Brown, Terry R; Zirkin, Barry R; Burnett, Arthur L

    2015-01-01

    Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle) exhibited decreased serum and intratesticular testosterone and increased luteinizing hormone (LH) levels compared with wild type (WT) mice, indicating primary hypogonadism in Sickle mice. LH-, dbcAMP-, and pregnenolone- (but not 22-hydroxycholesterol)- stimulated testosterone production by Leydig cells isolated from the Sickle mouse testis was decreased compared to that of WT mice, implying defective Leydig cell steroidogenesis. There also was reduced protein expression of steroidogenic acute regulatory protein (STAR), but not cholesterol side-chain cleavage enzyme (P450scc), in the Sickle mouse testis. These data suggest that the capacity of P450scc to support testosterone production may be limited by the supply of cholesterol to the mitochondria in Sickle mice. The sickle mouse testis exhibited upregulated NADPH oxidase subunit gp91phox and increased oxidative stress, measured as 4-hydroxy-2-nonenal, and unchanged protein expression of an antioxidant glutathione peroxidase-1. Mice heterozygous for the human sickle globin (Hemi) exhibited intermediate hypogonadal changes between those of WT and Sickle mice. These results demonstrate that testosterone deficiency occurs in Sickle mice, mimicking the human condition. The defects in the Leydig cell steroidogenic pathway in Sickle mice, mainly due to reduced availability of cholesterol for testosterone production, may be related to NADPH oxidase-derived oxidative stress. Our findings suggest that targeting testicular oxidative stress or steroidogenesis mechanisms in SCD offers a potential treatment for improving phenotypic changes associated with testosterone deficiency in this disease.

  2. Mechanism of testosterone deficiency in the transgenic sickle cell mouse.

    Directory of Open Access Journals (Sweden)

    Biljana Musicki

    Full Text Available Testosterone deficiency is associated with sickle cell disease (SCD, but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle exhibited decreased serum and intratesticular testosterone and increased luteinizing hormone (LH levels compared with wild type (WT mice, indicating primary hypogonadism in Sickle mice. LH-, dbcAMP-, and pregnenolone- (but not 22-hydroxycholesterol- stimulated testosterone production by Leydig cells isolated from the Sickle mouse testis was decreased compared to that of WT mice, implying defective Leydig cell steroidogenesis. There also was reduced protein expression of steroidogenic acute regulatory protein (STAR, but not cholesterol side-chain cleavage enzyme (P450scc, in the Sickle mouse testis. These data suggest that the capacity of P450scc to support testosterone production may be limited by the supply of cholesterol to the mitochondria in Sickle mice. The sickle mouse testis exhibited upregulated NADPH oxidase subunit gp91phox and increased oxidative stress, measured as 4-hydroxy-2-nonenal, and unchanged protein expression of an antioxidant glutathione peroxidase-1. Mice heterozygous for the human sickle globin (Hemi exhibited intermediate hypogonadal changes between those of WT and Sickle mice. These results demonstrate that testosterone deficiency occurs in Sickle mice, mimicking the human condition. The defects in the Leydig cell steroidogenic pathway in Sickle mice, mainly due to reduced availability of cholesterol for testosterone production, may be related to NADPH oxidase-derived oxidative stress. Our findings suggest that targeting testicular oxidative stress or steroidogenesis mechanisms in SCD offers a potential treatment for improving phenotypic changes associated with testosterone deficiency in this disease.

  3. Successful Management of Neutropenia in a Patient with CD40 Ligand Deficiency by Immunoglobulin Replacement Therapy

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    Lida Atarod

    2007-03-01

    Full Text Available Hyper-IgM syndromes are characterized by profound reduction of serum IgG, IgA, and IgE levels with normal or increased concentrations of serum IgM. CD40 ligand deficiency is X-linked form of the disease, which results in a lack of immunoglobulin class switching from IgM to IgG in B cells. In addition to the recurrent infections, a number of patients suffer from neutropenia. There are some evidences indicating the effect of G-CSF in combination with intravenous immunoglobulin (IVIG in improvement of neutrophil counts, which has become the most common procedure to control neutropenia.In this report we present a 6 year-old patient of CD40 ligand deficiency, who suffered from chronic, severe neutropenia. Administration of IVIG was started for him when the diagnosis was made at the age of 1.5 years and he was on the regular IVIG therapy after that time untill now for a period of 4.5 years. IVIG and prophylactic antibiotic therapy, despite cessation of granulocyte colony-stimulating factor, injection after one month, corrected the severe neutropenic state of this patient. It seems that regular administration of sufficient doses of IVIG can be useful in the management of neutropenia in CD40 ligand deficiency, which results in better quality of life with decreasing occurrence of infection.

  4. Vitamin D deficiency in a cohort of HIV-infected patients: clinical analysis

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    B Vandercam

    2012-11-01

    Full Text Available Purpose of the study: Observational studies have noted very high rates of low serum 25-hydroxyvitamin D [25(OHD3] levels in both general and HIV-infected populations. In HIV-infected patients, low 25(OHD3 levels are secondary to a combination of usual risk factors and HIV-specific risk factors, like antiretroviral therapy [1]. The objective of our study is to analyse the magnitude of vitamin D deficiency or insufficiency and the role of various factors such as age, sex, ethnicity, season, and antiretroviral medications in our cohort of HIV-infected patients. Methods: We prospectively collected data on 25-hydroxyvitamin D levels sampled between January 2009 and June 2011 from our cohort of 930 HIV-infected patients. Vitamin D dosage was performed using immunoassay (‘Diasorin’ - Saluggia, Italy. We divided vitamin D levels into 3 categories: 25-hydroxyvitamin D levels <20 mg/nl were considered deficient, insufficient between 20 and 29 ng/ml. Levels ≥30 ng/ml were defined as normal [2]. Data on demographic features (age, ethnicity, season, heterosexuality vs homosexuality, clinical features and laboratory findings (CD4 cell count, viral load, HAART, BMI were collected from patients’ medical records using our institutional database ‘Medical explorer v3r9, 2009’. Summary of results: Overall, 848 patients were included in our study (Table 1. Low levels of serum 25(OHD3 were seen in 89.3% of the study population, from which 69.5% were deficient and 19.8% were insufficient. On univariate analysis, female sex, high BMI, black African, heterosexuality, undetectable viral load and antiretroviral treatment were all predictors of vitamin D deficiency and insufficiency. Treatment with efavirenz and tenofovir were the most associated with low vitamin D levels. On multivariate analysis (multiple linear regression model only female sex (OR=1.14; 95% CI 0.84–0.96; p<0.001, dosage during winter months (OR=1.14; 95% CI 1–1.15; p<0.05 and HAART (OR=1

  5. Alterations of proteins in MDCK cells during acute potassium deficiency.

    Science.gov (United States)

    Peerapen, Paleerath; Ausakunpipat, Nardtaya; Chanchaem, Prangwalai; Thongboonkerd, Visith

    2016-06-01

    Chronic K(+) deficiency can cause hypokalemic nephropathy associated with metabolic alkalosis, polyuria, tubular dilatation, and tubulointerstitial injury. However, effects of acute K(+) deficiency on the kidney remained unclear. This study aimed to explore such effects by evaluating changes in levels of proteins in renal tubular cells during acute K(+) deficiency. MDCK cells were cultivated in normal K(+) (NK) (K(+)=5.3 mM), low K(+) (LK) (K(+)=2.5 mM), or K(+) depleted (KD) (K(+)=0 mM) medium for 24 h and then harvested. Cellular proteins were resolved by two-dimensional gel electrophoresis (2-DE) and visualized by SYPRO Ruby staining (5 gels per group). Spot matching and quantitative intensity analysis revealed a total 48 protein spots that had significantly differential levels among the three groups. Among these, 46 and 30 protein spots had differential levels in KD group compared to NK and LK groups, respectively. Comparison between LK and NK groups revealed only 10 protein spots that were differentially expressed. All of these differentially expressed proteins were successfully identified by Q-TOF MS and/or MS/MS analyses. The altered levels of heat shock protein 90 (HSP90), ezrin, lamin A/C, tubulin, chaperonin-containing TCP1 (CCT1), and calpain 1 were confirmed by Western blot analysis. Global protein network analysis showed three main functional networks, including 1) cell growth and proliferation, 2) cell morphology, cellular assembly and organization, and 3) protein folding in which the altered proteins were involved. Further investigations on these networks may lead to better understanding of pathogenic mechanisms of low K(+)-induced renal injury.

  6. Intrachromosomal recombination between highly diverged DNA sequences is enabled in human cells deficient in Bloom helicase.

    Science.gov (United States)

    Wang, Yibin; Li, Shen; Smith, Krissy; Waldman, Barbara Criscuolo; Waldman, Alan S

    2016-05-01

    Mutation of Bloom helicase (BLM) causes Bloom syndrome (BS), a rare human genetic disorder associated with genome instability, elevation of sister chromatid exchanges, and predisposition to cancer. Deficiency in BLM homologs in Drosophila and yeast brings about significantly increased rates of recombination between imperfectly matched sequences ("homeologous recombination," or HeR). To assess whether BLM deficiency provokes an increase in HeR in human cells, we transfected an HeR substrate into a BLM-null cell line derived from a BS patient. The substrate contained a thymidine kinase (tk)-neo fusion gene disrupted by the recognition site for endonuclease I-SceI, as well as a functional tk gene to serve as a potential recombination partner for the tk-neo gene. The two tk sequences on the substrate displayed 19% divergence. A double-strand break was introduced by expression of I-SceI and repair events were recovered by selection for G418-resistant clones. Among 181 events recovered, 30 were accomplished via HeR with the balance accomplished by nonhomologous end-joining. The frequency of HeR events in the BS cells was elevated significantly compared to that seen in normal human fibroblasts or in BS cells complemented for BLM expression. We conclude that BLM deficiency enables HeR in human cells.

  7. CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis

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    Michael P. Pender

    2012-01-01

    Full Text Available CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1 CD8+ T-cell deficiency, (2 primary EBV infection, (3 decreased CD8+ T-cell control of EBV, (4 increased EBV load and increased anti-EBV antibodies, (5 EBV infection in the target organ, (6 clonal expansion of EBV-infected autoreactive B cells in the target organ, (7 infiltration of autoreactive T cells into the target organ, and (8 development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.

  8. Stem cell selection in vivo using foamy vectors cures canine pyruvate kinase deficiency.

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    Grant D Trobridge

    Full Text Available BACKGROUND: Hematopoietic stem cell (HSC gene therapy has cured immunodeficiencies including X-linked severe combined immunodeficiency (SCID-X1 and adenine deaminase deficiency (ADA. For these immunodeficiencies corrected cells have a selective advantage in vivo, and low numbers of gene-modified cells are sufficient to provide therapeutic benefit. Strategies to efficiently transduce and/or expand long-term repopulating cells in vivo are needed for treatment of diseases that require higher levels of corrected cells, such as hemoglobinopathies. Here we expanded corrected stem cells in vivo in a canine model of a severe erythroid disease, pyruvate kinase deficiency. METHODOLOGY/PRINCIPAL FINDINGS: We used a foamy virus (FV vector expressing the P140K mutant of methylguanine methyltransferase (MGMTP140K for in vivo expansion of corrected hematopoietic repopulating cells. FV vectors are attractive gene transfer vectors for hematopoietic stem cell gene therapy since they efficiently transduce repopulating cells and may be safer than more commonly used gammaretroviral vectors. Following transplantation with HSCs transduced ex vivo using a tri-cistronic FV vector that expressed EGFP, R-type pyruvate kinase, and MGMTP140K, we were able to increase marking from approximately 3.5% to 33% in myeloid long-term repopulating cells resulting in a functional cure. CONCLUSIONS/SIGNIFICANCE: Here we describe in one affected dog a functional cure for a severe erythroid disease using stem cell selection in vivo. In addition to providing a potential cure for patients with pyruvate kinase deficiency, in vivo selection using foamy vectors with MGMTP140K has broad potential for several hematopoietic diseases including hemoglobinopathies.

  9. Prevalence and risk factors of vitamin D deficiency in patients with widespread musculoskeletal pain

    Directory of Open Access Journals (Sweden)

    Muharrem Çidem

    2013-12-01

    Full Text Available Objective: Vitamin D deficiency is a worldwide common health problems. Vitamin D deficiency in adults has been associated with proximal muscle weakness, skeletal mineralization defect, and an increased risk of falling. Patients with vitamin D deficiency commonly complain of widespread pain in the body. The aim of this study was to examine the prevalence and risk factors of 25-hydroxyvitamin D deficiency in patients complaining of widespread musculoskeletal pain. Methods: In this cross-sectional study, 8457 patients with widespread musculoskeletal pain (7772 females, 685 males, aged 46.7 (range 20-100 years were included. Serum 25-hydroxyvitamin D was measured with ELISA method. Patients were classified into two groups: 1 Patients with vitamin D deficiency (20 ng/ml. Results: Prevalence of vitamin D deficiency was found to be 71.7%. A binary logistic regression model showed that low 25(OHVit D level was associated with gender, age and month in which 25(OH hypovitaminosis was determined. The risk of low 25(OH Vit D was found to be 2.15 times higher in female patients and 1.52 times higher on March and 1.55 times higher on April. Conclusion: This study indicates that Vitamin D deficiency should be taken into consideration in patients with widespread musculoskeletal pain, and some precautions such as sunbathe during summer should be recommended patients having risk of vitamin D deficiency. J Clin Exp Invest 2013; 4 (4: 48-491

  10. Effects of an induced adenosine deaminase deficiency on T-cell differentiation in the rat

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    Barton, R.W.

    1985-10-15

    Inherited deficiency of the enzyme adenosine deaminase (ADA) has been found in a significant proportion of patients with severe combined immunodeficiency disease and inherited defect generally characterized by a deficiency of both B and T cells. Two questions are central to understanding the pathophysiology of this disease: (1) at what stage or stages in lymphocyte development are the effects of the enzyme deficiency manifested; (2) what are the biochemical mechanisms responsible for the selective pathogenicity of the lymphoid system. We have examined the stage or stages of rat T-cell development in vivo which are affected by an induced adenosine deaminase deficiency using the ADA inhibitors, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and 2'-deoxycoformycin (DCF). In normal rats given daily administration of an ADA inhibitor, cortical thymocytes were markedly depleted; peripheral lymphocytes and pluripotent hemopoietic stem cells (CFU-S) all were relatively unaffected. Since a deficiency of ADA affects lymphocyte development, the regeneration of cortical and medullary thymocytes and their precursors after sublethal irradiation was used as a model of lymphoid development. By Day 5 after irradiation the thymus was reduced to 0.10-0.5% of its normal size; whereas at Days 9 and 14 the thymus was 20-40% and 60-80% regenerated, respectively. When irradiated rats were given daily parenteral injections of the ADA inhibitor plus adenosine or deoxyadenosine, thymus regeneration at Days 9 and 14 was markedly inhibited, whereas the regeneration of thymocyte precursors was essentially unaffected. Thymus regeneration was at least 40-fold lower than in rats given adenosine or deoxyadenosine alone. Virtually identical results were obtained with both ADA inhibitors, EHNA and DCF.

  11. Renal AA amyloidosis in a patient with hereditary complete complement C4 deficiency

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    Imed Helal

    2011-01-01

    Full Text Available Hereditary complete C4 deficiency has until now been reported in 30 cases only. A disturbed clearance of immune- complexes probably predisposes these individuals to systemic lupus erythematosus, other immune- complex diseases and recurrent microbial infections. We present here a 20- year- old female with hereditary complete C4 deficiency. Renal biopsy demonstrated renal AA amyloidosis. This unique case further substantiates that deficiency of classical pathway components predisposes to the development of recurrent microbial infections and that the patients may develop AA amyloidosis. Furthermore, in clinical practice, the nephrotic syndrome occurring in a patient with hereditary complete complement C4 deficiency should lead to the suspicion of renal AA amyloidosis.

  12. Novel mechanism of regulation of the DNA repair enzyme OGG1 in tuberin-deficient cells

    Science.gov (United States)

    Habib, Samy L.; Bhandari, Besant K.; Sadek, Nahed; Abboud-Werner, Sherry L.; Abboud, Hanna E.

    2010-01-01

    Tuberin (protein encodes by tuberous sclerosis complex 2, Tsc2) deficiency is associated with the decrease in the DNA repair enzyme 8-oxoG-DNA glycosylase (OGG1) in tumour kidney of tuberous sclerosis complex (TSC) patients. The purpose of this study was to elucidate the mechanisms by which tuberin regulates OGG1. The partial deficiency in tuberin expression that occurs in the renal proximal tubular cells and kidney cortex of the Eker rat is associated with decreased activator protein 4 (AP4) and OGG1 expression. A complete deficiency in tuberin is associated with loss of AP4 and OGG1 expression in kidney tumour from Eker rats and the accumulation of significant levels of 8-oxo-deoxyguanosine. Knockdown of tuberin expression in human renal epithelial cells (HEK293) with small interfering RNA (siRNA) also resulted in a marked decrease in the expression of AP4 and OGG1. In contrast, overexpression of tuberin in HEK293 cells increased the expression of AP4 and OGG1 proteins. Downregulation of AP4 expression using siRNA resulted in a significant decrease in the protein expression of OGG1. Immunoprecipitation studies show that AP4 is associated with tuberin in cells. Gel shift analysis and chromatin immunoprecipitation identified the transcription factor AP4 as a positive regulator of the OGG1 promoter. AP4 DNA-binding activity is significantly reduced in Tsc2−/− as compared with Tsc2+/+ cells. Transcriptional activity of the OGG1 promoter is also decreased in tuberin-null cells compared with wild-type cells. These data indicate a novel role for tuberin in the regulation of OGG1 through the transcription factor AP4. This regulation may be important in the pathogenesis of kidney tumours in patients with TSC disease. PMID:20837600

  13. Red cell pyruvate kinase deficiency: from genetics to clinical manifestations.

    Science.gov (United States)

    Zanella, A; Bianchi, P

    2000-03-01

    Pyruvate kinase deficiency is the most frequent enzyme abnormality of the Embden-Meyerhof pathway causing hereditary non-spherocytic haemolytic anaemia. The degree of haemolysis varies widely, ranging from very mild or fully compensated forms, to life-threatening neonatal anaemia and jaundice necessitating exchange transfusions. Splenectomy should be reserved for young patients who require regular blood transfusions. The gene encoding for pyruvate kinase (PK-LR) has been localized to the long arm of chromosome I; the cDNA of R-type is 2060 bp long and codes for 574 amino acids. More than 130 different mutations, mostly missense, have so far been described in association with PK deficiency, 1529A and 1456T being considered to be the most common mutations in Caucasians. Analysis of the three-dimensional structure of the enzyme may help in predicting the severity of the molecular defect. Further data on clinical features of homozygous patients are needed, at least for some mutations, to allow a more precise genotype/phenotype correlation.

  14. [Iron deficiency in elderly patients: use of biomarkers].

    Science.gov (United States)

    Le Petitcorps, Hélène; Monti, Alexandra; Pautas, Éric

    2015-01-01

    Iron deficiency, due to blood loss or malabsorption, is commonly observed in geriatric practice. In elderly people, association of inflammatory diseases to iron loss makes diagnosis of absolute iron deficiency sometimes difficult. In case of inflammation, the interpretation of usual biomarkers of iron deficiency (serum ferritin, transferrin saturation, serum iron) may be difficult. The recent discovery of the role of hepcidine in the iron homeostasis, in physiological and pathological situation, contributes to better understanding of the iron regulation. The aim of this short paper is to underline some specificities of elderly iron physiology, to explain hepcidine's role in physiological and pathological situations and to propose a diagnostic approach for a better interpretation of usual biomarkers, in order to differentiate absolute iron deficiency and functional iron deficiency.

  15. Ectopic lignification in primary cellulose-deficient cell walls of maize cell suspension cultures

    Institute of Scientific and Technical Information of China (English)

    Hugo Melida; Antonio Encina; Asier Largo-Gosens; Esther Novo-Uzal; Rogelio Santiago; Federico Pomar; Pedro Garca; Penelope Garca-Angulo; Jose Luis Acebes; Jesus Alvarez

    2015-01-01

    Maize (Zea mays L.) suspension-cultured cells with up to 70% less cellulose were obtained by stepwise habituation to dichlobenil (DCB), a cellulose biosynthesis inhibitor. Cellulose deficiency was accompanied by marked changes in cell wall matrix polysaccharides and phenolics as revealed by Fourier transform infrared (FTIR) spectroscopy. Cell wall compositional analysis indicated that the cellulose-deficient cell walls showed an enhancement of highly branched and cross-linked arabinoxylans, as well as an increased content in ferulic acid, diferulates and p-coumaric acid, and the presence of a polymer that stained positive for phloroglucinol. In accordance with this, cellulose-deficient cell walls showed a fivefold increase in Klason-type lignin. Thioacidolysis/GC-MS analysis of cellulose-deficient cell walls indicated the presence of a lignin-like polymer with a Syringyl/Guaiacyl ratio of 1.45, which differed from the sensu stricto stress-related lignin that arose in response to short-term DCB-treatments. Gene expression analysis of these cells indicated an overexpression of genes specific for the biosynthesis of monolignol units of lignin. A study of stress signaling pathways revealed an overexpression of some of the jasmonate signaling pathway genes, which might trigger ectopic lignification in response to cell wall integrity disruptions. In summary, the structural plasticity of primary cell walls is proven, since a lignification process is possible in response to cellulose impoverishment.

  16. Leaky RAG Deficiency in Adult Patients with Impaired Antibody Production against Bacterial Polysaccharide Antigens.

    Science.gov (United States)

    Geier, Christoph B; Piller, Alexander; Linder, Angela; Sauerwein, Kai M T; Eibl, Martha M; Wolf, Hermann M

    2015-01-01

    Loss of function mutations in the recombination activating genes RAG1 and RAG2 have been reported to cause a T-B-NK+ type of severe combined immunodeficiency. In addition identification of hypomorphic mutations in RAG1 and RAG2 has led to an expansion of the spectrum of disease to include Omenn syndrome, early onset autoimmunity, granuloma, chronic cytomegalovirus- or EBV-infection with expansion of gamma/delta T-cells, idiophatic CD4 lymphopenia and a phenotype resembling common variable immunodeficiency. Herein we describe a novel presentation of leaky RAG1 and RAG2 deficiency in two unrelated adult patients with impaired antibody production against bacterial polysaccharide antigens. Clinical manifestation included recurrent pneumonia, sinusitis, otitis media and in one patient recurrent cutaneous vasculitis. Both patients harbored a combination of a null mutation on one allele with a novel hypomorphic RAG1/2 mutation on the other allele. One of these novel mutations affected the start codon of RAG1 and resulted in an aberrant gene and protein expression. The second novel RAG2 mutation leads to a truncated RAG2 protein, lacking the C-terminus with intact core RAG2 and reduced VDJ recombination capacity as previously described in a mouse model. Both patients presented with severely decreased numbers of naïve CD4+ T cells and defective T independent IgG responses to bacterial polysaccharide antigens, while T cell-dependent IgG antibody formation e.g. after tetanus or TBEV vaccination was intact. In conclusion, hypomorphic mutations in genes responsible for SCID should be considered in adults with predominantly antibody deficiency.

  17. Leaky RAG Deficiency in Adult Patients with Impaired Antibody Production against Bacterial Polysaccharide Antigens.

    Directory of Open Access Journals (Sweden)

    Christoph B Geier

    Full Text Available Loss of function mutations in the recombination activating genes RAG1 and RAG2 have been reported to cause a T-B-NK+ type of severe combined immunodeficiency. In addition identification of hypomorphic mutations in RAG1 and RAG2 has led to an expansion of the spectrum of disease to include Omenn syndrome, early onset autoimmunity, granuloma, chronic cytomegalovirus- or EBV-infection with expansion of gamma/delta T-cells, idiophatic CD4 lymphopenia and a phenotype resembling common variable immunodeficiency. Herein we describe a novel presentation of leaky RAG1 and RAG2 deficiency in two unrelated adult patients with impaired antibody production against bacterial polysaccharide antigens. Clinical manifestation included recurrent pneumonia, sinusitis, otitis media and in one patient recurrent cutaneous vasculitis. Both patients harbored a combination of a null mutation on one allele with a novel hypomorphic RAG1/2 mutation on the other allele. One of these novel mutations affected the start codon of RAG1 and resulted in an aberrant gene and protein expression. The second novel RAG2 mutation leads to a truncated RAG2 protein, lacking the C-terminus with intact core RAG2 and reduced VDJ recombination capacity as previously described in a mouse model. Both patients presented with severely decreased numbers of naïve CD4+ T cells and defective T independent IgG responses to bacterial polysaccharide antigens, while T cell-dependent IgG antibody formation e.g. after tetanus or TBEV vaccination was intact. In conclusion, hypomorphic mutations in genes responsible for SCID should be considered in adults with predominantly antibody deficiency.

  18. Fatal adult-onset antibody deficiency syndrome in a patient with cartilage hair hypoplasia.

    Science.gov (United States)

    Horn, Julia; Schlesier, Michael; Warnatz, Klaus; Prasse, Antje; Superti-Furga, Andrea; Peter, Hans-Hartmut; Salzer, Ulrich

    2010-09-01

    Cartilage hair hypoplasia (CHH) is an autosomal recessive disorder caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene. Although its most constant feature is metaphyseal dysplasia with short stature, CHH is associated with extraskeletal defects such as thin hair, anemia, immunodeficiency, and increased incidence of lymphomas. The spectrum of immunologic phenotypes in CHH translates into clinical severity. Whereas T-cell deficiency may remain subclinical or may result in severe combined immunodeficiency or Omenn syndrome, humoral immunodeficiency has only rarely been noted in these patients. Here we report the diagnosis of CHH in a woman who presented with severe short stature and a full-blown antibody deficiency, clinically resembling common variable immunodeficiency. Sequencing of the RMRP gene revealed compound heterozygosity for two novel mutations (g.68_69delinsTT and g.76C>T). Despite the late onset of immunodeficiency in the patient, its clinical course was severe, and the patient died 3 years after the first diagnosis.

  19. The influence of growth hormone (GH) deficiency and GH replacement on quality of life in GH-deficient patients.

    Science.gov (United States)

    Deijen, J B; van der Veen, E A

    1999-01-01

    The total absence of hormones such as cortisol or thyroxine causes death within weeks. Lack of estrogen or testosterone is followed by infertility and impaired sexual functioning. Relative deficiencies of almost all classical hormones have a substantial impact on quality of life (QOL). However, in contrast to virtually all aspects of metabolism, QOL is difficult to measure. Only recently have tests been developed to assess general QOL, whereas specific tests address those aspects of QOL affected only in specific situations or disease states. For example, in rheumatoid arthritis and other chronic disabling diseases, the use of measures of QOL to assess treatment modalities is almost routine. In diseases with overt metabolic disturbances attention is generally focused on changes in metabolic parameters and the issue of QOL is neglected. Although very few practising endocrinologists will not support the idea that they specialize in improving QOL, its assessment in patients with endocrinological disorders began only recently--in patients with growth hormone (GH) deficiency only 10 years ago. It became apparent that GH deficiency in adult life is unmistakably followed by changes in parameters that determine QOL. In adults with childhood-onset GH deficiency, the unemployment rate is higher and the marriage rate lower than in the general population. Another symbol of success in life, the possession of a driver's licence, is less frequently attained by these patients. Most patients with adult-onset GH deficiency score unfavourably in questionnaires such as the Nottingham Health Profile. GH substitution is now available on a scale large enough to enable studies to be made of the effects on QOL in adults. The first studies were reported in 1989. However, only in the last few years have studies appeared in which sufficient number of patients and sufficient length of treatment were reported to allow a more objective judgement of the effectiveness of GH substitution. Although

  20. Coexistence of Essential Thrombocythemia, Iron-Refractory Iron Deficiency Anemia and Renal Cell Carcinoma

    Science.gov (United States)

    Tekgündüz, Emre; Altuntaş, Fevzi

    2016-01-01

    Essential thrombocythemia (ET) is a Philadelphia chromosome (Ph)-negative myeloproliferative neoplasm. It is characterized by thrombocytosis and megakaryocytic hyperplasia of the bone marrow with JAK2V617F mutation. Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive disorder, which is mainly characterized by iron deficiency anemia not responding to oral iron intake, but partially responding to parenteral iron therapy. Recently, it has been shown that IRIDA has stemmed from mutations in the gene TMPRSS6, which encodes a transmembrane serine protease (matriptase-2) expressed by the liver. Renal cell carcinoma (RCC) accounts for 2-3% of all cancers. As the most common solid lesion in the kidneys, it represents approximately 90% of all renal malignancies. Approximately 30% of patients with symptomatic RCCs seem to display paraneoplastic syndromes. The symptom that may result from erythrocytosis is the most well-known paraneoplastic hematological event. Here, we report a patient who presents with coexistence of RCC and thrombocytosis, which hasn’t been caused by hormonal factors that are produced in tumor cells. This patient has been therefore diagnosed with ET. The patient who was expected to display RCC with polycythemia, conversely present with IRIDA. PMID:27103977

  1. Coexistence of essential thrombocythemia, iron-refractory iron deficiency anemia and renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Sinem Namdaroğlu

    2016-03-01

    Full Text Available Essential thrombocythemia (ET is a Philadelphia chromosome (Ph-negative myeloproliferative neoplasm. It is characterized by thrombocytosis and megakaryocytic hyperplasia of the bone marrow with JAK2V617F mutation. Iron-refractory iron deficiency anemia (IRIDA is an autosomal recessive disorder, which is mainly characterized by iron deficiency anemia not responding to oral iron intake, but partially responding to parenteral iron therapy. Recently, it has been shown that IRIDA has stemmed from mutations in the gene TMPRSS6, which encodes a transmembrane serine protease (matriptase- 2 expressed by the liver. Renal cell carcinoma (RCC accounts for 2-3% of all cancers. As the most common solid lesion in the kidneys, it represents approximately 90% of all renal malignancies. Approximately 30% of patients with symptomatic RCCs seem to display paraneoplastic syndromes. The symptom that may result from erythrocytosis is the most wellknown paraneoplastic hematological event. Here, we report a patient who presents with coexistence of RCC and thrombocytosis, which hasn’t been caused by hormonal factors that are produced in tumor cells. This patient has been therefore diagnosed with ET. The patient who was expected to display RCC with polycythemia, conversely present with IRIDA.

  2. Ciliary beating recovery in deficient human airway epithelial cells after lentivirus ex vivo gene therapy.

    Directory of Open Access Journals (Sweden)

    Brigitte Chhin

    2009-03-01

    Full Text Available Primary Ciliary Dyskinesia is a heterogeneous genetic disease that is characterized by cilia dysfunction of the epithelial cells lining the respiratory tracts, resulting in recurrent respiratory tract infections. Despite lifelong physiological therapy and antibiotics, the lungs of affected patients are progressively destroyed, leading to respiratory insufficiency. Recessive mutations in Dynein Axonemal Intermediate chain type 1 (DNAI1 gene have been described in 10% of cases of Primary Ciliary Dyskinesia. Our goal was to restore normal ciliary beating in DNAI1-deficient human airway epithelial cells. A lentiviral vector based on Simian Immunodeficiency Virus pseudotyped with Vesicular Stomatitis Virus Glycoprotein was used to transduce cultured human airway epithelial cells with a cDNA of DNAI1 driven by the Elongation Factor 1 promoter. Transcription and translation of the transduced gene were tested by RT-PCR and western blot, respectively. Human airway epithelial cells that were DNAI1-deficient due to compound heterozygous mutations, and consequently had immotile cilia and no outer dynein arm, were transduced by the lentivirus. Cilia beating was recorded and electron microscopy of the cilia was performed. Transcription and translation of the transduced DNAI1 gene were detected in human cells treated with the lentivirus. In addition, immotile cilia recovered a normal beat and outer dynein arms reappeared. We demonstrated that it is possible to obtain a normalization of ciliary beat frequency of deficient human airway epithelial cells by using a lentivirus to transduce cells with the therapeutic gene. This preliminary step constitutes a conceptual proof that is indispensable in the perspective of Primary Ciliary Dyskinesia's in vivo gene therapy. This is the first time that recovery of cilia beating is demonstrated in this disease.

  3. Alterations of coagulation and fibrinolysis in patients with angioedema due to C1-inhibitor deficiency

    NARCIS (Netherlands)

    Geffen, M. van; Cugno, M.; Lap, P.; Loof, A.; Cicardi, M.; Heerde, W.L. van

    2012-01-01

    Patients with functional deficiency of C1-inhibitor (C1-INH) suffer from recurrent acute attacks (AA) of localized oedema associated with activation of the contact system, complement and fibrinolysis. To unravel further the role of coagulation and fibrinolysis in the pathophysiology of C1-INH defici

  4. Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiency.

    NARCIS (Netherlands)

    Hinttala, R.; Smeets, R.; Moilanen, J.S.; Ugalde, C.; Uusimaa, J.; Smeitink, J.A.M.; Majamaa, K.

    2006-01-01

    BACKGROUND: Enzyme deficiencies of the oxidative phosphorylation (OXPHOS) system may be caused by mutations in the mitochondrial DNA (mtDNA) or in the nuclear DNA. OBJECTIVE: To analyse the sequences of the mtDNA coding region in 25 patients with OXPHOS system deficiency to identify the underlying g

  5. Clinical Features and Outcome of Patients With IRAK-4 and MyD88 Deficiency

    NARCIS (Netherlands)

    Picard, Capucine; von Bernuth, Horst; Ghandil, Pegah; Chrabieh, Maya; Levy, Ofer; Arkwright, Peter D.; McDonald, Douglas; Geha, Raif S.; Takada, Hidetoshi; Krause, Jens C.; Creech, C. Buddy; Ku, Cheng-Lung; Ehl, Stephan; Marodi, Laszlo; Al-Muhsen, Saleh; Al-Hajjar, Sami; Al-Ghonaium, Abdulaziz; Day-Good, Noorbibi K.; Holland, Steven M.; Gallin, John I.; Chapel, Helen; Speert, David P.; Rodriguez-Gallego, Carlos; Colino, Elena; Garty, Ben-Zion; Roifman, Chaim; Hara, Toshiro; Yoshikawa, Hideto; Nonoyama, Shigeaki; Domachowske, Joseph; Issekutz, Andrew C.; Tang, Mimi; Smart, Joanne; Zitnik, Simona Eva; Hoarau, Cyrille; Kumararatne, Dinakantha S.; Thrasher, Adrian J.; Davies, E. Graham; Bethune, Claire; Sirvent, Nicolas; de Ricaud, Dominique; Camcioglu, Yildiz; Vasconcelos, Julia; Guedes, Margarida; Vitor, Artur Bonito; Rodrigo, Carlos; Almazan, Francisco; Mendez, Maria; Ignacio Arostegui, Juan; Alsina, Laia; Fortuny, Claudia; Reichenbach, Janine; Verbsky, James W.; Bossuyt, Xavier; Doffinger, Rainer; Abel, Laurent; Puel, Anne; Casanova, Jean-Laurent

    2010-01-01

    Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD) 88 deficiencies impair Toll-like receptor (TLR)-and interleukin-1 receptor-mediated immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 pa

  6. Skeletal effects of vitamin D deficiency among patients with primary hyperparathyroidism.

    Science.gov (United States)

    Lee, J H; Kim, J H; Hong, A R; Kim, S W; Shin, C S

    2017-02-07

    Little is known about the association between vitamin D deficiency and the skeletal phenotypes in primary hyperparathyroidism (PHPT) patients. A low 25-hydroxyvitamin D level was associated with a low bone mineral density and deteriorated hip geometry in women with PHPT in an Asian population where vitamin D deficiency is prevalent.

  7. Non-infectious lung disease in patients with adenosine deaminase deficient severe combined immunodeficiency.

    Science.gov (United States)

    Booth, C; Algar, V E; Xu-Bayford, J; Fairbanks, L; Owens, C; Gaspar, H B

    2012-06-01

    Adenosine deaminase deficiency is a disorder of purine metabolism manifesting severe combined immunodeficiency (ADA-SCID) and systemic abnormalities. Increased levels of the substrate deoxyadenosine triphosphate (dATP) lead to immunodeficiency and are associated in a murine model with pulmonary insufficiency. We compared a cohort of patients with ADA-SCID and X-linked SCID and found that despite similar radiological and respiratory findings, positive microbiology is significantly less frequent in ADA-SCID patients (p < 0.0005), suggesting a metabolic pathogenesis for the lung disease. Clinicians should be aware of this possibility and correct metabolic abnormalities either through enzyme replacement or haematopoietic stem cell transplant, in addition to treating infectious complications.

  8. Deficient SOCS3 and SHP-1 Expression in Psoriatic T Cells

    DEFF Research Database (Denmark)

    Eriksen, Karsten W; Woetmann, Anders; Skov, Lone

    2010-01-01

    , we show that psoriatic T cells display deficient expression of the suppressor of cytokine signaling (SOCS)3 in response to IFN-alpha and a low baseline expression of the SH2-domain-containing protein-tyrosine phosphatase (SHP)-1 when compared with skin T cells from nonpsoriatic donors. Moreover, IFN......IFN-alpha and skin-infiltrating activated T lymphocytes have important roles in the pathogenesis of psoriasis. T cells from psoriatic patients display an increased sensitivity to IFN-alpha, but the pathological mechanisms behind the hyperresponsiveness to IFN-alpha remained unknown. In this study......-alpha-stimulated psoriatic T cells show enhanced activation of JAKs (JAK1 and TYK2) and signal transducers and activators of transcription. Increased expression of SOCS3 proteins resulting from proteasomal blockade partially inhibits IFN-alpha response. Similarly, forced expression of SOCS3 and SHP-1 inhibits IFN...

  9. Patient with Eating Disorder, Carnitine Deficiency and Dilated Cardiomyopathy.

    Science.gov (United States)

    Fotino, A Domnica; Sherma, A

    2015-01-01

    Dilated cardiomyopathy is characterized by a dilated and poorly functioning left ventricle and can result from several different etiologies including ischemic, infectious, metabolic, toxins, autoimmune processes or nutritional deficiencies. Carnitine deficiency-induced cardiomyopathy (CDIM) is an uncommon cause of dilated cardiomyopathy that can go untreated if not considered. Here, we describe a 30-year-old woman with an eating disorder and recent percutaneous endoscopic gastrotomy (PEG) tube placement for weight loss admitted to the hospital for possible PEG tube infection. Carnitine level was found to be low. Transthoracic echocardiogram (TTE) revealed ejection fraction 15%. Her hospital course was complicated by sepsis from a peripherally inserted central catheter (PICC). She was discharged on a beta-blocker and carnitine supplementation. One month later her cardiac function had normalized. Carnitine deficiency-induced myopathy is an unusual cause of cardiomyopathy and should be considered in adults with decreased oral intake or malabsorption who present with cardiomyopathy.

  10. Cobalamin Deficiency in Elderly Patients: A Personal View

    Directory of Open Access Journals (Sweden)

    Emmanuel Andrès

    2008-01-01

    Full Text Available Cobalamin (vitamin B12 deficiency is particularly common in the elderly (>65 years of age but is often unrecognized because its clinical manifestations are subtle; however, they are also potentially serious, particularly from a neuropsychiatric and hematological perspective. In the elderly, the main causes of cobalamin deficiency are pernicious anemia and food-cobalamin malabsorption. Food-cobalamin malabsorption syndrome is a disorder characterized by the inability to release cobalamin from food or its binding proteins. This syndrome is usually caused by atrophic gastritis, related or unrelated to Helicobacter pylori infection, and long-term ingestion of antacids and biguanides. Management of cobalamin deficiency with cobalamin injections is currently well documented but new routes of cobalamin administration (oral and nasal are being studied, especially oral cobalamin therapy for food-cobalamin malabsorption.

  11. [Salmonella typhi vaccination response study reveals defective antibody production selective IgA deficiency patient].

    Science.gov (United States)

    Pleguezuelo, Daniel E; Gianelli, Carla

    2015-01-01

    Selective IgA deficiency (SIgAD) is the most prevalent immunodeficiency worldwide, progressing to common variable immunodeficiency only in few reported cases. We report the case of a Spanish female aged 22 and diagnosed of selective IgA deficiency, a long history of bronchitis, several episodes of pneumonia, bilateral bronchiectasis, normal IgG, IgM, IgG subclasses, and detectable pre-vaccination IgG antibodies against tetanus toxoid and Streptococcus pneumoniae. She was evaluated in our clinic in order to rule out common variable immunodeficiency. We observed good antibody response to tetanus toxoid, absence of circulating switched memory B cells, decreased response to pneumococcal polysaccharide antigens and a lack of response to Salmonella typhi vaccine. Most SIgAD patients presents with upper respiratory tract infections or mild diarrhea. Those with lower tract infections, pneumonia or untreatable diarrhea should follow B-cell subpopulations' study and antibody response to vaccines. Absence of response to Salmonella typhi vaccine allowed us to expose the defective antibody production.

  12. Successful treatment of a guanidinoacetate methyltransferase deficient patient : Findings with relevance to treatment strategy and pathophysiology

    NARCIS (Netherlands)

    Verbruggen, Krijn T.; Sijens, Paul E.; Schulze, Andreas; Lunsing, Roelineke J.; Jakobs, Cornelis; Salomons, Gajja S.; van Spronsen, Francian J.

    2007-01-01

    Biochemical and developmental results of treatment of a guanidinoacetate methyltransferase (GAMT) deficient patient with a mild clinical presentation and remarkable developmental improvement after treatment are presented. Treatment with creatine (Cr) supplementation resulted in partial normalization

  13. Generation of glycosylphosphatidylinositol anchor protein-deficient blood cells from human induced pluripotent stem cells.

    Science.gov (United States)

    Yuan, Xuan; Braunstein, Evan M; Ye, Zhaohui; Liu, Cyndi F; Chen, Guibin; Zou, Jizhong; Cheng, Linzhao; Brodsky, Robert A

    2013-11-01

    PIG-A is an X-linked gene required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors; thus, PIG-A mutant cells have a deficiency or absence of all GPI-anchored proteins (GPI-APs). Acquired mutations in hematopoietic stem cells result in the disease paroxysmal nocturnal hemoglobinuria, and hypomorphic germline PIG-A mutations lead to severe developmental abnormalities, seizures, and early death. Human induced pluripotent stem cells (iPSCs) can differentiate into cell types derived from all three germ layers, providing a novel developmental system for modeling human diseases. Using PIG-A gene targeting and an inducible PIG-A expression system, we have established, for the first time, a conditional PIG-A knockout model in human iPSCs that allows for the production of GPI-AP-deficient blood cells. PIG-A-null iPSCs were unable to generate hematopoietic cells or any cells expressing the CD34 marker and were defective in generating mesodermal cells expressing KDR/VEGFR2 (kinase insert domain receptor) and CD56 markers. In addition, PIG-A-null iPSCs had a block in embryonic development prior to mesoderm differentiation that appears to be due to defective signaling through bone morphogenetic protein 4. However, early inducible PIG-A transgene expression allowed for the generation of GPI-AP-deficient blood cells. This conditional PIG-A knockout model should be a valuable tool for studying the importance of GPI-APs in hematopoiesis and human development.

  14. Zinc-deficiency acrodermatitis in a patient with chronic alcoholism and gastric bypass: a case report

    Directory of Open Access Journals (Sweden)

    Dariush Shahsavari

    2014-07-01

    Full Text Available Acquired adult-onset zinc deficiency is occasionally reported in patients with malnutrition states, such as alcoholism, or malabsorptive states, such as post-bariatric surgery. The defining symptoms of hypozincemia include a classic triad of necrolytic dermatitis, diffuse alopecia, and diarrhea. We report a case of zinc deficiency in a 39-year-old man with history of gastric bypass surgery and alcoholism. For this patient, severe hypozincemia confirmed acrodermatitis, and zinc supplementation was met with gradual improvement.

  15. 5FU and oxaliplatin-containing chemotherapy in two dihydropyrimidine dehydrogenase-deficient patients.

    Science.gov (United States)

    Reerink, O; Mulder, N H; Szabo, B G; Hospers, G A P

    2004-01-01

    Patients with a germline mutation leading to a deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme are at risk from developing severe toxicity on the administration of 5FU-containing chemotherapy. We report on the implications of this inborn genetic error in two patients who received 5FU and oxaliplatin. A possible co-medication effect of oxaliplatin is considered, as are the consequences of screening for DPD deficiency.

  16. Sequential swallows have no influence on esophageal contractions of patients with iron deficiency anemia

    OpenAIRE

    Roberto Oliveira DANTAS; Miranda,Adriana Leonarda Martins

    2004-01-01

    BACKGROUND: An experimental study showed that thyropharyngeal, cricopharyngeal and cervical esophageal muscles of rabbits with iron deficiency anemia had morphological changes similar to those observed in muscular dystrophy, causing myastenic changes in muscles involved in swallowing. Our hypothesis is that patients with iron deficiency anemia may have a decrease in esophageal contractions with successive swallows. PATIENTS AND METHOD: We studied the esophageal motility of 12 women with iron ...

  17. Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?

    Science.gov (United States)

    Hanna-El-Daher, Layane; Braissant, Olivier

    2016-08-01

    While it has long been thought that most of cerebral creatine is of peripheral origin, the last 20 years has provided evidence that the creatine synthetic pathway (AGAT and GAMT enzymes) is expressed in the brain together with the creatine transporter (SLC6A8). It has also been shown that SLC6A8 is expressed by microcapillary endothelial cells at the blood-brain barrier, but is absent from surrounding astrocytes, raising the concept that the blood-brain barrier has a limited permeability for peripheral creatine. The first creatine deficiency syndrome in humans was also discovered 20 years ago (GAMT deficiency), followed later by AGAT and SLC6A8 deficiencies, all three diseases being characterized by creatine deficiency in the CNS and essentially affecting the brain. By reviewing the numerous and latest experimental studies addressing creatine transport and synthesis in the CNS, as well as the clinical and biochemical characteristics of creatine-deficient patients, our aim was to delineate a clearer view of the roles of the blood-brain and blood-cerebrospinal fluid barriers in the transport of creatine and guanidinoacetate between periphery and CNS, and on the intracerebral synthesis and transport of creatine. This review also addresses the question of guanidinoacetate toxicity for brain cells, as probably found under GAMT deficiency.

  18. The Arteriovenous Difference in Hemostatic Parameters in Critically Ill Patients with Different Types of Energy Deficiency

    Directory of Open Access Journals (Sweden)

    I. B Zabolotskikh

    2013-01-01

    Full Text Available Objective: to reveal the patterns of hemostatic disorder development in the venous and arterial bed in relation to the type of energy deficiency. Subjects and methods. One hundred and ninety-nine patients who had undergone extensive abdominal surgeries (gastrectomy, pancreatoduodenectomies, hemicolectomies, hepatectomies, etc. were examined. Among the patients, there were 5 groups: a control group without energy deficiency and 4 groups of patients who were recorded to have one of the types of energy deficiency: substrate, hypermetabolic, hypoxic, and enzymatic. Results and discussion. The nature and degree of existing metabolic disturbances and changes in the arteriovenous difference in hemostasiological parameters have a statistically proven relationship (on the basis of ROC analysis. Substrate energy deficiency was characterized by the insignificant changes in the hemostatic system as a whole, which affect only its coagulation component; the arteriovenous difference in hemostasiological parameters was similar to that in the patients without energy deficiency. In hypermetabolic energy deficiency, the venous bed demonstrated the most pronounced hemostatic changes (hypercoagulation, suppressed fibrinolysis, and enhanced platelet aggregation. The hemostatic changes that were more significant than those in the above group were responsible for the formation of a significant arteriovenous difference in the hemostasiological parameters; however, the direction of this difference did not differ from that in the patients without energy deficiency. In hypoxic energy deficiency, hemostatic disorders were heterodirectional in the arterial and venous bed (these were most marked in the arterial bed — hypercoagulation, activated fibrinolysis, and enhanced platelet aggregation therefore there was a significant arteriovenous difference in the hemostasiological parameters, which was opposite as compared to that in the patients without energy deficiency. In

  19. Thymidine kinase 1 deficient cells show increased survival rate after UV-induced DNA damage

    DEFF Research Database (Denmark)

    Skovgaard, T; Rasmussen, Lene Juel; Munch-Petersen, Birgitte

    2010-01-01

    Balanced deoxynucleotide pools are known to be important for correct DNA repair, and deficiency for some of the central enzymes in deoxynucleotide metabolism can cause imbalanced pools, which in turn can lead to mutagenesis and cell death. Here we show that cells deficient for the thymidine salvage...

  20. Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency

    DEFF Research Database (Denmark)

    Qasim, Waseem; Cavazzana-Calvo, Marina; Davies, E Graham

    2009-01-01

    therapeutic option if a suitable HLA-matched stem-cell donation is available. Reduced-intensity conditioning was particularly safe, and mixed-donor chimerism seems sufficient to prevent significant symptoms, although careful long-term monitoring will be required for these patients....... Blood and Marrow Transplant Research. RESULTS: At a median follow-up of 62 months (extending to 14 years), the overall survival rate was 75%. Myeloablative conditioning regimens were used in 28 patients, and reduced-intensity conditioning in 8 patients, with no deaths in this subgroup. Survival rates...

  1. Sugar and chromosome stability: clastogenic effects of sugars in vitamin B6-deficient cells.

    Directory of Open Access Journals (Sweden)

    Antonio Marzio

    2014-03-01

    Full Text Available Pyridoxal 5'-phosphate (PLP, the active form of vitamin B6, has been implicated in preventing human pathologies, such as diabetes and cancer. However, the mechanisms underlying the beneficial effects of PLP are still unclear. Using Drosophila as a model system, we show that PLP deficiency, caused either by mutations in the pyridoxal kinase-coding gene (dPdxk or by vitamin B6 antagonists, results in chromosome aberrations (CABs. The CAB frequency in PLP-depleted cells was strongly enhanced by sucrose, glucose or fructose treatments, and dPdxk mutant cells consistently displayed higher glucose contents than their wild type counterparts, an effect that is at least in part a consequence of an acquired insulin resistance. Together, our results indicate that a high intracellular level of glucose has a dramatic clastogenic effect if combined with PLP deficiency. This is likely due to an elevated level of Advanced Glycation End-products (AGE formation. Treatment of dPdxk mutant cells with α-lipoic acid (ALA lowered both AGE formation and CAB frequency, suggesting a possible AGE-CAB cause-effect relationship. The clastogenic effect of glucose in PLP-depleted cells is evolutionarily conserved. RNAi-mediated silencing of PDXK in human cells or treatments with PLP inhibitors resulted in chromosome breakage, which was potentiated by glucose and reduced by ALA. These results suggest that patients with concomitant hyperglycemia and vitamin B6 deficiency may suffer chromosome damage. This might impact cancer risk, as CABs are a well-known tumorigenic factor.

  2. Relationship between cobalamin deficiency and delirium in elderly patients undergoing cardiac surgery

    Directory of Open Access Journals (Sweden)

    Sevuk U

    2015-08-01

    Full Text Available Utkan Sevuk,1 Erkan Baysal,2 Nurettin Ay,3 Yakup Altas,2 Rojhat Altindag,2 Baris Yaylak,2 Vahhac Alp,3 Ertan Demirtas4 1Department of Cardiovascular Surgery, Diyarbakir Gazi Yasargil Education and Research Hospital, Diyarbakir, 2Department of Cardiology, Diyarbakir Gazi Yasargil Education and Research Hospital, Diyarbakir, 3Department of General Surgery, Diyarbakir Gazi Yasargil Education and Research Hospital, Diyarbakir, 4Department of Cardiovascular Surgery, Liv Hospital, Ankara, Turkey Background: Delirium is common after cardiac surgery and is independently associated with increased morbidity, mortality, prolonged hospital stays, and higher costs. Cobalamin (vitamin B12 deficiency is a common cause of neuropsychiatric symptoms and affects up to 40% of elderly people. The relationship between cobalamin deficiency and the occurrence of delirium after cardiac surgery has not been examined in previous studies. We examined the relationship between cobalamin deficiency and delirium in elderly patients undergoing coronary artery bypass grafting (CABG surgery.Material and methods: A total of 100 patients with cobalamin deficiency undergoing CABG were enrolled in this retrospective study. Control group comprised 100 patients without cobalamin deficiency undergoing CABG. Patients aged 65 years or over were included. Diagnosis of delirium was made using Intensive Care Delirium Screening Checklist. Delirium severity was measured using the Delirium Rating Scale-revised-98.Results: Patients with cobalamin deficiency had a significantly higher incidence of delirium (42% vs 26%; P=0.017 and higher delirium severity scores (16.5±2.9 vs 15.03±2.48; P=0.034 than patients without cobalamin deficiency. Cobalamin levels were significantly lower in patients with delirium than patients without delirium (P=0.004. Delirium severity score showed a moderate correlation with cobalamin levels (Ρ=-0.27; P=0.024. Logistic regression analysis demonstrated that

  3. Severe Developmental B Lymphopoietic Defects in Foxp3-Deficient Mice are Refractory to Adoptive Regulatory T Cell Therapy.

    Science.gov (United States)

    Riewaldt, Julia; Düber, Sandra; Boernert, Marie; Krey, Martina; Dembinski, Marcin; Weiss, Siegfried; Garbe, Annette I; Kretschmer, Karsten

    2012-01-01

    The role of Foxp3-expressing regulatory T (T(reg)) cells in tolerance and autoimmunity is well-established. However, although of considerable clinical interest, the role of T(reg) cells in the regulation of hematopoietic homeostasis remains poorly understood. Thus, we analysed B and T lymphopoiesis in the scurfy (Sf) mouse model of T(reg) cell deficiency. In these experiments, the near-complete block of B lymphopoiesis in the BM of adolescent Sf mice was attributed to autoimmune T cells. We could exclude a constitutive lympho-hematopoietic defect or a B cell-intrinsic function of Foxp3. Efficient B cell development in the BM early in ontogeny and pronounced extramedullary B lymphopoietic activity resulted in a peripheral pool of mature B cells in adolescent Sf mice. However, marginal zone B and B-1a cells were absent throughout ontogeny. Developmental B lymphopoietic defects largely correlated with defective thymopoiesis. Importantly, neonatal adoptive T(reg) cell therapy suppressed exacerbated production of inflammatory cytokines and restored thymopoiesis but was ineffective in recovering defective B lymphopoiesis, probably due to a failure to compensate production of stroma cell-derived IL-7 and CXCL12. Our observations on autoimmune-mediated incapacitation of the BM environment in Foxp3-deficient mice will have direct implications for the rational design of BM transplantation protocols for patients with severe genetic deficiencies in functional Foxp3(+) T(reg) cells.

  4. Short-term outcome of Boston Type 1 keratoprosthesis for bilateral limbal stem cell deficiency

    Directory of Open Access Journals (Sweden)

    Sayan Basu

    2012-01-01

    Full Text Available This study reports the short-term functional and anatomical outcome of Boston Type 1 keratoprosthesis (Boston Kpro implantation for bilateral limbal stem cell deficiency (LCSD. Retrospective analysis was done on eight eyes of eight patients who underwent Boston Kpro implantation between July 2009 and October 2009. The best corrected visual acuity (BCVA and slit-lamp biomicroscopy findings were assessed at 1, 3 and 6 months postoperatively. All eight eyes retained the prosthesis. BCVA of 20/40 or better was achieved in 8, 6, and 5 eyes at 1, 3, and 6 months, respectively, postoperatively. One patient each developed epithelial defect, sterile stromal melt and fungal keratitis in the late postoperative period associated with antecedent loss of the soft contact lens from the eye. Boston Kpro has good short-term visual and anatomical outcome in patients with bilateral LSCD, provided compliance with postoperative care can be ensured.

  5. Deficient recovery from potentially lethal damage in some gamma-irradiated human fibroblast cell strains

    Energy Technology Data Exchange (ETDEWEB)

    Arlett, C.F.; Priestley, A. (Medical Research Council, Brighton (UK). Cell Mutation Unit)

    1984-01-01

    The repair of potentially lethal damage following treatment with gamma radiation was investigated in human fibroblasts held in a non-cycling state by maintenance in a medium containing 0.5% foetal calf serum. Normal cells were found to be competent in the repair of PLD. Ataxia-telangiectasia cells were deficient as was a heterozygote suggesting that a failure to repair PLD may make it possible to detect such heterozygotes. Fibroblasts from Huntington's disease patients were either slightly or no more sensitive than cells from normal individuals. Cultures from two individuals in the former class showed limited capacity to repair PLD but cells from the latter class were as competent as normals. Thus assays of radiosensitivity where conditions allow for the repair of PLD may maximise small differences in sensitivity. Cells taken from three patients suffering from Basal Cell Naevus Syndrome were also shown to be defective in the repair of PLD. The existence of such a defect may be related to the increased frequency of basal cell cancer observed in exposed fields following irradiation of such individuals.

  6. CCR7 deficiency on dendritic cells enhances fungal clearance in a murine model of pulmonary invasive aspergillosis.

    Science.gov (United States)

    Hartigan, Adam J; Westwick, John; Jarai, Gabor; Hogaboam, Cory M

    2009-10-15

    Aspergillus fumigatus is a sporulating fungus found ubiquitously in the environment and is easily cleared from immunocompetent hosts. Invasive aspergillosis develops in immunocompromised patients, and is a leading cause of mortality in hematopoietic stem cell transplant recipients. CCR7 and its ligands, CCL19 and CCL21, are responsible for the migration of dendritic cells from sites of infection and inflammation to secondary lymphoid organs. To investigate the role of CCR7 during invasive aspergillosis, we used a well-characterized neutropenic murine model. During invasive aspergillosis, mice with a CCR7 deficiency in the hematopoietic compartment exhibited increased survival and less pulmonary injury compared with the appropriate wild-type control. Flow cytometric analysis of the chimeric mice revealed an increase in the number of dendritic cells present in the lungs of CCR7-deficient chimeras following infection with Aspergillus conidia. An adoptive transfer of dendritic cells into neutropenic mice provided a protective effect during invasive aspergillosis, which was further enhanced with the adoptive transfer of CCR7-deficient dendritic cells. Additionally, CCR7-deficient dendritic cells activated in vitro with Aspergillus conidia expressed higher TNF-alpha, CXCL10, and CXCL2 levels, indicating a more activated cellular response to the fungus. Our results suggest that the absence of CCR7 is protective during invasive aspergillosis in neutropenic mice. Collectively, these data demonstrate a potential deleterious role for CCR7 during primary immune responses directed against A. fumigatus.

  7. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency.

    Science.gov (United States)

    Hassan, Amel; Booth, Claire; Brightwell, Alex; Allwood, Zoe; Veys, Paul; Rao, Kanchan; Hönig, Manfred; Friedrich, Wilhelm; Gennery, Andrew; Slatter, Mary; Bredius, Robbert; Finocchi, Andrea; Cancrini, Caterina; Aiuti, Alessandro; Porta, Fulvio; Lanfranchi, Arnalda; Ridella, Michela; Steward, Colin; Filipovich, Alexandra; Marsh, Rebecca; Bordon, Victoria; Al-Muhsen, Saleh; Al-Mousa, Hamoud; Alsum, Zobaida; Al-Dhekri, Hasan; Al Ghonaium, Abdulaziz; Speckmann, Carsten; Fischer, Alain; Mahlaoui, Nizar; Nichols, Kim E; Grunebaum, Eyal; Al Zahrani, Daifulah; Roifman, Chaim M; Boelens, Jaap; Davies, E Graham; Cavazzana-Calvo, Marina; Notarangelo, Luigi; Gaspar, H Bobby

    2012-10-25

    Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved.

  8. Cell-wall-deficient bacteria: a major etiological factor for psoriasis?

    Institute of Scientific and Technical Information of China (English)

    WANG Guo-li; LI Xiu-yun; WANG Ming-yi; XIAO De-gui; ZHANG Yong-yu; YUAN Xiao-yan; WANG Qi-you; SONG Jian-jing

    2009-01-01

    Background Psoriasis is a common inflammatory skin disease, yet knowledge of the factors that may induce, trigger, or exacerbate psoriasis is not fully delineated. Recent advances have improved our understanding of the link between psoriasis and cell-wall-deficient bacteria (CWDB) infections. In the present study we assessed the prevalence of CWDB infection in patients with psoriasis.Methods The carriage rate of CWDB in the tonsil or pharynx of psoriasis patients, chronic tonsillitis patients and controls were investigated using hypertonic medium. Psoriasis patients with CWDB were randomly assigned to two groups and respectively treated with antibiotics or systemic therapy without antibiotic. Human peripheral blood mononuclear cells (PBMC) from psoriasis patients, chronic tonsillitis patients and control subjects were stimulated with bacteria antigens and extra-cellular levels of interferon-γ (IFN-γ) and interleukin (IL)-10 were measured in the supernatants using the ELISA technique, in vitro. Meanwhile, the proliferation ability of PBMC to respond to bacteria antigens was detected by MTT assay.Results CWDB were isolated from 74.2% of psoriasis patients, 23.5% of chronic tonsillitis patients and only 6.3% of controls. Antibiotic therapy was appropriate for approximately 80% of psoriasis patients with CWDB infection, and in only 8.9% psoriasis patients CWDB infection was detected after antibiotic therapy. Meanwhile, our study showed that CWDB and wide-type bacteria did remarkably enhance the production of IFN-γ, in vitro, and PBMC proliferation. Conclusion CWDB infection may be a virtual triggering factor in psoriasis by regulating T-cell activation.

  9. Deficiência de ferro na insuficiência cardíaca Iron deficiency in heart failure patients

    Directory of Open Access Journals (Sweden)

    Antonio Carlos P. Barretto

    2010-06-01

    Full Text Available A anemia é uma comorbidade frequente nos pacientes com insuficiência cardíaca (IC e sua presença parece estar associada à pior evolução, sendo descrita em alguns estudos como fator de prognóstico independente tanto na IC sistólica quanto na diastólica. Entretanto, ainda não sabemos se a anemia causa pior evolução ou se é apenas um marcador do maior comprometimento cardíaco nos portadores de IC. A etiologia da anemia na IC é multifatorial e parece variar conforme a população estudada. Os fatores como a deficiência nutricional de ferro, presença de insuficiência renal, intensa atividade inflamatória sistêmica, uso de medicações que inibem a produção de eritropoetina ou que causam perda sanguínea são os mais frequentes causadores de anemia na IC. A prevalência de anemia citada nos estudos de IC é muito variável (de 9% a 79,1% e isto é dependente da população estudada, da fase da cardiopatia, do método e referências hematimétricas utilizadas para diagnóstico. A deficiência de ferro é um importante fator etiológico e está presente em um número significativo de pacientes com anemia e IC associada. Em estudo realizado em nosso grupo, a incidência de deficiência de ferro nos pacientes com anemia foi de 61,8%. Portanto, a anemia é um achado frequente, sua presença acentua as manifestações clínicas da IC e está associada a piora do prognóstico. Conhecer a causa da anemia facilita o seu tratamento e, apesar da sua correção ainda não ser consenso, os pacientes sem anemia têm melhor evolução.Anemia is common in heart failure (HF patients with its presence apparently associated to a worse prognosis, and as such is described in some studies as an independent predictor of death and hospitalization of patients suffering from systolic and diastolic dysfunction. It remains unknown whether anemia causes the worse evolution of HF patients or whether it is only one marker of a worse heart disease stage. The

  10. A deficiency of interstitial cells of Cajal in Chagasic megacolon.

    Science.gov (United States)

    Hagger, R; Finlayson, C; Kahn, F; De Oliveira, R; Chimelli, L; Kumar, D

    2000-04-12

    Disordered gut motor activity is a feature of patients with Chagas' disease: colonic involvement leads to the development of megacolon and symptoms of constipation. Interstitial cells of Cajal are thought to modulate gut motility. The aim of this study was to test the hypothesis that there is an abnormality of the density of distribution of interstitial cells of Cajal in Chagasic megacolon. Interstitial cells of Cajal were identified by immunohistochemistry using an anti-c-kit antibody. Six patients with Chagasic megacolon were compared with normal controls. The density of distribution of interstitial cells of Cajal was assessed in the longitudinal and circular muscle layers, and in the intermuscular plane of the Chagasic and normal colon. Statistical analysis was performed using Fisher's exact test. The interstitial cells of Cajal density in Chagasic megacolon was much reduced in comparison to normal colonic tissue in the longitudinal muscle layer (P=0.0084), intermuscular plane (P<0.0001), and circular muscle layer (P=0.0051). The lack of interstitial cells of Cajal may play a role in the pathophysiology of the disease, leading to the development of megacolon and symptoms of constipation.

  11. Lower-zone emphysema in young patients without α1-antitrypsin deficiency

    Science.gov (United States)

    Martelli, Nestor A.; Goldman, Ernesto; Roncoroni, Aquiles J.

    1974-01-01

    Martelli, N. A., Goldman, E., and Roncoroni, A. J. (1974).Thorax, 29, 237-244. Lowerzone emphysema in young patients without α1-antitrypsin deficiency. Three young patients with radiographic pulmonary emphysema predominantly in the lower zones are reported. The clinical and physiological features were those observed in severe pulmonary emphysema. Predominance of the main lesions in the lower zones was confirmed in two cases by selective pulmonary angiography. One of the patients died and extensive panlobular emphysema was found at necropsy. Although the similarities between our patients and those with emphysema and α1-antitrypsin deficiency were remarkable, the latter condition was ruled out. Images PMID:4545502

  12. Complementation of NADPH oxidase in p67-phox-deficient CGD patients p67-phox/p40-phox interaction.

    Science.gov (United States)

    Vergnaud, S; Paclet, M H; El Benna, J; Pocidalo, M A; Morel, F

    2000-02-01

    Chronic granulomatous disease (CGD) is due to a functional defect of the O2- generating NADPH oxidase of phagocytes. Epstein-Barr-virus-immortalized B lymphocytes express all the constituents of oxidase with activity 100 times less than that of neutrophils. As in neutrophils, oxidase activity of Epstein-Barr-virus-immortalized B lymphocytes was shown to be defective in the different forms of CGD; these cells were used as a model for the complementation studies of two p67-phox-deficient CGD patients. Reconstitution of oxidase activity was performed in vitro by using a heterologous cell-free assay consisting of membrane-suspended or solubilized and purified cytochrome b558 that was associated with cytosol or with the isolated cytosolic-activating factors (p67-phox, p47-phox, p40-phox) from healthy or CGD patients. In p67-phox-deficient CGD patients, two cytosolic factors are deficient or missing: p67-phox and p40-phox. Not more than 20% of oxidase activity was recovered by complementing the cytosol of p67-phox-deficient patients with recombinant p67-phox. On the contrary, a complete restoration of oxidase activity was observed when, instead of cytosol, the cytosolic factors were added in the cell-free assay after isolation in combination with cytochrome b558 purified from neutrophil membrane. Moreover, the simultaneous addition of recombinant p67-phox and recombinant p40-phox reversed the previous complementation in a p40-phox dose-dependent process. These results suggest that in the reconstitution of oxidase activity, p67-phox is the limiting factor; the efficiency of complementation depends on the membrane tissue and the cytosolic environment. In vitro, the transition from the resting to the activated state of oxidase, which results from assembling, requires the dissociation of p40-phox from p67-phox for efficient oxidase activity. In the process, p40-phox could function as a negative regulatory factor and stabilize the resting state.

  13. Bone Engineering of Maxillary Sinus Bone Deficiencies Using Enriched CD90+ Stem Cell Therapy: A Randomized Clinical Trial.

    Science.gov (United States)

    Kaigler, Darnell; Avila-Ortiz, Gustavo; Travan, Suncica; Taut, Andrei D; Padial-Molina, Miguel; Rudek, Ivan; Wang, Feng; Lanis, Alejandro; Giannobile, William V

    2015-07-01

    Bone engineering of localized craniofacial osseous defects or deficiencies by stem cell therapy offers strong prospects to improve treatment predictability for patient care. The aim of this phase 1/2 randomized, controlled clinical trial was to evaluate reconstruction of bone deficiencies of the maxillary sinus with transplantation of autologous cells enriched with CD90+ stem cells and CD14+ monocytes. Thirty human participants requiring bone augmentation of the maxillary sinus were enrolled. Patients presenting with 50% to 80% bone deficiencies of the maxillary sinus were randomized to receive either stem cells delivered onto a β-tricalcium phosphate scaffold or scaffold alone. Four months after treatment, clinical, radiographic, and histologic analyses were performed to evaluate de novo engineered bone. At the time of alveolar bone core harvest, oral implants were installed in the engineered bone and later functionally restored with dental tooth prostheses. Radiographic analyses showed no difference in the total bone volume gained between treatment groups; however, density of the engineered bone was higher in patients receiving stem cells. Bone core biopsies showed that stem cell therapy provided the greatest benefit in the most severe deficiencies, yielding better bone quality than control patients, as evidenced by higher bone volume fraction (BVF; 0.5 versus 0.4; p = 0.04). Assessment of the relation between degree of CD90+ stem cell enrichment and BVF showed that the higher the CD90 composition of transplanted cells, the greater the BVF of regenerated bone (r = 0.56; p = 0.05). Oral implants were placed and restored with functionally loaded dental restorations in all patients and no treatment-related adverse events were reported at the 1-year follow-up. These results provide evidence that cell-based therapy using enriched CD90+ stem cell populations is safe for maxillary sinus floor reconstruction and offers potential to accelerate and enhance

  14. Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma.

    Science.gov (United States)

    Kessler, Tobias; Sahm, Felix; Blaes, Jonas; Osswald, Matthias; Rübmann, Petra; Milford, David; Urban, Severino; Jestaedt, Leonie; Heiland, Sabine; Bendszus, Martin; Hertenstein, Anne; Pfenning, Philipp-Niclas; Ruiz de Almodóvar, Carmen; Wick, Antje; Winkler, Frank; von Deimling, Andreas; Platten, Michael; Wick, Wolfgang; Weiler, Markus

    2015-10-13

    Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.

  15. Anaesthesia management of caesarean section in a patient with severe factor XI deficiency

    Directory of Open Access Journals (Sweden)

    Debesh Bhoi

    2013-01-01

    Full Text Available Factor XI deficiency is a rare coagulation disorder associated with bleeding tendency and prolonged APTT. Parturients can have increased bleeding during vaginal delivery or cesarean section. Patients with severe factor XI deficiency should receive prophylactic fresh frozen plasma or factor XI transfusion in the peripartum period to maintain a near normal APTT. Limited evidence based on case reports and series is inconclusive as to the choice of anesthesia technique for cesarean section. We describe the anesthesia management of a parturient with severe factor XI deficiency for cesarean section and discuss the relevant literature.

  16. Deficient mRNA expression of specie protein 3 gene in peripheral blood mononuclear cells from patients with multiple sclerosis%多发性硬化患者外周血单个核细胞SP3基因mRNA表达缺失研究

    Institute of Scientific and Technical Information of China (English)

    林艾羽; 杨期东; 慕容慎行; 王柠; 吴秀丽; 林珉婷

    2008-01-01

    目的 研究我国多发性硬化(multiple sclerosis,Ms)患者外周血单个核细胞基因SP3(specificprotein 3)mRNA表达缺失的特点及其与临床表型的关系.方法 采集56例MS患者外周血单个核细胞,提取总RNA,设计SP3特异性引物,采用逆转录PCR方法观察SP3基因mRNA表达情况,并与其他疾病组、健康对照组进行比较.结果 56例MS患者中23例SP3为阴性结果,SP3表达缺失率为41.1%;健康对照组35例有5例为阴性结果,缺失率为8.6%;其它疾病对照组27例有4例为阴性结果,缺失率为14.3%.MS组与两对照组之间的差异有统计学意义(P<0.01).SP3表达缺失组与表达组急性期的改良残废程度量表评分差异无统计学意义,稳定期则差异有统计学意义(P<0.05).结论 通过对MS患者SP3基因mRNA表达的研究,观察到中国人MS存在该基因mRNA表达缺失.SP3与MS临床表现及其免疫学发病机制之间可能存在一定的相关性.%Objective To characterize the deficiency of the mRNA expression of specific protein 3(SP3)gene in peripheral blood mononuc|ear cells(PBMCs)from Chinese patients with multiple sclerosis(MS)and study its correlation with the disease phenotypes.Methods Fifty-six patients with definite MS were collected and total RNA was extracted from their PBMCs.Specific primers corresponding to SP3 gene were designed and the mRNA expression of SP3 gene was detected by reverse transcriptase-PCR(RT-PCR)method.The deficiency of SP3 expression was compared among MS patients,irrelavant disease group and normal controls.Results Of the 56 MS cases,23(41.1%)were SP3 -deficient.In contrast,the frequency of SP3-deficiency in normal subjects and irrelavant disease controls Was 8.6% (5/35)and 14.3%(4/27),respectively.The frequency of the SP3-expression deficiency in MS patients Was significantly higher than that in both control groups(P<0.01).Within the MS cases,the scores of expanded disability status scale(EDSS)in the SP3-expressing subjects

  17. Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

    Directory of Open Access Journals (Sweden)

    Sandra Almeida

    2012-10-01

    Full Text Available The pathogenic mechanisms of frontotemporal dementia (FTD remain poorly understood. Here we generated multiple induced pluripotent stem cell lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel heterozygous GRN mutation (progranulin [PGRN] S116X. In neurons and microglia differentiated from PGRN S116X induced pluripotent stem cells, the levels of intracellular and secreted PGRN were reduced, establishing patient-specific cellular models of PGRN haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by PGRN expression. Our findings identify cell-autonomous, reversible defects in patient neurons with PGRN deficiency, and provide a compelling model for studying PGRN-dependent pathogenic mechanisms and testing potential therapies.

  18. 'Renal phenotypic investigations of megalin-deficient patients'

    DEFF Research Database (Denmark)

    Storm, Tina; Tranebjærg, Lisbeth; Frykholm, Carina;

    2013-01-01

    The reabsorption of filtered plasma proteins, hormones and vitamins by the renal proximal tubules is vital for body homeostasis. Studies of megalin-deficient mice suggest that the large multi-ligand endocytic receptor megalin plays an essential role in this process. In humans, dysfunctional megalin...... causes the extremely rare Donnai-Barrow/Facio-Oculo-Acustico-Renal (DB/FOAR) syndrome characterized by a characteristic and multifaceted phenotype including low-molecular-weight proteinuria. In this study, we examined the role of megalin for tubular protein reabsorption in humans through analysis...

  19. Attenuated Heart Rate Response is Associated with Hypocretin Deficiency in Patients with Narcolepsy

    DEFF Research Database (Denmark)

    Sørensen, Gertrud Laura; Knudsen, Stine; Petersen, Eva Rosa;

    2013-01-01

    Our results show that autonomic dysfunction is part of the narcoleptic phenotype, and that hypocretin-1 deficiency is the primary predictor of this dysfunction. This finding suggests that the hypocretin system participates in the modulation of cardiovascular function at rest. CITATION: Sorensen G......; Knudsen S; Petersen ER; Kempfner J; Gammeltoft S; Sorensen HBD; Jennum P. Attenuated heart rate response is associated with hypocretin deficiency in patients with narcolepsy. SLEEP 2013;36(1):91-98....

  20. Growth Hormone Deficiency in a Patient with Becker Muscular Dystrophy: A Pediatric Case Report

    OpenAIRE

    Valeria Calcaterra; Annachiara Malvezzi; Rossana Toglia; Angela Berardinelli; Elena Bozzola; Mauro Bozzola; Daniela Larizza

    2013-01-01

    Objective. To describe a biochemical growth hormone (GH) deficiency and to evaluate therapeutic result in a six-year-old male with Becker muscular dystrophy (BMD). Methods. GH peak was evaluated after response to arginine and insulin. Bone age was evaluated according to Greulich and Pyle method. Results. The GH-supplementary therapy was very effective in terms of growth gain. Conclusion. The possibility of a growth hormone deficiency and treatment with GH in patients with BMD cannot be exclu...

  1. Isolated ACTH deficiency in a patient with empty sella as revealed by severe hyponatremia.

    Science.gov (United States)

    Doroftei, Nicoleta Alina; de Rudder, Catherine; de Visscher, Nathalie; Hanon, Francois

    2016-12-01

    Hyponatremia due to isolated adrenocorticotropic hormone (ACTH) deficiency is difficult to diagnose as it is usually indistinguishable from non-endocrine syndrome of inappropriate antidiuretic hormone secretion (SIADH). We present a case secondary to empty sella. Most patients with empty sella remain asymptomatic throughout life and require no treatment; however, in cases involving the development of isolated ACTH deficiency, corticosteroid treatment should be enforced to avoid fatal consequences.

  2. Lysosomal lipase deficiency: molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease.

    Science.gov (United States)

    Fasano, Tommaso; Pisciotta, Livia; Bocchi, Letizia; Guardamagna, Ornella; Assandro, Paola; Rabacchi, Claudio; Zanoni, Paolo; Filocamo, Mirella; Bertolini, Stefano; Calandra, Sebastiano

    2012-03-01

    Wolman Disease (WD) and cholesteryl ester storage disease (CESD) represent two distinct phenotypes of the same recessive disorder caused by the complete or partial deficiency of lysosomal acidic lipase (LAL), respectively. LAL, encoded by the LIPA gene, hydrolyzes cholesteryl esters derived from cell internalization of plasma lipoproteins. WD is a rapidly progressive and lethal disease characterized by intestinal malabsorption, hepatic and adrenal failure. CESD is characterized by hepatic fibrosis, hyperlipidemia and accelerated atherosclerosis. Aim of the study was the identification of LIPA mutations in three WD and eight CESD patients. The WD patients, all deceased before the first year of age, were homozygous for two novel mutations (c.299+1G>A and c.419G>A) or a mutation (c.796G>T) previously reported as compound heterozygosity in a CESD patient. The two mutations (c.419G>A and c.796G>T) resulting in truncated proteins (p.W140* and p.G266*) and the splicing mutation (c.229+1G>A) were associated with undetectable levels of LIPA mRNA in fibroblasts. All eight CESD patients carried the common mutation c.894G>A known to result not only in a major non-functional transcript with the skipping of exon 8 (p.S275_Q298del), but also in a minor normally spliced transcript producing 5-10% residual LAL activity. The c.894G>A mutation was found in homozygosity in four patients and, as compound heterozygosity, in association with a known (p.H295Y and p.G342R) or a novel (p.W140*) mutation in four other CESD patients. Segregation analysis performed in all patients harboring c.895G>A showed its occurrence on the same haplotype suggesting a common founder ancestor. The other WD and CESD mutations were associated with different haplotypes.

  3. BMP2 rescues deficient cell migration in Tgfbr3(-/-) epicardial cells and requires Src kinase.

    Science.gov (United States)

    Allison, Patrick; Espiritu, Daniella; Camenisch, Todd D

    2016-05-03

    During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. The type III transforming growth factor-β receptor (TGFβR3) is required for epicardial cell invasion and development of coronary vasculature in vivo. Bone Morphogenic Protein-2 (BMP2) is a driver of epicardial cell migration. Utilizing a primary epicardial cell line derived from Tgfbr3(+/+) and Tgfbr3(-/-) mouse embryos, we show that Tgfbr3(-/-) epicardial cells are deficient in BMP2 mRNA expression. Tgfbr3(-/-) epicardial cells are deficient in 2-dimensional migration relative to Tgfbr3(+/+) cells; BMP2 induces cellular migration to Tgfbr3(+/+) levels without affecting proliferation. We further demonstrate that Src kinase activity is required for BMP2 driven Tgfbr3(-/-) migration. BMP2 also requires Src for filamentous actin polymerization in Tgfbr3(-/-) epicardial cells. Taken together, our data identifies a novel pathway in epicardial cell migration required for development of the coronary vessels.

  4. Medication adherence to oral iron therapy in patients with iron deficiency anemia

    Science.gov (United States)

    Gereklioglu, Cigdem; Asma, Suheyl; Korur, Asli; Erdogan, Ferit; Kut, Altug

    2016-01-01

    Objective: This study aimed at investigating the factors affecting medication adherence in patients who use oral iron therapy due to iron deficiency anemia. Methods: A total of 96 female patients in fertile age with mean age of 30±10.1 years (range 18-53) who were admitted to Family Medicine Clinic between 01 January and 31 March 2015 and who had received iron therapy within the recent three years were enrolled in the study. Data were collected through a questionnaire form. Results: Of the patients, 39 (40,6%) were detected not to use the medication regularly or during the recommended period. A statistically significant relationship was found between non-adherence to therapy and gastrointestinal side effects and weight gain (p<0.05). Conclusion: Medication adherence is deficient in patients with iron deficiency anemia. The most important reason for this seems gastrointestinal side effects, in addition to weight gain under treatment. PMID:27375698

  5. Thrombophilia and dental surgery: a report of dental extraction in a patient with protein S deficiency.

    Science.gov (United States)

    Crean, S J; Sivarajasingam, V; Muhammed, J; Sharma, V; Fardy, M

    2000-01-01

    Most patients with thrombophilia are asymptomatic. A case is presented here of a young woman with protein S deficiency, one of the thrombophilias, who required dental extraction. Protein S deficiency predisposes a very small number of those affected to life-threatening thromboses and emboli, for which they are required to take lifelong prophylactic anticoagulation. This report emphasizes the need to liaise closely with haematology departments when deciding whether heparinization is required for patients already taking warfarin. The role of low-molecular-weight heparins is highlighted, a brief review of thrombophilia is given and the management of patients who are taking warfarin and need dental surgery is discussed.

  6. Vitamin D Deficiency Is Associated With the Severity of Radiation-Induced Proctitis in Cancer Patients

    Energy Technology Data Exchange (ETDEWEB)

    Ghorbanzadeh-Moghaddam, Amir [Medical Student' s Research Center, Isfahan University of Medical Sciences, Isfahan (Iran, Islamic Republic of); Gholamrezaei, Ali, E-mail: Gholamrezaei@med.mui.ac.ir [Medical Student' s Research Center, Isfahan University of Medical Sciences, Isfahan (Iran, Islamic Republic of); Poursina Hakim Research Institution, Isfahan (Iran, Islamic Republic of); Hemati, Simin [Department of Radiotherapy Oncology, Isfahan University of Medical Sciences, Isfahan (Iran, Islamic Republic of)

    2015-07-01

    Purpose: Radiation-induced injury to normal tissues is a common complication of radiation therapy in cancer patients. Considering the role of vitamin D in mucosal barrier hemostasis and inflammatory responses, we investigated whether vitamin D deficiency is associated with the severity of radiation-induced acute proctitis in cancer patients. Methods and Materials: This prospective observational study was conducted in cancer patients referred for pelvic radiation therapy. Serum concentration of 25-hydroxyvitamin D was measured before radiation therapy. Vitamin D deficiency was defined as 25-hydroxyvitamin D concentrations of <35 nmol/L and <40 nmol/L in male and female patients, respectively, based on available normative data. Acute proctitis was assessed after 5 weeks of radiation therapy (total received radiation dose of 50 Gy) and graded from 0 to 4 using Radiation Therapy Oncology Group (RTOG) criteria. Results: Ninety-eight patients (57.1% male) with a mean age of 62.8 ± 9.1 years were studied. Vitamin D deficiency was found in 57 patients (58.1%). Symptoms of acute proctitis occurred in 72 patients (73.4%) after radiation therapy. RTOG grade was significantly higher in patients with vitamin D deficiency than in normal cases (median [interquartile range] of 2 [0.5-3] vs 1 [0-2], P=.037). Vitamin D deficiency was associated with RTOG grade of ≥2, independent of possible confounding factors; odds ratio (95% confidence interval) = 3.07 (1.27-7.50), P=.013. Conclusions: Vitamin D deficiency is associated with increased severity of radiation-induced acute proctitis. Investigating the underlying mechanisms of this association and evaluating the effectiveness of vitamin D therapy in preventing radiation-induced acute proctitis is warranted.

  7. Zinc, copper, manganese, and selenium metabolism in patients with human growth hormone deficiency or acromegaly.

    Science.gov (United States)

    Aihara, K; Nishi, Y; Hatano, S; Kihara, M; Ohta, M; Sakoda, K; Uozumi, T; Usui, T

    1985-08-01

    This study was designed to evaluate trace metal metabolism in patients with known abnormalities of human growth hormone (hGH). The mean concentration of zinc in plasma and urine decreased in patients with hGH deficiency after hGH injection, whereas, after adenomectomy, in patients with acromegaly, zinc increased in plasma, remained the same in erythrocytes, and decreased in urine. There was a negative correlation between plasma zinc and serum hGH levels and a positive correlation between urinary zinc excretion and serum hGH levels in acromegaly. In hGH deficiency, the copper content remained unchanged in plasma and erythrocytes and rose in urine after treatment; however, in acromegaly, the copper content increased in plasma and remained unchanged in erythrocytes and urine after surgery. The mean concentration of erythrocyte manganese did not change significantly after treatment in patients with hGH deficiency or acromegaly, but the pre-hGH treatment level of erythrocyte manganese in hGH deficiency was lower than in the controls. Plasma selenium concentrations were decreased in hGH deficiency and increased in acromegaly patients after therapy. These results suggest that hGH affects the metabolism of zinc, copper, manganese, and selenium.

  8. 5FU and oxaliplatin-containing chemotherapy in two dihydropyrimidine dehydrogenase-deficient patients

    NARCIS (Netherlands)

    Reerink, O; Mulder, NH; Szabo, BG; Hospers, GAP

    2004-01-01

    Patients with a germline mutation leading to a deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme are at risk from developing severe toxicity on the administration of 5FU-containing chemotherapy. We report on the implications of this inborn genetic error in two patients who received 5FU

  9. Serum growth hormone (GH) profiles after nasally administered GH in normal subjects and GH deficient patients

    DEFF Research Database (Denmark)

    Møller, Jens; Laursen, Torben; Mindeholm, Linda

    1994-01-01

    Abstract OBJECTIVE: GH-deficient patients are at present treated with daily subcutaneous GH injections. Further improvements in patient compliance and effects of treatment may occur with nasal administration. We have examined the absorption of nasally administered GH in healthy subjects and in GH...

  10. Fuel utilization in patients with very long-chain acyl-coa dehydrogenase deficiency

    DEFF Research Database (Denmark)

    ØRngreen, Mette C; Nørgaard, Mette; Sacchetti, Massimo

    2004-01-01

    Fuel utilization in two adult patients with the myopathic form of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and five healthy subjects was investigated with stable isotopes during exercise at 50% of VO2max. The findings indicate that residual VLCAD activity in the patients...

  11. Clinical findings and a therapeutic trial in the first patient with beta-ureidopropionase deficiency.

    NARCIS (Netherlands)

    Assmann, B.; Gohlich, G.; Baethmann, M.; Wevers, R.A.; Gennip, A.H. van; Kuilenburg, A.B.P. van; Dietrich, C.; Wagner, L.; Rotteveel, J.J.; Schaper, J.; Mayatepek, E.; Hoffmann, G.F.; Voit, T.

    2006-01-01

    The clinical, neurophysiological and neuroradiological work-up as well as the results of a specific treatment trial are presented of the first patient diagnosed with beta-ureidopropionase deficiency (E.C. 3.5.1.6, McKusick 606673). The patient presented with an early-onset dystonic movement disorder

  12. Molecular basis of antithrombin deficiency in four Japanese patients with antithrombin gene abnormalities including two novel mutations.

    Science.gov (United States)

    Kyotani, Mayu; Okumura, Kaoru; Takagi, Akira; Murate, Takashi; Yamamoto, Koji; Matsushita, Tadashi; Sugimura, Motoi; Kanayama, Naohiro; Kobayashi, Takao; Saito, Hidehiko; Kojima, Tetsuhito

    2007-08-01

    We analyzed the antithrombin (AT) gene in four unrelated Japanese patients with an AT deficiency, and individually identified four distinct mutations in the heterozygous state. There were two novel mutations, 2417delT leading to a frameshift with a premature termination at amino acid -3 (FS-3Stop) and C2640T resulting in a missense mutation (Ala59Val). Previously reported mutations, T5342C (Ser116Pro) and T72C (Met-32Thr), were also found in the other two patients. To understand the molecular basis responsible for the AT deficiency in these patients, in vitro expression experiments were performed using HEK293 cells transfected with either wild type or respective mutant AT expression vector. We found that -3Stop-AT and -32Thr-AT were not secreted into the culture media, whereas 116Pro-AT and 59Val-AT were secreted normally. We further studied the heparin cofactor activity and the binding to heparin of each recombinant AT molecule. Ser116Pro mutation significantly impaired the binding affinity to heparin resulting in a reduced heparin cofactor activity. In contrast, we found that Ala59Val mutant AT unexpectedly showed a normal affinity to heparin, but severely impaired the heparin cofactor activity. Our findings suggested that FS-3Stop and Met-32Thr mutations are responsible for type I AT deficiency, whereas Ser116Pro and Ala59Val mutations contribute to type II AT deficiency, confirming that there were diverse molecular mechanisms of AT deficiency depend upon discrete AT gene abnormalities as reported previously.

  13. Sustained beta-cell dysfunction but normalized islet mass in aged thrombospondin-1 deficient mice.

    Directory of Open Access Journals (Sweden)

    Carl Johan Drott

    Full Text Available Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1, that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only ∼15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.

  14. ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression

    Science.gov (United States)

    Aryal, Binod; Rotllan, Noemi; Araldi, Elisa; Ramírez, Cristina M.; He, Shun; Chousterman, Benjamin G.; Fenn, Ashley M.; Wanschel, Amarylis; Madrigal-Matute, Julio; Warrier, Nikhil; Martín-Ventura, Jose L.; Swirski, Filip K.; Suárez, Yajaira; Fernández-Hernando, Carlos

    2016-07-01

    Lipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and it's absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. ANGPTL4-deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation.

  15. Novel Mutations in the PC Gene in Patients with Type B Pyruvate Carboxylase Deficiency

    DEFF Research Database (Denmark)

    Ostergaard, Elsebet; Duno, Morten; Møller, Lisbeth Birk

    2013-01-01

    We have investigated seven patients with the type B form of pyruvate carboxylase (PC) deficiency. Mutation analysis revealed eight mutations, all novel. In a patient with exon skipping on cDNA analysis, we identified a homozygous mutation located in a potential branch point sequence, the first...... possible branch point mutation in PC. Two patients were homozygous for missense mutations (with normal protein amounts on western blot analysis), and two patients were homozygous for nonsense mutations. In addition, a duplication of one base pair was found in a patient who also harboured a splice site...... mutation. Another splice site mutation led to the activation of a cryptic splice site, shown by cDNA analysis.All patients reported until now with at least one missense mutation have had the milder type A form of PC deficiency. We thus report for the first time two patients with homozygous missense...

  16. Under-diagnosing and under-treating iron deficiency in hospitalized patients with gastrointestinal bleeding

    Institute of Scientific and Technical Information of China (English)

    Mustapha M El-Halabi; Michael S Green; Christopher Jones; William J Salyers Jr

    2016-01-01

    AIM: To determine whether patients hospitalized with gastrointestinal(GI) blood loss anemia are being checked and treated for iron deficiency. METHODS: Retrospective chart review was conducted for all patients admitted to a single tertiary care hospital between 11/1/2011 and 1/31/2012 for any type of GI bleeding. The primary endpoint was the percentage of patients who had their iron studies checked during a hospitalization for GI blood loss anemia. Secondary outcomes included percentage of anemic GI bleeders who had adequate documentation of anemia and iron deficiency, and those who were treated for their iron deficiency. Then we tried to identify possible predictors of checking iron studies in an attempt to understand the thought process that physicians go through when managing these patients. Iron deficiency was defined as Iron saturation less than 15% or ferritin level less than 45 μg/L. Anemia was defined as hemoglobin level less than 13 g/dL for males and 12 g/dL for females.RESULTS: Three hundred and seven GI bleeders were hospitalized during the study period, and 282 of those(91.9%) had anemia during their hospital stay. Ninetyfive patients(30.9%) had iron studies performed during hospitalization, and 45 of those(47.4%) were actually found to be iron deficient. Only 29 of those 45 iron deficient patients were discharged home on iron supplements. Of the 282 patients that had anemia during hospitalization, 50(17.7%) had no documentation of the anemia in their hospital chart. Of the 45 patients that had lab proven iron deficiency anemia(IDA), only 22(48.5%) had documentation of IDA in at least one note in their chart. Predictors of checking iron studies in anemic GI bleeders were lower mean corpuscular volume, documentation of anemia, having fecal occult blood testing, not having hematemesis or past history of GI bleeding. There were no significant differences between the teaching and non-teaching services in any patient characteristics or outcomes. CONCLUSION

  17. Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency

    NARCIS (Netherlands)

    T. Turul (Tuba); I. Tezcan (Ilhan); S. de Bruin-Versteeg (Sandra); B.H. Barendregt (Barbara); I. Reisli (Ismail); O. Sanal (Ozden); J.J.M. van Dongen (Jacques); M. van der Burg (Mirjam)

    2009-01-01

    textabstractOne of the severe combined immunodeficiencies (SCIDs), which is caused by a genetic defect in the signal transduction pathways involved in T-cell activation, is the ZAP70 deficiency. Mutations in ZAP70 lead to both abnormal thymic development and defective T-cell receptor (TCR) signaling

  18. IS THERE A LINK BETWEEN SUNLIGHT EXPOSURE AND 25-HYDROXYVITAMIN D DEFICIENCY IN CHRONIC KIDNEY DISEASE PATIENTS?

    Directory of Open Access Journals (Sweden)

    Angela Yee-Moon Wang

    2012-06-01

    In conclusion, our study confirmed an extremely high prevalence of vitamin D deficiency and an important association between outdoor sunlight exposure and 25(OHD deficiency in Chinese stage 3-5 CKD patients. Further study is needed to determine whether increasing daily outdoor sunlight exposure may represent a cost-free treatment for correcting nutritional 25(OHD deficiency in the CKD population.

  19. Cognitive functioning in female patients with 21-hydroxylase deficiency.

    Science.gov (United States)

    Dittmann, R W; Kappes, M H; Kappes, M E

    1993-01-01

    The cognitive functioning of 27 female patients with congenital adrenal hyperplasia (CAH) (aged 11-41 yrs) and 13 of their healthy sisters (13-31 yrs) was compared using short versions of age-appropriate Wechsler scales. In contrast to other studies, neither a higher than average IQ level for CAH patients (mean: 99.0) nor for their sisters (97.7) was found. Unexpectedly, and in contrast to other reports, the subgroup of salt-wasting (SW) patients>16 yrs (N=6; mean score: 111.5) differed from their sisters as well as from simple-virilizing (SV) patients in "full IQ" (pgender-role behaviour were found.

  20. Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. Adult Growth Hormone Deficiency Study Group

    DEFF Research Database (Denmark)

    Attanasio, A F; Lamberts, S W; Matranga, A M

    1997-01-01

    -deficient adult patients have been compared. The first 6 months comprised randomized, double-blind treatment with GH or placebo, then all patients were GH-treated for a further 12 months. At baseline the height, body weight, body mass index, lean body mass, and waist/hip ratio of AO patients were significantly (P...

  1. Vitamin and Mineral Deficiencies Are Highly Prevalent in Newly Diagnosed Celiac Disease Patients

    Directory of Open Access Journals (Sweden)

    Ad A. van Bodegraven

    2013-09-01

    Full Text Available Malabsorption, weight loss and vitamin/mineral-deficiencies characterize classical celiac disease (CD. This study aimed to assess the nutritional and vitamin/mineral status of current “early diagnosed” untreated adult CD-patients in the Netherlands. Newly diagnosed adult CD-patients were included (n = 80, 42.8 ± 15.1 years and a comparable sample of 24 healthy Dutch subjects was added to compare vitamin concentrations. Nutritional status and serum concentrations of folic acid, vitamin A, B6, B12, and (25-hydroxy D, zinc, haemoglobin (Hb and ferritin were determined (before prescribing gluten free diet. Almost all CD-patients (87% had at least one value below the lower limit of reference. Specifically, for vitamin A, 7.5% of patients showed deficient levels, for vitamin B6 14.5%, folic acid 20%, and vitamin B12 19%. Likewise, zinc deficiency was observed in 67% of the CD-patients, 46% had decreased iron storage, and 32% had anaemia. Overall, 17% were malnourished (>10% undesired weight loss, 22% of the women were underweight (Body Mass Index (BMI 25. Vitamin deficiencies were barely seen in healthy controls, with the exception of vitamin B12. Vitamin/mineral deficiencies were counter-intuitively not associated with a (higher grade of histological intestinal damage or (impaired nutritional status. In conclusion, vitamin/mineral deficiencies are still common in newly “early diagnosed” CD-patients, even though the prevalence of obesity at initial diagnosis is rising. Extensive nutritional assessments seem warranted to guide nutritional advices and follow-up in CD treatment.

  2. Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients

    Science.gov (United States)

    Sauer, Aisha V.; Hernandez, Raisa Jofra; Fumagalli, Francesca; Bianchi, Veronica; Poliani, Pietro L.; Dallatomasina, Chiara; Riboni, Elisa; Politi, Letterio S.; Tabucchi, Antonella; Carlucci, Filippo; Casiraghi, Miriam; Carriglio, Nicola; Cominelli, Manuela; Forcellini, Carlo Alberto; Barzaghi, Federica; Ferrua, Francesca; Minicucci, Fabio; Medaglini, Stefania; Leocani, Letizia; la Marca, Giancarlo; Notarangelo, Lucia D.; Azzari, Chiara; Comi, Giancarlo; Baldoli, Cristina; Canale, Sabrina; Sessa, Maria; D’Adamo, Patrizia; Aiuti, Alessandro

    2017-01-01

    Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency. PMID:28074903

  3. Evidence of redox imbalance in a patient with succinic semialdehyde dehydrogenase deficiency

    Directory of Open Access Journals (Sweden)

    Anna-Kaisa Niemi

    2014-01-01

    Full Text Available The pathophysiology of succinic semialdehyde dehydrogenase (SSADH deficiency is not completely understood. Oxidative stress, mitochondrial pathology, and low reduced glutathione levels have been demonstrated in mice, but no studies have been reported in humans. We report on a patient with SSADH deficiency in whom we found low levels of blood reduced glutathione (GSH, and elevations of dicarboxylic acids in urine, suggestive of possible redox imbalance and/or mitochondrial dysfunction. Thus, targeting the oxidative stress axis may be a potential therapeutic approach if our findings are confirmed in other patients.

  4. The association between vitamin D deficiency and diabetic nephropathy in type 2 diabetic patients

    Institute of Scientific and Technical Information of China (English)

    李冬梅

    2013-01-01

    Objective To evaluate the association between vitamin D deficiency and diabetic nephropathy in type 2 diabetic patients.Methods A total of 594 patients with type2 diabetes were enrolled from the inpatients of the Nanjing Medical University Affiliated Nanjing Hospital.Fasting serum lipid profile,25-hydroxycalciferol vitamin D and urinary albumin excretion rate were investigated.The relationship between nephropathy and vitamin D deficiency (<20μg/L) or insufficiency (20-<30μg/L) was analyzed.Results Nephropathy was found in 177subjects (29.8%) with albuminuria in 141 and proteinu-

  5. Sexual dysfunction in dialysis patients: does vitamin D deficiency have a role?

    OpenAIRE

    Kidir, Veysel; Altuntas, Atila; Inal, Salih; Akpinar, Abdullah; Orhan, Hikmet; Sezer, Mehmet Tugrul

    2015-01-01

    Introduction: Sexual dysfunction and vitamin D deficiency are highly prevalent in dialysis patients. Low levels of vitamin D have been linked to many diseases. To the best of our knowledge, the relationship between vitamin D and sexual dysfunction in dialysis patients has not been previously reported in the literature. Materials and methods: Cholecalciferol, 50,000 IU/week, was orally administered to 37 dialysis patients with vitamin D insufficiency for 3 months followed by dosage of 10,000 I...

  6. Thioredoxin reductase deficiency potentiates oxidative stress, mitochondrial dysfunction and cell death in dopaminergic cells.

    Directory of Open Access Journals (Sweden)

    Pamela Lopert

    Full Text Available Mitochondria are considered major generators of cellular reactive oxygen species (ROS which are implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD. We have recently shown that isolated mitochondria consume hydrogen peroxide (H₂O₂ in a substrate- and respiration-dependent manner predominantly via the thioredoxin/peroxiredoxin (Trx/Prx system. The goal of this study was to determine the role of Trx/Prx system in dopaminergic cell death. We asked if pharmacological and lentiviral inhibition of the Trx/Prx system sensitized dopaminergic cells to mitochondrial dysfunction, increased steady-state H₂O₂ levels and death in response to toxicants implicated in PD. Incubation of N27 dopaminergic cells or primary rat mesencephalic cultures with the Trx reductase (TrxR inhibitor auranofin in the presence of sub-toxic concentrations of parkinsonian toxicants paraquat; PQ or 6-hydroxydopamine; 6OHDA (for N27 cells resulted in a synergistic increase in H₂O₂ levels and subsequent cell death. shRNA targeting the mitochondrial thioredoxin reductase (TrxR2 in N27 cells confirmed the effects of pharmacological inhibition. A synergistic decrease in maximal and reserve respiratory capacity was observed in auranofin treated cells and TrxR2 deficient cells following incubation with PQ or 6OHDA. Additionally, TrxR2 deficient cells showed decreased basal mitochondrial oxygen consumption rates. These data demonstrate that inhibition of the mitochondrial Trx/Prx system sensitizes dopaminergic cells to mitochondrial dysfunction, increased steady-state H₂O₂, and cell death. Therefore, in addition to their role in the production of cellular H₂O₂ the mitochondrial Trx/Prx system serve as a major sink for cellular H₂O₂ and its disruption may contribute to dopaminergic pathology associated with PD.

  7. Regulation of the viability of Nf1 deficient cells by PKC isoforms.

    Science.gov (United States)

    Zhou, Xiaodong; Shen, Ling; Parris, Toshima; Huang, Junchi; Yi, Bo; Helou, Khalil; Chen, Changyan

    2014-11-15

    Suppression of protein kinase C (PKC) is known to be synthetically lethal with ras mutations in various types of cancer cells. The studies also showed that blockade of PKC affected the viability of Nf1 deficient cells. Since PKC family consists of more than 10 isoforms, our study aimed at identifying which isoform(s) played the crucial role in sensitizing Nf1 deficient cells to apoptosis. Using genetic and chemical PKC inhibitors, we demonstrated that the concurrent inhibition of PKC α and β induced Nf1 deficient ST or 96.2 cells, but not SNF02.2 cells with a normal Nf1 or ST cells ectopically expressing Nf1 effective domain gene, to apoptosis. In this process, PKC δ in Nf1 deficient cells, but not in ST/Nf1 cells, was upregulated and translocated to the nucleus. Furthermore, caspase 3 was cleaved and cytochrome c was released to the cytosol. Thus, it appeared that PKC δ and α/β are the crucial components for sustaining the aberrant Ras signaling and further viability of Nf1 deficient cells. The abrogation of these two isoforms activated their opponent PKC δ for switching on the caspase 3-governed apoptotic machinery.

  8. Prevalence of Vitamin D Deficiency and Its Association With Metabolic Disease in Korean Orthopedic Patients.

    Science.gov (United States)

    Kim, Ki-Tack; Kang, Kyung-Chung; Shin, Dong-Eun; Lee, Sang-Hoon; Lee, Jung-Hee; Kwon, Tae-Yoon

    2015-10-01

    Vitamin D is considered essential for bone and muscle health, and some studies have demonstrated the positive effects of vitamin D on metabolic diseases and cancer. Nevertheless, a high prevalence of vitamin D deficiency has been reported in various populations, regardless of country or race. However, no studies regarding the prevalence of vitamin D deficiency in Korean orthopedic patients currently exist. This cross-sectional study included 272 male and 937 female patients aged 50 years and older who were consecutively admitted to the authors' orthopedic department. Vitamin D (25-hydroxy vitamin D), bone turnover markers (osteocalcin, c-telopeptide), and bone mineral density were measured. The prevalence of vitamin D deficiency and its association with other factors were evaluated. Mean patient age was 67.2 ± 8.9 years, and mean level of vitamin D was 16.1 ± 9.1 ng/mL. Overall, 91.2% of patients had deficient (orthopedic patients of this region was extremely low, regardless of sex and age. Although vitamin D was not directly associated with bone mineral density, there were significant associations between vitamin D and other factors related to bone health and metabolic diseases.

  9. Water-soluble vitamin deficiencies in complicated peptic ulcer patients soon after ulcer onset in Japan.

    Science.gov (United States)

    Miyake, Kazumasa; Akimoto, Teppei; Kusakabe, Makoto; Sato, Wataru; Yamada, Akiyoshi; Yamawaki, Hiroshi; Kodaka, Yasuhiro; Shinpuku, Mayumi; Nagoya, Hiroyuki; Shindo, Tomotaka; Ueki, Nobue; Kusunoki, Masafumi; Kawagoe, Tetsuro; Futagami, Seiji; Tsukui, Taku; Sakamoto, Choitsu

    2013-01-01

    We investigated over time whether contemporary Japanese patients with complicated peptic ulcers have any water-soluble vitamin deficiencies soon after the onset of the complicated peptic ulcers. In this prospective cohort study, fasting serum levels of water-soluble vitamins (vitamins B1, B2, B6, B12, C, and folic acid) and homocysteine were measured at 3 time points (at admission, hospital discharge, and 3 mo after hospital discharge). Among the 20 patients who were enrolled in the study, 10 consecutive patients who completed measurements at all 3 time points were analyzed. The proportion of patients in whom any of the serum water-soluble vitamins that we examined were deficient was as high as 80% at admission, and remained at 70% at discharge. The proportion of patients with vitamin B6 deficiency was significantly higher at admission and discharge (50% and 60%, respectively, ppeptic ulcers may have a deficiency of one or more water-soluble vitamins in the early phase of the disease after the onset of ulcer complications, even in a contemporary Japanese population.

  10. Chemokine Receptor Ccr6 Deficiency Alters Hepatic Inflammatory Cell Recruitment and Promotes Liver Inflammation and Fibrosis

    Science.gov (United States)

    Blaya, Delia; Morales-Ibanez, Oriol; Coll, Mar; Millán, Cristina; Altamirano, José; Arroyo, Vicente; Caballería, Joan; Bataller, Ramón; Ginès, Pere; Sancho-Bru, Pau

    2015-01-01

    Chronic liver diseases are characterized by a sustained inflammatory response in which chemokines and chemokine-receptors orchestrate inflammatory cell recruitment. In this study we investigated the role of the chemokine receptor CCR6 in acute and chronic liver injury. In the absence of liver injury Ccr6-/- mice presented a higher number of hepatic macrophages and increased expression of pro-inflammatory cytokines and M1 markers Tnf-α, Il6 and Mcp1. Inflammation and cell recruitment were increased after carbon tetrachloride-induced acute liver injury in Ccr6-/- mice. Moreover, chronic liver injury by carbon tetrachloride in Ccr6-/- mice was associated with enhanced inflammation and fibrosis, altered macrophage recruitment, enhanced CD4+ cells and a reduction in Th17 (CD4+IL17+) and mature dendritic (MHCII+CD11c+) cells recruitment. Clodronate depletion of macrophages in Ccr6-/- mice resulted in a reduction of hepatic pro-inflammatory and pro-fibrogenic markers in the absence and after liver injury. Finally, increased CCR6 hepatic expression in patients with alcoholic hepatitis was found to correlate with liver expression of CCL20 and severity of liver disease. In conclusion, CCR6 deficiency affects hepatic inflammatory cell recruitment resulting in the promotion of hepatic inflammation and fibrosis. PMID:26691857

  11. ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.

    Science.gov (United States)

    Wang, Chen; Jette, Nicholas; Moussienko, Daniel; Bebb, D Gwyn; Lees-Miller, Susan P

    2017-02-06

    The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor.

  12. Ca(2+) signalling in human proximal tubular epithelial cells deficient for cystinosin.

    Science.gov (United States)

    Ivanova, Ekaterina A; Elmonem, Mohamed A; Bongaerts, Inge; Luyten, Tomas; Missiaen, Ludwig; van den Heuvel, Lambertus P; Levtchenko, Elena N; Bultynck, Geert

    2016-10-01

    Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder caused by loss-of-function mutations in the CTNS gene coding for the lysosomal cystine transporter, cystinosin. Recent studies have demonstrated that, apart from cystine accumulation in the lysosomes, cystinosin-deficient cells, especially renal proximal tubular epithelial cells are characterized by abnormal vesicle trafficking and endocytosis, possible lysosomal dysfunction and perturbed intracellular signalling cascades. It is therefore possible that Ca(2+) signalling is disturbed in cystinosis, as it has been demonstrated for other disorders associated with lysosomal dysfunction, such as Gaucher, Niemann-Pick type C and Alzheimer's diseases. In this study we investigated ATP-induced, IP3-induced and lysosomal Ca(2+) release in human proximal tubular epithelial cells derived from control and cystinotic patients. No major dysregulation of intracellular Ca(2+) dynamics was found, although ATP-induced Ca(2+) release appeared slightly sensitized in cystinotic cells compared to control cells. Hence, these subtle changes in Ca(2+) signals elicited by agonists may contribute to the pathogenesis of the disease.

  13. Chemokine Receptor Ccr6 Deficiency Alters Hepatic Inflammatory Cell Recruitment and Promotes Liver Inflammation and Fibrosis.

    Directory of Open Access Journals (Sweden)

    Silvia Affò

    Full Text Available Chronic liver diseases are characterized by a sustained inflammatory response in which chemokines and chemokine-receptors orchestrate inflammatory cell recruitment. In this study we investigated the role of the chemokine receptor CCR6 in acute and chronic liver injury. In the absence of liver injury Ccr6-/- mice presented a higher number of hepatic macrophages and increased expression of pro-inflammatory cytokines and M1 markers Tnf-α, Il6 and Mcp1. Inflammation and cell recruitment were increased after carbon tetrachloride-induced acute liver injury in Ccr6-/- mice. Moreover, chronic liver injury by carbon tetrachloride in Ccr6-/- mice was associated with enhanced inflammation and fibrosis, altered macrophage recruitment, enhanced CD4+ cells and a reduction in Th17 (CD4+IL17+ and mature dendritic (MHCII+CD11c+ cells recruitment. Clodronate depletion of macrophages in Ccr6-/- mice resulted in a reduction of hepatic pro-inflammatory and pro-fibrogenic markers in the absence and after liver injury. Finally, increased CCR6 hepatic expression in patients with alcoholic hepatitis was found to correlate with liver expression of CCL20 and severity of liver disease. In conclusion, CCR6 deficiency affects hepatic inflammatory cell recruitment resulting in the promotion of hepatic inflammation and fibrosis.

  14. Chemokine Receptor Ccr6 Deficiency Alters Hepatic Inflammatory Cell Recruitment and Promotes Liver Inflammation and Fibrosis.

    Science.gov (United States)

    Affò, Silvia; Rodrigo-Torres, Daniel; Blaya, Delia; Morales-Ibanez, Oriol; Coll, Mar; Millán, Cristina; Altamirano, José; Arroyo, Vicente; Caballería, Joan; Bataller, Ramón; Ginès, Pere; Sancho-Bru, Pau

    2015-01-01

    Chronic liver diseases are characterized by a sustained inflammatory response in which chemokines and chemokine-receptors orchestrate inflammatory cell recruitment. In this study we investigated the role of the chemokine receptor CCR6 in acute and chronic liver injury. In the absence of liver injury Ccr6-/- mice presented a higher number of hepatic macrophages and increased expression of pro-inflammatory cytokines and M1 markers Tnf-α, Il6 and Mcp1. Inflammation and cell recruitment were increased after carbon tetrachloride-induced acute liver injury in Ccr6-/- mice. Moreover, chronic liver injury by carbon tetrachloride in Ccr6-/- mice was associated with enhanced inflammation and fibrosis, altered macrophage recruitment, enhanced CD4+ cells and a reduction in Th17 (CD4+IL17+) and mature dendritic (MHCII+CD11c+) cells recruitment. Clodronate depletion of macrophages in Ccr6-/- mice resulted in a reduction of hepatic pro-inflammatory and pro-fibrogenic markers in the absence and after liver injury. Finally, increased CCR6 hepatic expression in patients with alcoholic hepatitis was found to correlate with liver expression of CCL20 and severity of liver disease. In conclusion, CCR6 deficiency affects hepatic inflammatory cell recruitment resulting in the promotion of hepatic inflammation and fibrosis.

  15. Impaired telomere maintenance in Alazami syndrome patients with LARP7 deficiency

    Directory of Open Access Journals (Sweden)

    Brody Holohan

    2016-10-01

    Full Text Available Abstract Background Loss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation. Methods Because human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7. Results Depletion of LARP7 caused a reduction in telomerase enzymatic activity and progressively shorter telomeres in human cancer cell lines. Alazami syndrome patients from two separate cohorts exhibited very short lymphocyte telomeres. Further, wild-type offspring of LARP7 mutant individuals also had very short telomeres, comparable to what is observed in telomerase (hTERT mutant cohorts. Conclusions Together, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with LARP7 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals.

  16. [TOTAL PARENTERAL NUTRITION IN A PREGNANT PATIENT WITH ACUTE PANCREATITIS AND LIPOPROTEIN LIPASE DEFICIENCY].

    Science.gov (United States)

    Contreras-Bolívar, Victoria; González-Molero, Inmaculada; Valdivieso, Pedro; Olveira, Gabriel

    2015-10-01

    We present a case of severe acute pancreatitis induced by hypertriglyceridemia secondary to lipoprotein lipase (LPL) deficiency in a pregnant patient with gestational diabetes, initially maneged with diet but it was later necessary to carry out artificial nutricional support measures: total parenteral nutrition. LPL deficiency might cause severe hypertriglyceridemia, repetition acute pancreatitis which is an unwieldy and severe situation during pregnancy. Acute familial hypertriglyceridemia pancreatitis accounts for 5% of cases, including LPL deficiency. The goal of treatment is to reach triglycerides levels below 500 mg/dl, being very low fat diet the treatment of choice, drugs or plasmapheresis techniques can also be associated. TPN enriched in ω3 fatty acids and glutamine was safe and effective in our patient with significant decrease in triglyceride levels.

  17. System for tracking transplanted limbal epithelial stem cells in the treatment of corneal stem cell deficiency

    Science.gov (United States)

    Boadi, J.; Sangwal, V.; MacNeil, S.; Matcher, S. J.

    2015-03-01

    The prevailing hypothesis for the existence and healing of the avascular corneal epithelium is that this layer of cells is continually produced by stem cells in the limbus and transported onto the cornea to mature into corneal epithelium. Limbal Stem Cell Deficiency (LSCD), in which the stem cell population is depleted, can lead to blindness. LSCD can be caused by chemical and thermal burns to the eye. A popular treatment, especially in emerging economies such as India, is the transplantation of limbal stem cells onto damaged limbus with hope of repopulating the region. Hence regenerating the corneal epithelium. In order to gain insights into the success rates of this treatment, new imaging technologies are needed in order to track the transplanted cells. Optical Coherence Tomography (OCT) is well known for its high resolution in vivo images of the retina. A custom OCT system has been built to image the corneal surface, to investigate the fate of transplanted limbal stem cells. We evaluate two methods to label and track transplanted cells: melanin labelling and magneto-labelling. To evaluate melanin labelling, stem cells are loaded with melanin and then transplanted onto a rabbit cornea denuded of its epithelium. The melanin displays strongly enhanced backscatter relative to normal cells. To evaluate magneto-labelling the stem cells are loaded with magnetic nanoparticles (20-30nm in size) and then imaged with a custom-built, magneto-motive OCT system.

  18. TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis

    DEFF Research Database (Denmark)

    Davidsen, Marie Louise; Würts, S.Ø.; Rømer, Maria Unni Koefoed;

    2006-01-01

    in cancer. In this regard, several studies have demonstrated an antiapoptotic effect of TIMP-1 in a number of different cell types. Since chemotherapy works by inducing apoptosis in cancer cells, we raised the hypothesis that TIMP-1 promotes resistance against chemotherapeutic drugs. In order to investigate...... this hypothesis, we have established TIMP-1 gene-deficient and TIMP-1 wild-type fibrosarcoma cells from mouse lung tissue. We have characterised these cells with regard to TIMP-1 genotype, TIMP-1 expression, malignant transformation and sensitivity to chemotherapy-induced apoptosis. We show that TIMP-1 gene...... deficiency increases the response to chemotherapy considerably, confirming that TIMP-1 protects the cells from apoptosis. This is to our knowledge the first study investigating TIMP-1 and chemotherapy-induced apoptosis employing a powerful model system comprising TIMP-1 gene-deficient cells...

  19. Impaired precursor B cell differentiation in Bruton's tyrosine kinase-deficient mice

    NARCIS (Netherlands)

    S. Middendorp; G.M. Dingjan (Gemma); R.W. Hendriks (Rudi)

    2002-01-01

    textabstractBruton's tyrosine kinase (Btk) is a cytoplasmic signaling molecule that is crucial for precursor (pre-B) cell differentiation in humans. In this study, we show that during the transition of large cycling to small resting pre-B cells in the mouse, Btk-deficient cells fai

  20. MLH1-deficient tumor cells are resistant to lipoplatin, but retain sensitivity to lipoxal.

    Science.gov (United States)

    Fedier, André; Poyet, Cédric; Perucchini, Daniele; Boulikas, Teni; Fink, Daniel

    2006-03-01

    Lipoplatin, currently under phase III evaluation, is a novel liposomal cisplatin formulation highly effective against cancers. Lipoplatin has eliminated or reduced the systemic toxicity frequently seen for cisplatin. The objective of the present study was to determine whether the cytotoxic effect of lipoplatin is dependent on the functional integrity of DNA mismatch repair (MMR), a post-replicative DNA repair machinery implicated in cell cycle control and apoptosis. Clonogenic data revealed a significant (Plipoplatin of HCT116 human colorectal adenocarcinoma cells lacking MLH1, one of five proteins crucial to MMR function, as compared to MLH1-expressing HCT116 cells. In addition, MLH1-deficient cells were at least 3-fold less susceptible to apoptosis (DNA fragmentation) than MLH1-proficient cells. However, proteolytic processing of caspase-3, caspase-7 and poly(ADP-ribose)polymerase-1 following lipoplatin treatment was comparable in MLH1-deficient cells and -proficient cells. Furthermore, MLH1-deficient cells retained the ability to attenuate cell cycle progression past the G2/M checkpoint following lipoplatin treatment. In conclusion, our results indicate that the lipoplatin-sensitive phenotype of MLH1-proficient cells correlated with increased apoptosis which may occur via caspase-independent pathways. They also suggest that the integrity of MMR function is a relevant determinant accounting for the cytotoxicity of lipoplatin. However, this does not seem to apply to lipoxal, a novel liposomal formulation of oxaliplatin, because MLH1-deficient cells were as sensitive to lipoxal as MLH1-proficient cells.

  1. Impact of growth hormone (GH deficiency and GH replacement upon thymus function in adult patients.

    Directory of Open Access Journals (Sweden)

    Gabriel Morrhaye

    Full Text Available BACKGROUND: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis is maintained beyond puberty in adults. In rodents, growth hormone (GH, insulin-like growth factor-1 (IGF-1, and GH secretagogues reverse age-related changes in thymus cytoarchitecture and increase thymopoiesis. GH administration also enhances thymic mass and function in HIV-infected patients. Until now, thymic function has not been investigated in adult GH deficiency (AGHD. The objective of this clinical study was to evaluate thymic function in AGHD, as well as the repercussion upon thymopoiesis of GH treatment for restoration of GH/IGF-1 physiological levels. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-two patients with documented AGHD were enrolled in this study. The following parameters were measured: plasma IGF-1 concentrations, signal-joint T-cell receptor excision circle (sjTREC frequency, and sj/beta TREC ratio. Analyses were performed at three time points: firstly on GH treatment at maintenance dose, secondly one month after GH withdrawal, and thirdly one month after GH resumption. After 1-month interruption of GH treatment, both plasma IGF-1 concentrations and sjTREC frequency were decreased (p<0.001. Decreases in IGF-1 and sjTREC levels were correlated (r = 0.61, p<0.01. There was also a decrease in intrathymic T cell proliferation as indicated by the reduced sj/beta TREC ratio (p<0.01. One month after reintroduction of GH treatment, IGF-1 concentration and sjTREC frequency regained a level equivalent to the one before GH withdrawal. The sj/beta TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal. CONCLUSIONS: In patients with AGHD under GH treatment, GH withdrawal decreases thymic T cell output, as well as intrathymic T cell proliferation. These parameters of thymus function are completely or partially restored one month after GH resumption. These data indicate that the functional

  2. Hematologic and surgical management of the dental patient with plasminogen activator deficiency.

    Science.gov (United States)

    Scheitler, L E; Hart, N; Phillips, G; Weinberg, J B

    1988-12-01

    Anticoagulation therapy is used to treat patients with a variety of hemostatic disorders in an attempt to prevent thrombus formation. A thorough understanding of the patient's medical history is essential before dental treatment that may require alteration of this anticoagulation therapy. Alteration of anticoagulation therapy should be undertaken only after consultation with the patient's physician because some patients are at greater risk than others for thrombus formation or hemorrhage. This case of a 29-year-old man with plasminogen activator deficiency illustrates how consultation can result in a coordinated treatment plan for medical and dental management formulated to help ensure safe surgical treatment for these medically compromised patients.

  3. Loss of Cell Adhesion Increases Tumorigenic Potential of Polarity Deficient Scribble Mutant Cells.

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    Indrayani Waghmare

    Full Text Available Epithelial polarity genes are important for maintaining tissue architecture, and regulating growth. The Drosophila neoplastic tumor suppressor gene scribble (scrib belongs to the basolateral polarity complex. Loss of scrib results in disruption of its growth regulatory functions, and downregulation or mislocalization of Scrib is correlated to tumor growth. Somatic scribble mutant cells (scrib- surrounded by wild-type cells undergo apoptosis, which can be prevented by introduction of secondary mutations that provide a growth advantage. Using genetic tools in Drosophila, we analyzed the phenotypic effects of loss of scrib in different growth promoting backgrounds. We investigated if a central mechanism that regulates cell adhesion governs the growth and invasive potential of scrib mutant cells. Here we show that increased proliferation, and survival abilities of scrib- cells in different genetic backgrounds affect their differentiation, and intercellular adhesion. Further, loss of scrib is sufficient to cause reduced cell survival, activation of the JNK pathway and a mild reduction of cell adhesion. Our data show that for scrib cells to induce aggressive tumor growth characterized by loss of differentiation, cell adhesion, increased proliferation and invasion, cooperative interactions that derail signaling pathways play an essential role in the mechanisms leading to tumorigenesis. Thus, our study provides new insights on the effects of loss of scrib and the modification of these effects via cooperative interactions that enhance the overall tumorigenic potential of scrib deficient cells.

  4. Neuropathy caused by B12 deficiency in a patient with ileal tuberculosis: A case report

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    Toosi Taraneh

    2008-03-01

    Full Text Available Abstract Introduction Vitamin B12 deficiency can result in macrocytic anemia. Neurologic abnormalities of B12 deficiency include sensory deficits, loss of deep tendon reflexes, movement disorders, neuropsychiatric changes and seizures. Segmental involvement of the distal ileum, such as in tuberculosis, can cause vitamin B12 deficiency. To our knowledge, macrocytic anemia with unusual manifestations such as brain atrophy and seizures due to intestinal tuberculosis has not been reported in the literature. Case presentation A 14-year-old girl presented with complaints of paraplegia, ataxia, fever and fatigue that had started a few months earlier and which had been getting worse in the last three weeks. Her laboratory results were indicative of macrocytic anemia with a serum B12 level Conclusion Vitamin B12 deficiency should be considered in patients with neurologic features such as paresthesia, sensory deficits, urinary incontinence, dysarthria, and ataxia. The underlying cause of B12 deficiency should be determined and treated to obviate the patients' need for long term vitamin B12 therapy.

  5. Somatic complications of psychotropic medications in a patient with multiple CYP2 drug metabolism deficiencies.

    Science.gov (United States)

    Ruaño, Gualberto; Blair, C Lee; Bower, Bruce; Windemuth, Andreas; Kocherla, Mohan; Aleman, Yaraliz; Pearlson, Godfrey; Goethe, John W; Schwartz, Harold I

    2007-04-01

    A 54-year-old woman presented with severe anxiety, multiple somatic complaints, medication intolerance and adverse drug reactions (ADRs) to numerous prescribed psychotropic medications. Multiple drug metabolizing deficiencies were suspected. Molecular analysis was performed for the CYP2 family of Cytochrome P450 (CYP450) drug metabolism isoenzymes by DNA typing CYP2D6, CYP2C9, and CYP2C19 genes. A multiple deficiency in CYP2 drug metabolism was discovered. The patient was a double carrier of null alleles for CYP2D6, a carrier of a null allele for CYP2C19 and a carrier of a deficient allele for CYP2C9. These alleles were confirmed by Mendelian inheritance in her nuclear family, where her brother had a similar multigene CYP2 deficiency. The patient improved clinically with discontinuation of psychotropic medications, suggesting that much of her symptomatology was drug-induced. DNA typing for multigene CYP2 deficiencies is diagnostically useful in individuals with histories of multiple ADRs, which could be avoided by DNA-guided individualized prescription.

  6. A Patient With Pyruvate Carboxylase Deficiency and Nemaline Rods on Muscle Biopsy

    DEFF Research Database (Denmark)

    Unal, Ozlem; Orhan, Diclehan; Ostergaard, Elsebet;

    2013-01-01

    and nemaline rods detected on muscle biopsy. The nemaline rods may be due to cellular energy shortage and altered energy metabolism in pyruvate carboxylase deficiency, similar to that in the previously reported patients. The mechanism of nemaline rod formation may be associated with the role of pyruvate...

  7. Continuation of growth hormone therapy versus placebo in transition-phase patients with growth hormone deficiency

    DEFF Research Database (Denmark)

    Jørgensen, Jens; Nørrelund, Helene; Vahl, Nina

    2002-01-01

    In a placebo-controlled, parallel study of 18 patients with a mean age of 20 years who had confirmed growth hormone (GH) deficiency, we evaluated body composition, insulin sensitivity, and glucose turnover at baseline (when all were receiving GH replacement); after 12 months of continued GH therapy...

  8. Galactose-1-phosphate uridyl transferase deficiency is not associated with Mullerian aplasia in Dutch patients.

    NARCIS (Netherlands)

    Nijland, R.; Hartog, F.E.; Wevers, R.A.; Wanders, R.J.; Willemsen, W.N.P.

    2009-01-01

    STUDY OBJECTIVE: To study whether a deficiency in galactose-1-phosphate uridyl transferase (GALT) activity of mothers was an explanation for the occurrence of Mullerian aplasia of their daughters. DESIGN: A case control study. SETTING: The patients were selected from the outpatient clinic of the Uni

  9. Perioperative challenges in a patient of severe G6PD deficiency undergoing open heart surgery

    Directory of Open Access Journals (Sweden)

    Vivek Chowdhry

    2012-01-01

    Full Text Available We describe a successful perioperative management of a case of 38-year-old male, presented with chronic jaundice with severe mitral stenosis and moderate tricuspid regurgitation; upon evaluation, he was found to have severe glucose-6-phosphate dehydrogenase (G6PD deficiency. Usually, patients deficient in G6PD exhibit increased hemolysis andtherefore increased need for blood transfusion after cardiac surgery as well as impaired oxygenation in the postoperative period leading to prolonged ventilation. On reperfusion after a period of ischemia, the antioxidant system recruits all of its components in an attempt to neutralize the overwhelming oxidative stress of free radicals, as the free radical scavenging system is deficient in these patients, the chances of free-radical-induced injury is more. Our patient underwent mitral valve replacement and tricuspid annuloplasty under cardiopulmonary bypass with necessary precautions to reduce the formation of free radicals. Treatment was targeted toward theprevention of free radical injuryin the G6PD-deficient patient. He had an uneventful intraoperative and postoperative course.

  10. Triacylglycerol infusion improves exercise endurance in patients with mitochondrial myopathy due to complex I deficiency

    NARCIS (Netherlands)

    Roef, MJ; de Meer, K; Reijngoud, DJ; Straver, HWHC; de Barse, M; Kalhan, SC; Berger, R

    2002-01-01

    Background: A high-fat diet has been recommended for the treatment of patients with mitochondrial myopathy due to complex I (NADH dehydrogenase) deficiency (CID). Objective: This study evaluated the effects of intravenous infusion of isoenergetic amounts of triacylglycerol or glucose on substrate ox

  11. Acute myocardial ischemia in a patient with heterozygous alpha-2-plasmin inhibitor deficiency

    NARCIS (Netherlands)

    Brands-Nijenhuis, Angelique V. M.; van Geel, Peter P.; Meijer, Karina

    2009-01-01

    In this brief report we present a patient with heterozygous alpha 2 plasmin inhibitor (alpha 2PI) deficiency who developed atherosclerosis and myocardial ischemia in the presence of multiple classical risk factors. Management was complicated by fear of bleeding complications with the use of antiplat

  12. Gastric Polyposis: A Rare Cause of Iron Deficiency Anemia in a Patient With Portal Hypertension

    Science.gov (United States)

    Macaron, Carole; Pai, Rish K.; Alkhouri, Naim

    2015-01-01

    Portal hypertension leading to gastric polyposis has rarely been reported. More common gastric manifestations of portal hypertension are portal hypertensive gastropathy and gastric antral vascular ectasia (GAVE). We report a case of a patient in whom portal hypertension manifested as bleeding gastric polyps leading to transfusion-dependent iron deficiency anemia. PMID:26157923

  13. Proximal hypospadias in a male patient with 5α-reductase deficiency: A case reports

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    Erol Basuguy

    2014-01-01

    Full Text Available Hypospadias is a congenital disorder of male external genital. The newborn showed penoscrotal hypospadias with chordee and microphallus. Endocrine data and a normal male karyotype were suggestive of 5α-reductase deficiency. Penoscrotalhypospadias repair of the patient was made.

  14. Prion Protein Deficiency Causes Diverse Proteome Shifts in Cell Models That Escape Detection in Brain Tissue.

    Science.gov (United States)

    Mehrabian, Mohadeseh; Brethour, Dylan; Williams, Declan; Wang, Hansen; Arnould, Hélène; Schneider, Benoit; Schmitt-Ulms, Gerold

    2016-01-01

    A popular method for studying the function of a given protein is to generate and characterize a suitable model deficient for its expression. For the prion protein (PrP), best known for its role in several invariably fatal neurodegenerative diseases, a natural choice, therefore, would be to undertake such studies with brain samples. We recently documented the surprising observation that PrP deficiency caused a loss or enhancement of NCAM1 polysialylation, dependent on the cell model used. To identify possible causes for this disparity, we set out to systematically investigate the consequence of PrP deficiency on the global proteome in brain tissue and in four distinct cell models. Here we report that PrP deficiency causes robust but surprisingly divergent changes to the global proteomes of cell models but has no discernible impact on the global brain proteome. Amongst >1,500 proteins whose levels were compared in wild-type and PrP-deficient models, members of the MARCKS protein family exhibited pronounced, yet cell model-dependent changes to their steady-state levels. Follow-up experiments revealed that PrP collaborates with members of the MARCKS protein family in its control of NCAM1 polysialylation. We conclude that the physiological function of PrP may be masked in analyses of complex brain samples but its cell-type specific influence on a lipid raft-based NCAM1-related cell biology comes to the fore in investigations of specific cell types.

  15. Induction of mitotic catastrophe by PKC inhibition in Nf1-deficient cells.

    Science.gov (United States)

    Zhou, Xiaodong; Kim, Sung-Hoon; Shen, Ling; Lee, Hyo-Jung; Chen, Changyan

    2014-01-01

    Mutations of tumor suppressor Nf1 gene deregulate Ras-mediated signaling, which confers the predisposition for developing benign or malignant tumors. Inhibition of protein kinase C (PKC) was shown to be in synergy with aberrant Ras for the induction of apoptosis in various types of cancer cells. However, it has not been investigated whether loss of PKC is lethal for Nf1-deficient cells. In this study, using HMG (3-hydroxy-3-methylgutaryl, a PKC inhibitor), we demonstrate that the inhibition of PKC by HMG treatment triggered a persistently mitotic arrest, resulting in the occurrence of mitotic catastrophe in Nf1-deficient ST8814 cells. However, the introduction of the Nf1 effective domain gene into ST8814 cells abolished this mitotic crisis. In addition, HMG injection significantly attenuated the growth of the xenografted ST8814 tumors. Moreover, Chk1 was phosphorylated, accompanied with the persistent increase of cyclin B1 expression in HMG-treated ST8814 cells. The knockdown of Chk1 by the siRNA prevented the Nf1-deficient cells from undergoing HMG-mediated mitotic arrest as well as mitotic catastrophe. Thus, our data suggested that the suppression of PKC activates the Chk1-mediated mitotic exit checkpoint in Nf1-deficient cells, leading to the induction of apoptosis via mitotic catastrophe. Collectively, the study indicates that targeting PKC may be a potential option for developing new strategies to treat Nf1-deficiency-related diseases.

  16. Maintenance of condylar position in a patient with mandibular deficiency

    Directory of Open Access Journals (Sweden)

    Nicolaos TOPOUZELIS, Maria LAZARIDOU, Nicolaos LAZARIDIS, Christos ILIOPOULOS

    2011-12-01

    Full Text Available Maintaining the preoperative position of condyles within the temporal fossa is necessary in any orthognathic surgery, in order to ensure a stable postoperative result and the normal functioning of the temporomandibular joints. A variety of condylar positioning devices have been described to help preserve the preoperative position of condyles within the temporal fossa and prevent temporomandibular joint disorders or relapses.Case report: A 18-year-old female patient presented with a severe class II maxillofacial deformity, which was treated with sagittal split mandibular osteotomy and simultaneous genioplasty with the use of a polytetrafluoroethylene allograft. A condylar positioning device was used to maintain the preoperative position of the condyles. The patient did not develop any temporomandibular joint symptoms postoperatively, and the final skeletal result remained stable despite the considerable anterior displacement of the peripheral mandibular segment.

  17. Effects of Vitamin B6 Deficiency on the Composition and Functional Potential of T Cell Populations

    Science.gov (United States)

    Qian, Bingjun; Shen, Shanqi; Zhang, Jianhua

    2017-01-01

    The immune system is critical in preventing infection and cancer, and malnutrition can weaken different aspects of the immune system to undermine immunity. Previous studies suggested that vitamin B6 deficiency could decrease serum antibody production with concomitant increase in IL4 expression. However, evidence on whether vitamin B6 deficiency would impair immune cell differentiation, cytokines secretion, and signal molecule expression involved in JAK/STAT signaling pathway to regulate immune response remains largely unknown. The aim of this study is to investigate the effects of vitamin B6 deficiency on the immune system through analysis of T lymphocyte differentiation, IL-2, IL-4, and INF-γ secretion, and SOCS-1 and T-bet gene transcription. We generated a vitamin B6-deficient mouse model via vitamin B6-depletion diet. The results showed that vitamin B6 deficiency retards growth, inhibits lymphocyte proliferation, and interferes with its differentiation. After ConA stimulation, vitamin B6 deficiency led to decrease in IL-2 and increase in IL-4 but had no influence on IFN-γ. Real-time PCR analysis showed that vitamin B6 deficiency downregulated T-bet and upregulated SOCS-1 transcription. This study suggested that vitamin B6 deficiency influenced the immunity in organisms. Meanwhile, the appropriate supplement of vitamin B6 could benefit immunity of the organism.

  18. 25-Hydroxyvitamin D3 Deficiency Independently Predicts Cognitive Impairment in Patients with Systemic Lupus Erythematosus.

    Directory of Open Access Journals (Sweden)

    Sen Hee Tay

    Full Text Available Cognitive dysfunction has been reported in 20-80% of SLE patients. Converging evidence has indicated the importance of vitamin D as a neuroimmunomodulator for cognitive function. In this study, we evaluated the relationship between vitamin D and cognitive dysfunction.Consecutive age- and gender-matched SLE patients and healthy controls (HCs were administered Automated Neuropsychological Assessment Metrics in this cross-sectional study. The primary outcome was the total throughput score (TTS. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS. Levels of 25-hydroxyvitamin D [25(OHD3 and total 25(OHD] were measured using Liquid Chromatography-Tandem Mass Spectrometry.In total, 61 SLE patients and 61 HCs were studied. SLE patients scored significantly lower than HCs in the TTS (p = 0.004. There were no statistically significant differences in 25(OHD3 levels, total 25(OHD levels and total 25(OHD deficiency between SLE patients and HCs. However, more SLE patients had 25(OHD3 deficiency compared to HCs [12 (19.7% versus 2 (3.3%, p = 0.003]. Deficiency of 25(OHD3 (β = -63.667, SE = 27.456, p = 0.025, but not other vitamin D variables, independently predicted worse TTS after adjusting for age, education, gender, ethnicity, HADS-Total, duration of SLE, SELENA-SLEDAI, SLICC/ACR Damage Index and cumulative steroid dose in SLE patients. Age (β = -4.261, SE = 0.866, p < 0.001 was the only predictor of TTS after adjusting for education, gender, ethnicity, HADS-Total, vitamin D levels or status in HCs.Deficiency of 25(OHD3, a potentially modifiable risk factor, independently predicted cognitive impairment in SLE patients.

  19. Growth Hormone Deficiency in a Patient with Becker Muscular Dystrophy: A Pediatric Case Report

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    Valeria Calcaterra

    2013-01-01

    Full Text Available Objective. To describe a biochemical growth hormone (GH deficiency and to evaluate therapeutic result in a six-year-old male with Becker muscular dystrophy (BMD. Methods. GH peak was evaluated after response to arginine and insulin. Bone age was evaluated according to Greulich and Pyle method. Results. The GH-supplementary therapy was very effective in terms of growth gain. Conclusion. The possibility of a growth hormone deficiency and treatment with GH in patients with BMD cannot be excluded, especially considering the good therapeutic response.

  20. Growth hormone deficiency in a patient with becker muscular dystrophy: a pediatric case report.

    Science.gov (United States)

    Calcaterra, Valeria; Malvezzi, Annachiara; Toglia, Rossana; Berardinelli, Angela; Bozzola, Elena; Bozzola, Mauro; Larizza, Daniela

    2013-01-01

    Objective. To describe a biochemical growth hormone (GH) deficiency and to evaluate therapeutic result in a six-year-old male with Becker muscular dystrophy (BMD). Methods. GH peak was evaluated after response to arginine and insulin. Bone age was evaluated according to Greulich and Pyle method. Results. The GH-supplementary therapy was very effective in terms of growth gain. Conclusion. The possibility of a growth hormone deficiency and treatment with GH in patients with BMD cannot be excluded, especially considering the good therapeutic response.

  1. Reversal of the Symptoms of Diabetic Neuropathy through Correction of Vitamin D Deficiency in a Type 1 Diabetic Patient

    Directory of Open Access Journals (Sweden)

    David S. H. Bell

    2012-01-01

    Full Text Available Vitamin D deficiency has been associated with both type 1 and type 2 diabetes as well as both the microvascular and macrovascular complications of diabetes. Vitamin D deficiency has been shown to be more common in diabetic patients who have symptoms of distal symmetrical polyneuropathy. In addition, vitamin D deficiency has been associated with a lower pain threshold which increases when vitamin D deficiency is corrected. Herein, I describe a type 1 diabetic patient with neuropathic symptoms so severe that he could not work and for which he needed narcotics for pain management and whose symptoms improved dramatically with correction of the vitamin D deficiency. To my knowledge, this is the first report of an improvement in severe symptoms of diabetic neuropathy with correction of vitamin D deficiency in a single patient.

  2. THE CLINICAL SPECTRUM OF RESPIRATORY DISEASES IN PATIENTS WITH PRIMARY ANTIBODY DEFICIENCY

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    A. Aghamohammadi

    2000-08-01

    Full Text Available Primary Humoral Immunodeficiencies (PHID are currently increasingly being recognized. Patients with PHID frequently show respiratory complications.The objectives of the study is to determine the clinical spectrum of respiratory diseases in patients with PHID."We extracted data from the clinical files of patients with PHID, diagnosed according to WHO criteria. We encountered 125 patients (84 males, with the diagnosis of primary antibody deficiency including common-variable immunodeficiency (64 pts, x-linked agammaglobulinemia (29 pts, IgA deficiency (20 pts, IgG-subc!ass deficiency (8 pts, and hyper-IgM syndrome (4 pts. The mean age of the patients at the time of study was 11 years. In the evolution of their disease, 92 cases (73.6% developed upper respiratory tract infections, among which acute otitis media (68 pts, 54.4%, sinusitis (61 pts, 48.8%, and pharyngitis (12 pts, 10.4% were found to be the most frequent. Among the lower respiratory tract infections, pneumonia was the most common occurance (91 pts, 72.8%. The other lower respiratory tract complications were: bronchiectasis (22 pts, 17.6%, bronchitis (8 pts, tuberculosis (6 pts, lung abscess (4 pts, and Pneumocystis carinii pneumonia (2 pts.Respiratory infections constitute the most common presenting symptom of patients with primary humoral immunodeficiency. There may be some differences in the type and frequency of infections in each of these disorders.

  3. A nucleolytic lupus autoantibody is toxic to BRCA2-deficient cancer cells

    Science.gov (United States)

    Noble, Philip W.; Young, Melissa R.; Bernatsky, Sasha; Weisbart, Richard H.; Hansen, James E.

    2014-01-01

    Cancer cells with defects in DNA repair are highly susceptible to DNA-damaging agents, but delivery of therapeutic agents into cell nuclei can be challenging. A subset of lupus autoantibodies is associated with nucleolytic activity, and some of these antibodies are capable of nuclear penetration. We hypothesized that such antibodies might have potential as therapeutic agents targeted towards DNA repair-deficient malignancies. We identified the lupus autoantibody 5C6 as a cell-penetrating nucleolytic antibody and found that 5C6 has a differential effect on a matched pair of BRCA2-proficient and deficient DLD1 colon cancer cells. 5C6 selectively induced γH2AX in, and suppressed the growth of, the BRCA2-deficient cells. These findings demonstrate the potential utility of 5C6 in targeted therapy for DNA repair-deficient malignancies and strengthen the rationale for studies of additional lupus autoantibodies in order to identify the best candidates for development as therapeutic agents. In addition, the toxic effect of 5C6 on BRCA2-deficient cells provides further support for the hypothesis that some lupus autoantibodies contribute to the lower risk of specific cancers associated with systemic lupus erythematosus. PMID:25091037

  4. B7-deficient autoreactive T cells are highly susceptible to suppression by CD4(+)CD25(+) regulatory T cells.

    Science.gov (United States)

    May, Kenneth F; Chang, Xing; Zhang, Huiming; Lute, Kenneth D; Zhou, Penghui; Kocak, Ergun; Zheng, Pan; Liu, Yang

    2007-02-01

    CD4(+)CD25(+) regulatory T cells (Tregs) suppress immunity to infections and tumors as well as autoimmunity and graft-vs-host disease. Since Tregs constitutively express CTLA-4 and activated T cells express B7-1 and B7-2, it has been suggested that the interaction between CTLA-4 on Tregs and B7-1/2 on the effector T cells may be required for immune suppression. In this study, we report that autopathogenic T cells from B7-deficient mice cause multiorgan inflammation when adoptively transferred into syngeneic RAG-1-deficient hosts. More importantly, this inflammation is suppressed by adoptive transfer of purified wild-type (WT) CD4(+)CD25(+) T cells. WT Tregs also inhibited lymphoproliferation and acquisition of activation markers by the B7-deficient T cells. An in vitro suppressor assay revealed that WT and B7-deficient T cells are equally susceptible to WT Treg regulation. These results demonstrate that B7-deficient T cells are highly susceptible to immune suppression by WT Tregs and refute the hypothesis that B7-CTLA-4 interaction between effector T cells and Tregs plays an essential role in Treg function.

  5. Differences of Excess and Deficiency Zheng in Patients with Chronic Hepatitis B by Urinary Metabonomics

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    Shujun Sun

    2013-01-01

    Full Text Available Traditional Chinese medicine (TCM physicians stratify patients with the same disease into different subtypes in order to guide the appropriate treatment, which is called Zheng (TCM syndrome classification. Excess and deficiency ZHENG is a couple of basic ZHENGs of maladjusted body nature, reflecting the struggling state of human body and pathogenic factor and is important and prevalently exists in the ZHENG classification of many diseases. The present work using chronic hepatitis B (CHB as an entry point explored the substance connotation of excess and deficiency ZHENG with the metabonomic technology based on gas chromatography-mass spectrometry (GC-MS. The different substantial basis of two ZHENGs suggested that CHB patients could be categorized into two groups with diverse pathogenesis. The differential metabolites and disturbed pathways compared to not-obvious ZHENG characters patients (without ZHENG group/WZ were selected in both of the two ZHENGs. The ROC analysis demonstrated that five metabolites had a greater potential to be the clinic biomarkers of EZ or DZ. And excess ZHENG revealed a higher level of immune function than deficiency ZHENG. We are eager to transform the concept of traditional excess and deficiency ZHENGs to modern therapeutic approaches, with the prospect to help to promote personalized medicine.

  6. Genistein abrogates G2 arrest induced by curcumin in p53 deficient T47D cells

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    Astuti Puji

    2012-11-01

    Full Text Available Abstract Background The high cost and low level of cancer survival urge the finding of new drugs having better mechanisms. There is a high trend of patients to be “back to nature” and use natural products as an alternative way to cure cancer. The fact is that some of available anticancer drugs are originated from plants, such as taxane, vincristine, vinblastine, pacitaxel. Curcumin (diferuloylmethane, a dietary pigment present in Curcuma longa rizhome is reported to induce cell cycle arrest in some cell lines. Other study reported that genistein isolated from Glycine max seed inhibited phosphorylation of cdk1, gene involved during G2/M transition and thus could function as G2 checkpoint abrogator. The inhibition of cdk1 phosphorylation is one of alternative strategy which could selectively kill cancer cells and potentially be combined with DNA damaging agent such as curcumin. Methods T47D cell line was treated with different concentrations of curcumin and genistein, alone or in combination; added together or with interval time. Flow Cytometry and MTT assay were used to evaluate cell cycle distribution and viability, respectively. The presence of apoptotic cells was determined using acridine orange-ethidium bromide staining. Results In this study curcumin induced G2 arrest on p53 deficient T47D cells at the concentration of 10 μM. Increasing concentration up to 30 μM increased the number of cell death. Whilst genistein alone at low concentration (≤10 μM induced cell proliferation, addition of genistein (20 μM 16 h after curcumin resulted in more cell death (89%, 34% higher than that administered at the same time (56%. The combination treatment resulted in apoptotic cell death. Combining curcumin with high dose of genistein (50 μM induced necrotic cells. Conclusions Genistein increased the death of curcumin treated T47D cells. Appropriate timing of administration and concentration of genistein determine the outcome of

  7. Bone Mineral Density in Patients with Growth Hormone Deficiency - Does a Gender Difference Exist?

    DEFF Research Database (Denmark)

    Hitz, Mette Friberg; Jensen, Jens-Erik Beck; Eskildsen, PC

    2006-01-01

    OBJECTIVE: The aim of the study was to clarify whether a gender difference exists with respect to bone mineral density (BMD) and bone mineral content (BMC) in adult patients with growth hormone deficiency (GHD). DESIGN: A case-control design. METHODS: Blood sampling for measurements of calcium...... identical BMD values at all regions. This gender difference was even more obvious when BMD values were expressed as Z-scores or as three-dimensional BMD of the total body. The bone formation and bone resorption markers, as well as calcium and vitamin D, were all at the same levels in GH...... to healthy control subjects GH-deficient males had, in contrast to GH-deficient females, significantly reduced BMD and BMC. This obvious gender difference seems to be caused by the oestrogen substitution given to the females, compensating for the lack of GH, an effect testosterone does not seem to possess....

  8. 19-Year Follow-up of A Patient With Severe Glutathione Synthetase Deficiency

    Science.gov (United States)

    Atwal, Paldeep S.; Medina, Casey R.; Burrage, Lindsay C.; Sutton, V. Reid

    2016-01-01

    Glutathione synthetase deficiency is a rare autosomal recessive disorder resulting in low levels of glutathione and an increased susceptibility to oxidative stress. Patients with glutathione synthetase deficiency typically present in the neonatal period with hemolytic anemia, metabolic acidosis and neurological impairment. Lifelong treatment with antioxidants has been recommended in an attempt to prevent morbidity and mortality associated with the disorder. Here we present a 19-year-old female who was diagnosed with glutathione synthetase deficiency shortly after birth and who has been closely followed in our metabolic clinic. Despite an initial severe presentation, she has had normal intellectual development and few complications of her disorder with a treatment regimen that includes polycitra (citric acid, potassium citrate and sodium citrate), vitamin C, vitamin E and selenium. PMID:26984560

  9. Biologic characteristic studies of DNA mismatch—repair enzyme hMSH2—deficient cell strain

    Institute of Scientific and Technical Information of China (English)

    HeY; ZhuaZX

    2002-01-01

    The effect of hMSH2 enzyme-deficiency on the cell growing phenotypes,cell ultrastructure,growth character and cell cycle were observed with electronic microscopy examination,cell counting and flow cytometry.hMSH2-deficient cell strain was constructed by transfecting hMSH2 recombination plasmid of antisense RNA into human embryo lung fibroblasts(HLF).In hMSH2-deficient cells,there were a lot of morphological changes under electronic microscopy,such as irregular shape,a lot of protuberances on the surface of cell,the enlarged nuclei.The average time of double increment of HLF and hMSH2-deficient cells were 1.0d and 0.78d,respectively.This suggested that the cell proliferation of hMSH2-deficient cells was greater than that of HLF.The distribution of HLF and hMSH2-deficient cells in G1,G2 and S phases was different.A large part of hMSH2-deficient cells was blocked in G1 phase.hMSH2-deficient cells increased,but it is still not a typical malignant cells.Thus,this cell strain could be used as biologic material to detect mutagenesis of environmental chemicals.

  10. Fibromyalgia syndrome: is it related to vitamin D deficiency in premenopausal female patients?

    Science.gov (United States)

    Okumus, Muyesser; Koybası, Mine; Tuncay, Figen; Ceceli, Esma; Ayhan, Figen; Yorgancioglu, Rezan; Borman, Pinar

    2013-12-01

    There are a number of studies that have evaluated the relationship between fibromyalgia (FM) and vitamin D deficiency with conflicting results. The aim of this study was to assess vitamin D deficiency in patients with FM and to evaluate the relationship with the common symptoms of FM and levels of serum vitamin D. Forty premenopausal female fibromyalgia patients and 40 age- and sex-matched control subjects were included in the study. The demographic characteristics of all subjects, including age, sex, and body mass index, were recorded. The number of tender points was recorded, and the intensity of the widespread pain of the subjects was measured by the visual analog scale. The activities of daily living component of the Fibromyalgia Impact Questionnaire (FIQ-ADL), was used to assess physical functional capacity. Serum vitamin D was measured in both groups, and vitamin D levels vitamin D deficiency. The vitamin D levels and clinical and laboratory characteristics of the patient and control groups were comparatively analyzed. The relationship between vitamin D levels and clinical findings of the FM patients were also determined. The mean age was 41.23 ± 4.8 and 39.48 ± 4.08 years for the patient and control groups, respectively. The pain intensity, number of tender points, and FIQ-ADL scores were higher in FM patients than in control subjects. The mean levels of vitamin D in the patient and control groups were determined to be 31.97 ± 15.50 and 28.97 ± 13.31 nmol/L, respectively (p > .05). The incidence of vitamin D deficiency was similar between the patient and control groups (67.5% vs. 70%). Vitamin D levels significantly correlated with pain intensity (r = -0.653; p = .001) and FIQ-ADL scores in the FM group (r = -0.344; p = .030). In conclusion, the results of this study indicate that deficiency of vitamin D is not more common in premenopausal female patients with FM than in control subjects without FM. However, the association between pain and vitamin D

  11. Orientação nutricional do paciente com deficiência de ferro Nutritional guidelines for patients with iron deficiency

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    Gisele A. Bortolini

    2010-06-01

    Full Text Available A deficiência de ferro ocorre quando as reservas nutricionais de ferro são esgotadas, principalmente devido ao balanço negativo entre ingestão e requerimentos de ferro. Quando a deficiência de ferro é severa desenvolve-se então a anemia por deficiência de ferro. A reposição dos estoques deve ser feita por meio de suplementação medicamentosa. A estratégia de educação nutricional, que visa o consumo quantitativo e qualitativo adequado de alimentos, fontes dos diversos nutrientes, é uma alternativa que possui baixo custo e não produz efeitos indesejáveis. O presente trabalho apresenta as recomendações nutricionais para a prevenção da deficiência de ferro e para o paciente com deficiência de ferro. A avaliação da ingestão alimentar e posterior orientação alimentar são importantes para contribuir com o tratamento e para mudar práticas alimentares, evitando assim a reocorrência da deficiência de ferro. Os grupos mais vulneráveis para a deficiência de ferro e que merecem atenção especial são as crianças, gestantes e mulheres em idade fértil.Iron deficiency occurs when nutritional iron reserves are used up mainly as a result of a negative balance between intake and requirements. When iron deficiency is severe, the patient evolves with iron deficiency anaemia. Replacement of iron reserves is normally by means of a medicinal supplement. One low cost alternative that does not present unwanted side effects is nutritional education which aims at quantitatively and qualitatively improving the consumption of foods and thus provide a healthy diet. The current study presents nutritional guidelines both for the prevention and treatment of iron deficiency anaemia. It is important that an evaluation of dietary intake is made and that dietary counseling is followed to assist treatment and to change eating habits, thereby preventing the recurrence of iron deficiency. The most vulnerable groups for iron deficiency warrant

  12. Does corticosteroid treatment cause prolonged recovery and increased total bilirubin level in severe ADAMTS-13-deficient TTP patient?

    Science.gov (United States)

    Sayiner, Zeynel Abidin; Acik, Didar Yanardag; Yilmaz, Mehmet; Subari, Salih; Mete, Ayse Ozlem; Dai, M Sinan

    2015-10-01

    A 41-year-old female patient complaining of fatigue, headache, mild confusion, and rush on her lower extremities was admitted to our emergency department. Laboratory tests revealed that he had anemia, thrombocytopenia, and increased levels of indirect bilirubin and lactic dehydrogenase (LDH) in blood tests. Direct and indirect Coombs tests were negative, and fragmented erythrocytes were observed in peripheral blood smears. The patient was diagnosed with thrombotic thrombocytopenic purpura (TTP). The best supportive care was provided. Therapeutic plasma exchange (TPE) and 1 mg/kg methylprednisolone treatments were administered. On the 10th day of treatment, LDH level and fragmented red blood cells in peripheral blood smear were decreased, but his direct and indirect bilirubin levels increased despite the fact that he was treated with 1 mg/kg methylprednisolone and TPE. The patient had severe ADAMTS-13 deficiency. After discontinued steroids treatment, his bilirubin level normalized within 4 days. On the 4th day after bilirubin level normalized, vincristine treatment was administered. TPE was also continued. There was no consensus about the optimal schedule for discontinuing plasmapheresis therapy, and also we observed total bilirubin level improvement with discontinued corticosteroid treatment. In this case, corticosteroid treatment was linked with the increase of total bilirubin level in severe ADAMTS-13-deficient TTP patient.

  13. A place of androgen deficiency in a clinical portrait of the modern urological patient

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    I. A. Tyuzikov

    2013-01-01

    Full Text Available In article on the basis of literary given both own clinical supervision and researches applied aspects of androgen deficiency in urological practice are considered. True androgen deficiency’ frequency in man’s population remains precisely not established as decrease in testosterone synthesis is connected not only with the age, but also varieties of other factors, including features of geography of area of residing, presence or absence of other hormonal and metabolic disorders, accompanying somatic comorbidity etc. Results of the newest foreign epidemiological researches of androgen deficiency prevalence worldwide, and also results of the first Russian pilot epidemiological research of androgen deficiency at men prevalence in practice of urologists and doctors of adjacent specialities (Yaroslavl Study, 2013 present in the article. Intime pathogenetic communication of androgen deficiency both the most widespread uroandrological and somatic diseases at men is shown. On the basis of own clinical experience optimum algorithms of complex diagnostics of androgen deficiency at urological patients are offered and also the necessity of inclusion of testosterone preparations for pharmacotherapy of the majority of male urinogenital diseases is shown. The review of indications, contra-indications, estimations of risk factors and preparations for androgen replacement therapy is spent. Features of transdermal forms of testosterone preparations (Аndrogel are described and the clinical analysis of their present and perspective application within the limits of modern androgen replacement therapy is carried out.

  14. A place of androgen deficiency in a clinical portrait of the modern urological patient

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2014-11-01

    Full Text Available In article on the basis of literary given both own clinical supervision and researches applied aspects of androgen deficiency in urological practice are considered. True androgen deficiency’ frequency in man’s population remains precisely not established as decrease in testosterone synthesis is connected not only with the age, but also varieties of other factors, including features of geography of area of residing, presence or absence of other hormonal and metabolic disorders, accompanying somatic comorbidity etc. Results of the newest foreign epidemiological researches of androgen deficiency prevalence worldwide, and also results of the first Russian pilot epidemiological research of androgen deficiency at men prevalence in practice of urologists and doctors of adjacent specialities (Yaroslavl Study, 2013 present in the article. Intime pathogenetic communication of androgen deficiency both the most widespread uroandrological and somatic diseases at men is shown. On the basis of own clinical experience optimum algorithms of complex diagnostics of androgen deficiency at urological patients are offered and also the necessity of inclusion of testosterone preparations for pharmacotherapy of the majority of male urinogenital diseases is shown. The review of indications, contra-indications, estimations of risk factors and preparations for androgen replacement therapy is spent. Features of transdermal forms of testosterone preparations (Аndrogel are described and the clinical analysis of their present and perspective application within the limits of modern androgen replacement therapy is carried out.

  15. Gait adaptation in ACL deficient patients before and after anterior cruciate ligament reconstruction surgery.

    Science.gov (United States)

    Knoll, Zsolt; Kiss, Rita M; Kocsis, László

    2004-06-01

    The objective of this study is to determine how kinematical parameters and electromyography data of selected muscles may change as a result of anterior cruciate ligament (ACL) deficiency and following ACL reconstruction. The study was conducted on 25 anterior cruciate ligament deficient subjects prior to and 6 weeks, 4 months, 8 months and 12 months following ACL reconstructive surgery using the bone-patellar tendon-bone technique. Gait analysis was performed by applying the zebris three-dimensional ultrasound-based system with surface electromyograph (zebris). Kinematic data were recorded for the lower limb. The muscles surveyed include vastus lateralis and medialis, biceps femoris and adductor longus. The results obtained from the injured subjects were compared with those of 51 individuals without any ACL damage whatsoever. Acute ACL deficient patients exhibited a quadriceps avoidance pattern prior to and 6 weeks following surgery. No quadriceps avoidance phenomenon develops in chronic ACL deficient patients. In operated individuals, tempo-spatial parameters and the knee angle regained a normal pattern for the ACL-deficient limb during gait as early as 4 months following surgery. However, the relative ACL movement parameter, which describes the tibial translation into the direction of ACL, and the EMG traces show no significant statistical difference compared with the same values of the healthy control group just 8 months following surgery. The analysis of spatial-temporal parameters and EMG traces show that the development of a quadriceps avoidance pattern is less common than previously reported. These data suggest that anterior cruciate ligament deficiency and reconstruction produce considerable changes in the lower extremity gait pattern. The results suggest that gait parameters tend to shift towards a normal value pattern; and the re-establishment of pre-injury gait patterns-including the normal biphase of muscles-takes at least 8 months to occur.

  16. The effects of weekly augmentation therapy in patients with PiZZ α1-antitrypsin deficiency

    Directory of Open Access Journals (Sweden)

    Schmid ST

    2012-09-01

    Full Text Available ST Schmid,1 J Koepke,1 M Dresel,1 A Hattesohl,1 E Frenzel,2 J Perez,3 DA Lomas,4 E Miranda,5 T Greulich,1 S Noeske,1 M Wencker,6 H Teschler,6 C Vogelmeier,1 S Janciauskiene,2,* AR Koczulla1,*1Department of Internal Medicine, Division for Pulmonary Diseases, University Hospital Marburg, Marburg, Germany; 2Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; 3Department of Cellular Biology, University of Malaga, Malaga, Spain; 4Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; 5Department of Biology and Biotechnology, Istituto Pasteur – Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy; 6Department of Pneumology, West German Lung Clinic, Essen University Hospital, Essen, Germany*These authors contributed equally to this workBackground: The major concept behind augmentation therapy with human α1-antitrypsin (AAT is to raise the levels of AAT in patients with protease inhibitor phenotype ZZ (Glu342Lys-inherited AAT deficiency and to protect lung tissues from proteolysis and progression of emphysema.Objective: To evaluate the short-term effects of augmentation therapy (Prolastin® on plasma levels of AAT, C-reactive protein, and chemokines/cytokines.Materials and methods: Serum and exhaled breath condensate were collected from individuals with protease inhibitor phenotype ZZ AAT deficiency-related emphysema (n = 12 on the first, third, and seventh day after the infusion of intravenous Prolastin. Concentrations of total and polymeric AAT, interleukin-8 (IL-8, monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, vascular endothelial growth factor, and C-reactive protein were determined. Blood neutrophils and primary epithelial cells were also exposed to Prolastin (1 mg/mL.Results: There were significant fluctuations in serum (but not in exhaled breath condensate levels of AAT polymers, IL-8, monocyte chemotactic protein-1, IL

  17. Concomitant therapies (glucocorticoids and sex hormones) in adult patients with growth hormone deficiency.

    Science.gov (United States)

    Scaroni, C; Ceccato, F; Rizzati, S; Mantero, F

    2008-09-01

    Adult-onset GH deficiency (GHD), mostly due to organic lesions of the pituitary-hypothalamic region, is frequently associated with multiple anterior pituitary deficiencies that need long-term substitutive treatment. The GH-IGF-I axis may play an important role in modulating peripheral metabolism of hormones (adrenal, thyroid, and sex hormones) and these interactions may have clinically significant implications on the phenotypes of adult GHD patients and on the effects of the combined replacement hormonal treatment of this condition. By accelerating the peripheral metabolism of cortisol, GH therapy may precipitate adrenal insufficiency in susceptible hypopituitary patients; estrogen replacement blunts the response to GH in women whereas in men with androgen substitution the responsivity increases over time. Endocrinologists should be mindful of these phenomena when starting patients with hypopituitarism on GH replacement therapy.

  18. CRISPR/Cas9-generated p47phox-deficient cell line for Chronic Granulomatous Disease gene therapy vector development

    Science.gov (United States)

    Wrona, Dominik; Siler, Ulrich; Reichenbach, Janine

    2017-01-01

    Development of gene therapy vectors requires cellular models reflecting the genetic background of a disease thus allowing for robust preclinical vector testing. For human p47phox-deficient chronic granulomatous disease (CGD) vector testing we generated a cellular model using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 to introduce a GT-dinucleotide deletion (ΔGT) mutation in p47phox encoding NCF1 gene in the human acute myeloid leukemia PLB-985 cell line. CGD is a group of hereditary immunodeficiencies characterized by impaired respiratory burst activity in phagocytes due to a defective phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In Western countries autosomal-recessive p47phox-subunit deficiency represents the second largest CGD patient cohort with unique genetics, as the vast majority of p47phox CGD patients carries ΔGT deletion in exon two of the NCF1 gene. The established PLB-985 NCF1 ΔGT cell line reflects the most frequent form of p47phox-deficient CGD genetically and functionally. It can be differentiated to granulocytes efficiently, what creates an attractive alternative to currently used iPSC models for rapid testing of novel gene therapy approaches. PMID:28287132

  19. CRISPR/Cas9-generated p47(phox)-deficient cell line for Chronic Granulomatous Disease gene therapy vector development.

    Science.gov (United States)

    Wrona, Dominik; Siler, Ulrich; Reichenbach, Janine

    2017-03-13

    Development of gene therapy vectors requires cellular models reflecting the genetic background of a disease thus allowing for robust preclinical vector testing. For human p47(phox)-deficient chronic granulomatous disease (CGD) vector testing we generated a cellular model using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 to introduce a GT-dinucleotide deletion (ΔGT) mutation in p47(phox) encoding NCF1 gene in the human acute myeloid leukemia PLB-985 cell line. CGD is a group of hereditary immunodeficiencies characterized by impaired respiratory burst activity in phagocytes due to a defective phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In Western countries autosomal-recessive p47(phox)-subunit deficiency represents the second largest CGD patient cohort with unique genetics, as the vast majority of p47(phox) CGD patients carries ΔGT deletion in exon two of the NCF1 gene. The established PLB-985 NCF1 ΔGT cell line reflects the most frequent form of p47(phox)-deficient CGD genetically and functionally. It can be differentiated to granulocytes efficiently, what creates an attractive alternative to currently used iPSC models for rapid testing of novel gene therapy approaches.

  20. Intravenous Iron Repletion Does Not Significantly Decrease Platelet Counts in CKD Patients with Iron Deficiency Anemia

    Directory of Open Access Journals (Sweden)

    Neville R. Dossabhoy

    2013-01-01

    Full Text Available Purpose. We sought to investigate the effect of IV iron repletion on platelet (PLT counts in CKD patients with iron deficiency anemia (IDA. Methods. We conducted a retrospective chart review, including all patients with CKD and IDA who were treated with iron dextran total dose infusion (TDI between 2002 and 2007. Patient demographics were noted, and laboratory values for creatinine, hemoglobin (Hgb, iron stores and PLT were recorded pre- and post-dose. Results. 153 patients received a total of 251 doses of TDI (mean ± SD = 971 ± 175 mg; age years and Creatinine  mg/dL. All CKD stages were represented (stage 4 commonest. Hgb and Fe stores improved post-TDI (. There was a very mild decrease in PLT (pre-TDI 255 versus post-TDI 244, . The mild reduction in PLT after TDI remained non-significant ( when data was stratified by molecular weight (MW of iron dextran used (low versus high, as well as by dose administered (<1000 versus ≥1000 mg. Linear regression analysis between pre-dose PLT and Tsat and Fe showed R2 of 0.01 and 0.04, respectively. Conclusion. Correction of iron deficiency did not significantly lower PLT in CKD patients, regardless of MW or dose used. Correlation of PLT to severity of iron deficiency was very weak.

  1. Effects of short-term cycling on knee joint proprioception in ACL-deficient patients.

    Science.gov (United States)

    Roberts, David; Ageberg, Eva; Andersson, Gert; Fridén, Thomas

    2004-09-01

    It has previously been shown that knee injuries with ACL ruptures may lead to decreased proprioception and that exercise in a normal population, uninjured individuals, may reduce the proprioceptive ability. How proprioception is affected by exercise in patients with ACL deficiency has, to our knowledge, not been studied before. Knee joint proprioception was estimated in 36 patients, 18 males and 18 females, with ACL deficiency by measuring thresholds for detection of slow passive motion before and after a short period of exercise on an ergometer bicycle. In addition, the results were compared with a control group of 24 individuals of the same age. We found trends of enhanced proprioception towards extension in the patient group after cycling, but not in the control group. Towards flexion, both groups showed poorer proprioception after cycling. When difference scores of proprioceptive change in each group were compared, a trend towards different reaction upon cycling between the groups was seen in measurement towards extension from 20 degrees where the patients seemed to improve proprioception, which the controls did not. The results are not conclusive in this pilot study, but the possibility that ACL-deficient patients and controls may not react likewise to cycling, as regards their proprioceptive ability, is discussed.

  2. Usefulness of Iron Deficiency Correction in Management of Patients With Heart Failure [from the Registry Analysis of Iron Deficiency-Heart Failure (RAID-HF) Registry].

    Science.gov (United States)

    Wienbergen, Harm; Pfister, Otmar; Hochadel, Matthias; Michel, Stephan; Bruder, Oliver; Remppis, Björn Andrew; Maeder, Micha Tobias; Strasser, Ruth; von Scheidt, Wolfgang; Pauschinger, Matthias; Senges, Jochen; Hambrecht, Rainer

    2016-12-15

    Iron deficiency (ID) has been identified as an important co-morbidity in patients with heart failure (HF). Intravenous iron therapy reduced symptoms and rehospitalizations of iron-deficient patients with HF in randomized trials. The present multicenter study investigated the "real-world" management of iron status in patients with HF. Consecutive patients with HF and ejection fraction ≤40% were recruited and analyzed from December 2010 to October 2015 by 11 centers in Germany and Switzerland. Of 1,484 patients with HF, iron status was determined in only 923 patients (62.2%), despite participation of the centers in a registry focusing on ID and despite guideline recommendation to determine iron status. In patients with determined iron status, a prevalence of 54.7% (505 patients) for ID was observed. Iron therapy was performed in only 8.5% of the iron-deficient patients with HF; 2.6% were treated with intravenous iron therapy. The patients with iron therapy were characterized by a high rate of symptomatic HF and anemia. In conclusion, despite strong evidence of beneficial effects of iron therapy on symptoms and rehospitalizations, diagnostic and therapeutic efforts on ID in HF are low in the actual clinical practice, and the awareness to diagnose and treat ID in HF should be strongly enforced.

  3. Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report.

    Science.gov (United States)

    Engel, Barbara C; Podsakoff, Greg M; Ireland, Joanna L; Smogorzewska, E Monika; Carbonaro, Denise A; Wilson, Kathy; Shah, Ami; Kapoor, Neena; Sweeney, Mirna; Borchert, Mark; Crooks, Gay M; Weinberg, Kenneth I; Parkman, Robertson; Rosenblatt, Howard M; Wu, Shi-Qi; Hershfield, Michael S; Candotti, Fabio; Kohn, Donald B

    2007-01-15

    A patient with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) was enrolled in a study of retroviral-mediated ADA gene transfer to bone marrow hematopoietic stem cells. After the discontinuation of ADA enzyme replacement, busulfan (75 mg/m2) was administered for bone marrow cytoreduction, followed by infusion of autologous, gene-modified CD34+ cells. The expected myelosuppression developed after busulfan but then persisted, necessitating the administration of untransduced autologous bone marrow back-up at day 40. Because of sustained pancytopenia and negligible gene marking, diagnostic bone marrow biopsy and aspirate were performed at day 88. Analyses revealed hypocellular marrow and, unexpectedly, evidence of trisomy 8 in 21.6% of cells. Trisomy 8 mosaicism (T8M) was subsequently diagnosed by retrospective analysis of a pretreatment marrow sample that might have caused the lack of hematopoietic reconstitution. The confounding effects of this preexisting marrow cytogenetic abnormality on the response to gene transfer highlights another challenge of gene therapy with the use of autologous hematopoietic stem cells.

  4. Early Results of Autologous Cultivated Limbal Stem Cell Transplantation in Total Limbal Stem Cell Deficiency

    Directory of Open Access Journals (Sweden)

    Mohammad Ali Javadi

    2008-12-01

    Full Text Available

    PURPOSE: To report the early results of transplantation of autologous limbal stem cells cultivated on amniotic membrane (AM in patients with total unilateral limbal stem cell deficiency (LSCD. METHODS: Four eyes of 4 patients with total unilateral LSCD confirmed with impression cytology underwent transplantation of autologous limbal stem cell cultivated on AM. At each follow up visit, a complete eye examination with special attention to recurrence or regression of vascularization, corneal opacification, and epithelial defect healing was performed. Digital imaging was performed at each follow up visit. Impression cytology was repeated in all cases after surgery. RESULTS: The patients were followed for 5-13 months. Visual acuity improved in all cases. Decrease in corneal opacification and vascularization was obvious in 3 cases with coverage of the cornea with corneal epithelium. Sectoral conjunctivalization was evident in these 3 cases, however the corneas were ready for transplantation. The procedure failed in one case with total corneal conjunctivalization. CONCLUSION: Transplantation of autologous stem cells cultivated on AM seems to be an effective way for total LSCD. More definite judgment needs longer follow up together with long-term results of corneal transplantation in these patients.

  1. The prevalence of vitamin D deficiency in consecutive new patients seen over a 6-month period in general rheumatology clinics.

    Science.gov (United States)

    Haroon, Muhammad; Bond, Ursula; Quillinan, Niamh; Phelan, Mark J; Regan, Michael J

    2011-06-01

    The objectives of this study are to assess: (a) the prevalence of vitamin D deficiency among new patients attending rheumatology outpatient departments, (b) the age profile of these low vitamin D patients and (c) whether any diagnostic category had a particularly high number of vitamin D-deficient patients. All new patients seen consecutively in general rheumatology clinics between January to June 2007 inclusive were eligible to partake in this study, and 231 out of 264 consented to do so. Parathyroid hormone, 25-hydroxyvitamin D, creatinine, calcium, phosphate, albumin and alkaline phosphatase levels were measured. We defined vitamin D deficiency as ≤53 nmol/l and severe deficiency as ≤25 nmol/l. Overall, 70% of 231 patients had vitamin D deficiency, and 26% had severe deficiency. Sixty-five percent of patients aged ≥65 and 78% of patients aged ≤30 years had low vitamin D levels. Vitamin D deficiency in each diagnostic category was as follows: (a) inflammatory joint diseases/connective tissue diseases (IJD/CTD), 69%; (b) soft tissue rheumatism, 77%; (c) osteoarthritis, 62%; (d) non-specific musculoskeletal back pain, 75% and (e) osteoporosis, 71%. Seasonal variation of vitamin D levels was noted in all diagnostic groups apart from IJD/CTD group, where the degree of vitamin D deficiency persisted from late winter to peak summer. Very high prevalence of vitamin D deficiency was noted in all diagnostic categories (p = 0.006), and it was independent of age (p = 0.297). The results suggest vitamin D deficiency as a possible modifiable risk factor in different rheumatologic conditions, and its role in IJD/CTD warrants further attention.

  2. Rapid eye movement sleep behaviour disorder in patients with narcolepsy is associated with hypocretin-1 deficiency

    DEFF Research Database (Denmark)

    Knudsen, Stine; Gammeltoft, Steen; Jennum, Poul J

    2010-01-01

    Rapid eye movement sleep behaviour disorder is characterized by dream-enacting behaviour and impaired motor inhibition during rapid eye movement sleep. Rapid eye movement sleep behaviour disorder is commonly associated with neurodegenerative disorders, but also reported in narcolepsy with cataplexy....... Most narcolepsy with cataplexy patients lack the sleep-wake, and rapid eye movement sleep, motor-regulating hypocretin neurons in the lateral hypothalamus. In contrast, rapid eye movement sleep behaviour disorder and hypocretin deficiency are rare in narcolepsy without cataplexy. We hypothesized...... that rapid eye movement sleep behaviour disorder coexists with cataplexy in narcolepsy due to hypocretin deficiency. In our study, rapid eye movement sleep behaviour disorder was diagnosed by the International Classification of Sleep Disorders (2nd edition) criteria in 63 narcolepsy patients with or without...

  3. Perforin-deficient CD8+ T cells mediate fatal lymphocytic choriomeningitis despite impaired cytokine production

    DEFF Research Database (Denmark)

    Storm, Pernille; Bartholdy, Christina; Sørensen, Maria Rathmann;

    2006-01-01

    Intracerebral (i.c.) infection with lymphocytic choriomeningitis virus (LCMV) is one of the most studied models for virus-induced immunopathology, and based on results from perforin-deficient mice, it is currently assumed that fatal disease directly reflects perforin-mediated cell lysis. However,...... for the delayed onset of fatal disease in perforin-deficient mice. However, once accumulated in the CNS, virus-specific CD8(+) T cells can induce fatal CNS pathology despite the absence of perforin-mediated lysis and reduced capacity to produce several key cytokines....

  4. Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency.

    Science.gov (United States)

    Jiang, Dewei; Zhang, Ying; Hart, Ronald P; Chen, Jianmin; Herrup, Karl; Li, Jiali

    2015-12-01

    A long-standing mystery surrounding ataxia-telangiectasia is why it is mainly cerebellar neurons, Purkinje cells in particular, that appear vulnerable to ATM deficiency. Here we present data showing that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human ataxia-telangiectasia and Atm(-/-) mouse cerebellar Purkinje cells. We further show that TET1, an enzyme that converts 5-methylcytosine (5mC) to 5hmC, responds to DNA damage and manipulation of TET1 activity directly affects the DNA damage signalling and ATM-deficient neuronal cell cycle re-entry and death. Quantitative genome-wide analysis of 5hmC-containing sequences shows that in ATM deficiency there is a cerebellum- and Purkinje cell-specific shift in 5hmC enrichment in both regulatory elements and repeated sequences. Finally, we verify that TET1-mediated 5hmC production is linked to the degenerative process of Purkinje cells and behavioural deficits in Atm(-/-) mice. Taken together, the selective loss of 5hmC plays a critical role in driving Purkinje cell vulnerability in ATM deficiency.

  5. H. pylori May Not Be Associated with Iron Deficiency Anemia in Patients with Normal Gastrointestinal Tract Endoscopy Results

    OpenAIRE

    Tayyibe Saler; Şakir Özgür Keşkek; Sibel Kırk; Süleyman Ahbab; Gülay Ortoğlu

    2014-01-01

    Background. The aim of this study was to investigate the association between iron deficiency anemia and H. pylori in patients with normal gastrointestinal tract endoscopy results. Materials and Methods. A total of 117 male patients with normal gastrointestinal tract endoscopy results were included in this retrospective study. The study and control groups included 69 and 48 patients with and without iron deficiency anemia, respectively. The prevalence of H. pylori, the number of RBCs, and the ...

  6. The effect of iron-deficiency anemia on cytolytic activity of mice spleen and peritoneal cells against allogenic tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Kuvibidila, S.R.; Baliga, B.S.; Suskind, R.M.

    1983-08-01

    The capacity of spleen and peritoneal cells from iron deficient mice, ad libitum fed control mice, and pair-fed mice to kill allogenic tumor cells (mastocytoma tumor P815) has been investigated. In the first study, mice were sensitized in vivo with 10(7) viable tumor cells 51 and 56 days after weaning. The capacity of splenic cells and peritoneal cells from sensitized and nonsensitized mice to kill tumor cells was evaluated 5 days after the second dose of tumor cells. At ratios of 2.5:1 to 100:1 of attacker to target cells, the percentage /sup 51/Cr release after 4 h of incubation was significantly less in iron-deficient mice than control and/or pair-fed mice (p less than 0.05). Protein-energy undernutrition in pair-fed mice had no significant effect. In the second study, spleen cells and enriched T cell fractions were incubated in vitro for 5 days with uv irradiated Balb/C spleen cells in a 2:1 ratio. The cytotoxic capacity against the same allogenic tumor cells was again evaluated. The percentage chromium release at different attacker to target cells was less than 30% in the iron-deficient group compared to either control or pair-fed supporting the results of in vivo sensitized cells. The possible mode of impairment of the cytotoxic capacity is discussed.

  7. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria.

    Science.gov (United States)

    Evans, Maureen; Andresen, Brage S; Nation, Judy; Boneh, Avihu

    2016-08-01

    Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of fatty acid oxidation. Treatment practices of the disorder have changed over the past 10-15years since this disorder was included in newborn screening programs and patients were diagnosed pre-symptomatically. A genotype-phenotype correlation has been suggested but the discovery of novel mutations make this knowledge limited. Herein, we describe our experience in treating patients (n=22) diagnosed through newborn screening and mutational confirmation and followed up over a median period of 104months. We report five novel mutations. In 2013 we formalised our treatment protocol, which essentially follows a European consensus paper from 2009 and our own experience. The prescribed low natural fat diet is relaxed for patients who are asymptomatic when reaching age 5years but medium-chain triglyceride oil is recommended before and after physical activity regardless of age. Metabolic stability, growth, development and cardiac function are satisfactory in all patients. There were no episodes of encephalopathy or hypoglycaemia but three patients had episodes of muscle pain with our without rhabdomyolysis. Body composition studies showed a negative association between dietary protein intake and percent body fat. Larger patient cohort and longer follow up time are required for further elucidation of genotype-phenotype correlations and for establishing the role of dietary protein in metabolic stability and long-term healthier body composition in patients with VLCAD deficiency.

  8. Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

    Institute of Scientific and Technical Information of China (English)

    Wei-Ren Li; Zhe-Zhu Gao; Zhong-Cheng Xin; Liang Chen; Zhi-Jie Chang; Hua Xin; Tao Liu; Yan-Quan Zhang; Guang-Yong Li; Feng Zhou; Yan-Qing Gong

    2011-01-01

    Late-onset hypogonadism (LOH) is closely related to secondary androgen deficiency in aged males,but the mechanism remains unclear.In this study,we found that reduced testosterone production in aged rat Leydig cells is associated with decreased autophagic activity.Primary rat Leydig cells and the TM3 mouse Leydig cell line were used to study the effect of autophagic deficiency on Leydig cell testosterone production.In Leydig cells from young and aged rats,treatment with wortmannin,an autophagy inhibitor,inhibited luteinising hormone (LH)-stimulated steroidogenic acute regulatory (StAR) protein expression and decreased testosterone production.In contrast,treatment with rapamycin,an autophagy activator,enhanced LH-stimulated steroidogenesis in Leydig cells from aged,but not young,rats.Intracellular reactive oxygen species (ROS) levels were increased in both young and aged Leydig cells treated with wortmannin but decreased only in aged Leydig cells treated with rapamycin.Furthermore,an increased level of ROS,induced by H2O2,resulted in LH-stimulated steroidogenic inhibition.Finally,knockdown of Beclin 1 decreased LH-stimulated StAR expression and testosterone production in TM3 mouse Leydig cells,which were associated with increased intracellular ROS level.These results suggested that autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells,which might be influenced by intracellular ROS levels.

  9. The prevalence of iron deficiency anaemia in patients undergoing bariatric surgery.

    Science.gov (United States)

    Khanbhai, M; Dubb, S; Patel, K; Ahmed, A; Richards, T

    2015-01-01

    As bariatric surgery rates continue to climb, anaemia will become an increasing concern. We assessed the prevalence of anaemia and length of hospital stay in patients undergoing bariatric surgery. Prospective data (anaemia [haemoglobin bariatric surgery. Results from a prospective database of 1530 patients undergoing elective general surgery were used as a baseline. Fifty-seven patients (14%) were anaemic pre-operatively, of which 98% were females. Median MCV (fL) and overall median ferritin (μg/L) was lower in anaemic patients (83 vs. 86, p=0.001) and (28 vs. 61, psurgery patients, prevalence of anaemia was similar (14% vs. 16%) but absolute iron deficiency was more common in those undergoing bariatric surgery; microcytosis pbariatric surgery. In bariatric patients with anaemia there was an overall increased length of hospital stay.

  10. Serum Prohepcidin Levels in Helicobacter Pylori Infected Patients with Iron Deficiency Anemia

    OpenAIRE

    Lee, Sun-Young; Song, Eun Young; Yun, Yeo Min; Yoon, So Young; Cho, Yo Han; Kim, Sung-Yong; Lee, Mark Hong

    2010-01-01

    Background/Aims Helicobacter pylori (H. pylori) infection appears to subvert the human iron regulatory mechanism and thus upregulates hepcidin, resulting in unexplained iron-deficiency anemia (IDA). We evaluated serum prohepcidin levels before and after eradication of H. pylori in IDA patients to assess whether it plays a role in IDA related to H. pylori infection. Methods Subjects diagnosed with unexplained IDA underwent upper gastrointestinal endoscopy and colonoscopy to confirm H. pylori i...

  11. [Treatment of vitamin D deficiency in the general population and in patients with chronic kidney disease].

    Science.gov (United States)

    Mozzillo, Giusi Rosaria; Scognamiglio, Bernadette; Russo, Domenico

    2015-01-01

    Vitamin D is an essential micronutrient for humans. Vitamin D functions are not limited to the regulation of bone; it plays many pleiotropic effects due to ubiquitous distribution of VDR (Vitamin D Receptor). The vitamin D deficiency (defined as plasma levels of 25 - OH - vitamin D vitamin D in the general population and in patients with Chronic Kidney Disease and indications on the use of different Vitamins D available.

  12. Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency.

    Science.gov (United States)

    El Euch-Fayache, Ghada; Bouhlal, Yosr; Amouri, Rim; Feki, Moncef; Hentati, Fayçal

    2014-02-01

    Ataxia with vitamin E deficiency is an autosomal recessive cerebellar ataxia caused by mutations in the α-tocopherol transfer protein coding gene localized on chromosome 8q, leading to lower levels of serum vitamin E. More than 91 patients diagnosed with ataxia with vitamin E deficiency have been reported worldwide. The majority of cases originated in the Mediterranean region, and the 744delA was the most common mutation among the 22 mutants previously described. We examined the clinical and molecular features of a large cohort of 132 Tunisian patients affected with ataxia with vitamin E deficiency. Of these patients, nerve conduction studies were performed on 45, and nerve biopsy was performed on 13. Serum vitamin E was dramatically reduced for 105 of the patients analysed. Molecular analysis revealed that 91.7% of the patients (n = 121) were homozygous for the 744delA mutation. Three other mutations were detected among the remaining patients (8.3%, n = 11) in the homozygous state. Two were previously reported (400C>T and 205-1G>T), and one was novel (553+1T>A). Age of onset was 13.2 ± 5.9 years, with extremes of 2 and 37 years. All described patients exhibited persistent progressive cerebellar ataxia with generally absent tendon reflexes. Deep sensory disturbances, pyramidal syndrome and skeletal deformities were frequent. Head tremor was present in 40% of the patients. Absence of neuropathy or mild peripheral neuropathy was noted in more than half of the cohort. This is the largest study of the genetic, clinical and peripheral neuropathic characteristics in patients with ataxia and vitamin E deficiency. The 744delA mutation represents the most common pathological mutation in Tunisia and worldwide, likely because of a Mediterranean founder effect. Our study led us to suggest that any patient displaying an autosomal recessive cerebellar ataxia phenotype with absent tendon reflexes and minor nerve abnormalities should first be screened for the 744delA mutation

  13. Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.

    Directory of Open Access Journals (Sweden)

    Sander Barnhoorn

    2014-10-01

    Full Text Available As part of the Nucleotide Excision Repair (NER process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS, or the infantile lethal cerebro-oculo-facio-skeletal (COFS syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.

  14. Co-existence of clonal expanded autologous and transplacental-acquired maternal T cells in recombination activating gene-deficient severe combined immunodeficiency.

    Science.gov (United States)

    Lev, A; Simon, A J; Ben-Ari, J; Takagi, D; Stauber, T; Trakhtenbrot, L; Rosenthal, E; Rechavi, G; Amariglio, N; Somech, R

    2014-06-01

    It is commonly accepted that the presence of high amounts of maternal T cells excludes Omenn syndrome (OS) in severe combined immunodeficiency (SCID). We report a SCID patient with a novel mutation in the recombination activating gene (RAG)1 gene (4-BP DEL.1406 TTGC) who presented with immunodeficiency and OS. Several assays, including representatives of specific T cell receptors (TCR), Vβ families and TCR-γ rearrangements, were performed in order to understand more clearly the nature and origin of the patient's T cells. The patient had oligoclonal T cells which, based on the patient-mother human leucocyte antigen (HLA)-B50 mismatch, were either autologous or of maternal origin. These cell populations were different in their numbers of regulatory T cells (T(reg)) and the diversity of TCR repertoires. This is the first description of the co-existence of large amounts of clonal expanded autologous and transplacental-acquired maternal T cells in RAG1-deficient SCID.

  15. Short-term efficacy of N-carbamylglutamate in a patient with N-acetylglutamate synthase deficiency.

    Science.gov (United States)

    Kim, Ja Hye; Kim, Yoo-Mi; Lee, Beom Hee; Cho, Ja Hyang; Kim, Gu-Hwan; Choi, Jin-Ho; Yoo, Han-Wook

    2015-07-01

    N-acetylglutamate synthase (NAGS) deficiency is a rare inborn error regarding the urea cycle, however, its diagnosis is important as it can be effectively treated by N-carbamylglutamate. We evaluated a patient with NAGS deficiency who harbored two novel NAGS mutations and who showed excellent responsiveness during 1 year of N-carbamylglutamate treatment.

  16. Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene

    DEFF Research Database (Denmark)

    Mercimek-Mahmutoglu, Saadet; Ndika, Joseph; Kanhai, Warsha

    2014-01-01

    Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients 5...

  17. Patient reported out-come in posttraumatic pituitary deficiency: results from The Danish National Study on Posttraumatic Hypopituitarism

    DEFF Research Database (Denmark)

    Klose, Marianne; Krag, Kirstine Stochholm; Janukonyté, Jurgita

    2015-01-01

    OBJECTIVE: Posttraumatic pituitary hormone deficiency is often suggested. The impact of these predominantly mild and often irreproducible deficiencies on outcome is less clear. The aim of the present study was to describe patient reported outcome in a national a priori unselected cohort of patien...

  18. Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms

    Directory of Open Access Journals (Sweden)

    Cheillan David

    2012-12-01

    Full Text Available Abstract A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD. Urine guanidinoacetate (GAA and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2] and 10 X-linked creatine transporter (SLC6A8 but no AGAT (GATM [L-arginine/glycine amidinotransferase (EC 2.1.4.1] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families. The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively. Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene. No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.

  19. A Study of Malnutrition in Iranian Patients with Primary Antibody Deficiency

    Directory of Open Access Journals (Sweden)

    Azam Kouhkan

    2004-12-01

    Full Text Available Nutrition is an important factor that influences immunity, and nutritional deficiencies can impair resistance to infections. Malnutrition is the most common cause of immunodeficiency worldwide. Trace elements such as zinc, selenium, iron, and copper can influence several components of immunity. Primary antibody deficiency disorders are a group of disorders characterized by an unusual susceptibility to infections and malnutrition. Impaired nutritional status has been reported in immunodeficient patients. The aim of this study was to determine anthropometric indices and trace elements status in these patients. Thirty-eight children (28 males, 10 females, aged 2-18 years with primary antibody deficiency referring to Children’s Medical Center of Tehran University of Medical Science were enrolled in this research. Primary immunodeficiency disorders consisting of CVID, XLA, IgA deficiency, IgG subclass deficiency, and hyper IgM were assessed. Anthropometric indices, comprised of height, weight that were measured and body mass index (BMI was calculated. Height-for-age (HAZ, weight-for-height (WHZ and weight-for-age (WAZ were determined according to Z-score to study mild, moderate and severe malnutrition. Serum copper, zinc, selenium and iron levels were measured by an atomic absorption spectrometer. The most common disorders were CVID 52.5% and X-linked agammaglobulinaemia 27.5%. Based on BMI measurements 21.1% of patients had malnutrition. According to HAZ, 13.2%, 13.2% and 36.8% had severe, moderate and mild malnutrition, respectively. According to WAZ, 10.5%, 18.4% and 28.6% had severe, moderate and mild malnutrition, respectively. Regarding to WHZ, 14.3% and 28.6% had moderate and mild malnutrition, respectively. Low selenium levels and high copper levels were observed in 37.5% and 70.3%, respectively. Anthropometric data showed that the frequency of malnutrition in these patients was higher than the CDC standard. Low serum selenium levels and

  20. ADVERSE EFFECTS OF INTRAVENOUS IMMUNOGLOBULIN THERAPY IN PATIENTS WITH ANTIBODY DEFICIENCY

    Directory of Open Access Journals (Sweden)

    A. Aghamohammadi

    2003-09-01

    Full Text Available Long-term intravenous immunoglobulin (IVIG infusion is an effective treatment for children with humoral immunodeficiencies, already be complicated by systemic ad¬verse effects. In order to determine the adverse effects of intravenous immunoglobulin inpatients with antibody deficiency, 45 immunodeficientpatients receiving intravenous immunoglobulin were studied during a 36-month period at Children's Medical Center. The investigated group included 25 patients with common variable immunodeficiency, 14 patients with X-linked agammaglobulinemia and 6 patients with IgG subclass defi¬ciency. A total of fifty adverse effects occurred through 955 infusions (5.2%. The most frequent immediate adverse effects were mild (40 infusions out of 955 in 22 cases, including: chills, flushing, fever, nausea and headache. Three patients experienced mod¬erate effects (10 infusions out of 955 such as rash, severe headache, joint pain and chest tightness. None of the effects was anaphylactic type. It can be concluded that intravenous immunoglobulin is generally a well-tolerated medical agent for patients with antibody deficiency, but all patients should be monitored by a physician who is familiar with its indications, risks, adverse effects and their appropriate management.

  1. Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells.

    Science.gov (United States)

    Katz, Samuel G; Labelle, James L; Meng, Hailong; Valeriano, Regina P; Fisher, Jill K; Sun, Heather; Rodig, Scott J; Kleinstein, Steven H; Walensky, Loren D

    2014-02-06

    Mantle cell lymphoma (MCL) is a highly aggressive B-cell lymphoma resistant to conventional chemotherapy. Although defined by the characteristic t(11;14) translocation, MCL has not been recapitulated in transgenic mouse models of cyclin D1 overexpression alone. Indeed, several genetic aberrations have been identified in MCL that may contribute to its pathogenesis and chemoresistance. Of particular interest is the frequent biallelic deletion of the proapoptotic BCL-2 family protein BIM. BIM exerts its pro-death function via its α-helical BH3 death domain that has the dual capacity to inhibit antiapoptotic proteins such as BCL-2 and MCL-1 and directly trigger proapoptotic proteins such as the mitochondrial executioner protein BAX. To evaluate a functional role for Bim deletion in the pathogenesis of MCL, we generated cyclin D1-transgenic mice harboring Bim-deficient B cells. In response to immunization, Eμ(CycD1)CD19(CRE)Bim(fl/fl) mice manifested selective expansion of their splenic mantle zone compartment. Three distinct immune stimulation regimens induced lymphomas with histopathologic and molecular features of human MCL in a subset of mice. Thus, deletion of Bim in B cells, in the context of cyclin D1 overexpression, disrupts a critical control point in lymphoid maturation and predisposes to the development of MCL. This genetic proof of concept for MCL pathogenesis suggests an opportunity to reactivate the death pathway by pharmacologic mimicry of proapoptotic BIM.

  2. Characterizing T Cells in SCID Patients Presenting with Reactive or Residual T Lymphocytes

    Directory of Open Access Journals (Sweden)

    Atar Lev

    2012-01-01

    Full Text Available Introduction. Patients with severe combined immunodeficiency (SCID may present with residual circulating T cells. While all cells are functionally deficient, resulting in high susceptibility to infections, only some of these cells are causing autoimmune symptoms. Methods. Here we compared T-cell functions including the number of circulating CD3+ T cells, in vitro responses to mitogens, T-cell receptor (TCR repertoire, TCR excision circles (TREC levels, and regulatory T cells (Tregs enumeration in several immunodeficinecy subtypes, clinically presenting with nonreactive residual cells (MHC-II deficiency or reactive cells. The latter includes patients with autoreactive clonal expanded T cell and patients with alloreactive transplacentally maternal T cells. Results. MHC-II deficient patients had slightly reduced T-cell function, normal TRECs, TCR repertoires, and normal Tregs enumeration. In contrast, patients with reactive T cells exhibited poor T-cell differentiation and activity. While the autoreactive cells displayed significantly reduced Tregs numbers, the alloreactive transplacentally acquired maternal lymphocytes had high functional Tregs. Conclusion. SCID patients presenting with circulating T cells show different patterns of T-cell activity and regulatory T cells enumeration that dictates the immunodeficient and autoimmune manifestations. We suggest that a high-tolerance capacity of the alloreactive transplacentally acquired maternal lymphocytes represents a toleration advantage, yet still associated with severe immunodeficiency.

  3. Prion Protein Deficiency Causes Diverse Proteome Shifts in Cell Models That Escape Detection in Brain Tissue.

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    Mohadeseh Mehrabian

    Full Text Available A popular method for studying the function of a given protein is to generate and characterize a suitable model deficient for its expression. For the prion protein (PrP, best known for its role in several invariably fatal neurodegenerative diseases, a natural choice, therefore, would be to undertake such studies with brain samples. We recently documented the surprising observation that PrP deficiency caused a loss or enhancement of NCAM1 polysialylation, dependent on the cell model used. To identify possible causes for this disparity, we set out to systematically investigate the consequence of PrP deficiency on the global proteome in brain tissue and in four distinct cell models. Here we report that PrP deficiency causes robust but surprisingly divergent changes to the global proteomes of cell models but has no discernible impact on the global brain proteome. Amongst >1,500 proteins whose levels were compared in wild-type and PrP-deficient models, members of the MARCKS protein family exhibited pronounced, yet cell model-dependent changes to their steady-state levels. Follow-up experiments revealed that PrP collaborates with members of the MARCKS protein family in its control of NCAM1 polysialylation. We conclude that the physiological function of PrP may be masked in analyses of complex brain samples but its cell-type specific influence on a lipid raft-based NCAM1-related cell biology comes to the fore in investigations of specific cell types.

  4. GLP-1 derivative liraglutide in rats with beta-cell deficiencies: influence of metabolic state on beta-cell mass dynamics

    DEFF Research Database (Denmark)

    Sturis, Jeppe; Gotfredsen, Carsten F; Rømer, John

    2003-01-01

    (1) Liraglutide is a long-acting GLP-1 derivative, designed for once daily administration in type II diabetic patients. To investigate the effects of liraglutide on glycemic control and beta-cell mass in rat models of beta-cell deficiencies, studies were performed in male Zucker diabetic fatty (ZDF...... was 2-3-fold higher during a normal 24-h feeding period (PJudged by pair feeding, approximately 53% of the antihyperglycemic effect observed on 24-h glucose profiles was mediated by a reduction in food intake, which persisted throughout the study and averaged 16% (P

  5. Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies.

    Science.gov (United States)

    Durandy, Anne; Taubenheim, Nadine; Peron, Sophie; Fischer, Alain

    2007-01-01

    B-cell intrinsic immunoglobulin class switch recombination (Ig-CSR) deficiencies, previously termed hyper-IgM syndromes, are genetically determined conditions characterized by normal or elevated serum IgM levels and an absence or very low levels of IgG, IgA, and IgE. As a function of the molecular mechanism, the defective CSR is variably associated to a defect in the generation of somatic hypermutations (SHMs) in the Ig variable region. The study of Ig-CSR deficiencies contributed to a better delineation of the mechanisms underlying CSR and SHM, the major events of antigen-triggered antibody maturation. Four Ig-CSR deficiency phenotypes have been so far reported: the description of the activation-induced cytidine deaminase (AID) deficiency (Ig-CSR deficiency 1), caused by recessive mutations of AICDA gene, characterized by a defect in CSR and SHM, clearly established the role of AID in the induction of the Ig gene rearrangements underlying CSR and SHM. A CSR-specific function of AID has, however, been detected by the observation of a selective CSR defect caused by mutations affecting the C-terminus of AID. Ig-CSR deficiency 2 is the consequence of uracil-N-glycosylase (UNG) deficiency. Because UNG, a molecule of the base excision repair machinery, removes uracils from DNA and AID deaminates cytosines into uracils, that observation indicates that the AID-UNG pathway directly targets DNA of switch regions from the Ig heavy-chain locus to induce the CSR process. Ig-CSR deficiencies 3 and 4 are characterized by a selective CSR defect resulting from blocks at distinct steps of CSR. A further understanding of the CSR machinery is expected from their molecular definition.

  6. Red cell indices and discriminant functions in the detection of beta-thalassaemia trait in a population with high prevalence of iron deficiency anaemia.

    Science.gov (United States)

    Madan, N; Sikka, M; Sharma, S; Rusia, U; Kela, K

    1999-01-01

    Red cell indices and discriminant functions were studied in 463 heterozygous beta-thalassaemics (337 without iron deficiency, 126 with iron deficiency) and 195 patients of iron deficiency anaemia (IDA) to ascertain their utility in the detection of betathalassaemia trait (BTT). Majority of traits in both groups had an elevated RBC count (> or = 5.0 x 10(12)/L). The counts were significantly higher than of patients with IDA, only 4.6% of whom had this degree of erythrocytosis. Mean Hb concentration was significantly higher in traits as compared to iron deficient subjects (p < 0.0001). Mean MCV and MCH were significantly (p < 0.0001) lower in traits more so in those with ID as compared to patients of IDA. MCV < 80 fl and MCH < 27 pg were found to be sensitive markers in the detection of traits even in the presence of ID. Of the four discriminant functions studied MCSQ was found to be most sensitive in detection of BTT and it identified 97.9% traits. DF of England and Fraser was most specific for BTT being < 8.4 in only 6.2% patients with IDA. Detection of erythrocytosis especially in the presence of mild anaemia and calculation of discriminant functions derived from red cell indices were found to play an important role in screening for BTT even in the presence of ID and helped identify those patients who required further laboratory evaluation.

  7. Plesiomonas shigelloides Septic Shock Leading to Death of Postsplenectomy Patient with Pyruvate Kinase Deficiency and Hemochromatosis

    Science.gov (United States)

    2016-01-01

    Although Plesiomonas shigelloides, a water-borne bacterium of the Enterobacteriaceae family, usually causes self-limiting gastroenteritis with diarrhea, several cases of sepsis have been reported. We report the case of a 43-year-old male patient with hemochromatosis, pyruvate kinase deficiency, and asplenia via splenectomy who developed septic shock caused by P. shigelloides complicated by respiratory failure, renal failure, liver failure, and disseminated intravascular coagulation. Early aggressive antimicrobial therapy and resuscitation measures were unsuccessful and the patient passed away. We kindly suggest clinicians to implement early diagnosis of septic shock, empirical coverage with antibiotics, and prompt volume resuscitation based on the high mortality rate of P. shigelloides bacteremia. PMID:27610253

  8. ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency

    Science.gov (United States)

    Mohni, Kareem N.; Kavanaugh, Gina M.; Cortez, David

    2014-01-01

    The DNA damage response kinase ATR and its effector kinase CHEK1 are required for cancer cells to survive oncogene-induced replication stress. ATR inhibitors exhibit synthetic lethal interactions with deficiencies in the DNA damage response enzymes ATM and XRCC1 and with overexpression of the cell cycle kinase Cyclin E. Here we report a systematic screen to identify synthetic lethal interactions with ATR-pathway targeted drugs, rationalized by their predicted therapeutic utility in the oncology clinic. We found that reduced function in the ATR pathway itself provided the strongest synthetic lethal interaction. In addition, we found that loss of the structure specific-endonuclease ERCC1-XPF (ERCC4) is synthetic lethal with ATR pathway inhibitors. ERCC1-deficient cells exhibited elevated levels of DNA damage, which was increased further by ATR inhibition. When treated with ATR or CHEK1 inhibitors, ERCC1-deficient cells arrested in S phase and failed to complete cell cycle transit even after drug removal. Notably, triple-negative breast cancer cells and non-small cell lung cancer cells depleted of ERCC1 exhibited increased sensitivity to ATR-pathway targeted drugs. Overall, we concluded that ATR pathway-targeted drugs may offer particular utility in cancers with reduced ATR pathway function or reduced levels of ERCC4 activity. PMID:24662920

  9. T cells exacerbate Lyme borreliosis in TLR2-deficient mice

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    Carrie E. Lasky

    2016-11-01

    Full Text Available Infection of humans with the spirochete, Borrelia burgdorferi, causes Lyme borreliosis and can lead to clinical manifestations such as, arthritis, carditis and neurological conditions. Experimental infection of mice recapitulates many of these symptoms and serves as a model system for the investigation of disease pathogenesis and immunity. Innate immunity is known to drive the development of Lyme arthritis and carditis, but the mechanisms driving this response remain unclear. Innate immune cells recognize B. burgdorferi surface lipoproteins primarily via Toll-like receptor (TLR2; however, previous work has demonstrated TLR2-/- mice had exacerbated disease and increased bacterial burden. We demonstrate increased CD4 and CD8 T cell infiltrates in B. burgdorferi-infected joints and hearts of C3H TLR2-/- mice. In vivo depletion of either CD4 or CD8 T cells reduced Borrelia-induced joint swelling and lowered tissue spirochete burden, while depletion of CD8 T cells alone reduced disease severity scores. Exacerbation of Lyme arthritis correlated with increased production of CXCL9 by synoviocytes and this was reduced with CD8 T cell depletion. These results demonstrate T cells can exacerbate Lyme disease pathogenesis and prolong disease resolution possibly through dysregulation of inflammatory responses and inhibition of bacterial clearance.

  10. Correlation between atherogenic index of plasma level and metabolism components in adult growth hormone deficiency patients

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    Jia-jia XIA

    2015-01-01

    Full Text Available Objective To investigate the correlation of atherogenic index of plasma (AIP levels with anthropometrics, glycolipid metabolism markers and high-sensitivity C-reactive protein (hs-CRP, interleukin-6 (IL-6 in adult growth hormone deficiency (AGHD patients. Methods Retrospective analysis were carried out in 40 AGHD patients (AGHD group, admitted to First Affiliated Hospital of Chongqing Medical University and 40 healthy adults from physical examination centre (control group during June 2009 to September 2012. The general anthropometries and blood biochemical indexes were collected and compared between two groups. AIP, homeostasis model assessment-insulin resistance (HOMA-IR, homeostasis model assessment β-cell function (HOMA-β, LDL-C/HDL-C, TC/HDL-C, and TG/LDL-C were calculated and compared between two groups. The correlation between AIP and these indexes was analyzed using Pearson correlation. Results Compared with control group, body mass index (BMI, waist circumference (WC, waist-hip ratio (WHR, fasting insulin (FINS, HOMA-β, HOMA-IR, total cholesterol (TC, triglyceride (TG, LDL-C/HDL-C, TC/HDL-C, hs-CPR, IL-6, AIP were significant higher, but HDL-C levels were lower in AGHD group (P0.05. There was a positive association between AIP and all the WC, WHR, FINS, HOMA-β, HOMA-IR, TC, LDL-C/HDL-C, TC/HDL-C, TG/LDL-C, hs-CRP and IL-6 (r=0.349, 0.314, 0.347, 0.335, 0.297, 0.256, 0.576, 0.749, 0.702, 0.477, 0.226, respectively, P<0.05. Multiple linear regression analysis revealed that hs-CRP and IL-6 were independent risk factors of AIP. Conclusion AIP is significantly higher in AGHD patients than healthy people, and it shows a strong correlation with many risk factors for cardiovascular diseases. DOI: 10.11855/j.issn.0577-7402.2014.12.10

  11. Effect of iron deficiency on c-kit⁺ cardiac stem cells in vitro.

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    Dongqiang Song

    Full Text Available AIM: Iron deficiency is a common comorbidity in chronic heart failure (CHF which may exacerbate CHF. The c-kit⁺ cardiac stem cells (CSCs play a vital role in cardiac function repair. However, much is unknown regarding the role of iron deficiency in regulating c-kit⁺ CSCs function. In this study, we investigated whether iron deficiency regulates c-kit⁺ CSCs proliferation, migration, apoptosis, and differentiation in vitro. METHOD: All c-kit⁺ CSCs were isolated from adult C57BL/6 mice. The c-kit⁺ CSCs were cultured with deferoxamine (DFO, an iron chelator, mimosine (MIM, another iron chelator, or a complex of DFO and iron (Fe(III, respectively. Cell migration was assayed using a 48-well chamber system. Proliferation, cell cycle, and apoptosis of c-kit⁺ CSCs were analyzed with BrdU labeling, population doubling time assay, CCK-8 assay, and flow cytometry. Caspase-3 protein level and activity were examined with Western blotting and spectrophotometric detection. The changes in the expression of cardiac-specific proteins (GATA-4,TNI, and β-MHC and cell cycle-related proteins (cyclin D1, RB, and pRB were detected with Western blotting. RESULT: DFO and MIM suppressed c-kit⁺ CSCs proliferation and differentiation. They also modulated cell cycle and cardiac-specific protein expression. Iron chelators down-regulated the expression and phosphorylation of cell cycle-related proteins. Iron reversed those suppressive effects of DFO. DFO and MIM didn't affect c-kit⁺ CSCs migration and apoptosis. CONCLUSION: Iron deficiency suppressed proliferation and differentiation of c-kit⁺ CSCs. This may partly explain how iron deficiency affects CHF prognosis.

  12. THE PREVALENCE OF CELIAC DISEASE IN PATIENTS WITH IRON-DEFICIENCY ANEMIA IN CENTER AND SOUTH AREA OF IRAN

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    Mahmud BAGHBANIAN

    2015-12-01

    Full Text Available Background - Celiac disease is an immune-mediated enteropathy due to a permanent sensitivity to gluten in genetically susceptible people. Iron-deficiency anemia is the most widely experienced anemia in humans. Iron-deficiency anemia additionally is a common extra intestinal manifestation of celiac disease. Objective - To investigate correlation between tTg levels and histological alterations and then to determine the prevalence of celiac disease in Center and South area patients of Iran with iron deficiency anemia. Methods - A total of 402 patients aged 12-78 years who presented with iron-deficiency anemia were included in this study. Hemoglobin, mean corpuscular volume and serum ferritin were determined. Venous blood samples for anti-tissue transglutaminase antibody immunoglobuline A and G were obtained from these patients. Upper gastrointestinal endoscopy was recommended to patients who had positive serology. Results - Of 402 patients with iron-deficiency anemia, 42 (10.4% had positive serology for celiac disease. The small intestine biopsy of all patients with positive serology showed pathological changes (Marsh I, II & III. There was not significant difference in the mean hemoglobin level between iron-deficiency anemia patients with celiac disease and without celiac disease, duodenal biopsy results did not show significant relationship between the severity of pathological changes and levels of anti-tTG IgG (P -value: 0/869 but significant relationship was discovered between pathological changes and levels of anti-tTG IgA (P -value: 0/004. Conclusion - Screening of celiac disease by anti-tissue transglutaminase antibody should be completed as a routine investigation in patients with iron-deficiency anemia. Also physicians must consider celiac disease as a possible reason of anemia in all patients with iron deficiency anemia.

  13. AMIGO2 modulates T cell functions and its deficiency in mice ameliorates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Li, Zhilin; Khan, Mohd Moin; Kuja-Panula, Juha; Wang, Hongyun; Chen, Yu; Guo, Deyin; Chen, Zhi Jane; Lahesmaa, Riitta; Rauvala, Heikki; Tian, Li

    2017-05-01

    The immune function of AMIGO2 is currently unknown. Here, we revealed novel roles of AMIGO2 in modulating T-cell functions and EAE using Amigo2-knockout (AMG2KO) mice. Amigo2 was abundantly expressed by murine T helper (Th) cells. Its deficiency impaired transplanted T-cell infiltration into the secondary lymphoid organs and dampened Th-cell activation, but promoted splenic Th-cell proliferation and abundancy therein. AMG2KO Th cells had respectively elevated T-bet in Th1- and GATA-3 in Th2-lineage during early Th-cell differentiation, accompanied with increased IFN-γ and IL-10 but decreased IL-17A production. AMG2KO mice exhibited ameliorated EAE, dampened spinal T-cell accumulation, decreased serum IL-17A levels and enhanced splenic IL-10 production. Adoptive transfer of encephalitogenic AMG2KO T cells induced milder EAE and dampened spinal Th-cell accumulation and Tnf expression. Mechanistically, Amigo2-overexpression in 293T cells dampened NF-kB transcriptional activity, while Amigo2-deficiency enhanced Akt but suppressed GSK-3β phosphorylation and promoted nuclear translocations of NF-kB and NFAT1 in Th-cells. Collectively, our data demonstrate that AMIGO2 is important in regulating T-cell functions and EAE, and may be harnessed as a potential therapeutic target for multiple sclerosis.

  14. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency

    NARCIS (Netherlands)

    Hassan, Amel; Booth, Claire; Brightwell, Alex; Allwood, Zoe; Veys, Paul; Rao, Kanchan; Hoenig, Manfred; Friedrich, Wilhelm; Gennery, Andrew; Slatter, Mary; Bredius, Robbert; Finocchi, Andrea; Cancrini, Caterina; Aiuti, Alessandro; Porta, Fulvio; Lanfranchi, Arnalda; Ridella, Michela; Steward, Colin; Filipovich, Alexandra; Marsh, Rebecca; Bordon, Victoria; Al-Muhsen, Saleh; Al-Mousa, Hamoud; Alsum, Zobaida; Al-Dhekri, Hasan; Al Ghonaium, Abdulaziz; Speckmann, Carsten; Fischer, Alain; Mahlaoui, Nizar; Nichols, Kim E.; Grunebaum, Eyal; Al Zahrani, Daifulah; Roifman, Chaim M.; Boelens, Jaap; Davies, E. Graham; Cavazzana-Calvo, Marina; Notarangelo, Luigi; Gaspar, H. Bobby

    2012-01-01

    Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed o

  15. Differential programming of p53-deficient embryonic cells during rotenone block

    Science.gov (United States)

    Mitochondrial dysfunction has been implicated in chemical toxicities. The present study used an in vitro model to investigate the differential expression of metabolic pathways during cellular stress in p53- efficient embryonic fibroblasts compared to p53-deficient cells. These c...

  16. Effectiveness of potassium iodide in the treatment of GERD patients in combination with iodine deficiency states

    Directory of Open Access Journals (Sweden)

    V. B. Boychuk

    2015-04-01

    Full Text Available GERD and iodine deficiency conditions are not only limited by similar clinical symptoms. They influence on each other by regulatory kinetic mechanisms of upper gastrointestinal tract. Aim. We examined 40 patients with GERD on a background of iodine deficiency in order to study the efficacy of using potassium iodide in these patients. Methods and results. Iodine deficiency was detected by level of iodine in urine, level of TSH, free T4 and free T3. Also was determined motor-evacuational function of the stomach according to 13C-octanoic breath test and levels of regulatory peptides (gastrin, cholecystokinin-pankreozymin and pepsinogens. Conclusion. Positive dynamics of iodine absorption and motor-evacuational function of the stomach were found after 1 month of treatment. Decreasing frequency and duration of acid reflux and reducing pepsinogen levels and improvement of indicators of intestinal hormones were also found in these patiens. This shows the optimization of regulatory mechanisms and kinetics of upper gastrointestinal tract.

  17. Anaesthesia management in a patient with a severe biotinidase deficiency for congenital scoliosis repair

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    Ebrahim Almasri

    2016-01-01

    Full Text Available A 17 year old female patient with a biotinidase enzyme deficiency, cerebral palsy, aphamis, generalized hyperreflexia and spasticity, epilepsy and mental retardation came for the severe kyphoscoliotic deformity correction. Biotinidase enzyme deficiency is an autosomal recessive disorder with incidence of 1:60,000 neonatal birth. Treatment with biotin results in a rapid biochemical and clinical improvement. This enzyme deficiency involves neurological, neuromuscular, respiratory, dermatological and immunological problems. If untreated it can lead to convulsions, coma and death. Cobb’s angle that measures the curvature of scoliosis, determined by measurements made on X rays in this case was 120° with clinical presentation of recurrent respiratory tract infection, inability to maintain sagittal posture, inability to eat or feed and difficulty in nursing care. Anaesthetic management in these patients should focus primarily on associated comorbidities and congenital anomalies affecting the course of the perioperative management and thereafter comprehensive preoperative strategies must be executed to enhance the safety profile during the surgery.

  18. Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3

    Science.gov (United States)

    Pfaender, Stefanie; Sauer, Ann Katrin; Hagmeyer, Simone; Mangus, Katharina; Linta, Leonhard; Liebau, Stefan; Bockmann, Juergen; Huguet, Guillaume; Bourgeron, Thomas; Boeckers, Tobias M.; Grabrucker, Andreas M.

    2017-01-01

    Phelan McDermid Syndrome (PMDS) is a genetic disorder characterized by features of Autism spectrum disorders. Similar to reports of Zn deficiency in autistic children, we have previously reported high incidence of Zn deficiency in PMDS. However, the underlying mechanisms are currently not well understood. Here, using inductively coupled plasma mass-spectrometry to measure the concentration of Zinc (Zn) and Copper (Cu) in hair samples from individuals with PMDS with 22q13.3 deletion including SHANK3 (SH3 and multiple ankyrin repeat domains 3), we report a high rate of abnormally low Zn/Cu ratios. To investigate possible underlying mechanisms, we generated enterocytes from PMDS patient-derived induced pluripotent stem cells and used Caco-2 cells with knockdown of SHANK3. We detected decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. We demonstrated that especially ZIP4 exists in a complex with SHANK3. Furthermore, we performed immunohistochemistry on gut sections from Shank3αβ knockout mice and confirmed a link between enterocytic SHANK3, ZIP2 and ZIP4. We conclude that apart from its well-known role in the CNS, SHANK3 might play a specific role in the GI tract. PMID:28345660

  19. 芪参扶正胶囊联合TP方案对晚期非小细胞肺癌脾肾亏虚型患者生活质量的影响%The influence of Qishenfuzheng capsule combined with TP in improving the quality of life of patients with advanced non-small cell lung cancer of spleen and kidney deficiency type

    Institute of Scientific and Technical Information of China (English)

    张子志; 张永杰

    2016-01-01

    Objective To evaluate the efficacy and safety of Qishenfuzheng capsule combined with TP in improving the quality of life of patients with advanced non-small cell lung cancer of spleen and kidney deficiency type. Methods37 cases of patients with advanced non-small cell lung cancer proposed TP chemotherapy in Department of Internal Medicine-Oncology of Shouguang Traditional Chinese Medicine Hospital from March 2012 to February 2015 were selected and divided into therapy group (18 cases) and control group (19 cases) with the ratio of 1: 1 parity packets. Patients in therapy group were treated with Qishenfuzheng capsule combined with TP chemotherapy. Patients in control group were treated with TP chemotherapy.ResultsCompared with before treatment, field of role function, physical function and emotional function of therapy group were significantly improved, the differences were significant (P<0.05).TCM clinical symptom score of therapy group was significantly reduced,the difference was significant (P<0.05).KPS score after treatment was significantly higher than that of control group, the difference was statistically significant (P<0.05).Hematologic toxicity and gastrointestinal reactions of therapy group were much better than those of control group.ConclusionQishenfuzheng capsule could improve the quality of life of patients with advanced non-small cell lung cancer (NSCLC) of spleen and kidney deficiency type, and could reduce the toxicity of chemotherapy drugs.%目的:评价芪参扶正胶囊联合TP方案在提高脾肾亏虚型晚期非小细胞肺癌生活质量方面的有效性、安全性。方法选择寿光市中医医院肿瘤科2012年3月~2015年2月拟TP方案化疗的晚期非小细胞肺癌37例,按1∶1的比例奇偶分组,治疗组18例,对照组19例治疗组采用芪参扶正胶囊加TP化疗方案。对照组采用TP方案化疗。结果治疗组的角色功能、躯体功能、情绪功能领域有明显改善,与治疗前比较,

  20. Comparative study of intravenous iron sucrose versus ferric carboxymaltose for the treatment of iron deficiency anemia in postpartum patients

    Directory of Open Access Journals (Sweden)

    Kishorkumar Vitthal Hol

    2015-06-01

    Conclusions: Fixed dose iron sucrose and ferric carboxymaltose are equally effective and safe for the treatment of iron deficiency anemia in postpartum patients. [Int J Reprod Contracept Obstet Gynecol 2015; 4(3.000: 669-673

  1. BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin

    Energy Technology Data Exchange (ETDEWEB)

    Oommen, Deepu [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom); Yiannakis, Dennis [Plymouth Oncology Centre, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth PL6 8DH (United Kingdom); Jha, Awadhesh N., E-mail: a.jha@plymouth.ac.uk [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom)

    2016-02-15

    Highlights: • BRCA1 deficient cancer cells exhibit increased DNA damage upon auranofin treatment. • Auranofin induces apoptosis in BRCA1 deficient cancer cells despite the activation of Nrf2. • Antioxidant protects BRCA1 deficient cancer cells from auranofin. - Abstract: Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2—related factor 2 (Nrf2) via direct protein–protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.

  2. Cutting edge: NKT cell development is selectively impaired in Fyn- deficient mice.

    Science.gov (United States)

    Eberl, G; Lowin-Kropf, B; MacDonald, H R

    1999-10-15

    Most NK1.1+ T (NKT) cells express a biased TCRalphabeta repertoire that is positively selected by the monomorphic MHC class I-like molecule CD1d. The development of CD1d-dependent NKT cells is thymus dependent but, in contrast to conventional T cells, requires positive selection by cells of hemopoietic origin. Here, we show that the Src protein tyrosine kinase Fyn is required for development of CD1d-dependent NKT cells but not for the development of conventional T cells. In contrast, another Src kinase, Lck, is required for the development of both NKT and T cells. Impaired NKT cell development in Fyn-deficient mice cannot be rescued by transgenic expression of CD8, which is believed to increase the avidity of CD1d recognition by NKT cells. Taken together, our data reveal a selective and nonredundant role for Fyn in NKT cell development.

  3. MSH3-deficiency initiates EMAST without oncogenic transformation of human colon epithelial cells.

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    Christoph Campregher

    Full Text Available BACKGROUND/AIM: Elevated microsatellite instability at selected tetranucleotide repeats (EMAST is a genetic signature in certain cases of sporadic colorectal cancer and has been linked to MSH3-deficiency. It is currently controversial whether EMAST is associated with oncogenic properties in humans, specifically as cancer development in Msh3-deficient mice is not enhanced. However, a mutator phenotype is different between species as the genetic positions of repetitive sequences are not conserved. Here we studied the molecular effects of human MSH3-deficiency. METHODS: HCT116 and HCT116+chr3 (both MSH3-deficient and primary human colon epithelial cells (HCEC, MSH3-wildtype were stably transfected with an EGFP-based reporter plasmid for the detection of frameshift mutations within an [AAAG]17 repeat. MSH3 was silenced by shRNA and changes in protein expression were analyzed by shotgun proteomics. Colony forming assay was used to determine oncogenic transformation and double strand breaks (DSBs were assessed by Comet assay. RESULTS: Despite differential MLH1 expression, both HCT116 and HCT116+chr3 cells displayed comparable high mutation rates (about 4×10(-4 at [AAAG]17 repeats. Silencing of MSH3 in HCECs leads to a remarkable increased frameshift mutations in [AAAG]17 repeats whereas [CA]13 repeats were less affected. Upon MSH3-silencing, significant changes in the expression of 202 proteins were detected. Pathway analysis revealed overexpression of proteins involved in double strand break repair (MRE11 and RAD50, apoptosis, L1 recycling, and repression of proteins involved in metabolism, tRNA aminoacylation, and gene expression. MSH3-silencing did not induce oncogenic transformation and DSBs increased 2-fold. CONCLUSIONS: MSH3-deficiency in human colon epithelial cells results in EMAST, formation of DSBs and significant changes of the proteome but lacks oncogenic transformation. Thus, MSH3-deficiency alone is unlikely to drive human colon

  4. Psychological functioning after growth hormone therapy in adult growth hormone deficient patients: endocrine and body composition correlates

    OpenAIRE

    Lašaitė, Lina; Bunevičius, Robertas; Lašienė, Danutė Teresė; Lašas, Liudvikas

    2004-01-01

    Growth hormone replacement in adult growth hormone deficient patients improves psychological well-being and the quality of life. The aim of this study was to investigate relationship between changes in mood, cognitive functioning, quality of life, changes in body composition and hormone concentration at baseline and six months after treatment with human recombinant growth hormone. Eighteen adult patients with growth hormone deficiency syndrome were recruited to the study. Growth hormone was a...

  5. Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency

    DEFF Research Database (Denmark)

    Abolhassani, Hassan; Edwards, Emily S. J.; Ikinciogullari, Aydan

    2017-01-01

    is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70-CD27 interactions therefore play a nonredundant role in T and B cell-mediated immunity, especially for protection against EBV and humoral immunity.......In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)-related diseases. Three patients presented with EBV-associated Hodgkin's lymphoma...... and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal...

  6. Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells.

    Science.gov (United States)

    Zou, Jianlong; Hu, Bo; Arpag, Sezgi; Yan, Qing; Hamilton, Audra; Zeng, Yuan-Shan; Vanoye, Carlos G; Li, Jun

    2015-04-29

    Loss of function of FIG4 leads to Charcot-Marie-Tooth disease Type 4J, Yunis-Varon syndrome, or an epilepsy syndrome. FIG4 is a phosphatase with its catalytic specificity toward 5'-phosphate of phosphatidylinositol-3,5-diphosphate (PI3,5P2). However, the loss of FIG4 decreases PI3,5P2 levels likely due to FIG4's dominant effect in scaffolding a PI3,5P2 synthetic protein complex. At the cellular level, all these diseases share similar pathology with abnormal lysosomal storage and neuronal degeneration. Mice with no FIG4 expression (Fig4(-/-)) recapitulate the pathology in humans with FIG4 deficiency. Using a flow cytometry technique that rapidly quantifies lysosome sizes, we detected an impaired lysosomal fission, but normal fusion, in Fig4(-/-) cells. The fission defect was associated with a robust increase of intralysosomal Ca(2+) in Fig4(-/-) cells, including FIG4-deficient neurons. This finding was consistent with a suppressed Ca(2+) efflux of lysosomes because the endogenous ligand of lysosomal Ca(2+) channel TRPML1 is PI3,5P2 that is deficient in Fig4(-/-) cells. We reactivated the TRPML1 channels by application of TRPML1 synthetic ligand, ML-SA1. This treatment reduced the intralysosomal Ca(2+) level and rescued abnormal lysosomal storage in Fig4(-/-) culture cells and ex vivo DRGs. Furthermore, we found that the suppressed Ca(2+) efflux in Fig4(-/-) culture cells and Fig4(-/-) mouse brains profoundly downregulated the expression/activity of dynamin-1, a GTPase known to scissor organelle membranes during fission. This downregulation made dynamin-1 unavailable for lysosomal fission. Together, our study revealed a novel mechanism explaining abnormal lysosomal storage in FIG4 deficiency. Synthetic ligands of the TRPML1 may become a potential therapy against diseases with FIG4 deficiency.

  7. Social capital of Iranian patients living with acquired immune deficiency syndrome and associated factors.

    Science.gov (United States)

    Ansari, S K; Nedjat, S; Jabbari, H; Saiepour, N; Heris, M J

    2015-12-13

    This study investigated the social capital of Iranian patients living with acquired immune deficiency syndrome (AIDS) and the associated factors. In a cross-sectional study the Integrated Social Capital Questionnaire was filled by a sequential sample of 300 patients visiting a referral counselling centre in Tehran. The patients' social capital scores were around 50% in the trust, social cohesion, collective action and cooperation and political empowerment domains. The groups and networks membership domain scored the lowest (27.1%). In regression analysis, employment status was significantly associated with groups and networks membership; age, marital status and financial status were associated with collective action and cooperation; period of disease awareness and marital status affected social cohesion and inclusion; and having risky behaviour affected empowerment and political action. Efforts are needed to enhance the social capital of those patients living with AIDS who are younger, unemployed, divorced/widowed, with risky behaviours and shorter disease awareness.

  8. Molecular Mechanisms Underlying Genomic Instability in Brca-Deficient Cells

    Science.gov (United States)

    2014-03-01

    stimu- lation to undergo antibody class switching and was shown to be highly expressed in primary human and murine germinal center B cells from tonsil ...online September 4, 2012. Robbiani, D.F., Bunting, S., Feldhahn, N., Bothmer, A., Camps, J., Deroubaix, S., McBride, K.M., Klein, I.A., Stone , G

  9. Co-existence of clonal expanded autologous and transplacental-acquired maternal T cells in recombination activating gene-deficient severe combined immunodeficiency

    Science.gov (United States)

    Lev, A; Simon, A J; Ben-Ari, J; Takagi, D; Stauber, T; Trakhtenbrot, L; Rosenthal, E; Rechavi, G; Amariglio, N; Somech, R

    2014-01-01

    It is commonly accepted that the presence of high amounts of maternal T cells excludes Omenn syndrome (OS) in severe combined immunodeficiency (SCID). We report a SCID patient with a novel mutation in the recombination activating gene (RAG)1 gene (4-BP DEL.1406 TTGC) who presented with immunodeficiency and OS. Several assays, including representatives of specific T cell receptors (TCR), Vβ families and TCR-γ rearrangements, were performed in order to understand more clearly the nature and origin of the patient's T cells. The patient had oligoclonal T cells which, based on the patient–mother human leucocyte antigen (HLA)-B50 mismatch, were either autologous or of maternal origin. These cell populations were different in their numbers of regulatory T cells (Treg) and the diversity of TCR repertoires. This is the first description of the co-existence of large amounts of clonal expanded autologous and transplacental-acquired maternal T cells in RAG1-deficient SCID. PMID:24666246

  10. Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase

    OpenAIRE

    Bowles, Tawnya L.; Kim, Randie; Galante, Joseph; Parsons, Colin M.; Virudachalam, Subbulakshmi; Kung, Hsing-Jien; Bold, Richard J.

    2008-01-01

    Eukaryotic cells can synthesize the non-essential amino acid arginine from aspartate and citrulline using the enzyme argininosuccinate synthetase (ASS). It has been observed that ASS is under-expressed in various types of cancers ASS, for which arginine become auxotrophic. Arginine deiminase (ADI) is a prokaryotic enzyme that metabolizes arginine to citrulline and has been found to inhibit melanoma and hepatoma cancer cells deficient of ASS. We tested the hypothesis that pancreatic cancers ha...

  11. Estimated red blood cell thickness in microcytic anemia due to iron deficiency anemia and thalassemia

    Directory of Open Access Journals (Sweden)

    Viroj Wiwanitkit

    2009-05-01

    Full Text Available "nAnemia is one of the most common hematological disorders that are still the present in all countries around the world. Microcytic anemia is a specific kind of anemia presenting with small red blood cell. In this paper, the author discusses on the estimated red blood cell thickness, a new proposed parameter, comparing between that of iron deficiency anemia and thalassemia and further extrapolate on the clinical implication.

  12. Refractory platelet transfusion in a patient with CD36 deficiency due to pseudothrombocytopenia.

    Science.gov (United States)

    Yin, Xiao-Lin; Shen, Wei-Dong; Chen, Yong-Sheng; Zhou, Yan; Zhang, Xin-Huan

    2011-01-01

    Type I CD36 deficiency is defined by the absence of CD36 on both platelets and monocytes. Pseudothrombocytopenia (PTCP) is characterized by a false reduction in the number of platelets in ethylenediaminetetraacetic acid (EDTA)-anticoagulated blood. Here we report a rare case of concomitant CD36 deficiency and PTCP. The patient was a 7-year-old boy who suffered comminuted fractures of the left humeral condyle. In the pre-operative examination, he was found to have thrombopenia and assumed to have idiopathic thrombocytopenic purpura. After immunotherapy and platelet transfusion, the platelet count remained low, suggesting that the patient was refractory to platelet transfusion. Serum was collected for the detection of platelet antibodies, and antibodies against CD36 were found. Flow cytometry verified the absence of CD36 on both the platelets and monocytes of this patient. However, the platelet count was normal when capillary blood smears were analysed; in addition, platelet coagulation was noted under the microscope when EDTA-anticoagulated peripheral blood was used. The patient underwent surgery without platelet transfusion and recovered uneventfully.

  13. Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis.

    Science.gov (United States)

    Zhang, Ling; Ren, Xiaoyang; Alt, Eckhard; Bai, Xiaowen; Huang, Shaoyi; Xu, Zhengming; Lynch, Patrick M; Moyer, Mary P; Wen, Xian-Feng; Wu, Xiangwei

    2010-04-15

    Cancer chemoprevention uses natural, synthetic, or biological substances to reverse, suppress, or prevent either the initial phase of carcinogenesis or the progression of neoplastic cells to cancer. It holds promise for overcoming problems associated with the treatment of late-stage cancers. However, the broad application of chemoprevention is compromised at present by limited effectiveness and potential toxicity. To overcome these challenges, here we developed a new chemoprevention approach that specifically targets premalignant tumour cells for apoptosis. We show that a deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of beta-catenin lead to the repression of cellular caspase-8 inhibitor c-FLIP (also known as CFLAR) expression through activation of c-Myc, and that all-trans-retinyl acetate (RAc) independently upregulates tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. In addition, we show that short-term and non-continuous TRAIL and RAc treatment induce apoptosis specifically in intestinal polyps, strongly inhibit tumour growth, and prolong survival in multiple intestinal neoplasms C57BL/6J-Apc(Min)/J (Apc(Min)) mice. With our approach, we further demonstrate that TRAIL and RAc induce significant cell death in human colon polyps, providing a potentially selective approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis.

  14. Automatic analysis of image of surface structure of cell wall-deficient EVC.

    Science.gov (United States)

    Li, S; Hu, K; Cai, N; Su, W; Xiong, H; Lou, Z; Lin, T; Hu, Y

    2001-01-01

    Some computer applications for cell characterization in medicine and biology, such as analysis of surface structure of cell wall-deficient EVC (El Tor Vibrio of Cholera), operate with cell samples taken from very small areas of interest. In order to perform texture characterization in such an application, only a few texture operators can be employed: the operators should be insensitive to noise and image distortion and be reliable in order to estimate texture quality from images. Therefore, we introduce wavelet theory and mathematical morphology to analyse the cellular surface micro-area image obtained by SEM (Scanning Electron Microscope). In order to describe the quality of surface structure of cell wall-deficient EVC, we propose a fully automatic computerized method. The image analysis process is carried out in two steps. In the first, we decompose the given image by dyadic wavelet transform and form an image approximation with higher resolution, by doing so, we perform edge detection of given images efficiently. In the second, we introduce many operations of mathematical morphology to obtain morphological quantitative parameters of surface structure of cell wall-deficient EVC. The obtained results prove that the method can eliminate noise, detect the edge and extract the feature parameters validly. In this work, we have built automatic analytic software named "EVC.CELL".

  15. Root graviresponsiveness and columella cell structure in carotenoid-deficient seedlings of Zea mays

    Science.gov (United States)

    Moore, R.; McClelen, C. E.

    1985-01-01

    Root graviresponsiveness in normal and carotenoid-deficient mutant seedlings of Zea mays was not significantly different. Columella cells in roots of mutant seedlings were characterized by fewer, smaller, and a reduced relative volume of plastids as compared to columella cells of normal seedlings. Plastids in columella cells of mutant seedlings possessed reduced amounts of starch. Although approximately 10 per cent of the columella cells in mutant seedlings lacked starch, their plastids were located at the bottom of the cell. These results suggest that (i) carotenoids are not necessary for root gravitropism, (ii) graviresponsiveness is not necessarily proportional to the size, number, or relative volume of plastids in columella cells, and (iii) sedimentation of plastids in columella cells may not result directly from their increased density due to starch content. Plastids in columella cells of normal and mutant seedlings were associated with bands of microtubule-like structures, suggesting that these structures may be involved in 'positioning' plastids in the cell.

  16. Occurrence of GLUT1 deficiency syndrome in patients treated with ketogenic diet.

    Science.gov (United States)

    Ramm-Pettersen, Anette; Nakken, Karl O; Haavardsholm, Kathrine Cammermeyer; Selmer, Kaja Kristine

    2014-03-01

    Glucose transporter 1 deficiency syndrome (GLUT1-DS) is a treatable metabolic encephalopathy caused by a mutation in the SLC2A1 gene. This mutation causes a compromised transport of glucose across the blood-brain barrier. The treatment of choice is ketogenic diet, with which most patients become seizure-free. At the National Centre for Epilepsy, we have, since 2005, offered treatment with ketogenic diet (KD) and modified Atkins diet (MAD) to children with difficult-to-treat epilepsy. As we believe many children with GLUT1-DS are unrecognized, the aim of this study was to search for patients with GLUT1-DS among those who had been responders (>50% reduction in seizure frequency) to KD or MAD. Of the 130 children included, 58 (44%) were defined as responders. Among these, 11 were already diagnosed with GLUT1-DS. No mutations in the SLC2A1 gene were detected in the remaining patients. However, the clinical features of these patients differed considerably from the patients diagnosed with GLUT1-DS. While 9 out of 10 patients with GLUT1-DS became seizure-free with dietary treatment, only 3 out of the 33 remaining patients were seizure-free with KD or MAD treatment. We therefore conclude that a seizure reduction of >50% following dietary treatment is not a suitable criterion for identifying patients with GLUT1-DS, as these patients generally achieve complete seizure freedom shortly after diet initiation.

  17. Prevalence of glucose-6-phosphate dehydrogenase deficiency and sickle cell trait among blood donors in Riyadh

    Directory of Open Access Journals (Sweden)

    Alabdulaali Mohammed

    2010-01-01

    Full Text Available Background and Aims: Blood donation from glucose-6-phosphate dehydrogenase (G6PD-deficient and sickle cell trait (SCT donors might alter the quality of the donated blood during processing, storage or in the recipient′s circulatory system. The aim of this study was to determine the prevalence of G6PD deficiency and SCT among blood donors coming to King Khalid University Hospital (KKUH in Riyadh. It was also reviewed the benefits and risks of transfusing blood from these blood donors. Materials and Methods: This cross-sectional study was conducted on 1150 blood samples obtained from blood donors that presented to KKUH blood bank during the period April 2006 to May 2006. All samples were tested for Hb-S by solubility test, alkaline gel electrophoresis; and for G6PD deficiency, by fluorescent spot test. Results: Out of the 1150 donors, 23 (2% were diagnosed for SCT, 9 (0.78% for G6PD deficiency and 4 (0.35% for both conditions. Our prevalence of SCT and G6PD deficiency is higher than that of the general population of Riyadh. Conclusion: We recommend to screen all units for G6PD deficiency and sickle cell trait and to defer donations from donors with either of these conditions, unless if needed for special blood group compatibility, platelet apheresis or if these are likely to affect the blood bank inventory. If such blood is to be used, special precautions need to be undertaken to avoid complications in high-risk recipients.

  18. Molecular Mechanisms Underlying Genomic Instability in Brca-Deficient Cells

    Science.gov (United States)

    2012-03-01

    rejoining is then completed by activi- ties of the XRCC4/ DNA ligase IV (Lig4) complex (Critchlow and Jackson, 1998). The importance of double-strand break...Recombination in DNA Interstrand Crosslink Repair, Molecular Cell (2012), doi:10.1016/j.molcel.2012.02.015 found that loss of DNA ligase IV (Lig4) in FANCC...either C-NHEJ or A-NHEJ. The C-NHEJ pathway requires DNA ligase IV, XRCC4, Ku70, and Ku80, and is necessary for efficient repair of intrachromosomal

  19. B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus.

    Science.gov (United States)

    Jiang, Chao; Loo, William M; Greenley, Erin J; Tung, Kenneth S; Erickson, Loren D

    2011-06-01

    Systemic lupus erythematosus and its preclinical lupus-prone mouse models are autoimmune disorders involving the production of pathogenic autoantibodies. Genetic predisposition to systemic lupus erythematosus results in B cell hyperactivity, survival of self-reactive B cells, and differentiation to autoantibody-secreting plasma cells (PCs). These corrupt B cell responses are, in part, controlled by excess levels of the cytokine BAFF that normally maintains B cell homeostasis and self-tolerance through limited production. B cell maturation Ag (BCMA) is a receptor for BAFF that, under nonautoimmune conditions, is important for sustaining enduring Ab protection by mediating survival of long-lived PCs but is not required for B cell maturation and homeostasis. Through analysis of two different lupus-prone mouse models deficient in BCMA, we identify BCMA as an important factor in regulating peripheral B cell expansion, differentiation, and survival. We demonstrate that a BCMA deficiency combined with the lpr mutation or the murine lupus susceptibility locus Nba2 causes dramatic B cell and PC lymphoproliferation, accelerated autoantibody production, and early lethality. This study unexpectedly reveals that BCMA works to control B cell homeostasis and self-tolerance in systemic autoimmunity.

  20. Heme oxygenase-1 deficiency alters erythroblastic island formation, steady-state erythropoiesis and red blood cell lifespan in mice.

    Science.gov (United States)

    Fraser, Stuart T; Midwinter, Robyn G; Coupland, Lucy A; Kong, Stephanie; Berger, Birgit S; Yeo, Jia Hao; Andrade, Osvaldo Cooley; Cromer, Deborah; Suarna, Cacang; Lam, Magda; Maghzal, Ghassan J; Chong, Beng H; Parish, Christopher R; Stocker, Roland

    2015-05-01

    Heme oxygenase-1 is critical for iron recycling during red blood cell turnover, whereas its impact on steady-state erythropoiesis and red blood cell lifespan is not known. We show here that in 8- to 14-week old mice, heme oxygenase-1 deficiency adversely affects steady-state erythropoiesis in the bone marrow. This is manifested by a decrease in Ter-119(+)-erythroid cells, abnormal adhesion molecule expression on macrophages and erythroid cells, and a greatly diminished ability to form erythroblastic islands. Compared with wild-type animals, red blood cell size and hemoglobin content are decreased, while the number of circulating red blood cells is increased in heme oxygenase-1 deficient mice, overall leading to microcytic anemia. Heme oxygenase-1 deficiency increases oxidative stress in circulating red blood cells and greatly decreases the frequency of macrophages expressing the phosphatidylserine receptor Tim4 in bone marrow, spleen and liver. Heme oxygenase-1 deficiency increases spleen weight and Ter119(+)-erythroid cells in the spleen, although α4β1-integrin expression by these cells and splenic macrophages positive for vascular cell adhesion molecule 1 are both decreased. Red blood cell lifespan is prolonged in heme oxygenase-1 deficient mice compared with wild-type mice. Our findings suggest that while macrophages and relevant receptors required for red blood cell formation and removal are substantially depleted in heme oxygenase-1 deficient mice, the extent of anemia in these mice may be ameliorated by the prolonged lifespan of their oxidatively stressed erythrocytes.

  1. Identification of a novel mutation in an Indian patient with CAII deficiency syndrome

    Directory of Open Access Journals (Sweden)

    Shivaprasad C

    2010-01-01

    Full Text Available Carbonic anhydrase II (CAII deficiency syndrome characterized by osteopetrosis (OP, renal tubular acidosis (RTA, and cerebral calcifications is caused by mutations in the carbonic anhydrase 2 (CA2 gene. Severity of this disorder varies depending on the nature of the mutation and its effect on the protein. We present here, the clinical and radiographic details along with, results of mutational analysis of the CA2 gene in an individual clinically diagnosed with renal tubular acidosis, osteopetrosis and mental retardation and his family members to establish genotype-phenotype correlation. A novel homozygous deletion mutation c.251delT was seen in the patient resulting in a frameshift and a premature stop codon at amino acid position 90 generating a truncated protein leading to a complete loss of function and a consequential deficiency of the enzyme making this a pathogenic mutation. Confirmation of clinical diagnosis by molecular methods is essential as the clinical features of the CAII deficiency syndrome are similar to other forms of OP but the treatment modalities are different. Genetic confirmation of the diagnosis at an early age leads to the timely institution of therapy improving the growth potential, reduces other complications like fractures, and aids in providing prenatal testing and genetic counseling to the parents planning a pregnancy.

  2. Biotinidase deficiency: a reversible metabolic encephalopathy. Neuroimaging and MR spectroscopic findings in a series of four patients

    Energy Technology Data Exchange (ETDEWEB)

    Desai, Shrinivas [Jaslok Hospital and Research Centre, Department of CT and MRI, Mumbai (India); Ganesan, Karthik [Jaslok Hospital and Research Centre, Department of CT and MRI, Mumbai (India); University of California, San Diego, Department of Radiology, San Diego, CA (United States); Hegde, Anaita [Jaslok Hospital and Research Centre, Department of Paediatrics, Mumbai (India)

    2008-08-15

    Biotinidase deficiency is a metabolic disorder characterized by inability to recycle biotin with resultant delayed myelination. Clinical findings include seizures, ataxia, alopecia and dermatitis with atypical findings of myoclonic jerks, neuropathy and spastic paraparesis. Neuroradiological findings include cerebral atrophy, encephalopathy and widened extracerebral CSF spaces. Many of the clinical and neuroradiological features are reversible except sensorineural hearing loss and optic atrophy. To understand and describe the neuroimaging and spectroscopic findings of biotinidase deficiency. We evaluated the spectrum of neuroimaging and spectroscopic findings in four patients with biotinidase deficiency with follow-up studies in three patients. The imaging findings were encephalopathy, low cerebral volume, ventriculomegaly and widened extracerebral CSF spaces. Uncommon findings were caudate involvement, parieto-occipital cortical abnormalities and one patient with restricted diffusion. Two patients had subdural effusions, which is uncommon in biotinidase deficiency. {sup 1}H-MR spectroscopy revealed elevated lactate, reversal of the choline/creatine ratio and decreased NAA peaks. Follow-up studies revealed complete reversal of imaging findings in two patients. Biotinidase deficiency is a reversible metabolic encephalopathy. This study highlights the importance of early and prompt cliniconeuroradiological diagnosis of biotinidase deficiency as it has an extremely good clinical outcome if treatment is initiated from early infancy. (orig.)

  3. Absence of exercise-induced leptin suppression associated with insufficient epinephrine reserve in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

    NARCIS (Netherlands)

    Riepe, F.G.; Krone, N.; Kruger, S.N.; Sweep, C.G.J.; Lenders, J.W.M.; Dotsch, J.; Monig, H.; Sippell, W.G.; Partsch, C.J.

    2006-01-01

    OBJECTIVE: Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency suffer from glucocorticoid and mineralocorticoid deficiency. They have insufficient epinephrine reserves and increased basal leptin levels and are often insulin resistant. In healthy subjects, an inhibitor

  4. Impact of Dietary Intake on Bone Turnover in Patients with Phenylalanine Hydroxylase Deficiency.

    Science.gov (United States)

    Coakley, Kathryn E; Felner, Eric I; Tangpricha, Vin; Wilson, Peter W F; Singh, Rani H

    2017-01-28

    Phenylalanine hydroxylase (PAH) deficiency is a genetic disorder characterized by deficiency of the PAH enzyme. Patients follow a phenylalanine-restricted diet low in intact protein, and must consume synthetic medical food (MF) to supply phenylalanine-free protein. We assessed relationships between dietary intake and nutrient source (food or MF) on bone mineral density (BMD) and bone turnover markers (BTM) in PAH deficiency. Blood from 44 fasted females 11-52 years of age was analyzed for plasma phenylalanine, serum BTM [CTx (resorption), P1NP (formation)], vitamin D, and parathyroid hormone (PTH). BTM ratios were calculated to assess resorption relative to formation (CTx/P1NP). Dual energy X-ray absorptiometry measured total BMD and age-matched Z-scores. Three-day food records were analyzed for total nutrient intake, nutrients by source (food, MF), and compliance with MF prescription. Spearman's partial coefficients (adjusted for age, BMI, energy intake, blood phenylalanine) assessed correlations. All had normal BMD for age (Z-score >-2). Sixty-four percent had high resorption and normal formation indicating uncoupled bone turnover. CTx/P1NP was positively associated with food phenylalanine (r (2) = 0.39; p-value = 0.017), energy (r (2) = 0.41; p-value = 0.011) and zinc (r (2) = 0.41; p-value = 0.014). CTx/P1NP was negatively associated with MF fat (r (2) = -0.44; p-value = 0.008), MF compliance (r (2) = -0.34; p-value = 0.056), and positively with food sodium (r (2) = 0.43; p-value = 0.014). CTx/P1NP decreased significantly with age (p-value = 0.002) and higher PTH (p-value = 0.0002). Phenylalanine was not correlated with any bone indicator. Females with PAH deficiency had normal BMD but elevated BTM, particularly resorption. More favorable ratios were associated with nutrients from MF and compliance. Younger females had less favorable BTM ratios. Promoting micronutrient intake through compliance with MF may impact bone metabolism in

  5. [The antioxidant effects of emoxipin in patients with iron-deficiency anemia].

    Science.gov (United States)

    Shved, M I; Palamar, T O

    1995-01-01

    A total of 78 female patients of child-bearing age with iron deficiency anemia (IDA) of varying genesis and degree of severity were examined for effectiveness of a synthetic antioxidant emoxypine in a combined treatment of IDA. IDA was found to be associated with activation of lipid peroxidation processes (LPO) and decrement in antioxidant defence of the body. Conventional antianemic therapy does not lead to normalization of parameters characterizing LPO. Incorporation into a complex therapy of a synthetic antioxidant emoxypine reduces activity of free-radical oxidation of lipids, which fact prevents the pathological process from progressing and leads to more rapid and lasting clinical remission.

  6. Optical Coherence Tomography Assessment Before and After Vitamin Supplementation in a Patient With Vitamin A Deficiency

    OpenAIRE

    Saenz-de-Viteri, Manuel; Sádaba, Luis M.

    2016-01-01

    Abstract Vitamin A is an essential fat-soluble vitamin important for the function of various body systems. In the eye, vitamin A is essential for the synthesis of visual pigments in photoreceptors. Vitamin A deficiency is a rare condition in the developed countries and might follow bariatric or intestinal bypass surgery. We present the case of a 67-year-old male that complained of visual loss and nyctalopia. Patient had bariatric surgery 15 years before for weight loss. Low serum levels of vi...

  7. B cells assist allograft rejection in the deficiency of protein kinase c-theta.

    Science.gov (United States)

    Yan, Wenwei; Xu, Rui; Ma, Lian Li; Han, Wei; Geevarghese, Sunil K; Williams, Phillip E; Sciammas, Roger; Chong, Anita S; Yin, Deng Ping

    2013-09-01

    We have previously shown that mice deficient in protein kinase C theta (PKCθ) have the ability to reject cardiac allografts, but are susceptible to tolerance induction. Here we tested role of B cells in assisting alloimmune responses in the absence of PKCθ. Mouse cardiac allograft transplantations were performed from Balb/c (H-2d) to PKCθ knockout (PKCθ(-/-)), PKCθ and B cell double-knockout (PBDK, H-2b) mice and wild-type (WT) C57BL/6 (H-2b) mice. PBDK mice spontaneously accepted the allografts with the inhibition of NF-κB activation in the donor cardiac allograft. Anti-B cell antibody (rituximab) significantly delayed allograft rejection in PKCθ(-/-), but not in WT mice. Co-transfer of PKCθ(-/-) T plus PKCθ(-/-) B cells or primed sera triggered allograft rejection in Rag1(-/-) mice, and only major histocompatibility complex class II-enriched B cells, but not class I-enriched B cells, were able to promote rejection. This, together with the inability of PKCθ(-/-) and CD28(-/-) double-deficient (PCDK) mice to acutely reject allografts, suggested that an effective cognate interaction between PKCθ(-/-) T and B cells for acute rejection is CD28 molecule dependent. We conclude that T-B cell interactions synergize with PKCθ(-/-) T cells to mediate acute allograft rejection.

  8. Potassium deficiency triggers the development of dormant cells (akinetes) in Aphanizomenon ovalisporum (Nostocales, Cyanoprokaryota)(1).

    Science.gov (United States)

    Sukenik, Assaf; Kaplan-Levy, Ruth N; Viner-Mozzini, Yehudit; Quesada, Antonio; Hadas, Ora

    2013-06-01

    Akinetes are spore-like nonmotile cells that differentiate from vegetative cells of filamentous cyanobacteria from the order Nostocales. They play a key role in the survival and distribution of these species and contribute to their perennial blooms. Various environmental factors were reported to trigger the differentiation of akinetes including light intensity and quality, temperature, and nutrient deficiency. Here, we report that deprivation of potassium ion (K(+) ) triggers akinete development in the cyanobacterium Aphanizomenon ovalisporum. Akinetes formation is initiated 3 d-7 d after an induction by K(+) depletion, followed by 2-3 weeks of a maturation process. Akinete formation occurs within a restricted matrix of environmental conditions such as temperature, light intensity or photon flux. Phosphate is essential for akinete maturation and P-limitation restricts the number of mature akinetes. DNA replication is essential for akinete maturation and akinete development is limited in the presence of Nalidixic acid. While our results unequivocally demonstrated the effect of K(+) deficiency on akinete formation in laboratory cultures of A. ovalisporum, this trigger did not cause Cylindrospermopsis raciborskii to produce akinetes. Anabaena crassa however, produced akinetes upon potassium deficiency, but the highest akinete concentration was achieved at conditions that supported vegetative growth. It is speculated that an unknown internal signal is associated with the cellular response to K(+) deficiency to induce the differentiation of a certain vegetative cell in a trichome into an akinete. A universal stress protein that functions as mediator in K(+) deficiency signal transduction cascade, may communicate between the lack of K(+) and akinete induction.

  9. The effect of zinc deficiency on salt taste acuity, preference, and dietary sodium intake in hemodialysis patients.

    Science.gov (United States)

    Kim, So Mi; Kim, Miyeon; Lee, Eun Kyoung; Kim, Soon Bae; Chang, Jai Won; Kim, Hyun Woo

    2016-07-01

    Introduction High sodium intake is the main cause of fluid overload in hemodialysis (HD) patients, leading to increased cardiovascular mortality. High sodium intake is known to be associated with low salt taste acuity and/or high preference. As the zinc status could influence taste acuity, we analyzed the effect of zinc deficiency on salt taste acuity, preference, and dietary sodium intake in HD patients. Methods A total of 77 HD patients was enrolled in this cross-sectional study. Zinc deficiency was defined as serum zinc level with below 70 µg/mL. The patients were divided into two groups based on serum zinc level. Salt taste acuity and preference were determined by a sensory test using varying concentrations of NaCl solution, and dietary sodium intake was estimated using 3-day dietary recall surveys. Findings The mean salt recognition threshold and salt taste preference were significantly higher in the zinc deficient group than in the non-zinc deficient group. And there was significant positive correlation between salt taste preference and dietary sodium intake in zinc deficient group (r = 0.43, P = 0.002). Although, the dietary sodium intake showed a high tendency with no significance (P = 0.052), interdialytic weight gain was significantly higher in the zinc deficient group than in the non-zinc deficient group (2.68 ± 1.02 kg vs. 3.18 ± 1.02 kg; P = 0.047). Discussion Zinc deficiency may be related to low salt taste acuity and high salt preference, leading to high dietary sodium intake in HD patients.

  10. Intravenous Iron Therapy in Patients with Iron Deficiency Anemia: Dosing Considerations

    Science.gov (United States)

    Koch, Todd A.; Myers, Jennifer; Goodnough, Lawrence Tim

    2015-01-01

    Objective. To provide clinicians with evidence-based guidance for iron therapy dosing in patients with iron deficiency anemia (IDA), we conducted a study examining the benefits of a higher cumulative dose of intravenous (IV) iron than what is typically administered. Methods. We first individually analyzed 5 clinical studies, averaging the total iron deficit across all patients utilizing a modified Ganzoni formula; we then similarly analyzed 2 larger clinical studies. For the second of the larger studies (Study 7), we also compared the efficacy and retreatment requirements of a cumulative dose of 1500 mg ferric carboxymaltose (FCM) to 1000 mg iron sucrose (IS). Results. The average iron deficit was calculated to be 1531 mg for patients in Studies 1–5 and 1392 mg for patients in Studies 6-7. The percentage of patients who were retreated with IV iron between Days 56 and 90 was significantly (p < 0.001) lower (5.6%) in the 1500 mg group, compared to the 1000 mg group (11.1%). Conclusions. Our data suggests that a total cumulative dose of 1000 mg of IV iron may be insufficient for iron repletion in a majority of patients with IDA and a dose of 1500 mg is closer to the actual iron deficit in these patients. PMID:26257955

  11. Abolishment of TNBS-induced visceral hypersensitivity in mast cell deficient rats.

    Science.gov (United States)

    Ohashi, Katsuyo; Sato, Yasushi; Kawai, Mitsuhisa; Kurebayashi, Yoichi

    2008-02-13

    Mucosal mast cells are implicated in visceral hypersensitivity associated with irritable bowel syndrome (IBS). In this study, we investigated the role of mast cells in the development of visceral hypersensitivity by using mast cell deficient (Ws/Ws) rats and their control (W+/W+). In W+/W+ rats, an injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the proximal colon produced a significant decrease in pain threshold of the distal colon. Severe mucosal necrosis and inflammatory cell infiltration with concomitant increase in tissue myeloperoxidase activity were observed in the proximal colon that was directly insulted by TNBS, whereas neither necrosis nor increased myeloperoxidase activity occurred in the distal colon, indicating that TNBS-induced hypersensitivity is not caused by the local tissue damage or inflammation in the region of the gut where distention stimuli were applied. On the other hand, TNBS failed to elicit visceral hypersensitivity in Ws/Ws rats. This finding indicates that mast cells are essential for development of TNBS-induced visceral hypersensitivity in rats. Since the severity of TNBS-induced proximal colon injury and MPO activity was not affected by mast cell deficiency, it is unlikely that abolishment of visceral hypersensitivity in mast cell deficient rats was a result of altered development of the primary injury in the proximal colon. There was no difference between sham-operated Ws/Ws and W+/W+ rats in colonic pain threshold to distention stimuli, indicating that mast cells play no modulatory roles in normal colonic nociception. The present results support the view that mucosal mast cells play key roles in the pathogenesis of IBS.

  12. Synthetic lethal targeting of DNA double strand break repair deficient cells by human apurinic/apyrimidinic endonuclease (APE1) inhibitors

    Science.gov (United States)

    Sultana, Rebeka; McNeill, Daniel R.; Abbotts, Rachel; Mohammed, Mohammed Z.; Zdzienicka, Małgorzata Z.; Qutob, Haitham; Seedhouse, Claire; Laughton, Charles A.; Fischer, Peter M.; Patel, Poulam M.; Wilson, David M.; Madhusudan, Srinivasan

    2013-01-01

    An apurinic/apyrimidinic (AP) site is an obligatory cytotoxic intermediate in DNA Base Excision Repair (BER) that is processed by human AP endonuclease 1 (APE1). APE1 is essential for BER and an emerging drug target in cancer. We have isolated novel small molecule inhibitors of APE1. In the current study we have investigated the ability of APE1 inhibitors to induce synthetic lethality in a panel of DNA double strand break (DSB) repair deficient and proficient cells; a) Chinese hamster (CH) cells: BRCA2 deficient (V-C8), ATM deficient (V-E5), wild type (V79) and BRCA2 revertant (V-C8(Rev1)). b) Human cancer cells: BRCA1 deficient (MDA-MB-436), BRCA1 proficient (MCF-7), BRCA2 deficient (CAPAN-1 and HeLa SilenciX cells), BRCA2 proficient (PANC1 and control SilenciX cells). We also tested synthetic lethality (SL) in CH ovary cells expressing a dominant–negative form of APE1 (E8 cells) using ATM inhibitors and DNA-PKcs inhibitors (DSB inhibitors). APE1 inhibitors are synthetically lethal in BRCA and ATM deficient cells. APE1 inhibition resulted in accumulation of DNA DSBs and G2/M cell cycle arrest. Synthetic lethality was also demonstrated in CH cells expressing a dominant–negative form of APE1 treated with ATM or DNA-PKcs inhibitors. We conclude that APE1 is a promising synthetic lethality target in cancer. PMID:22377908

  13. QDPR gene mutation and clinical follow-up in Chinese patients with dihydropteridine reductase deficiency

    Institute of Scientific and Technical Information of China (English)

    De-Yun Lu; Jun Ye; Lian-Shu Han; Wen-Juan Qiu; Hui-Wen Zhang; Jian-De Zhou; Pei-Zhong Bao; Ya-Fen Zhang; Xue-Fan Gu

    2014-01-01

    Background: This study aimed to investigate the mutation spectrum of the QDPR gene, to determine the effect of mutations on dihydropteridine reductase (DHPR) structure/function, to discuss the potential genotypephenotype correlation, and to evaluate the clinical outcome of Chinese patients after treatment. Methods: Nine DHPR-deficient patients were enrolled in this study and seven of them underwent neonatal screening. QDPR gene mutations were analyzed and confi rmed by routine methods. The potential pathogenicity of missense variants was analyzed using Clustal X, PolyPhen program and Swiss-PDB Viewer 4.04_OSX software, respectively. The clinical outcomes of the patients were evaluated after long-term treatment. Results: In 10 mutations of the 9 patients, 4 were novel mutations (G20V, V86D, G130S and A175R), 4 were reported by us previously, and 2 known mutations were identified. R221X was a hotspot mutation (27.7%) in our patients. Eight missense mutations probably had damage to protein. Six patients in this series were treated with a good control of phenylalanine level. The height and weight of the patients were normal at the age of 4 months to 7.5 years. Four patients, who underwent a neonatal screening and were treated early, showed a normal mental development. In 2 patients diagnosed late, neurological symptoms were signifi cantly improved. Conclusions: The mutation spectrum of the QDPR gene is different in the Chinese population. Most mutations are related to severe phenotype. The determination of DHPR activity should be performed in patients with hyperphenylalaninemia. DHPR-defi cient patients who were treated below the age of 2 months may have a near normal mental development.

  14. Effect of Iron Deficiency on the Respiration of Sycamore (Acer pseudoplatanus L.) Cells.

    Science.gov (United States)

    Pascal, N.; Douce, R.

    1993-12-01

    The effects of iron deficiency on cell culture growth, cell respiration, mitochondrial oxidative properties, and the electron transport chain were studied with suspension-cultured sycamore (Acer pseudoplatanus L.) cells. Iron deprivation considerably decreased the initial growth rates and limited the maximum density of the cells. Under these conditions, the cells remained swollen throughout their growth. The absence of iron led to a steady decline in the uncoupled rate of O2 consumption. When the uncoupled rate of O2 uptake closely approximated the respiratory rate, the cells began to collapse. At this stage, the level of all the cytochromes and electron paramagnetic resonance-detectable Fe-S clusters of the mitochondrial inner membrane were dramatically decreased. Nevertheless, it appeared from substrate oxidation measurements that this overall depletion in iron-containing components solely disturbed the functioning of complex II, whereas neither complexes I, III, or IV, nor the machinery involved in ATP synthesis, was apparently impaired in iron-deficient mitochondria. However, our results suggest that the impairment of complex II resulted in a strong reduction of the overall capacity of the mitochondrial electron transport chain, which was responsible for determining the rate of endogenous respiration in sycamore cells. Finally, this situation led to a depletion of various energy metabolites that could contribute to the premature cell death.

  15. Splenectomy and proximal lieno-renal shunt in a factor five deficient patient with extra-hepatic portal vein obstruction

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    Sahni Peush

    2006-05-01

    Full Text Available Abstract Background The clinico-surgical implication and successful management of a rare case of factor five (V deficiency with portal hypertension and hypersplenism due to idiopathic extra-hepatic portal venous obstruction is presented. Case presentation A 16-year old boy had gastro-esophageal variceal bleeding, splenomegaly and hypersplenism. During preoperative workup prolonged prothrombin time and activated partial thromboplastin time were detected, which on further evaluation turned out to be due to factor V deficiency. Proximal lieno-renal shunt and splenectomy were successfully performed with transfusion of fresh frozen plasma during and after the surgical procedure. At surgery there was no excessive bleeding. The perioperative course was uneventful and the patient is doing well on follow up. Conclusion Surgical portal decompressive procedures can be safely undertaken in clotting factor deficient patients with portal hypertension if meticulous surgical hemostasis is achieved at operation and the deficient factor is adequately replaced in the perioperative period.

  16. Optical Coherence Tomography Assessment Before and After Vitamin Supplementation in a Patient With Vitamin A Deficiency: A Case Report and Literature Review.

    Science.gov (United States)

    Saenz-de-Viteri, Manuel; Sádaba, Luis M

    2016-02-01

    Vitamin A is an essential fat-soluble vitamin important for the function of various body systems. In the eye, vitamin A is essential for the synthesis of visual pigments in photoreceptors. Vitamin A deficiency is a rare condition in the developed countries and might follow bariatric or intestinal bypass surgery.We present the case of a 67-year-old male that complained of visual loss and nyctalopia. Patient had bariatric surgery 15 years before for weight loss. Low serum levels of vitamin A confirmed the diagnosis and patient started vitamin A supplementation. Visual fields, macular thickness, and ganglion cell layer thickness were recorded and monitored 1 month, 6 months, and 1 year after the beginning of therapy. Visual fields were significantly altered and central macular thickness and ganglion cell layer thickness were reduced, but the first 2 showed a significant recovery with vitamin supplementation therapy. By the 1st month of treatment patient referred a complete remission of visual symptoms. Further, we observed hyperreflective material accumulating beneath a partially disrupted ellipsoid band in the high definition optical coherence tomography that also improved progressively with vitamin repletion.Newer and more sophisticated imaging systems have increased our knowledge of the mechanisms responsible for retinal diseases. To our knowledge, this is the first description of the effect of vitamin A deficiency and vitamin supplementation on macular thickness. This case also highlights the importance of considering bariatric bypass surgery as a cause of vitamin A deficiency in developed countries.

  17. Accumulation of phosphorylated beta-catenin enhances ROS-induced cell death in presenilin-deficient cells.

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    Jung H Boo

    Full Text Available Presenilin (PS is involved in many cellular events under physiological and pathological conditions. Previous reports have revealed that PS deficiency results in hyperproliferation and resistance to apoptotic cell death. In the present study, we investigated the effects of PS on beta-catenin and cell mortality during serum deprivation. Under these conditions, PS1/PS2 double-knockout MEFs showed aberrant accumulation of phospho-beta-catenin, higher ROS generation, and notable cell death. Inhibition of beta-catenin phosphorylation by LiCl reversed ROS generation and cell death in PS deficient cells. In addition, the K19/49R mutant form of beta-catenin, which undergoes normal phosphorylation but not ubiquitination, induced cytotoxicity, while the phosphorylation deficient S37A beta-catenin mutant failed to induce cytotoxicity. These results indicate that aberrant accumulation of phospho-beta-catenin underlies ROS-mediated cell death in the absence of PS. We propose that the regulation of beta-catenin is useful for identifying therapeutic targets of hyperproliferative diseases and other degenerative conditions.

  18. 皮肤T细胞淋巴瘤外周血免疫表型CD7缺失的临床分析%CD7 Deficiency in Peripheral Blood of Patients with Cutaneous T Cell Lymphoma

    Institute of Scientific and Technical Information of China (English)

    李可嘉; 沈小雁; 施若非; 李霞; 郑捷

    2011-01-01

    目的:比较不同分期的皮肤T细胞淋巴瘤( cutaneous T cell lymphoma,CTCL)患者外周血淋巴细胞表面抗原CD7的缺失情况.方法 回顾性分析2006年1月-2010年7月本科收治的41例CTCL患者及9例炎症性皮肤病患者外周血淋巴细胞免疫表型的流式细胞检测结果,分析外周血CD7表达.结果 41例CTCL患者中,早期(ⅠA~ⅡA)23例和进展期(ⅡB~ⅣB)18例,CD3+ CD7 -T细胞比例进展期组与炎症性皮肤病组及早期组比较,均明显升高(P<0.05).进展期18例患者中6例CD7缺失(33.33%),早期23例患者中仅1例CD7缺失(4.35%),提示CD7缺失在进展期显著高于早期(P<0.05).无外周血累及的25例蕈样肉芽肿(mycosis fungoides,MF)患者中有2例CD7缺失,均为进展期,提示进展期MF较早期MF更易出现CD7缺失(P<0.05);在进展期MF的CD3+ CD7-T细胞比例均高于早期MF和炎症性皮肤病组(P<0.05).结论 进展期CTCL和无外周血累及的进展期MF外周血CD3+ CD7 -T细胞比例明显高于早期及炎症性皮肤病组,CTCL进展期较早期更容易发生外周血CD7缺失.

  19. Molecular Basis of Inherited Factor XIII- A Deficiency among Patients from Sistan - Baluchestan

    Directory of Open Access Journals (Sweden)

    Hejazi Shabnam

    2010-03-01

    Full Text Available Background: Factor ХШ, the last zymogene in the clotting cascade, converts the loose fibrin polymer into a firm polymer. In the absence of factor ХШ the abnormal fibrin is soluble in acetic acid, as well as 5M urea. Factor ХШ is composed of 2 catalytic A subunit bounds and 2 B subunits as carriers (A2B2. The gene of A chain is located on chromosome 6. Factor ХШ deficiency is rare; with a prevalence of only 1 in 2 million in the general population. The overwhelming majority of cases are due to mutations in subunit A. The aim of this study was to detect the mutations of subunit A.Materials & Methods: In this study we investigated the molecular basis of inherited factor ХШ deficiency among 10 unrelated patients from Sistan and Balouchestan province in 2006. Mutations were detected by amplifying each exon. Those exons exhibiting the presence of heteroduplex by conformation sensitive gel electrophoresis (CSGE were selected for direct sequencing. Sequencing of mutations was carried out by restriction fragment length polymorphism (RFLP.Results: All patients had homologous subsitiation of TGG to CGG in exon 4 which led to change of arginine to tryptophan.Conclusion: The mutation found in this study was in the core domain of enzyme. It seems that the changs in electric charge and affinity of enzyme to substrate‚as a result decreases the level of factor XIII-A activity.

  20. Zinc Deficiency Induces Apoptosis via Mitochondrial p53- and Caspase-Dependent Pathways in Human Neuronal Precursor Cells

    Science.gov (United States)

    Seth, Rohit; Corniola, Rikki S.; Gower-Winter, Shannon D.; Morgan, Thomas J., Jr.; Bishop, Brian; Levenson, Cathy W.

    2015-01-01

    Previous studies have shown that zinc deficiency leads to apoptosis of neuronal precursor cells in vivo and in vitro. In addition to the role of p53 as a nuclear transcription factor in zinc deficient cultured human neuronal precursors (NT-2), we have now identified the translocation of phosphorylated p53 to the mitochondria and p53-dependent…

  1. Different patterns of {sup 123}I-BMIPP myocardial accumulation in patients with type I and II CD36 deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, Kenichi; Nagatomo, Takafumi [Niigata Coll. of Pharmacy (Japan); Toba, Ken; Ogawa, Yusuke; Aizawa, Yoshifusa; Tanabe, Naohito; Miyajima, Seiichi; Kusano, Yoriko; Hirokawa, Yoichi

    1997-12-01

    The CD36 molecule is a multifunctional membrane type receptor glycoprotein that reacts with thrombospondin, collagen, oxidized LDL and long-chain fatty acids (LCFA). LCFA are one of the major cardiac energy substrates, hence LCFA metabolism may have an important role in cardiac diseases. In this study, we analyzed CD36 expression in 200 patients with heart diseases (44 patients with hypertrophic cardiomyopathy (HCM), 16 with dilated cardiomyopathy (DCM), 26 with old myocardial infarction (OMI), 55 with angina pectoris (AP) and 59 with other miscellaneous heart diseases) using a flow cytometer. {sup 123}I-{beta}-methyl-p-iodophenylpentadecanoic acid (BMIPP) myocardial accumulation was also examined in some patients. Eight patients (2 with HCM, 1 with DCM, 2 with OMI, and 3 with AP) were diagnosed as having type I CD36 deficiency (neither platelets nor monocytes expressed CD36). Sixteen patients (3 with HCM, 1 with DCM, 1 with OMI, 8 with AP, and 3 with other heart diseases) showed type II CD36 deficiency (monocytes expressed CD36 but platelets did not). In all 8 patients with type I CD36 deficiency, there was no BMIPP accumulation in the heart. However, in 13 patients with type II CD36 deficiency, focally reduced BMIPP accumulation was observed, but there were no patients without BMIPP accumulation. CD36 deficiency was observed in a higher proportion (12%) of patients with heart disease in this study than in a reported control study. Type I CD36 deficiency is associated with absence of BMIPP accumulation in the heart, hence it may have an important role in LCFA metabolic disorders and some types of cardiac hypertrophy as well as other heart diseases. (author)

  2. Effect of Equiguard in Treating Patients with Shen-Yang Deficiency Syndrome

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Objective:To observe the therapeutic effect of Equiguard in old patients with Shen (肾)-yang deficiency syndrome (SYDS).Methods:Twenty old patients with diagnosis matching the criteria of SYDS selected from out-patients were administered with Equiguard capsule 3 times per day,0.70 g each time for 3 successive months.The changes in general condition,peripheral blood picture,function of the liver and kidney,and sex hormones before and after treatment were observed.The changes in the American Urinary Surgery Association (AUA) score of prostatism,urosis and residue urine in the urinary bladder were also estimated.Results:After the 3-month treatment,no significant change was found in the patients' general condition,peripheral blood picture,liver and kidney function and sex hormones,while the symptoms of prostatism and urosis were markedly improved (P<0.01),and the volume of residue urine in the urinary bladder was obviously reduced.Conclusion:Equiguard shows a significant therapeutic effect in treating old patients with SYDS,which could effectively improve the symptoms of prostatism and urosis in patients and is highly safe.

  3. The prevalence of vitamin D deficiency in patients with vertebral fragility fractures.

    Science.gov (United States)

    Maier, G S; Seeger, J B; Horas, K; Roth, K E; Kurth, A A; Maus, U

    2015-01-01

    Hypovitaminosis D has been identified as a common risk factor for fragility fractures and poor fracture healing. Epidemiological data on vitamin D deficiency have been gathered in various populations, but the association between vertebral fragility fractures and hypovitaminosis D, especially in males, remains unclear. The purpose of this study was to evaluate serum levels of 25-hydroxyvitamin D (25-OH D) in patients presenting with vertebral fragility fractures and to determine whether patients with a vertebral fracture were at greater risk of hypovitaminosis D than a control population. Furthermore, we studied the seasonal variations in the serum vitamin D levels of tested patients in order to clarify the relationship between other known risk factors for osteoporosis and vitamin D levels. We measured the serum 25-OH D levels of 246 patients admitted with vertebral fractures (105 men, 141 female, mean age 69 years, sd 8.5), and in 392 orthopaedic patients with back pain and no fractures (219 men, 173 female, mean age 63 years, sd 11) to evaluate the prevalence of vitamin D insufficiency. Statistical analysis found a significant difference in vitamin D levels between patients with vertebral fragility fracture and the control group (p = 0.036). In addition, there was a significant main effect of the tested variables: obesity (p vitamin D levels and gender (p = 0.34). Vitamin D insufficiency was shown to be a risk factor for vertebral fragility fractures in both men and women.

  4. Vitamin D deficiency is independently associated with mortality among critically ill patients

    Directory of Open Access Journals (Sweden)

    Rafael Barberena Moraes

    2015-05-01

    Full Text Available OBJECTIVE: Studies suggest an association between vitamin D deficiency and morbidity/mortality in critically ill patients. Several issues remain unexplained, including which vitamin D levels are related to morbidity and mortality and the relevance of vitamin D kinetics to clinical outcomes. We conducted this study to address the association of baseline vitamin D levels and vitamin D kinetics with morbidity and mortality in critically ill patients. METHOD: In 135 intensive care unit (ICU patients, vitamin D was prospectively measured on admission and weekly until discharge from the ICU. The following outcomes of interest were analyzed: 28-day mortality, mechanical ventilation, length of stay, infection rate, and culture positivity. RESULTS: Mortality rates were higher among patients with vitamin D levels 12 ng/mL (32.2% vs. 13.2%, with an adjusted relative risk of 2.2 (95% CI 1.07-4.54; p< 0.05. There were no differences in the length of stay, ventilation requirements, infection rate, or culture positivity. CONCLUSIONS: This study suggests that low vitamin D levels on ICU admission are an independent risk factor for mortality in critically ill patients. Low vitamin D levels at ICU admission may have a causal relationship with mortality and may serve as an indicator for vitamin D replacement among critically ill patients.

  5. Risk of cancer in patients with iron deficiency anemia: a nationwide population-based study.

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    Ning Hung

    Full Text Available This study evaluated the risk of cancer among patients with iron deficiency anemia (IDA by using a nationwide population-based data set.Patients newly diagnosed with IDA and without antecedent cancer between 2000 and 2010 were recruited from the Taiwan National Health Insurance Research Database. The standardized incidence ratios (SIRs of cancer types among patients with IDA were calculated.Patients with IDA exhibited an increased overall cancer risk (SIR: 2.15. Subgroup analysis showed that patients of both sexes and in all age groups had an increased SIR. After we excluded patients diagnosed with cancer within the first and first 5 years of IDA diagnosis, the SIRs remained significantly elevated at 1.43 and 1.30, respectively. In addition, the risks of pancreatic (SIR: 2.31, kidney (SIR: 2.23, liver (SIR: 1.94, and bladder cancers (SIR: 1.74 remained significantly increased after exclusion of patients diagnosed with cancer within 5 years after IDA diagnosis.The overall cancer risk was significantly elevated among patients with IDA. After we excluded patients diagnosed with IDA and cancer within 1 and 5 years, the SIRs remained significantly elevated compared with those of the general population. The increased risk of cancer was not confined to gastrointestinal cancer when the SIRs of pancreatic, kidney, liver, and bladder cancers significantly increased after exclusion of patients diagnosed with IDA and cancer within the first 5 years. This finding may be caused by immune activities altered by IDA. Further study is necessary to determine the association between IDA and cancer risk.

  6. Improving the management of iron deficiency in ambulatory heart failure patients.

    Science.gov (United States)

    Hayward, Carl; Patel, Hitesh; Allen, Chris; Vazir, Ali

    2016-01-01

    Based on clinical trial data patients with heart failure (HF) and evidence of iron deficiency should be offered intravenous (iv) iron with the aim of improving exercise capacity and symptoms. Baseline measurement in outpatient HF clinics demonstrated that only 50% of patients who may be eligible for iv iron were investigated with iron studies. Our aim was to make sure that 90% of the patients attending our heart failure clinics who were symptomatic and had an ejection fraction (EF) ≤45% should have their iron studies checked within the last six months. In an effort to increase the proportion of suitable patients in whom iron studies are requested, we carried out three plan-do-study-act (PDSA) cycles each with a different intervention. These interventions included a presentation of the clinical trial evidence at a HF multidisciplinary meeting, email reminders prior to clinic and stickers in the patient notes (repeated twice). The effect of each intervention was measured with the outcome being the proportion of eligible patients in whom iron studies were documented within the previous 6 months. The interventions increased the number of suitable patients who had iron studies checked, to as high as 100%, however this effect was not sustained. Root cause analysis revealed that clinicians were unenthusiastic to continue performing iron studies due to inefficiency in the process of admitting patients and giving them iv iron. For example median in-hospital stay of seven hours for an infusion that is given over 15 minutes. In an attempt to improve patient and physician satisfaction we piloted an ambulatory outpatient service to deliver iv iron. We demonstrated that this service was feasible and more efficient as less time was required waiting for a bed or spent in hospital and was less costly. In summary we have demonstrated interventions which can increase the identification of patients who would benefit from iv iron and piloted a new time and cost efficient system of

  7. Risk of Cancer in Patients with Iron Deficiency Anemia: A Nationwide Population-Based Study

    Science.gov (United States)

    Hu, Yu-Wen; Hu, Li-Yu; Yeh, Chiu-Mei; Teng, Chung-Jen; Kuan, Ai-Seon; Chen, San-Chi; Chen, Tzeng-Ji; Liu, Chia-Jen

    2015-01-01

    Objective This study evaluated the risk of cancer among patients with iron deficiency anemia (IDA) by using a nationwide population-based data set. Method Patients newly diagnosed with IDA and without antecedent cancer between 2000 and 2010 were recruited from the Taiwan National Health Insurance Research Database. The standardized incidence ratios (SIRs) of cancer types among patients with IDA were calculated. Results Patients with IDA exhibited an increased overall cancer risk (SIR: 2.15). Subgroup analysis showed that patients of both sexes and in all age groups had an increased SIR. After we excluded patients diagnosed with cancer within the first and first 5 years of IDA diagnosis, the SIRs remained significantly elevated at 1.43 and 1.30, respectively. In addition, the risks of pancreatic (SIR: 2.31), kidney (SIR: 2.23), liver (SIR: 1.94), and bladder cancers (SIR: 1.74) remained significantly increased after exclusion of patients diagnosed with cancer within 5 years after IDA diagnosis. Conclusion The overall cancer risk was significantly elevated among patients with IDA. After we excluded patients diagnosed with IDA and cancer within 1 and 5 years, the SIRs remained significantly elevated compared with those of the general population. The increased risk of cancer was not confined to gastrointestinal cancer when the SIRs of pancreatic, kidney, liver, and bladder cancers significantly increased after exclusion of patients diagnosed with IDA and cancer within the first 5 years. This finding may be caused by immune activities altered by IDA. Further study is necessary to determine the association between IDA and cancer risk. PMID:25781632

  8. Zinc Deficiency With Dermatitis in a Parenteral Nutrition-Dependent Patient Due to National Shortage of Trace Minerals.

    Science.gov (United States)

    Sant, Vivek R; Arnell, Tracey D; Seres, David S

    2016-05-01

    The shortages of intravenous drugs remains critical, with sterile injectables accounting for 80% of the approximately 300 shortages. The impact is being felt in patients dependent on parenteral nutrition (PN), and severe deficiencies are becoming more commonplace. We report here a man who developed severe zinc deficiency, manifesting as a painful desquamative rash, due to an inability to obtain multi-trace element additives for his PN.

  9. Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease.

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    Christine Bernsmeier

    Full Text Available BACKGROUND & AIMS: The incretins glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD. However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients. METHODS: N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH patients and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration. RESULTS: Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001. In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH. CONCLUSIONS: Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.

  10. Bone Mineral Density in Patients with Growth Hormone Deficiency - Does a Gender Difference Exist?

    DEFF Research Database (Denmark)

    Hitz, Mette; Jensen, Jens-Erik Beck; Eskildsen, PC

    2006-01-01

    OBJECTIVE: The aim of the study was to clarify whether a gender difference exists with respect to bone mineral density (BMD) and bone mineral content (BMC) in adult patients with growth hormone deficiency (GHD). DESIGN: A case-control design. METHODS: Blood sampling for measurements of calcium......, phosphate, creatinine, PTH, vitamin D, IGF-1, markers of bone formation and bone resorption, and dual energy X-ray absorptiometry (DEXA), to determine BMD and BMC of the lumbar spine, hip, distal arm and total body, were performed in 34 patients with GHD (19 females) and 34 sex-, age- and weight...... identical BMD values at all regions. This gender difference was even more obvious when BMD values were expressed as Z-scores or as three-dimensional BMD of the total body. The bone formation and bone resorption markers, as well as calcium and vitamin D, were all at the same levels in GH...

  11. Bone mineral density in patients with growth hormone deficiency: does a gender difference exist?

    DEFF Research Database (Denmark)

    Hitz, Mette Friberg; Jensen, Jens-Erik Beck; Eskildsen, Peter C

    2006-01-01

    OBJECTIVE: The aim of the study was to clarify whether a gender difference exists with respect to bone mineral density (BMD) and bone mineral content (BMC) in adult patients with growth hormone deficiency (GHD). DESIGN: A case-control design. METHODS: Blood sampling for measurements of calcium......, phosphate, creatinine, PTH, vitamin D, IGF-1, markers of bone formation and bone resorption, and dual energy X-ray absorptiometry (DEXA), to determine BMD and BMC of the lumbar spine, hip, distal arm and total body, were performed in 34 patients with GHD (19 females) and 34 sex-, age- and weight...... identical BMD values at all regions. This gender difference was even more obvious when BMD values were expressed as Z-scores or as three-dimensional BMD of the total body. The bone formation and bone resorption markers, as well as calcium and vitamin D, were all at the same levels in GH...

  12. Defective Gonadotropin-Dependent Ovarian Folliculogenesis and Granulosa Cell Gene Expression in Inhibin-Deficient Mice

    Science.gov (United States)

    Nagaraja, Ankur K.; Middlebrook, Brooke S.; Rajanahally, Saneal; Myers, Michelle; Li, Qinglei; Matzuk, Martin M.; Pangas, Stephanie A.

    2010-01-01

    Inhibin-α knockout (Inha−/−) female mice develop sex cord-stromal ovarian cancer with complete penetrance and previous studies demonstrate that the pituitary gonadotropins (FSH and LH) are influential modifiers of granulosa cell tumor development and progression in inhibin-deficient females. Recent studies have demonstrated that Inha−/− ovarian follicles develop precociously to the early antral stage in prepubertal mice without any increase in serum FSH. These studies suggest that in the absence of inhibins, granulosa cells differentiate abnormally and thus at sexual maturity may undergo an abnormal response to gonadotropin signaling contributing to tumor development. To test this hypothesis, we stimulated immature wild-type and Inha−/− female mice with gonadotropin analogs prior to tumor formation and subsequently examined gonadotropin-induced ovarian follicle development as well as preovulatory and human chorionic gonadotropin-induced gene expression changes in granulosa cells. We find that at 3 wk of age, inhibin-deficient ovaries do not show further antral development or undergo cumulus expansion. In addition, there are widespread alterations in the transcriptome of gonadotropin-treated Inha−/− granulosa cells, with significant changes in genes involved in extracellular matrix and cell-cell communication. These data indicate the gonadotropins initiate an improper program of cell differentiation prior to tumor formation in the absence of inhibins. PMID:20739397

  13. A deficiency of uPAR alters endothelial angiogenic function and cell morphology

    Directory of Open Access Journals (Sweden)

    Balsara Rashna D

    2011-05-01

    Full Text Available Abstract The angiogenic potential of a cell requires dynamic reorganization of the cytoskeletal architecture that involves the interaction of urokinase-type plasminogen activator receptor (uPAR with the extracellular matrix. This study focuses on the effect of uPAR deficiency (uPAR-/- on angiogenic function and associated cytoskeletal organization. Utilizing murine endothelial cells, it was observed that adhesion, migration, proliferation, and capillary tube formation were altered in uPAR-/- cells compared to wild-type (WT cells. On a vitronectin (Vn matrix, uPAR-/- cells acquired a "fried egg" morphology characterized by circular actin organization and lack of lamellipodia formation. The up-regulation of β1 integrin, FAK(P-Tyr925, and paxillin (P-Tyr118, and decreased Rac1 activation, suggested increased focal adhesions, but delayed focal adhesion turnover in uPAR-/- cells. This accounted for the enhanced adhesion, but attenuated migration, on Vn. VEGF-enriched Matrigel implants from uPAR-/- mice demonstrated a lack of mature vessel formation compared to WT mice. Collectively, these results indicate that a uPAR deficiency leads to decreased angiogenic functions of endothelial cells.

  14. Mutator Phenotype and DNA Double-Strand Break Repair in BLM Helicase-Deficient Human Cells

    Science.gov (United States)

    Suzuki, Tetsuya; Yasui, Manabu

    2016-01-01

    Bloom syndrome (BS), an autosomal recessive disorder of the BLM gene, predisposes sufferers to various cancers. To investigate the mutator phenotype and genetic consequences of DNA double-strand breaks (DSBs) in BS cells, we developed BLM helicase-deficient human cells by disrupting the BLM gene. Cells with a loss of heterozygosity (LOH) due to homologous recombination (HR) or nonhomologous end joining (NHEJ) can be restored with or without site-directed DSB induction. BLM cells exhibited a high frequency of spontaneous interallelic HR with crossover, but noncrossover events with long-tract gene conversions also occurred. Despite the highly interallelic HR events, BLM cells predominantly produced hemizygous LOH by spontaneous deletion. These phenotypes manifested during repair of DSBs. Both NHEJ and HR appropriately repaired DSBs in BLM cells, resulting in hemizygous and homozygous LOHs, respectively. However, the magnitude of the LOH was exacerbated in BLM cells, as evidenced by large deletions and long-tract gene conversions with crossover. BLM helicase suppresses the elongation of branch migration and crossover of double Holliday junctions (HJs) during HR repair, and a deficiency in this enzyme causes collapse, abnormal elongation, and/or preferable resolution to crossover of double HJs, resulting in a large-scale LOH. This mechanism underlies the predisposition for cancer in BS. PMID:27601585

  15. Lipidomic dataset of plasma from patients infected with wild type and nef-deficient HIV-1 strain

    Directory of Open Access Journals (Sweden)

    Peter Meikle

    2016-03-01

    Full Text Available Previous in vitro and in vivo studies demonstrated that HIV protein nef plays a key role in impairing cellular and systemic cholesterol metabolism in HIV disease, but clinical support for these findings is lacking. Here we present the data of comparative lipidomic analysis (330 lipid species of plasma samples from HIV-negative subjects, patients infected with WT HIV-1 strain and patients infected with nef-deficient strain of HIV-1. We determine which effects of HIV on plasma lipidome are explained by the presence of nef. The data can be used to evaluate cardiovascular risk in HIV disease and to assess the role of nef in HIV-induced disturbances in systemic lipid metabolism. The full impact of nef deficiency on lipid and lipoprotein metabolism in HIV-infected patients is presented in the accompanying study “Lipid Metabolism in Patients Infected with Nef-deficient HIV-1 Strain” [1].

  16. Clinical Significance and Changes of ECG in the Patients with Cardiac Deficiency of the Qi and the Yin

    Institute of Scientific and Technical Information of China (English)

    LIN Qi-Shanxi

    2005-01-01

    In order to explore the changes and clinical significance of ECG in the patients with cardiac deficiency of the Qi and Yin, 124 patients with heart diseases were examined by means of ECG. The results showed that the prevalence of left ventricular hypertrophy in cardiac deficiency of the Qi (CDQ) was obviously higher than that of cardiac deficiency of the Yin (CDY). The higher prevalence of tachycardia occurred in the patients with CDY.The prevalence of the Q - T interval prolongation and abnormalities of ST - T segment in the patients with CDY was also higher than that of CDQ. The difference between two groups suggests that the diagnosis of two syndromes by ECG may be of important value.

  17. Prevalence of Relative Deficiencies in Testosterone and Vitamin B12 Among Patients Referred for Chronic Orchialgia: Implications for Management.

    Science.gov (United States)

    Cui, Tao; Terlecki, Ryan

    2016-04-08

    Chronic testicular pain (CTP) is a complex pain syndrome that is widely variable in presentation and etiology. Many cases of CTP are thought to be associated with neuropathy and recent data suggest an inflammation-mediated process is more common among patients with CTP. Deficiencies in vitamin B12 and testosterone are common in chronic pain syndromes may play a role in CTP. A retrospective review of men treated for CTP by a single provider over a 2-year period was performed. Patients with serum screening of testosterone and B12 were selected. Patients with total testosterone below 300 ng/dl, free testosterone below 46 pg/ml, or B12 below 400 pg/ml were deemed deficient and offered repletion. Efficacy of treatment was measured based on patient report with a minimum follow-up of either 3 months or resolution of pain symptoms. One hundred and fifty-four (154) men with CTP were identified, with 125 assessed for testosterone and B12 levels. Of these, 95 patients (76%) were deemed deficient. Fifty-six (56) patients elected to receive B12/testosterone replacement. In patients with sufficient follow-up, 24 patients (65%) reported significant improvement of symptoms, 6 patients (16%) reported some improvement, and 7 patients (19%) reported no improvement. The prevalence of testosterone and B12 deficiencies in this study is much higher than that reported for the general population. In addition, when chemical deficiencies were corrected, greater than 80% of patients with sufficient follow-up reported some improvement in pain. This suggests that screening of B12 and testosterone should be incorporated into the assessment of patients with CTP.

  18. Heart failure caused by atrial fibrillation in a patient with isolated adrenocorticotropic hormone deficiency and hashimoto′s thyroiditis

    Directory of Open Access Journals (Sweden)

    Ryo Maemura

    2014-01-01

    Full Text Available We report the case of a 75-year-old female patient with a history of Hashimoto′s thyroiditis who presented with congestive heart failure caused by atrial fibrillation associated with isolated adrenocorticotropic hormone (ACTH deficiency. This is the first case of the combination of these complex conditions. Clinical conditions in a patient with isolated ACTH deficiency and Hashimoto′s thyroiditis can be variable. Thus, it is sometimes difficult to establish a diagnosis. The mechanism underlying heart failure may be complex in some cases. Various conditions can affect patients simultaneously. Therefore, making a proper diagnosis is necessary to improve the patient′s prognosis.

  19. Mutations of the tyrosinase gene in Indo-Pakistani patients with type I (tyrosinase-deficient) oculocutaneous albinsm (OCA)

    Energy Technology Data Exchange (ETDEWEB)

    Tripathi, R.K.; Droetto, S.; Strunk, K.M.; Holmes, S.A.; Spritz, R.A. (Univ. of Wisconsin, Madison, WI (United States)); Bundey, S.; Musarella, M.A.

    1993-12-01

    Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders characterized by deficient synthesis of melanin pigment. Type I (tyrosinase-deficient) OCA results from mutations of the tyrosinase gene (TYR gene) encoding tyrosinase, the enzyme that catalyzes the first two steps of melanin biosynthesis. Mutations of the TYR gene have been identified in a large number of patients, most of Caucasian ethnic origin, with various forms of type I OCA. The authors present an analysis of the TYR gene in eight Indo-Pakistani patients with type I OCA. The authors describe four novel TYR gene mutations and a fifth mutation previously observed in a Caucasian patient. 16 refs., 6 figs.

  20. Optimising glucocorticoid replacement therapy in severely adrenocorticotropin (ACTH) deficient hypopituitary male patients.

    LENUS (Irish Health Repository)

    Behan, Lucy-Ann

    2011-04-18

    Context:  The optimal replacement regimen of hydrocortisone in adults with severe ACTH deficiency remains unknown. Management strategies vary from treatment with 15mg to 30mg or higher in daily divided doses, reflecting the paucity of prospective data on the adequacy of different glucocorticoid regimens. Objective:  Primarily to define the hydrocortisone regimen which results in a 24hour cortisol profile that most closely resembles that of healthy controls and secondarily to assess the impact on quality of life (QoL). Design:  10 male hypopituitary patients with severe ACTH deficiency (basal cortisol <100nM and peak response to stimulation <400nM) were enrolled in a prospective, randomised, crossover study of 3 hydrocortisone dose regimens. Following 6 weeks of each regimen patients underwent 24hour serum cortisol sampling and QoL assessment with the Short Form 36 and the Nottingham Health Profile questionnaires. Free cortisol was calculated using Coolen\\'s equation. All results were compared to those of healthy, matched controls. Results:  CBG was significantly lower across all dose regimens compared to controls (p<0.05). The lower dose regimen C(10mg mane\\/5mg tarde) produced a 24hour free cortisol profile which most closely resembled that of controls. Both regimen A(20mg mane\\/10mg tarde) and B(10mg mane\\/10mg tarde) produced supraphysiological post-absorption peaks. There was no significant difference in QoL in patients between the three regimens, however energy level was significantly lower across all dose regimens compared to controls (p<0.001). Conclusions:  The lower dose of HC(10mg\\/5mg) produces a more physiological cortisol profile, without compromising quality of life, compared to higher doses still used in clinical practice. This may have important implications in these patients, known to have excess cardiovascular mortality.

  1. Optimizing glucocorticoid replacement therapy in severely adrenocorticotropin-deficient hypopituitary male patients.

    LENUS (Irish Health Repository)

    Behan, Lucy-Ann

    2012-02-01

    BACKGROUND: The optimal replacement regimen of hydrocortisone in adults with severe ACTH deficiency remains unknown. Management strategies vary from treatment with 15-30 mg or higher in daily divided doses, reflecting the paucity of prospective data on the adequacy of different glucocorticoid regimens. OBJECTIVE: Primarily to define the hydrocortisone regimen which results in a 24 h cortisol profile that most closely resembles that of healthy controls and secondarily to assess the impact on quality of life (QoL). DESIGN: Ten male hypopituitary patients with severe ACTH deficiency (basal cortisol <100 nm and peak response to stimulation <400 nm) were enrolled in a prospective, randomized, crossover study of 3 hydrocortisone dose regimens. Following 6 weeks of each regimen patients underwent 24 h serum cortisol sampling and QoL assessment with the Short Form 36 (SF36) and the Nottingham Health Profile (NHP) questionnaires. Free cortisol was calculated using Coolen\\'s equation. All results were compared to those of healthy, matched controls. RESULTS: Corticosteroid binding globulin (CBG) was significantly lower across all dose regimens compared to controls (P < 0.05). The lower dose regimen C (10 mg mane\\/5 mg tarde) produced a 24 h free cortisol profile (FCP) which most closely resembled that of controls. Both regimen A(20 mg mane\\/10 mg tarde) and B(10 mg mane\\/10 mg tarde) produced supraphysiological post-absorption peaks. There was no significant difference in QoL in patients between the three regimens, however energy level was significantly lower across all dose regimens compared to controls (P < 0.001). CONCLUSIONS: The lower dose of hydrocortisone (10 mg\\/5 mg) produces a more physiological cortisol profile, without compromising QoL, compared to higher doses still used in clinical practice. This may have important implications in these patients, known to have excess cardiovascular mortality.

  2. Wernicke’s Encephalopathy, Wet Beriberi, and Polyneuropathy in a Patient with Folate and Thiamine Deficiency Related to Gastric Phytobezoar

    Directory of Open Access Journals (Sweden)

    Nuria Huertas-González

    2015-01-01

    Full Text Available Background. Wernicke’s encephalopathy (WE is an acute neurological disorder resulting from thiamine deficiency. It is mainly related to alcohol abuse but it can be associated with other conditions such as gastrointestinal disorders. This vitamin deficiency can also present with cardiovascular symptoms, called “wet beriberi.” Association with folate deficit worsens the clinical picture. Subject. A 70-year-old man with gastric phytobezoar presented with gait instability, dyspnoea, chest pain associated with right heart failure and pericarditis, and folate deficiency. Furosemide was administered and cardiac symptoms improved but he soon developed vertiginous syndrome, nystagmus, diplopia, dysmetria, and sensitive and motor deficit in all four limbs with areflexia. Results. A cerebral magnetic resonance imaging (MRI showed typical findings of WE. He was immediately treated with thiamine. Neurological symptoms improved in a few days and abnormal signals disappeared in a follow-up MRI two weeks later. Conclusion. Patients with malabsorption due to gastrointestinal disorders have an increased risk of thiamine deficiency, and folate deficiency can make this vitamin malabsorption worse. An established deficiency mainly shows neurological symptoms, WE, or rarely cardiovascular symptoms, wet beriberi. Early vitamin treatment in symptomatic patients improves prognosis. We recommend administration of prophylactic multivitamins supplements in patients at risk as routine clinical practice.

  3. Wernicke's Encephalopathy, Wet Beriberi, and Polyneuropathy in a Patient with Folate and Thiamine Deficiency Related to Gastric Phytobezoar

    Science.gov (United States)

    Huertas-González, Nuria; Hernando-Requejo, Virgilio; Luciano-García, Zaida; Cervera-Rodilla, Juan Luis

    2015-01-01

    Background. Wernicke's encephalopathy (WE) is an acute neurological disorder resulting from thiamine deficiency. It is mainly related to alcohol abuse but it can be associated with other conditions such as gastrointestinal disorders. This vitamin deficiency can also present with cardiovascular symptoms, called “wet beriberi.” Association with folate deficit worsens the clinical picture. Subject. A 70-year-old man with gastric phytobezoar presented with gait instability, dyspnoea, chest pain associated with right heart failure and pericarditis, and folate deficiency. Furosemide was administered and cardiac symptoms improved but he soon developed vertiginous syndrome, nystagmus, diplopia, dysmetria, and sensitive and motor deficit in all four limbs with areflexia. Results. A cerebral magnetic resonance imaging (MRI) showed typical findings of WE. He was immediately treated with thiamine. Neurological symptoms improved in a few days and abnormal signals disappeared in a follow-up MRI two weeks later. Conclusion. Patients with malabsorption due to gastrointestinal disorders have an increased risk of thiamine deficiency, and folate deficiency can make this vitamin malabsorption worse. An established deficiency mainly shows neurological symptoms, WE, or rarely cardiovascular symptoms, wet beriberi. Early vitamin treatment in symptomatic patients improves prognosis. We recommend administration of prophylactic multivitamins supplements in patients at risk as routine clinical practice. PMID:26697247

  4. Vitamin D deficiency in HIV-infected patients: a systematic review

    Directory of Open Access Journals (Sweden)

    Giusti A

    2011-11-01

    Full Text Available Andrea Giusti1, Giovanni Penco2, Giulio Pioli31Bone Clinic, Department of Gerontology and Musculoskeletal Sciences, Galliera Hospital, Genoa, Italy; 2Department of Infectious Diseases, Galliera Hospital, Genoa, Italy; 3Department of Geriatrics, ASMN Hospital, Reggio Emilia, ItalyAbstract: Advances in the diagnosis and management of human immunodeficiency virus (HIV have resulted in a dramatic decrease in mortality in HIV-infected individuals (HIV+. The subsequent increase in life expectancy of HIV+ has led to the need to consider the long-term complications of the disease and its treatment. Abnormalities in vitamin D status and metabolism are increasingly recognized as a major concern in HIV infection. In the last 5 years a number of cross-sectional and prospective studies have suggested a high prevalence of vitamin D deficiency in HIV+. Although few case-control studies have been published, it has been suggested that the prevalence of hypovitaminosis D in HIV+ is higher than in the general population, and at least in part, is related to the course of the disease and/or the antiretroviral drugs used to treat the disease. An adequate vitamin D status is important not only for bone tissue, but also for the global health status of HIV+ individuals, since a growing body of evidence has demonstrated the detrimental effects of vitamin D deficiency on multiple health outcomes. Therefore, definition of the size of the problem and identification of effective protocols for the prevention and management of vitamin D deficiency in HIV+ patients represent important steps in improving health status and reducing long-term chronic complications in individuals with HIV. Due to its immunomodulatory effects, vitamin D may also have implications in the progression of HIV infection. This systematic review was designed to determine the prevalence of vitamin D deficiency in HIV+ patients; to identify risk factors (related to the HIV infection or not potentially

  5. Is some better than none: are TEG and TGA profiles different in severe FVIII-deficient patients with inhibitors?

    Science.gov (United States)

    Salinas, V; Carmona, R; Mohammed, B M; Martin, E J; Brophy, D F; Young, G

    2015-05-01

    Severe factor VIII (FVIII)-deficient patients with and without FVIII inhibitors cannot be distinguished using FVIII levels. The FVIII assay is sensitive to detect factor levels below 1%. While severe FVIII-deficient, non-inhibitor patients have FVIII < 1%, they may retain unmeasurable residual factor activity. In contrast, inhibitor patients have a FVIII antibody that presumably fully eliminates FVIII activity. It is unknown whether thromboelastography (TEG) and thrombin generation assay (TGA) can differentiate between patients with FVIII < 1% with and without the presence of FVIII inhibitors. The primary objective was to discern whether TEG and TGA could differentiate between severe FVIII-deficient patients with and without the presence of FVIII inhibitors. A secondary objective was to correlate TEG and TGA to annualized bleeding rates. This observational study performed TEG and TGA in healthy volunteers (N = 15), severe FVIII-deficient (N = 15) and severe FVIII-deficient patients with inhibitors (N = 15). Kaolin-activated TEG was better at differentiating reaction time (31.3 vs. 120 min respectively, P = 0.004) and kinetics time (6.1 vs. 23.1 min respectively, P = 0.028) between the non-inhibitor and inhibitor patients. TEG activated by tissue factor in plasma-containing corn trypsin inhibitor failed to differentiate groups. The TGA failed to differentiate peak thrombin, endogenous thrombin potential and lag time between groups. There was no correlation between TEG and TGA with annualized bleeding rates. Kaolin-activated TEG, but not TGA, differentiated between severe FVIII-deficient patients with and without inhibitors. These assays did not find a correlation to annualized bleeding rate.

  6. Health-Related Quality of Life in Primary Immune Deficient Patients

    Directory of Open Access Journals (Sweden)

    "Habibeh Mozaffari

    2006-03-01

    Full Text Available The primary immunodeficiency (PI disorders are abnormalities in development and maturation of the immune system. Individuals with PI disease may experience frequent infections, which limit their abilities to exhibit physical and psychological well-being secondary to their illness. In this survey we compared health-related quality of life of primary immune deficient patients with healthy children. The case-control study was designed for patients with PI disease who were referred to Children Medical Center in 2004-2005. Demographic information was taken and Pediatric Quality Of Life (PEDQOL questionnaire were filled for 50 PI patients and 100 healthy children. The mean age in PI patients was 12.62± 3.65 (range from 8 to 18 years and in the control group was 11.04± 3.3 years. In PI patients 68% were male and 32% female .Most patients with PI disease had a diagnosis of common variable immunodeficiency (54% or X-linked agammaglobulinemia (24%. Patients with PI disease had great limitations in physical functioning and psychological well-being (p<0.001 and p<0.001 respectively compared with children without a chronic health condition. Patients had lower PEDQOL scores in all age groups compared with normal sample (p<0.001. Long duration of disease significantly correlated with low psychological score. (r = -3.23. P= 0.03 Children with PI disease experience poorer health related quality of life than healthy children, indicating more attention should be paid to early diagnosis and treatment of PI disease, as well as more attention to their social limitation. PI patients may need psychological consultation for better coping with their illness.

  7. Oral and Dental Health Status in Patients with Primary Antibody Deficiencies

    Directory of Open Access Journals (Sweden)

    Ghasem Meighani

    2011-12-01

    Full Text Available Primary antibody deficiencies (PAD are a group of immune system disorders, associated with decreased levels of secretory and protective immunoglobulins. Because of the important role of immunoglobulins in the protection  of oral cavity, patients with PADs  are more susceptible to dental caries or oral manifestations.This study was performed  to investigate the oral and dental manifestations of PADs patients. In this study, 33 patients with PADs (21 common variable immunodeficiency, 8 X- linked agammaglobulinemia and 4 hyper IgM syndrome and 66 controls were examined; the number of decayed, missed and filled teeth (DMFT were investigated.Aphthous  was the most frequent manifestation in PADs patients (38.7%, which wassignificantly16.7% higher than  the  controls  (p=0.03. The  patients  with  PADs  showed significantly higher presentation of other oral and dental manifestations, including herpes sores, candidiasis tonsillitis, gingivitis, calculus, enamel hypoplasia and other ulcerations. The mean DMFT scores were 6.15±3.6 and 1.93±0.4 in PADs patients and controls, respectively (p<0.001. Although the patients with common variable immunodeficiency had higher means of DMFT in comparison with other groups of PADs, this difference was not statistically significant.This study showed significantly higher frequency of oral and dental manifestations in the patients with PADs  compared to controls. Therefore, regular examination of oral cavity could be suggested in this group of immunodeficient patients.

  8. International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency

    DEFF Research Database (Denmark)

    Farkas, H; Martinez-Saguer, I; Bork, K;

    2016-01-01

    BACKGROUND: The consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagn...

  9. International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency

    DEFF Research Database (Denmark)

    Farkas, H; Martinez-Saguer, I; Bork, K

    2017-01-01

    BACKGROUND: The consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagn...

  10. Lactate disposal via gluconeogenesis is increased during exercise in patients with mitochondrial myopathy due to complex I deficiency

    NARCIS (Netherlands)

    Roef, MJ; Kalhan, SC; Reijngoud, DJ; De Meer, K; Berger, Ruud

    2002-01-01

    This study evaluated lactate disposal via gluconeogenesis as well as effects of FFA availability on gluconeogenesis via pyruvate (GNG(PYR)) in patients with mitochondrial myopathy due to complex I deficiency (CID). The rates of GNG(PYR) were measured in three CID patients and six healthy controls at

  11. Extensively coated revision stems in proximally deficient femur: Early results in 15 patients

    Directory of Open Access Journals (Sweden)

    Marya SKS

    2008-01-01

    Full Text Available Background: Hip replacement following failed internal fixation (dynamic hip screw for intertrochanteric fractures or previous hip arthroplasty presents a major surgical challenge. Proximal fitting revision stems do not achieve adequate fixation. Distal fixation with long-stemmed extensively coated cementless implants (like the Solution™ system affords a suitable solution. We present our early results of 15 patients treated with extensively coated cementless revision stems. Materials and Methods: Fifteen patients with severely compromised proximal femora following either failed hip arthroplasty or failed internal fixation (dynamic hip screw fixation for intertrochanteric fractures were operated by the senior author over a two-year period. Eight patients had aseptic loosening of their femoral stems following cemented hip replacements, with severe thinning of their proximal cortices and impending stress fractures. Seven had secondary hip arthritis following failure of long implants for comminuted intertrochanteric or subtrochanteric femoral fractures. All patients were treated by removal of implant (cemented stems/DHS implants and insertion of long-stemmed extensively coated cementless revision (′ Solution™; DePuy, Warsaw (IN, US′ stems along with press-fit acetabular component (Duraloc Cup, DePuy, Warsaw (IN, US. All eight hip revisions needed extended trochanteric osteotomies. Results: All patients were primarily kept in bed on physiotherapy for six weeks and then gradually progressed to weight-bearing walking over the next six to eight weeks. The Harris Hip Scores and patient satisfaction were used for final evaluation. We achieved good results in the short term studied. In our first three patients (all following failed cemented total hip replacements, we resorted to cerclage wiring to hold osteotomised segments (done to facilitate stem removal. The subsequent 12 proceeded without the need for cerclage wiring. One patient had a

  12. Effects of PARP-1 Deficiency on Th1 and Th2 Cell Differentiation

    Directory of Open Access Journals (Sweden)

    M. Sambucci

    2013-01-01

    Full Text Available T cell differentiation to effector Th cells such as Th1 and Th2 requires the integration of multiple synergic and antagonist signals. Poly(ADP-ribosylation is a posttranslational modification of proteins catalyzed by Poly(ADP-ribose polymerases (PARPs. Recently, many reports showed that PARP-1, the prototypical member of the PARP family, plays a role in immune/inflammatory responses. Consistently, its enzymatic inhibition confers protection in several models of immune-mediated diseases, mainly through an inhibitory effect on NF-κB (and NFAT activation. PARP-1 regulates cell functions in many types of immune cells, including dendritic cells, macrophages, and T and B lymphocytes. Our results show that PARP-1KO cells displayed a reduced ability to differentiate in Th2 cells. Under both nonskewing and Th2-polarizing conditions, naïve CD4 cells from PARP-1KO mice generated a reduced frequency of IL-4+ cells, produced less IL-5, and expressed GATA-3 at lower levels compared with cells from wild type mice. Conversely, PARP-1 deficiency did not substantially affect differentiation to Th1 cells. Indeed, the frequency of IFN-γ+ cells as well as IFN-γ production, in nonskewing and Th1-polarizing conditions, was not affected by PARP-1 gene ablation. These findings demonstrate that PARP-1 plays a relevant role in Th2 cell differentiation and it might be a target to be exploited for the modulation of Th2-dependent immune-mediated diseases.

  13. Cholesteryl ester transfer protein levels and gene deficiency in Chinese patients with cardio-cerebrovascular diseases

    Institute of Scientific and Technical Information of China (English)

    庄一义; 汪俊军; 张宏娟; 李勇; 刘小传; 李露言; 陈光辉

    2002-01-01

    Objective To detect cholesteryl ester transfer protein (CETP) levels, frequencies of CETP D442G and Ⅰ14A mutations and characteristics of abnormal lipids in patients with cardio-cerebro vascular diseases. Methods Ninety-four myocardial infarction (MI) patients,110 stroke patients and 335 healthy controls were selected. The CETP concentration was determined using ELISA. The CETP activity was measured using a substrate of 14 C-radiolabeled discoidal bilayer particles. The CETP gene mutations were detected by PCR-RFLP. Results The CETP concentrations in the MI and stroke group, were higher than those in the controls. The gene mutation frequencies of D442G in the MI, stroke and control group were 3.5%, 3.6% and 5%, respectively, and the frequencies of Ⅰ14A were 1.05%, 0.91% and 1%, respectively. One case of D442G homozygote was detected in the healthy group. The frequency of two CETP gene mutations showed no significant difference among the patients and controls. The CETP concentration and activity in subjects with CETP mutations were one-third of those in the control group. The level of HDL-C, apo-A1 increased in the mutation subjects, while the TG level decreased. Conclusions The CETP level increased significantly in patients with cardio-cerebrovascular diseases. The carriers of CETP deficiency had CETP and lipid abnormalities.

  14. Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients.

    Science.gov (United States)

    Tazawa, Yusaku; Kobayashi, Keiko; Abukawa, Daiki; Nagata, Ikuo; Maisawa, Shunichi; Sumazaki, Ryo; Iizuka, Toshiyuki; Hosoda, Yoshito; Okamoto, Manabu; Murakami, Jun; Kaji, Shunsaku; Tabata, Ayako; Lu, Yao Bang; Sakamoto, Osamu; Matsui, Akira; Kanzaki, Susumu; Takada, Goro; Saheki, Takeyori; Iinuma, Kazuie; Ohura, Toshihiro

    2004-11-01

    A deficiency of citrin, which is encoded by the SLC25A13 gene, causes both adult-onset type II citrullinemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). We analyzed 16 patients with NICCD to clarify the clinical features of the disease. Severe intrahepatic cholestasis with fatty liver was the most common symptom, but the accompanying clinical features were variable, namely; suspected cases of neonatal hepatitis or biliary atresia, positive results from newborn screening, tyrosinemia, failure to thrive, hemolytic anemia, bleeding tendencies and ketotic hypoglycemia. Laboratory data showed elevated serum bile acid levels, hypoproteinemia, low levels of vitamin K-dependent coagulation factors, and hypergalactosemia. Hypercitrullinemia was detected in 11 out of 15 patients examined. Most of the patients were given a lactose-free and/or medium chain triglycerides-enriched formula and lipid-soluble vitamins. The prognosis of the 16 patients is going fairy well at present, but we should observe these patients carefully to see if they manifest any symptom of CTLN2 in the future.

  15. Estrogen deficiency leads to telomerase inhibition,telomere shortening and reduced cell proliferation in the adrenal gland of mice

    Institute of Scientific and Technical Information of China (English)

    Sharyn Bayne; Margaret EE Jones; He Li; Alex R Pinto; Evan R Simpson; Jun-Ping Liu

    2008-01-01

    Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition oftelomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase (TERT) gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter telomeres in the adrenal cortex than that in wild-type (WT) control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.

  16. Excretion of laccase by sycamore (Acer pseudoplatanus L.) cells. Effects of a copper deficiency.

    Science.gov (United States)

    Bligny, R; Gaillard, J; Douce, R

    1986-07-15

    Copper-deprived sycamore (Acer pseudoplatanus) cells do not excrete molecules of active laccase in their culture medium. In the range of 2-100 micrograms of copper initially present per litre of nutrient solution, the total laccase activity measured in the cell suspensions at the end of the exponential phase of growth was closely proportional to the amount of added copper. However, copper-deprived cells excreted the laccase apoprotein (laccase without copper) at the same rate as copper-supplied cells excreted the active, copper-containing, laccase. When the culture medium was initially supplied with limiting amounts of copper, the active laccase was excreted until all copper molecules were metabolized. Thereafter, the laccase apoprotein was excreted. Consequently, at the end of the exponential phase of growth, the cell supernatants contained a mixture of apoprotein and copper-containing laccase. After purification and concentration, this mixture of copper-containing laccase (blue) and laccase apoprotein (slightly yellow) showed a yellow-green colour. Under copper-limiting culture conditions an equivalent decrease of Type 1, Type 2 and Type 3 Cu2+ was observed. Addition of copper to copper-deficient enzyme solutions does not result in a recovery of the enzyme activity. However, when added to copper-deficient sycamore-cell suspensions, copper induced a recovery of the excretion of active enzyme, at a normal rate, within about 10 h. The first molecules of active laccase were excreted after 3-4 h.

  17. Establishment of HeLa cell mutants deficient in sphingolipid-related genes using TALENs.

    Directory of Open Access Journals (Sweden)

    Toshiyuki Yamaji

    Full Text Available Sphingolipids are essential components in eukaryotes and have various cellular functions. Recent developments in genome-editing technologies have facilitated gene disruption in various organisms and cell lines. We here show the disruption of various sphingolipid metabolic genes in human cervical carcinoma HeLa cells by using transcription activator-like effector nucleases (TALENs. A TALEN pair targeting the human CERT gene (alternative name COL4A3BP encoding a ceramide transport protein induced a loss-of-function phenotype in more than 60% of HeLa cells even though the cell line has a pseudo-triploid karyotype. We have isolated several loss-of-function mutant clones for CERT, UGCG (encoding glucosylceramide synthase, and B4GalT5 (encoding the major lactosylceramide synthase, and also a CERT/UGCG double-deficient clone. Characterization of these clones supported previous proposals that CERT primarily contributes to the synthesis of SM but not GlcCer, and that B4GalT5 is the major LacCer synthase. These newly established sphingolipid-deficient HeLa cell mutants together with our previously established stable transfectants provide a 'sphingolipid-modified HeLa cell panel,' which will be useful to elucidate the functions of various sphingolipid species against essentially the same genomic background.

  18. T cells from Programmed Death-1 deficient mice respond poorly to Mycobacterium tuberculosis infection.

    Directory of Open Access Journals (Sweden)

    Sultan Tousif

    Full Text Available BACKGROUND: Programmed Death-1 (PD-1; CD279 receptor molecule is widely believed to be a negative regulator predominantly expressed by exhausted/activated mouse T cells. Upon interaction with its ligands, PD-L1 and PD-L2, PD-1 inhibits activation of T cells and cytokine production, which has been documented in various viral and fungal infections as well as in vitro studies. Therefore, inhibition of T cell responses by PD-1 resulted in disease resistance in a variety of mouse infection models studied heretofore. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that PD-1 deficient (PD-1(-/- mice infected with Mycobacterium tuberculosis (M. tb H37Rv by the aerosol route have increased susceptibility as compared with their wild type littermates. Surprisingly, M. tb antigen-specific T cell proliferation was dramatically reduced in PD-1 deficient animals compared with wild-type littermates, and this was due to increased numbers of regulatory T cells (Tregs and recruitment of mesenchymal stem cells. Furthermore, PD-1(-/- mice exhibited decreases in the autophagy-induced LC3-B marker protein in macrophages. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that PD-1 does not play an inhibitory role during M. tb infection and instead promotes mycobacterial clearance in mice.

  19. RAD51AP1-deficiency in vertebrate cells impairs DNA replication.

    Science.gov (United States)

    Parplys, Ann C; Kratz, Katja; Speed, Michael C; Leung, Stanley G; Schild, David; Wiese, Claudia

    2014-12-01

    RAD51-associated protein 1 (RAD51AP1) is critical for homologous recombination (HR) by interacting with and stimulating the activities of the RAD51 and DMC1 recombinases. In human somatic cells, knockdown of RAD51AP1 results in increased sensitivity to DNA damaging agents and to impaired HR, but the formation of DNA damage-induced RAD51 foci is unaffected. Here, we generated a genetic model system, based on chicken DT40 cells, to assess the phenotype of fully inactivated RAD51AP1 in vertebrate cells. Targeted inactivation of both RAD51AP1 alleles has no effect on either viability or doubling-time in undamaged cells, but leads to increased levels of cytotoxicity after exposure to cisplatin or to ionizing radiation. Interestingly, ectopic expression of GgRAD51AP1, but not of HsRAD51AP1 is able to fully complement in cell survival assays. Notably, in RAD51AP1-deficient DT40 cells the resolution of DNA damage-induced RAD51 foci is greatly slowed down, while their formation is not impaired. We also identify, for the first time, an important role for RAD51AP1 in counteracting both spontaneous and DNA damage-induced replication stress. In human and in chicken cells, RAD51AP1 is required to maintain wild type speed of replication fork progression, and both RAD51AP1-depleted human cells and RAD51AP1-deficient DT40 cells respond to replication stress by a slow-down of replication fork elongation rates. However, increased firing of replication origins occurs in RAD51AP1-/- DT40 cells, likely to ensure the timely duplication of the entire genome. Taken together, our results may explain why RAD51AP1 commonly is overexpressed in tumor cells and tissues, and we speculate that the disruption of RAD51AP1 function could be a promising approach in targeted tumor therapy.

  20. Height outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

    Institute of Scientific and Technical Information of China (English)

    Feng Yun-lin; Zhu Hui-juan; Gong Feng-ying; Li Nai-shi; Pan Hui; Lu Zhao-lin; Shi Yi-fan

    2007-01-01

    Objective: To retrospectively investigate the height outcome of patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD).Methods: The 135 CAH patients with 21-OHD diagnosed in our hospital from Jan 1980 to Oct 2006 were retrospectively analyzed.The investigated parameters included final height(FH), FH standard deviation score(FH SDS), target height SDS (TH SDS), difference between TH and FH (TH-FH), FH SDS-TH SDS, the age of onset of sexual development, and the difference between bone age and chronological age(BA-CA) when patients got the FH.Results: Among the 135 patients, female/male=108/27.Mean FH was (156.84±5.4) cm (n=14) and (150.8±6.8) cm (n=76) for males and females, respectively.Mean FH SDS was (-0.6±0.8) (n=13) and (0.2±1.2) (n=54) for males and females, respectively.Sexual development began at (5.2±1.7) years old (y/o) (n=13) and (7.9±3.2) y/o (n=43) in males and females, respectively.Conclusions: The FH of CAH patients with 21-OHD was lower than that of the normal range.Effect of the disease on the height growth in male patients was more severe than that in females.All patients began sexual development much earlier than the normal age-matched group.Male patients began their sexual development even earlier.

  1. Testosterone Deficiency Increases Hospital Readmission and Mortality Rates in Male Patients with Heart Failure

    Energy Technology Data Exchange (ETDEWEB)

    Santos, Marcelo Rodrigues dos; Sayegh, Ana Luiza Carrari; Groehs, Raphaela Vilar Ramalho; Fonseca, Guilherme [Instituto do Coração (InCor) - Faculdade de Medicina da Universidade de São Paulo (Brazil); Trombetta, Ivani Credidio [Instituto do Coração (InCor) - Faculdade de Medicina da Universidade de São Paulo (Brazil); Universidade Nove de Julho (UNINOVE) (Brazil); Barretto, Antônio Carlos Pereira [Instituto do Coração (InCor) - Faculdade de Medicina da Universidade de São Paulo (Brazil); Arap, Marco Antônio [Faculdade de medicina da Universidade de São Paulo - Urologia (Brazil); Negrão, Carlos Eduardo [Instituto do Coração (InCor) - Faculdade de Medicina da Universidade de São Paulo (Brazil); Escola de Educação Física e Esporte da Universidade de São Paulo, São Paulo, SP (Brazil); Middlekauff, Holly R. [Division of Cardiology - David Geffen School of Medicine - University of California (United States); Alves, Maria-Janieire de Nazaré Nunes, E-mail: janieire.alves@incor.usp.br [Instituto do Coração (InCor) - Faculdade de Medicina da Universidade de São Paulo (Brazil)

    2015-09-15

    Testosterone deficiency in patients with heart failure (HF) is associated with decreased exercise capacity and mortality; however, its impact on hospital readmission rate is uncertain. Furthermore, the relationship between testosterone deficiency and sympathetic activation is unknown. We investigated the role of testosterone level on hospital readmission and mortality rates as well as sympathetic nerve activity in patients with HF. Total testosterone (TT) and free testosterone (FT) were measured in 110 hospitalized male patients with a left ventricular ejection fraction < 45% and New York Heart Association classification IV. The patients were placed into low testosterone (LT; n = 66) and normal testosterone (NT; n = 44) groups. Hypogonadism was defined as TT < 300 ng/dL and FT < 131 pmol/L. Muscle sympathetic nerve activity (MSNA) was recorded by microneurography in a subpopulation of 27 patients. Length of hospital stay was longer in the LT group compared to in the NT group (37 ± 4 vs. 25 ± 4 days; p = 0.008). Similarly, the cumulative hazard of readmission within 1 year was greater in the LT group compared to in the NT group (44% vs. 22%, p = 0.001). In the single-predictor analysis, TT (hazard ratio [HR], 2.77; 95% confidence interval [CI], 1.58–4.85; p = 0.02) predicted hospital readmission within 90 days. In addition, TT (HR, 4.65; 95% CI, 2.67–8.10; p = 0.009) and readmission within 90 days (HR, 3.27; 95% CI, 1.23–8.69; p = 0.02) predicted increased mortality. Neurohumoral activation, as estimated by MSNA, was significantly higher in the LT group compared to in the NT group (65 ± 3 vs. 51 ± 4 bursts/100 heart beats; p < 0.001). These results support the concept that LT is an independent risk factor for hospital readmission within 90 days and increased mortality in patients with HF. Furthermore, increased MSNA was observed in patients with LT.

  2. Germ-cell deficient (gcd), an insertional mutation manifested as infertility in transgenic mice.

    Science.gov (United States)

    Pellas, T C; Ramachandran, B; Duncan, M; Pan, S S; Marone, M; Chada, K

    1991-10-01

    A genetic analysis is necessary to gain a greater understanding of the complex developmental processes in mammals. Toward this end, an insertional transgenic mouse mutant has been isolated that results in abnormal germ-cell development. This recessive mutation manifests as infertility in both males and females and is specific for the reproductive organs, since all other tissues examined were histologically normal. A developmental analysis of the gonadal tissues demonstrated that the germ cells were specifically depleted as early as day 11.5 of embryonic development, while the various somatic cells were apparently unaffected. Therefore, the mutated locus must play a critical role in the migration/proliferation of primordial germ cells to the genital ridges of developing embryos. In addition, females homozygous for the mutation could potentially be a valuable animal model of a human syndrome, premature ovarian failure. This mutation has been named germ-cell deficient, gcd.

  3. Myalgias or non-specific muscle pain in Arab or Indo-Pakistani patients may indicate vitamin D deficiency.

    Science.gov (United States)

    Badsha, Humeira; Daher, Mirna; Ooi Kong, Kok

    2009-08-01

    The aim of our study was to determine the prevalence of vitamin D deficiency (fibromyalgia or muscle pain in a musculoskeletal clinic in the United Arab Emirates. Consecutive patients who were diagnosed with fibromyalgia and/or non-specific musculoskeletal pain (ICD-9 729.1) were screened for vitamin D deficiency. Patients were seen at follow-up after treatment with vitamin D was given. Improvement was assessed by a simple questionnaire. Patients (139) with muscle pain were seen in 2007. Average age was 40 +/- year; 95% were female; 69 (49%) were Arab, of whom 92% were veiled; 43 (30%) Indian of whom 11% were veiled; 23 (16%) were Caucasian; and four were East Asian (3%) and all wore western clothes. One hundred three (74%) of these patients had a low vitamin D level. Vitamin D deficiency was most common among Arab patients (86%) and Indo-Pakistani (87%) and least common among the Caucasians (8%) and was equally prevalent among veiled and non-veiled patients. Treatment resulted in clinical improvement in 90% of patients. Non-specific muscle pains among Arab and Indian-Pakistani populations may indicate vitamin D deficiency, and prompt treatment can result in resolution of symptoms.

  4. Gluten sensitive enteropathy in patients with iron deficiency anemia of unknown origin

    Institute of Scientific and Technical Information of China (English)

    Farhad Zamani; Mehdi Mohamadnejad; Ramin Shakeri; Afsaneh Amiri; Safa Najafi; Seyed Meysam Alimohamadi; Seyed Mohamad Tavangar; Ardeshir Ghavamzadeh; Reza Malekzadeh

    2008-01-01

    AIM:To determine the prevalence of gluten sensitive enteropathy (GSE) in a large group of patients with iron deficiency anemia (IDA) of obscure origin.METHODS:In this cross-sectional study,patients with IDA of obscure origin were screened for GSE.Antiendomysial antibody (EMA) and tissue transglutaminase antibody (tTG) levels were evaluated and duodenal biopsies were taken and scored according to the Marsh classification.The diagnosis of GSE was based on a positive serological test and abnormal duodenal histology.Gluten free diet (GFD) was advised for all the GSE patients.RESULTS:Of the 4120 IDA patients referred to our Hematology departments,206 (95 male) patients were found to have IDA of obscure origin.Thirty out of 206 patients (14.6%) had GSE.The mean age of GSE patients was 34.6±17.03 (range 10-72 years).The female to male ratio was 1,3:1.Sixteen patients had Marsh 3,12 had Marsh 2,and 2 had Marsh 1 lesions.The severity of anemia was in parallel with the severity of duodenal lesions.Twenty-two GSE patients (73.3%) had no gastrointestinal symptoms.Fourteen GSE patients who adhered to GFD without receiving iron supplementation agreed to undergo follow up visits.After 6 mo of GFD,their mean hemoglobin levels (Hb) increased from 9.9 ±1.6 to 12.8 ± 1.0 g/dL (P<0.01).Interestingly,in 6 out of 14 patients who had Marsh 1/2 lesions (e.g.no villous atrophy) on duodenal biopsy,mean Hb increased from 11.0 ± 1.1 to 13.1 ±1.0 g/dL (P<0.01) while they did not receive any iron supplementation.CONCLUSION:There is a high prevalence (e.g.14.6%) of GSE in patients with IDA of obscure origin.Gluten free diet can improve anemia in GSE patients who have mild duodenal lesions without villous atrophy.

  5. Endo-lysosomal dysfunction in human proximal tubular epithelial cells deficient for lysosomal cystine transporter cystinosin.

    Directory of Open Access Journals (Sweden)

    Ekaterina A Ivanova

    Full Text Available Nephropathic cystinosis is a lysosomal storage disorder caused by mutations in the CTNS gene encoding cystine transporter cystinosin that results in accumulation of amino acid cystine in the lysosomes throughout the body and especially affects kidneys. Early manifestations of the disease include renal Fanconi syndrome, a generalized proximal tubular dysfunction. Current therapy of cystinosis is based on cystine-lowering drug cysteamine that postpones the disease progression but offers no cure for the Fanconi syndrome. We studied the mechanisms of impaired reabsorption in human proximal tubular epithelial cells (PTEC deficient for cystinosin and investigated the endo-lysosomal compartments of cystinosin-deficient PTEC by means of light and electron microscopy. We demonstrate that cystinosin-deficient cells had abnormal shape and distribution of the endo-lysosomal compartments and impaired endocytosis, with decreased surface expression of multiligand receptors and delayed lysosomal cargo processing. Treatment with cysteamine improved surface expression and lysosomal cargo processing but did not lead to a complete restoration and had no effect on the abnormal morphology of endo-lysosomal compartments. The obtained results improve our understanding of the mechanism of proximal tubular dysfunction in cystinosis and indicate that impaired protein reabsorption can, at least partially, be explained by abnormal trafficking of endosomal vesicles.

  6. Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming.

    Science.gov (United States)

    Gu, Ruinan; Zhang, Fali; Chen, Gang; Han, Chaojun; Liu, Jay; Ren, Zhaoxiang; Zhu, Yi; Waddington, John L; Zheng, Long Tai; Zhen, Xuechu

    2017-02-01

    Clock (Clk)1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (coenzyme Q or UQ). Here, we investigate the role of Clk1 in neuroinflammation and consequentially dopaminergic (DA) neuron survival. Reduced expression of Clk1 in microglia enhanced the LPS-induced proinflammatory response and promoted aerobic glycolysis. Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to the inflammatory stimulation. Mechanistic studies demonstrated that mTOR/HIF-1α and ROS/HIF-1α signaling pathways were involved in Clk1 deficiency-induced aerobic glycolysis. The increase in neuronal cell death was observed following treatment with conditioned media from Clk1 deficient microglia. Increased DA neuron loss and microgliosis were observed in Clk1(+/-) mice after treatment with MPTP, a rodent model of Parkinson's disease (PD). This increase in DA neuron loss was due to an exacerbated microglial inflammatory response, rather than direct susceptibility of Clk1(+/-) DA cells to MPP(+), the active species of MPTP. Exaggerated expressions of proinflammatory genes and loss of DA neurons were also observed in Clk1(+/-) mice after stereotaxic injection of LPS. Our results suggest that Clk1 regulates microglial metabolic reprogramming that is, in turn, involved in the neuroinflammatory processes and PD.

  7. Red blood cell PK deficiency: An update of PK-LR gene mutation database.

    Science.gov (United States)

    Canu, Giulia; De Bonis, Maria; Minucci, Angelo; Capoluongo, Ettore

    2016-03-01

    Pyruvate kinase (PK) deficiency is known as being the most common cause of chronic nonspherocytic hemolytic anemia (CNSHA). Clinical PK deficiency is transmitted as an autosomal recessive trait, that can segregate neither in homozygous or in a compound heterozygous modality, respectively. Two PK genes are present in mammals: the pyruvate kinase liver and red blood cells (PK-LR) and the pyruvate kinase muscle (PK-M), of which only the first encodes for the isoenzymes normally expressed in the red blood cells (R-type) and in the liver (L-type). Several reports have been published describing a large variety of genetic defects in PK-LR gene associated to CNSHA. Herein, we present a review of about 250 published mutations and six polymorphisms in PK-LR gene with the corresponding clinical and molecular data. We consulted the PubMed website for searching mutations and papers, along with two main databases: the Leiden Open Variation Database (LOVD, https://grenada.lumc.nl/LOVD2/mendelian_genes/home.php?select_db=PKLR) and Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PKLR) for selecting, reviewing and listing the annotated PK-LR gene mutations present in literature. This paper is aimed to provide useful information to clinicians and laboratory professionals regarding overall reported PK-LR gene mutations, also giving the opportunity to harmonize data regarding PK-deficient individuals.

  8. Deficient Fas expression by CD4+ CCR5+ T cells in multiple sclerosis

    DEFF Research Database (Denmark)

    Julià, Eva; Montalban, Xavier; Al-Zayat, Hammad;

    2006-01-01

    OBJECTIVE: To evaluate whether T cells expressing CCR5 and CXCR3 from multiple sclerosis (MS) patients are more resistant to apoptosis. METHODS: Expression of CD69, TNF-R1, Fas, FasL, bcl-2, and bax was investigated in 41 MS patients and 12 healthy controls by flow cytometry in CD4+ and CD8+ T...... cells expressing CCR5 and CXCR3. RESULTS: In MS patients, the percentage of CD69 was increased and Fas expression decreased in CD4+ CCR5+ T cells. INTERPRETATION: The lower Fas expression in activated CD4+ CCR5+ T cells might contribute to disease pathogenesis by prolonging cell survival and favoring...

  9. Leukocyte TLR5 deficiency inhibits atherosclerosis by reduced macrophage recruitment and defective T-cell responsiveness

    Science.gov (United States)

    Ellenbroek, Guilielmus H.J.M.; van Puijvelde, Gijs H.M.; Anas, Adam A.; Bot, Martine; Asbach, Miriam; Schoneveld, Arjan; van Santbrink, Peter J.; Foks, Amanda C.; Timmers, Leo; Doevendans, Pieter A.; Pasterkamp, Gerard; Hoefer, Imo E.; van der Poll, Tom; Kuiper, Johan; de Jager, Saskia C.A.

    2017-01-01

    Toll-like receptors (TLR) provide a critical link between innate and adaptive immunity, both important players in atherosclerosis. Since evidence for the role of TLR5 is lacking, we aimed to establish this in the immune axis of atherosclerosis. We assessed the effect of the TLR5-specific ligand Flagellin on macrophage maturation and T-cell polarisation. Next, we generated TLR5−/−LDLr−/− chimeras to study the effect of hematopoietic TLR5 deficiency on atherosclerosis formation. Flagellin stimulation did not influence wildtype or TLR5−/− macrophage maturation. Only in wildtype macrophages, Flagellin exposure increased MCP-1 and IL6 expression. Flagellin alone reduced T-helper 1 proliferation, which was completely overruled in the presence of T-cell receptor activation. In vivo, hematopoietic TLR5 deficiency attenuated atherosclerotic lesion formation by ≈25% (1030*103 ± 63*103 vs. 792*103 ± 61*103 μm2; p = 0.013) and decreased macrophage area (81.3 ± 12.0 vs. 44.2 ± 6.6 μm2; p = 0.011). In TLR5−/− chimeric mice, we observed lower IL6 plasma levels (36.4 ± 5.6 vs. 15.1 ± 2.2 pg/mL; p = 0.003), lower (activated) splenic CD4+ T-cell content (32.3 ± 2.1 vs. 21.0 ± 1.2%; p = 0.0018), accompanied by impaired T-cell proliferative responses. In conclusion, hematopoietic TLR5 deficiency inhibits atherosclerotic lesion formation by attenuated macrophage accumulation and defective T-cell responsiveness. PMID:28202909

  10. Ceramide transfer protein deficiency compromises organelle function and leads to senescence in primary cells.

    Directory of Open Access Journals (Sweden)

    Raghavendra Pralhada Rao

    Full Text Available Ceramide transfer protein (CERT transfers ceramide from the endoplasmic reticulum (ER to the Golgi complex. Its deficiency in mouse leads to embryonic death at E11.5. CERT deficient embryos die from cardiac failure due to defective organogenesis, but not due to ceramide induced apoptotic or necrotic cell death. In the current study we examined the effect of CERT deficiency in a primary cell line, namely, mouse embryonic fibroblasts (MEFs. We show that in MEFs, unlike in mutant embryos, lack of CERT does not lead to increased ceramide but causes an accumulation of hexosylceramides. Nevertheless, the defects due to defective sphingolipid metabolism that ensue, when ceramide fails to be trafficked from ER to the Golgi complex, compromise the viability of the cell. Therefore, MEFs display an incipient ER stress. While we observe that ceramide trafficking from ER to the Golgi complex is compromised, the forward transport of VSVG-GFP protein is unhindered from ER to Golgi complex to the plasma membrane. However, retrograde trafficking of the plasma membrane-associated cholera toxin B to the Golgi complex is reduced. The dysregulated sphingolipid metabolism also leads to increased mitochondrial hexosylceramide. The mitochondrial functions are also compromised in mutant MEFs since they have reduced ATP levels, have increased reactive oxygen species, and show increased glutathione reductase activity. Live-cell imaging shows that the mutant mitochondria exhibit reduced fission and fusion events. The mitochondrial dysfunction leads to an increased mitophagy in the CERT mutant MEFs. The compromised organelle function compromise cell viability and results in premature senescence of these MEFs.

  11. A genetic screen for components of the mammalian RNA interference pathway in Bloom-deficient mouse embryonic stem cells

    OpenAIRE

    2009-01-01

    Genetic screens performed in model organisms have helped identify key components of the RNA interference (RNAi) pathway. Recessive genetic screens have recently become feasible through the use of mouse embryonic stem (ES) cells that are Bloom's syndrome protein (Blm) deficient. Here, we developed and performed a recessive genetic screen to identify components of the mammalian RNAi pathway in Blm-deficient ES cells. Genome-wide mutagenesis using a retroviral gene trap strategy resulted in the ...

  12. Molecular Analysis of Activation-Induced Cytidine Deaminase Gene in Immunoglobulin-E Deficient Patients

    Directory of Open Access Journals (Sweden)

    Sergio Roa

    2008-01-01

    Full Text Available Understanding how class switch recombination (CSR is regulated to produce immunoglobulin E (IgE has become fundamental because of the dramatic increase in the prevalence of IgE-mediated hypersensitivity reactions. CSR requires the induction of the enzyme AICDA in B cells. Mutations in AICDA have been linked to Hyper-IgM syndrome (HIGM2, which shows absence of switching to IgE as well as to IgG and IgA. Although isolated IgE deficiency is a rare entity, here we show some individuals with normal serum IgM, IgG, and IgA levels that had undetectable total serum IgE levels. We have analyzed the AICDA gene in these individuals to determine if there are mutations in AICDA that could lead to selective IgE deficiency. Conformational sensitive gel electrophoresis (CSGE and sequencing analysis of AICDA coding sequences demonstrated sequence heterogeneity due to 5923A/G and 7888C/T polymorphisms, but did not reveal any novel mutation that might explain the selective IgE deficit.

  13. Sensory Neuronopathy Revealing Severe Vitamin B12 Deficiency in a Patient with Anorexia Nervosa: An Often-Forgotten Reversible Cause.

    Science.gov (United States)

    Franques, Jérôme; Chiche, Laurent; Mathis, Stéphane

    2017-03-15

    Vitamin B12 (B12) deficiency is known to be associated with various neurological manifestations. Although central manifestations such as dementia or subacute combined degeneration are the most classic, neurological manifestations also include sensory neuropathies. However, B12 deficiency is still rarely integrated as a potential cause of sensory neuronopathy. Moreover, as many medical conditions can falsely normalize serum B12 levels even in the context of a real B12 deficiency, some cases may easily remain underdiagnosed. We report the illustrating case of an anorexic patient with sensory neuronopathy and consistently normal serum B12 levels. After all classical causes of sensory neuronopathy were ruled out, her clinical and electrophysiological conditions first worsened after folate administration, but finally improved dramatically after B12 administration. B12 deficiency should be systematically part of the etiologic workup of sensory neuronopathy, especially in a high risk context such as anorexia nervosa.

  14. Sensory Neuronopathy Revealing Severe Vitamin B12 Deficiency in a Patient with Anorexia Nervosa: An Often-Forgotten Reversible Cause

    Directory of Open Access Journals (Sweden)

    Jérôme Franques

    2017-03-01

    Full Text Available Vitamin B12 (B12 deficiency is known to be associated with various neurological manifestations. Although central manifestations such as dementia or subacute combined degeneration are the most classic, neurological manifestations also include sensory neuropathies. However, B12 deficiency is still rarely integrated as a potential cause of sensory neuronopathy. Moreover, as many medical conditions can falsely normalize serum B12 levels even in the context of a real B12 deficiency, some cases may easily remain underdiagnosed. We report the illustrating case of an anorexic patient with sensory neuronopathy and consistently normal serum B12 levels. After all classical causes of sensory neuronopathy were ruled out, her clinical and electrophysiological conditions first worsened after folate administration, but finally improved dramatically after B12 administration. B12 deficiency should be systematically part of the etiologic workup of sensory neuronopathy, especially in a high risk context such as anorexia nervosa.

  15. A Rare Case of Stroke Secondary to Iron Deficiency Anemia in a Young Female Patient

    Science.gov (United States)

    Gopalratnam, Kavitha; Sena, Kanaga; Gupta, Manisha

    2017-01-01

    Ischemic strokes occur when there is a sudden obstruction of an artery supplying blood flow to an area of the brain, leading to a focal neurological deficit. Strokes can be thrombotic or embolic in etiology and are associated with underlying conditions such as hypertension and atherosclerosis. Possible etiologies of strokes include cardioembolic disease, hematologic disorders, connective tissue disorders, and substance abuse or can be cryptogenic. Most stroke cases are seen in patients over 65 years of age. However, about one-fourth of strokes occur in young adults. Iron deficiency anemia (IDA) has been described as a known cause for strokes in children, but very few case reports describe this association in adults. We describe a 20-year-old female who presented with sudden onset left side weakness. Magnetic Resonance Imaging (MRI) of the brain demonstrated ischemic infarctions. Patient was also found to be severely anemic. Patient had a thorough work-up including Magnetic Resonance Angiography (MRA) of the brain, echocardiogram, and an extensive screen for thrombophilia disorders. This, however, did not demonstrate a clear etiology. As it has been suggested that IDA is a potential cause for stroke, it is possible the stroke in this young patient was attributable to severe IDA. PMID:28348599

  16. The Hypothesis of the Human iNKT/Innate CD8(+) T-Cell Axis Applied to Cancer: Evidence for a Deficiency in Chronic Myeloid Leukemia

    Science.gov (United States)

    Jacomet, Florence; Cayssials, Emilie; Barbarin, Alice; Desmier, Deborah; Basbous, Sara; Lefèvre, Lucie; Levescot, Anaïs; Robin, Aurélie; Piccirilli, Nathalie; Giraud, Christine; Guilhot, François; Roy, Lydia; Herbelin, André; Gombert, Jean-Marc

    2017-01-01

    We recently identified a new human subset of NK-like [KIR/NKG2A(+)] CD8(+) T cells with a marked/memory phenotype, high Eomesodermin expression, potent antigen-independent cytotoxic activity, and the capacity to generate IFN-γ rapidly after exposure to pro-inflammatory cytokines. These features support the hypothesis that this new member of the innate T cell family in humans, hereafter referred to as innate CD8(+) T cells, has a role in cancer immune surveillance analogous to invariant natural killer T (iNKT) cells. Here, we report the first quantitative and functional analysis of innate CD8(+) T cells in a physiopathological context in humans, namely chronic myeloid leukemia (CML), a well-characterized myeloproliferative disorder. We have chosen CML based on our previous report that IL-4 production by iNKT cells was deficient in CML patients at diagnosis and considering the recent evidence in mice that IL-4 promotes the generation/differentiation of innate CD8(+) T cells. We found that the pool of innate CD8(+) T cells was severely reduced in the blood of CML patients at diagnosis. Moreover, like iNKT and NK cells, innate CD8(+) T cells were functionally impaired, as attested by their loss of antigen-independent cytotoxic activity and IFN-γ production in response to innate-like stimulation with IL-12 + IL-18. Remarkably, as previously reported for IL-4 production by iNKT cells, both quantitative and functional deficiencies of innate CD8(+) T cells were at least partially corrected in patients having achieved complete cytogenetic remission following tyrosine kinase inhibitor therapy. Finally, direct correlation between the functional potential of innate CD8(+) T and iNKT cells was found when considering all healthy donors and CML patients in diagnosis and remission, in accordance with the iNKT cell-dependent generation of innate CD8(+) T cells reported in mice. All in all, our data demonstrate that CML is associated with deficiencies of innate CD8(+) T cells

  17. Outcome of endoscopy-negative iron deficiency anemia in patients above 65

    Science.gov (United States)

    Clere-Jehl, Raphaël; Sauleau, Erik; Ciuca, Stefan; Schaeffer, Mickael; Lopes, Amanda; Goichot, Bernard; Vogel, Thomas; Kaltenbach, Georges; Bouvard, Eric; Pasquali, Jean-Louis; Sereni, Daniel; Andres, Emmanuel; Bourgarit, Anne

    2016-01-01

    Abstract After the age of 65 years, iron deficiency anemia (IDA) requires the elimination of digestive neoplasia and is explored with upper and lower gastrointestinal (GI) endoscopy. However, such explorations are negative in 14% to 37% of patients. To further evaluate this issue, we evaluated the outcomes of patients aged over 65 years with endoscopy-negative IDA. We retrospectively analyzed the outcomes of in-patients over the age of 65 years with IDA (hemoglobin <12 g/dL and ferritin <70 μg/L) who had negative complete upper and lower GI endoscopies in 7 tertiary medical hospitals. Death, the persistence of anemia, further investigations, and the final diagnosis for IDA were analyzed after at least 12 months by calling the patients’ general practitioners and using hospital records. Between 2004 and 2011, 69 patients (74% women) with a median age of 78 (interquartile range (IQR) 75–82) years and hemoglobin and ferritin levels of 8.4 (IQR 6.8–9.9) g/dL and 14 (IQR 8–27) μg/L, respectively, had endoscopy-negative IDA, and 73% of these patients received daily antithrombotics. After a follow-up of 41 ± 22 months, 23 (33%) of the patients were dead; 5 deaths were linked with the IDA, and 45 (65%) patients had persistent anemia, which was significantly associated with death (P = 0.007). Further investigations were performed in 45 patients; 64% of the second-look GI endoscopies led to significant changes in treatment compared with 25% for the capsule endoscopies. Conventional diagnoses of IDA were ultimately established for 19 (27%) patients and included 3 cancer patients. Among the 50 other patients, 40 (58%) had antithrombotics. In endoscopy-negative IDA over the age of 65 years, further investigations should be reserved for patients with persistent anemia, and second-look GI endoscopy should be favored. If the results of these investigations are negative, the role of antithrombotics should be considered. PMID:27893668

  18. High risk of severe anaemia after chlorproguanil-dapsone+artesunate antimalarial treatment in patients with G6PD (A- deficiency.

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    Caterina I Fanello

    Full Text Available BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD deficiency is the most common inherited human enzyme defect. This deficiency provides some protection from clinical malaria, but it can also cause haemolysis after administration of drugs with oxidant properties. METHODS: The safety of chlorproguanil-dapsone+artesunate (CD+A and amodiaquine+sulphadoxine-pyrimethamine (AQ+SP for the treatment of uncomplicated P. falciparum malaria was evaluated according to G6PD deficiency in a secondary analysis of an open-label, randomized clinical trial. 702 children, treated with CD+A or AQ+SP and followed for 28 days after treatment were genotyped for G6PD A- deficiency. FINDINGS: In the first 4 days following CD+A treatment, mean haematocrit declined on average 1.94% (95% CI 1.54 to 2.33 and 1.05% per day (95% CI 0.95 to 1.15 respectively in patients with G6PD deficiency and normal patients; a mean reduction of 1.3% per day was observed among patients who received AQ+SP regardless of G6PD status (95% CI 1.25 to 1.45. Patients with G6PD deficiency recipients of CD+A had significantly lower haematocrit than the other groups until day 7 (p = 0.04. In total, 10 patients had severe post-treatment haemolysis requiring blood transfusion. Patients with G6PD deficiency showed a higher risk of severe anaemia following treatment with CD+A (RR = 10.2; 95% CI 1.8 to 59.3 or AQ+SP (RR = 5.6; 95% CI 1.0 to 32.7. CONCLUSIONS: CD+A showed a poor safety profile in individuals with G6PD deficiency most likely as a result of dapsone induced haemolysis. Screening for G6PD deficiency before drug administration of potentially pro-oxidants drugs, like dapsone-containing combinations, although seldom available, is necessary.

  19. Correlation Study of PtfV1 with Heart-Qi Deficiency Syndrome in Patients with Hypertensive Left Ventricular Hypertrophy

    Institute of Scientific and Technical Information of China (English)

    杨传华; 陆峰

    2002-01-01

    @@ It is generally believed that the change of p-wave terminal force in lead V1 (PtfV1) is associated with the inner diameter of left atrium, left ventricular compliance,and ventricular diastolic function. The increase of negative value of PtfV1 in essential hypertensive (EH) patients with left ventricular hypertrophy (LVH) indicates the cardiac function may be damaged. In order to explore the relationship between Heart-Qi Deficiency Syndrome (HQDS) of TCM and PtfV1 level in hypertensive LVH patients, correlation analysis of scores of Heart-Qi Deficiency Syndrome and negative value of PtfV1 was made by the authors.

  20. Type I and III procollagen propeptides in growth hormone-deficient patients

    DEFF Research Database (Denmark)

    Jensen, L T; Jørgensen, J O; Risteli, J;

    1991-01-01

    The effect of increasing doses of growth hormone on collagen synthesis in GH-treated GH-deficient patients was determined in a short-term study. The synthesis of type I and III collagen was estimated by measurements of the carboxyterminal propeptide of type I procollagen and the aminoterminal...... propeptide of type III procollagen. Type I collagen is mainly found in bone and type III collagen in loose connective tissue. We observed a GH dose dependency of both procollagen propeptides. Serum type I procollagen propeptide was significantly higher following GH doses of 4 and 6 IU/day for 14 days...... procollagen propeptide increased twice as much as type I procollagen propeptide, by 47 vs 25%, at a GH dose of 6 IU/day compared with 2 IU/day. The differences between the effects on type I and type III collagen may reflect differences in secretion or turn-over rate of collagen in bone and loose connective...

  1. Acquired absolute vitamin K deficiency in a patient undergoing warfarin therapy.

    Science.gov (United States)

    Takada, Hiroaki; Toru, Hifumi; Bunya, Naofumi; Kiriu, Nobuaki; Kato, Hiroshi; Koido, Yuichi; Yasuhiro, Kuroda

    2014-06-01

    We report a case of absolute vitamin K deficiency (VKD) diagnosed by measuring serum VK levels in an elderly woman undergoing warfarin therapy. A 78-year-old woman was admitted to our hospital because of dyspnea and sore throat diagnosed as pharyngitis 1 week before admission. On admission, the sore throat had exacerbated and dyspnea developed. She had history of atrial fibrillation, for which warfarin 1.5 mg/d was started approximately 10 years prior and her international normalized ratio (INR) had been maintained at an acceptable therapeutic level. Blood results revealed unmeasurable INR and abnormally prolonged activated partial thromboplastin time (APTT). She was diagnosed with adenoiditis and warfarin-related coagulopathy and administered intravenous VK (20 mg) and fresh frozen plasma (FFP; 4 U), which improved INR and APTT. Since the coagulopathy responded to intravenous VK administration, the patient was clinically diagnosed with warfarin-related relative VKD. Approximately 1 month later, she returned with complaints of sore throat. Blood results indicated abnormal INR (7.22) and APTT (N80.0 s). She was diagnosed with recurrent adenoiditis and VK deficient coagulopathy. The patient’s serum VK levels were low (VK1 level, 0.13 ng/mL; VK2 levels, 0.85 ng/mL). Initial treatment of VK (20 mg) and FFP followed by intravenous VK (20 mg/d) for 6 days, her symptoms dissipated. Warfarin was suspected to have caused absolute VKD. Severe coagulopathy in patients undergoing warfarin therapy is primarily caused by, relative VKD. However, the possibility of warfarin-related absolute VKD should be suspected when INRis not sufficiently improved by intravenous VK administration.

  2. Hematopoietic stem cell gene therapy for adenosine deaminase deficient-SCID.

    Science.gov (United States)

    Aiuti, Alessandro; Brigida, Immacolata; Ferrua, Francesca; Cappelli, Barbara; Chiesa, Robert; Marktel, Sarah; Roncarolo, Maria-Grazia

    2009-01-01

    Gene therapy is a highly attractive strategy for many types of inherited disorders of the immune system. Adenosine deaminase (ADA) deficient-severe combined immunodeficiency (SCID) has been the target of several clinical trials based on the use of hematopoietic stem/progenitor cells engineered with retroviral vectors. The introduction of a low intensity conditioning regimen has been a crucial factor in achieving stable engrafment of hematopoietic stem cells and therapeutic levels of ADA-expressing cells. Recent studies have demonstrated that gene therapy for ADA-SCID has favorable safety profile and is effective in restoring normal purine metabolism and immune functions. Stem cell gene therapy combined with appropriate conditioning regimens might be extended to other genetic disorders of the hematopoietic system.

  3. Aberrant gene expression profiles, during in vitro osteoblast differentiation, of telomerase deficient mouse bone marrow stromal stem cells (mBMSCs)

    DEFF Research Database (Denmark)

    Saeed, H.; Iqtedar, M.

    2015-01-01

    Background: Telomerase deficiency has been associated with inadequate differentiation of mesenchymal stem cells. However, the effect of telomerase deficiency on differential regulation of osteoblast specific genes, based on functional gene grouping, during in vitro osteoblast differentiation has ...

  4. Small intestinal bacterial overgrowth and thiamine deficiency after Roux-en-Y gastric bypass surgery in obese patients.

    Science.gov (United States)

    Lakhani, Shilen V; Shah, Hiral N; Alexander, Kenneth; Finelli, Frederick C; Kirkpatrick, John R; Koch, Timothy R

    2008-05-01

    It has been proposed that thiamine deficiency after gastric bypass surgery in obese patients results from prolonged nausea and emesis. We hypothesized that thiamine deficiency is induced by altered gut ecology. This report includes 2 retrospective studies of obese patients who underwent Roux-en-Y gastric bypass surgery at our institution from 1999 to 2005. In the first study, 80 patients (52 women and 28 men) had measurement of whole-blood thiamine diphosphate level and serum folate level. In these 80 patients, 39 (49%) had thiamine diphosphate levels less than the lower limit of the reference range, and 28 (72%) of the 39 had folate levels higher than the upper limit of the reference range, an indicator of small intestinal bacterial overgrowth. In 41 patients with normal thiamine levels, only 14 (34%) had folate levels higher than the upper limit of the reference range (chi(2) test, P thiamine diphosphate levels less than the lower limit of the reference range and abnormal glucose-hydrogen breath tests, consistent with small intestinal bacterial overgrowth. Fifteen patients received oral thiamine supplements, but repeated thiamine levels remained low in all 15. Nine of these patients then received oral antibiotic therapy; repeated thiamine levels were found to be normal in all 9 patients. These results support the hypothesis that small intestinal bacterial overgrowth results from altered gut ecology and induces thiamine deficiency after gastric bypass surgery in obese patients.

  5. Effect of vitamin D deficiency on the development of postoperative atrial fibrillation in coronary artery bypass patients.

    Science.gov (United States)

    Gode, Safa; Aksu, Timuçin; Demirel, Aylin; Sunbul, Murat; Gul, Mehmet; Bakır, Ihsan; Yeniterzi, Mehmet

    2016-01-01

    Introduction: Various factors may be responsible for the development of postoperative atrial fibrillation (POAF) in coronary artery bypass graft (CABG) patients. In our study, we demonstrated the effect of vitamin D deficiency on the development of POAF. Methods: In this prospective case control study, patients undergoing elective, isolated CABG were considered. A total of 15 patients (16.6%) who developed POAF during the first five days after surgery made up the POAF group. Seventy-five patients that had a sinus rhythm in the same period were the non-POAF group. The two groups were compared statistically in terms of laboratory, clinical, echocardiographic, operative, and postoperative parameters. Results: All patients were in sinus rhythm at discharge. The baseline characteristics of the study groups were comparable. The POAF group had a lower vitamin D level than the non-POAF group (9.0 ± 5.0 and 15.0 ± 8.4 ng/mL, respectively; P=0.007). In the POAF group, the patients' left atrium diameter and incidence of hypertension (HT) were higher than those of the non-POAF group. Conclusion: Incidence of POAF was significantly higher in patients with vitamin D deficiency or insufficiency than the patients with vitamin D level in normal range. Therefore vitamin D deficiency or insufficiency may be a predictor of POAF in patients with CABG.

  6. Deficient Cholesterol Esterification in Plasma of apoc2 Knockout Zebrafish and Familial Chylomicronemia Patients

    Science.gov (United States)

    Liu, Chao; Gaudet, Daniel; Miller, Yury I.

    2017-01-01

    Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Apolipoprotein C-II (APOC2) is an obligatory cofactor for lipoprotein lipase (LPL), the major enzyme catalyzing plasma triglyceride hydrolysis. We have created an apoc2 knockout zebrafish model, which mimics the familial chylomicronemia syndrome (FCS) in human patients with a defect in the APOC2 or LPL gene. In this study, we measured plasma levels of free cholesterol (FC) and cholesterol esters (CE) and found that apoc2 mutant zebrafish have a significantly higher FC to CE ratio (FC/CE), when compared to the wild type. Feeding apoc2 mutant zebrafish a low-fat diet reduced triglyceride levels but not the FC/CE ratio. In situ hybridization and qPCR results demonstrated that the hepatic expression of lecithin-cholesterol acyltransferase (lcat), the enzyme responsible for esterifying plasma FC to CE, and of apolipoprotein A-I, a major protein component of HDL, were dramatically decreased in apoc2 mutants. Furthermore, the FC/CE ratio was significantly increased in the whole plasma and in a chylomicron-depleted fraction of human FCS patients. The FCS plasma LCAT activity was significantly lower than that of healthy controls. In summary, this study, using a zebrafish model and human patient samples, reports for the first time the defect in plasma cholesterol esterification associated with LPL deficiency. PMID:28107429

  7. Lethal Hyperammonemia due to Ornithine Transcarbamylase Deficiency in a Patient with Severe Septic Shock

    Directory of Open Access Journals (Sweden)

    Ji An Hwang

    2016-05-01

    Full Text Available Severe hyperammonemia can occur as a result of inherited or acquired liver enzyme defects in the urea cycle, among which ornithine transcarbamylase deficiency (OTCD is the most common form. We report a very rare case of a 45-year-old Korean male who was admitted to the intensive care unit (ICU due to severe septic shock with acute respiratory failure caused by Pneumocystis jiroveci pneumonia. During his ICU stay with ventilator care, the patient suffered from marked hyperammonemia (>1,700 μg/dL with abrupt mental change leading to life-threatening cerebral edema. Despite every effort including continuous renal replacement therapy and use of a molecular adsorbent recirculating system (extracorporeal liver support–albumin dialysis to lower his serum ammonia level, the patient was not recovered. The lethal hyperammonemia in the patient was later proven to be a manifestation of acquired liver enzyme defect known as OTCD, which is triggered by serious catabolic conditions, such as severe septic shock with acute respiratory failure.

  8. A trial with N-carbamylglutamate may not detect all patients with NAGS deficiency and neonatal onset.

    Science.gov (United States)

    Nordenström, A; Halldin, M; Hallberg, B; Alm, J

    2007-06-01

    N-acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder. An effective treatment, N-carbamoyl-L-glutamic acid (NCGA), is now available, increasing the importance of identifying and treating these patients early. We describe a case with genetically verified NAGS deficiency and neonatal onset of severe hyperammonaemia. The ammonia levels increased above 1400 micromol/L. The patient did not respond to NCGA treatment during the first 15 h, indicating that a delayed response or no response cannot be used as a safe indicator for excluding NAGS deficiency in the acute situation. Hence, conventional treatment should not be delayed by a diagnostic procedure, such as a loading test. Furthermore, at 3 years of age this patient has normal psychomotor development, underlining the possibility of a favourable outcome despite markedly elevated ammonia levels, coma, and seizures in the neonatal period. Including NCGA early in the treatment of patients with hyperammonaemia may be of clinical importance. In order to detect patients with NAGS deficiency and neonatal onset and to optimize care, it is important to use the available treatment strategies to reduce plasma ammonia concentrations without delay. We propose the use of combined symptomatic treatment, i.e. glucose infusion, sodium benzoate, arginine or citrulline, and when indicated haemodialysis, as well as NCGA treatment in all neonates presenting with severe hyperammonaemia. The treatment should be continued until laboratory investigations are complete or indicate another disorder.

  9. H. pylori May Not Be Associated with Iron Deficiency Anemia in Patients with Normal Gastrointestinal Tract Endoscopy Results

    Directory of Open Access Journals (Sweden)

    Tayyibe Saler

    2014-01-01

    Full Text Available Background. The aim of this study was to investigate the association between iron deficiency anemia and H. pylori in patients with normal gastrointestinal tract endoscopy results. Materials and Methods. A total of 117 male patients with normal gastrointestinal tract endoscopy results were included in this retrospective study. The study and control groups included 69 and 48 patients with and without iron deficiency anemia, respectively. The prevalence of H. pylori, the number of RBCs, and the levels of HGB, HTC, MCV, iron, and ferritin were calculated and compared. Results. There was no statistically significant difference found between the groups according to the prevalence of H. pylori (65.2% versus 64.6%, P=0.896. Additionally, the levels of RBCs, HGB, HTC, MCV, iron, and ferritin in the patients in the study group were lower than those in the control group (P<0.05. Finally, there was no association between iron deficiency anemia and H. pylori (OR 1.02, Cl 95% 0.47–2.22, and P=0.943. Conclusion. H. pylori is not associated with iron deficiency anemia in male patients with normal gastrointestinal tract endoscopy results.

  10. Vitamin D Deficiency in Unselected Patients from Swiss Primary Care: A Cross-Sectional Study in Two Seasons.

    Directory of Open Access Journals (Sweden)

    Christoph Merlo

    Full Text Available As published data on 25-hydroxy-cholecalciferol (25(OHD deficiency in primary care settings is scarce, we assessed the prevalence of hypovitaminosis D, potential associations with clinical symptoms, body mass index, age, Vitamin D intake, and skin type in unselected patients from primary care, and the extent of seasonal variations of serum 25(OHD concentrations.25(OHD was measured at the end of summer and/or winter in 1682 consecutive patients from primary care using an enzyme-linked immunosorbant assay. Clinical symptoms were assessed by self-report (visual analogue scale 0 to 10, and vitamin D deficiency was defined as 25(OHD concentrations < 50 nmol/l. 25(OHD deficiency was present in 995 (59.2% patients. 25(OHD deficient patients reported more intense muscle weakness (visual analogue scale 2.7, 95% confidence interval 2.5 to 2.9 and had a higher body mass index (25.9kg/m2, 25.5 to 26.2 than non-deficient patients (2.5, 2.3 to 2.7; and 24.2, 23.9 to 24.5, respectively. 25(OHD concentrations also weakly correlated with muscle weakness (Spearman's rho -0.059, 95% confidence interval -0.107 to -0.011 and body mass index (-0.156, -0.202 to -0.108. Self-reported musculoskeletal pain, fatigue, and age were not associated with deficiency, nor with concentrations. Mean 25(OHD concentrations in patients with vitamin D containing medication were higher (60.6 ± 22.2 nmol/l than in patients without medication (44.8 ± 19.2 nmol/l, p < 0.0001 but still below the targeted level of 75 nmol/l. Summer and winter 25(OHD concentrations differed (53.4 ± 19.9 vs. 41.6 ± 19.3nmol/l, p < 0.0001, which was confirmed in a subgroup of 93 patients who were tested in both seasons (p = 0.01.Nearly 60% of unselected patients from primary care met the criteria for 25(OHD deficiency. Self-reported muscle weakness and high body mass index were associated with lower 25(OHD levels. As expected 25(OHD concentrations were lower in winter compared to summer.

  11. The Value of Erythrocyte Indices and Red Cell Volume Distribution Width in Differential Diagnosis of Iron Deficiency Anemia and Anemia of Chronic Disease

    Directory of Open Access Journals (Sweden)

    Abdullah Altıntaş

    2007-01-01

    Full Text Available Iron deficiency anemia (IDA and anemia of chronic disease are the most commonly confused anemias. We investigate the diagnostic value of erythrocyte indices, red cell volume distribution width, and serum ferritin levels to make differential diagnosis of anemia in controls and anemic patients.Iron deficiency anemia (44 patients, anemia of chronic disease (41, IDA with anemia of chronic disease (17 and control (50 groups were compared. We performed serum ferritin, CBC, and sedimentation rate in all patientsand bone marrow aspiration in patients with anemia of chronic disease.Although mean cell volume (MCV and mean corpuscular hemoglobin (MCH are low in IDA and anemia of chronic disease, it is much striking in the former one (p<0.001, p<0.001. Only 7.3% of patients with anemia of chronic disease had a MCV<70 fL and MCH<24 pg, 90.0% of patients with IDA were below that cut-off point. Serum ferritin means were in patients with IDA and anemia of chronic disease were 4.6±3.3 and 489.6 ±519.9 ng/ml, respectively.The probability of IDA is low when RDW is normal in microcytic anemias. RDW is high in half of patients with anemia of chronic disease. Reference values for ferritin must be changed in patients with anemia of chronic disease and IDA. If serum ferritin is 57.6-146.4 ng/ml anemia of chronic disease and iron deficiency must ruled out by other diagnostic tests.

  12. Deficiency in the 15 kDa Selenoprotein Inhibits Human Colon Cancer Cell Growth

    Directory of Open Access Journals (Sweden)

    Ryuta Tobe

    2011-09-01

    Full Text Available Selenium is an essential micronutrient for humans and animals, and is thought to provide protection against some forms of cancer. These protective effects appear to be mediated, at least in part, through selenium-containing proteins (selenoproteins. Recent studies in a mouse colon cancer cell line have shown that the 15 kDa selenoprotein (Sep15 may also play a role in promoting colon cancer. The current study investigated whether the effects of reversing the cancer phenotype observed when Sep15 was removed in mouse colon cancer cells, were recapitulated in HCT116 and HT29 human colorectal carcinoma cells. Targeted down-regulation of Sep15 using RNAi technology in these human colon cancer cell lines resulted in similarly decreased growth under anchorage-dependent and anchorage-independent conditions. However, the magnitude of reduction in cell growth was much less than in the mouse colon cancer cell line investigated previously. Furthermore, changes in cell cycle distribution were observed, indicating a delayed release of Sep15 deficient cells from the G0/G1 phase after synchronization. The potential mechanism by which human colon cancer cells lacking Sep15 revert their cancer phenotype will need to be explored further.

  13. Loss of Acetylcholine Signaling Reduces Cell Clearance Deficiencies in Caenorhabditis elegans.

    Science.gov (United States)

    Pinto, Sérgio M; Almendinger, Johann; Cabello, Juan; Hengartner, Michael O

    2016-01-01

    The ability to eliminate undesired cells by apoptosis is a key mechanism to maintain organismal health and homeostasis. Failure to clear apoptotic cells efficiently can cause autoimmune diseases in mammals. Genetic studies in Caenorhabditis elegans have greatly helped to decipher the regulation of apoptotic cell clearance. In this study, we show that the loss of levamisole-sensitive acetylcholine receptor, but not of a typical neuronal acetylcholine receptor causes a reduction in the number of persistent cell corpses in worms suffering from an engulfment deficiency. This reduction is not caused by impaired or delayed cell death but rather by a partial restoration of the cell clearance capacity. Mutants in acetylcholine turn-over elicit a similar phenotype, implying that acetylcholine signaling is the process responsible for these observations. Surprisingly, tissue specific RNAi suggests that UNC-38, a major component of the levamisole-sensitive receptor, functions in the dying germ cell to influence engulfment efficiency. Animals with loss of acetylcholine receptor exhibit a higher fraction of cell corpses positive for the "eat-me" signal phosphatidylserine. Our results suggest that modulation by ion channels of ion flow across plasma membrane in dying cells can influence the dynamics of phosphatidylserine exposure and thus clearance efficiency.

  14. Loss of Acetylcholine Signaling Reduces Cell Clearance Deficiencies in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Sérgio M Pinto

    Full Text Available The ability to eliminate undesired cells by apoptosis is a key mechanism to maintain organismal health and homeostasis. Failure to clear apoptotic cells efficiently can cause autoimmune diseases in mammals. Genetic studies in Caenorhabditis elegans have greatly helped to decipher the regulation of apoptotic cell clearance. In this study, we show that the loss of levamisole-sensitive acetylcholine receptor, but not of a typical neuronal acetylcholine receptor causes a reduction in the number of persistent cell corpses in worms suffering from an engulfment deficiency. This reduction is not caused by impaired or delayed cell death but rather by a partial restoration of the cell clearance capacity. Mutants in acetylcholine turn-over elicit a similar phenotype, implying that acetylcholine signaling is the process responsible for these observations. Surprisingly, tissue specific RNAi suggests that UNC-38, a major component of the levamisole-sensitive receptor, functions in the dying germ cell to influence engulfment efficiency. Animals with loss of acetylcholine receptor exhibit a higher fraction of cell corpses positive for the "eat-me" signal phosphatidylserine. Our results suggest that modulation by ion channels of ion flow across plasma membrane in dying cells can influence the dynamics of phosphatidylserine exposure and thus clearance efficiency.

  15. T-cell intracellular antigen (TIA-proteins deficiency in murine embryonic fibroblasts alters cell cycle progression and induces autophagy.

    Directory of Open Access Journals (Sweden)

    Carmen Sánchez-Jiménez

    Full Text Available Mice lacking either T-cell intracellular antigen 1 (TIA1 or TIA1 related/like protein (TIAR/TIAL1 show high rates of embryonic lethality, suggesting a relevant role for these proteins during embryonic development. However, intrinsic molecular and cellular consequences of either TIA1 or TIAR deficiency remain poorly defined. By using genome-wide expression profiling approach, we demonstrate that either TIA1 or TIAR inactivation broadly alter normal development-associated signalling pathways in murine embryonic fibroblasts (MEF. Indeed, these analyses highlighted alterations of cytokine-cytokine and ECM-receptor interactions and Wnt, MAPK, TGF-beta dependent signalling pathways. Consistent with these results, TIA1 and TIAR knockout (KO MEF show reduced rates of cell proliferation, cell cycle progression delay and increased cell size. Furthermore, TIA-proteins deficiency also caused metabolic deficiencies, increased ROS levels and DNA damage, promoting a gentle rise of cell death. Concomitantly, high rates of autophagy were detected in both TIA1 and TIAR KO MEF with induction of the formation of autophagosomes, as evidenced by the up-regulation of the LC3B protein, and autolysosomes, measured by colocalization of LC3B and LAMP1, as a survival mechanism attempt. Taken together, these observations support that TIA proteins orchestrate a transcriptome programme to activate specific developmental decisions. This program is likely to contribute to mouse physiology starting at early stages of the embryonic development. TIA1/TIAR might function as cell sensors to maintain homeostasis and promote adaptation/survival responses to developmental stress.

  16. Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Milewicz, A.; Vecsei, P.; Korth-Schuetz, S.; Haack, D.; Lichtwald, K.; Lewicka, S. (Heidelberg Univ. (Germany, F.R.)); Roesler, A. (Hadassah Medical School, Jerusalem (Israel)); Mittelstaedt, G.V. (Heidelberg Univ. (Germany, F.R.). Dept of Nephrology, Medical Faculty)

    1984-08-01

    Specific 21-deoxycortisol (21-DF) antiserum was raised in rabbits using a 21-DF-3,20-oxime-bovine serum albumin complex. Plasma radioimmunoassay of 21-DF was developed and used together with a radioimmunoassay of 17-hydroxyprogesterone (17-OH-P) for diagnosis of patients with 21-hydroxylase deficiency of congenital and postpubertal forms. The response of plasma 21-DF and 17-OH-P to iv.v. ACTH (25 IU) was studied in 15 adult controls and compared to 8 women with the late onset form of 21-hydroxylase deficiency and 23 women with idiopathic hirsutism. Normal 21-DF values for women were 6.9 +- 3.6 ng/dl and for men 9.71 +- 2.73 ng/dl. Newborn children (age: 3-10 days) had a value of 8.3 +- 4.8 ng/dl. During the menstrual cycle the 21-DF values did not change. The baseline and post-stimulated concentrations of hormone were similar in controls and women with hirsutism but significantly higher in women with the late onset form of 21-hydroxylase deficiency. In the congenital form of 21-hydroxylase deficiency, 21-DF values (baseline) were high. In general, the 21-DF and 17-OH-P values have shown parallel changes. However, one case of 21-hydroxylase deficiency with elevated 21-DF but normal 17-OH-P was observed. The use of 21-DF for the diagnosis of 21-hydroxylase deficiency is suggested.

  17. Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency.

    Science.gov (United States)

    Tricarico, Paola Maura; Piscianz, Elisa; Monasta, Lorenzo; Kleiner, Giulio; Crovella, Sergio; Marcuzzi, Annalisa

    2015-08-01

    Mevalonate kinase deficiency is a rare disease whose worst manifestation, characterised by severe neurologic impairment, is called mevalonic aciduria. The progressive neuronal loss associated to cell death can be studied in vitro with a simplified model based on a biochemical block of the mevalonate pathway and a subsequent inflammatory trigger. The aim of this study was to evaluate the effect of the mevalonate blocking on glial cells (BV-2) and the following effects on neuronal cells (SH-SY5Y) when the two populations were cultured together. To better understand the cross-talk between glial and neuronal cells, as it happens in vivo, BV-2 and SH-SY5Y were co-cultured in different experimental settings (alone, transwell, direct contact); the effect of mevalonate pathway biochemical block by Lovastatin, followed by LPS inflammatory trigger, were evaluated by analysing programmed cell death and mitochondrial membrane potential, cytokines' release and cells' morphology modifications. In this experimental condition, glial cells underwent an evident activation, confirmed by elevated pro-inflammatory cytokines release, typical of these disorders, and a modification in morphology. Moreover, the activation induced an increase in apoptosis. When glial cells were co-cultured with neurons, their activation caused an increase of programmed cell death also in neuronal cells, but only if the two populations were cultured in direct contact. Our findings, being aware of the limitations related to the cell models used, represent a preliminary step towards understanding the pathological and neuroinflammatory mechanisms occurring in mevalonate kinase diseases. Contact co-culture between neuronal and microglial cells seems to be a good model to study mevalonic aciduria in vitro, and to contribute to the identification of potential drugs able to block microglial activation for this orphan disease. In fact, in such a pathological condition, we demonstrated that microglial cells are

  18. The predictive factors of low serum 25-hydroxyvitamin D and vitamin D deficiency in patients with systemic lupus erythematosus.

    Science.gov (United States)

    Sumethkul, Kittiwan; Boonyaratavej, Smonporn; Kitumnuaypong, Tasanee; Angthararuk, Sungchai; Cheewasat, Patcharin; Manadee, Naruimon; Sumethkul, Vasant

    2013-06-01

    Vitamin D is a steroid hormone with pleiotropic effects. The association between serum 25-hydroxyvitamin D level [25(OH) D] and lupus nephritis are not clearly known. We aim to determine serum 25(OH) D levels in patients with inactive SLE, active SLE without lupus nephritis (LN) and active SLE with LN and to identify clinical predictor of vitamin D deficiency. One hundred and eight SLE patients were included. Patients were classified as Group (Gr) 1, 2 and 3 if they had SLE disease activity index (SLEDAI) vitamin D insufficiency and 29.6 % had vitamin D deficiency. Mean 25(OH) D in each groups was 28.3 (8.0), 26.7 (9.5) and 19.9 (7.6) ng/ml (p Vitamin D deficiency was found in 11.1, 22.2 and 55.6 % of Gr1, 2 and 3. Linear regression analysis found that 25(OH) D was significantly correlated with serum albumin (r = 0.28, p = 0.004), inversely correlated with SLEDAI (r = -0.22, p = 0.03) and urinary protein creatinine index (UPCI) (r = -0.28, p = 0.005), but not with sun exposure score, body mass index and estimated GFR. Only UPCI was significantly inversely correlated with 25(OH) D (p = 0.02) from multiple linear regression. LN was a significant predictor of vitamin D deficiency from multivariate logistic regression (OR 5.97; p = 0.006). Vitamin D deficiency and insufficiency was found in 93 and 86 % of LN with proteinuria ≥ and vitamin D level than inactive SLE and active SLE without LN. Hence, nephritis is a significant predictor of vitamin D deficiency in SLE patients.

  19. True deficiency of antioxidant vitamins E and A in dialysis patients. Relationship with clinical patterns of atherosclerosis.

    Science.gov (United States)

    Aguilera, Abelardo; Bajo, M Auxiliadora; del Peso, Gloria; Diez, Juan J; Codoceo, Rosa; Rebollo, Francisco; Mariano, Mario; Selgas, Rafael

    2002-01-01

    , 22 from the normal-value group, and 1 from the high-value group). The group with normal vitamin E/carrier complex contained 21 patients (15 from the group with high vitamin E values, and 6 from the normal-value group). By univariate logistic regression analysis, significant associations between CAS and vitamin E plasma levels, vitamin E/carrier, age, and serum albumin were found. In the multiple logistic regression analysis, we confirmed that vitamin E/carrier complex, age, and serum albumin showed independent associations with CAS, but not with vitamin-only plasma levels. Our results in PD patients show a vitamin/carrier complex disorder that results in elevated vitamin mobilization from pool and target cells. Our results and the findings of other researchers about intracellular vitamin A and E deficiencies may change the traditional concept of hypervitaminosis A and E in uremic patients.

  20. A Turkish Patient With Succinyl-CoA:3-Oxoacid CoA Transferase Deficiency Mimicking Diabetic Ketoacidosis

    Directory of Open Access Journals (Sweden)

    Sahin Erdol MD

    2016-05-01

    Full Text Available Succinyl-CoA:3-oxoacid CoA transferase (SCOT deficiency is an autosomal recessive disorder of ketone body utilization that is clinically characterized with intermittent ketoacidosis crises. We report here the second Turkish case with SCOT deficiency. She experienced 3 ketoacidotic episodes: The first ketoacidotic crisis mimicked diabetic ketoacidosis because of the associated hyperglycemia. Among patients with SCOT deficiency, the blood glucose levels at the first crises were variable, and this case had the highest ever reported blood glucose level. She is a compound heterozygote with 2 novel mutations, c.517A>G (K173E and c.1543A>G (M515V, in exons 5 and 17 of the OXCT1 gene, respectively. In patient’s fibroblasts, SCOT activity was deficient and, by immunoblot analysis, SCOT protein was much reduced. The patient attained normal development and had no permanent ketosis. The accurate diagnosis of SCOT deficiency in this case had a vital impact on the management strategy and outcome.

  1. A distinct pattern of memory and attention deficiency in patients with depression

    Institute of Scientific and Technical Information of China (English)

    LUO Lan-lan; CHEN Xin; CHAI Yan; LI Jin-hong; ZHANG Mian; ZHANG Jian-ning

    2013-01-01

    ,and attention extent,stability and rearrangement deficiency.Even though anti-depressive drugs sufficiently relieve the cardinal presentation of depression,they could not successfully alleviate the accompanying cognitive deficits.This might indicate a distinct pattern of cognitive deficits in patients with depression.

  2. Effect of a 5-mo nutritional intervention on nutritional status and quality of life for patient with 3-hydroxyisobutyryl-coenzyme A hydrolase deficiency: A case report.

    Science.gov (United States)

    Li, Chun-Wei; Yu, Kang; Xu, Yan; Sun, Xia-Yuan; Li, Rong-Rong; Wang, Fang

    2015-01-01

    3-Hydroxy-isobutyryl-coenzyme A (CoA) hydrolase (HBICH) deficiency is a rare cerebral organic aciduria caused by disturbance of valine catabolism that leads to the accumulation of toxic metabolites, methacrylyl-CoA. The major feature exhibited by a patient with HBICH deficiency includes multiple congenital malformations and abnormal neurologic findings. However, the pathophysiology of this disease remains unknown. The major treatment for HBICH deficiency involves a low-protein diet, especially restricting valine, supplemented with micronutrients and carnitine. To our knowledge, only four patients with HBICH deficiency have been reported. These patients were boys and presented with different clinical, biochemical, and genetic features than our patient. In this report, we described what was to our knowledge the first genetically confirmed girl with HBICH deficiency in China. A 5-mo nutritional intervention was given to the patient by a nutritional support team. On this regimen, the patient's symptoms were alleviated and her quality of life was improved.

  3. Deficiency of acyl-CoA: Dihydroxyacetone phosphate acyltransferase in patients with Zellweger (cerebro-hepato-renal) syndrome

    NARCIS (Netherlands)

    Bosch, H. van den; Schutgens, R.B.H.; Romeyn, G.J.; Wanders, R.J.A.; Schrakamp, G.; Heymans, H.S.A.

    1984-01-01

    We have recently reported on plasmalogen deficiency in tissues and fibroblasts from patients with Zellweger syndrome. In this paper we have analyzed the activity of the first enzyme in the pathway leading to plasmalogen biosynthesis, i.e. acyl-CoA: dihydroxyacetone phosphate acyltransferase in liver

  4. Increasing fat in the diet does not improve muscle performance in patients with mitochondrial myopathy due to complex I deficiency

    NARCIS (Netherlands)

    de Meer, K; Roef, MJ; de Klerk, JBC; Bakker, HD; Smit, GPA; Poll-The, BT

    2005-01-01

    Four myopathic patients with complex I deficiency followed diets containing 55 energy per cent (En%) as fat or 25 En% as fat, both for three weeks. Maximal workload and muscle force were not different on either diet. Exercise endurance time, oxygen consumption and lactate levels were also not differ

  5. Triacylglycerol infusion does not improve hyperlactemia in resting patients with mitochondrial myopathy due to complex I deficiency

    NARCIS (Netherlands)

    Roef, MJ; de Meer, K; Reijngoud, DJ; Straver, HWHC; de Barse, M; Kalhan, SC; Berger, R

    2002-01-01

    Background: A high-fat diet has been recommended for correction of biochemical abnormalities and muscle energy state in patients with complex I (NADH dehydrogenase) deficiency (CID). Objective: This study evaluated the effects of intravenous infusion of isoenergetic amounts of triacylglycerol or glu

  6. Prevention of exacerbations in patients with COPD and vitamin D deficiency through vitamin D supplementation (PRECOVID): a study protocol

    NARCIS (Netherlands)

    Rafiq, R.; Aleva, F.E.; Schrumpf, J.A.; Heijdra, Y.F.; Taube, C.; Daniels, J.M.; Lips, P.; Bet, P.M.; Hiemstra, P.S.; Ven, A.J.A.M. van der; Heijer, M. den; Jongh, R.T. de

    2015-01-01

    BACKGROUND: Vitamin D is well known for its function in calcium homeostasis and bone mineralisation, but is increasingly studied for its potential immunomodulatory properties. Vitamin D deficiency is a common problem in patients with COPD. Previous studies have not demonstrated a beneficial effect o

  7. Early growth and development impairments in patients with ganglioside GM3 synthase deficiency.

    Science.gov (United States)

    Wang, H; Wang, A; Wang, D; Bright, A; Sency, V; Zhou, A; Xin, B

    2016-05-01

    Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GSD) causes a complete absence of GM3 and all downstream biosynthetic derivatives. The individuals affected by this disorder manifest severe irritability, intractable seizures and profound intellectual disability. However, we have found that most newborns seem symptom-free for a period of time after birth. In order to further understand the onset of the disease, we investigated the early growth and development of patients with this condition through this study. We compared 37 affected individuals with their normal siblings and revealed that all children with GSD had relatively normal intrauterine growth and development, as their weight, length and head circumference were similar to their normal siblings at birth. However, the disease progresses quickly after birth and causes significant constitutional impairments of growth and development by 6 months of age. Neither breastfeeding nor gastrostomy tube placement made significant difference on growth and development as all groups of patients showed the similar pattern. We conclude that GSD causes significant postnatal growth and developmental impairments and the amount of gangliosides in breast milk and general nutritional intervention do not seem to alter these outcomes.

  8. NKCC1-deficiency results in abnormal proliferation of neural progenitor cells of the lateral ganglionic eminence

    Directory of Open Access Journals (Sweden)

    Ana Cathia Magalhães

    2016-08-01

    Full Text Available The proliferative pool of neural progenitor cells is maintained by exquisitely controlled mechanisms for cell cycle regulation. The Na-K-Cl cotransporter NKCC1 is important for regulating cell volume and the proliferation of different cell types in vitro. NKCC1 is expressed in ventral telencephalon of embryonic brains suggesting a potential role in neural development of this region. The ventral telencephalon is a major source for both interneuron and oligodendrocyte precursor cells. Whether NKCC1 is involved in the proliferation of these cell populations remains unknown. In order to assess this question, we monitored several markers for neural, neuronal, and proliferating cells in wild-type and NKCC1 knockout mouse brains. We found that NKCC1 was expressed in neural progenitor cells from the lateral ganglionic eminence (LGE at E12.5. Mice lacking NKCC1 expression displayed reduced PH3-labeled mitotic cells in the ventricular zone and reduced cell cycle reentry. Accordingly, we found a significant reduction of Sp8-labeled immature interneurons migrating from the dorsal LGE in NKCC1-deficient mice at a later developmental stage. Interestingly, at E14.5, NKCC1 regulated also the formation of Olig2-labeled oligodendrocyte precursor cells. Collectively, these findings show that NKCC1 serves in vivo as a modulator of the cell cycle decision in the developing ventral telencephalon at the early stage of neurogenesis. These results present a novel mechanistic avenue to be considered in the recent proposed involvement of chloride transporters in a number of developmentally related diseases such as epilepsy, autism, and schizophrenia.

  9. Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1.

    Directory of Open Access Journals (Sweden)

    Anna Sandebring

    Full Text Available PTEN-induced novel kinase 1 (PINK1 mutations are associated with autosomal recessive parkinsonism. Previous studies have shown that PINK1 influences both mitochondrial function and morphology although it is not clearly established which of these are primary events and which are secondary. Here, we describe a novel mechanism linking mitochondrial dysfunction and alterations in mitochondrial morphology related to PINK1. Cell lines were generated by stably transducing human dopaminergic M17 cells with lentiviral constructs that increased or knocked down PINK1. As in previous studies, PINK1 deficient cells have lower mitochondrial membrane potential and are more sensitive to the toxic effects of mitochondrial complex I inhibitors. We also show that wild-type PINK1, but not recessive mutant or kinase dead versions, protects against rotenone-induced mitochondrial fragmentation whereas PINK1 deficient cells show lower mitochondrial connectivity. Expression of dynamin-related protein 1 (Drp1 exaggerates PINK1 deficiency phenotypes and Drp1 RNAi rescues them. We also show that Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. Accordingly, the calcineurin inhibitor FK506 blocks both Drp1 dephosphorylation and loss of mitochondrial integrity in PINK1 deficient cells but does not fully rescue mitochondrial membrane potential. We propose that alterations in mitochondrial connectivity in this system are secondary to functional effects on mitochondrial membrane potential.

  10. Regulatory T-cell depletion in the gut caused by integrin β7 deficiency exacerbates DSS colitis by evoking aberrant innate immunity.

    Science.gov (United States)

    Zhang, H L; Zheng, Y J; Pan, Y D; Xie, C; Sun, H; Zhang, Y H; Yuan, M Y; Song, B L; Chen, J F

    2016-03-01

    Integrin α4β7 controls lymphocyte trafficking into the gut and has essential roles in inflammatory bowel disease (IBD). The α4β7-blocking antibody vedolizumab is approved for IBD treatment; however, high dose of vedolizumab aggravates colitis in a small percentage of patients. Herein, we show that integrin β7 deficiency results in colonic regulatory T (Treg) cell depletion and exacerbates dextran sulfate sodium (DSS) colitis by evoking aberrant innate immunity. In DSS-treated β7-deficient mice, the loss of colonic Treg cells induces excessive macrophage infiltration in the colon via upregulation of colonic epithelial intercellular adhesion molecule 1 and increases proinflammatory cytokine expression, thereby exacerbating DSS-induced colitis. Moreover, reconstitution of the colonic Treg cell population in β7-deficient mice suppresses aberrant innate immune response in the colon and attenuates DSS colitis. Thus, integrin α4β7 is essential for suppression of DSS colitis as it regulates the colonic Treg cell population and innate immunity.

  11. Iron deficiency.

    Science.gov (United States)

    Scrimshaw, N S

    1991-10-01

    The world's leading nutritional problem is iron deficiency. 66% of children and women aged 15-44 years in developing countries have it. Further, 10-20% of women of childbearing age in developed countries are anemic. Iron deficiency is identified with often irreversible impairment of a child's learning ability. It is also associated with low capacity for adults to work which reduces productivity. In addition, it impairs the immune system which reduces the body's ability to fight infection. Iron deficiency also lowers the metabolic rate and the body temperature when exposed to cold. Hemoglobin contains nearly 73% of the body's iron. This iron is always being recycled as more red blood cells are made. The rest of the needed iron does important tasks for the body, such as binds to molecules that are reservoirs of oxygen for muscle cells. This iron comes from our diet, especially meat. Even though some plants, such as spinach, are high in iron, the body can only absorb 1.4-7% of the iron in plants whereas it can absorb 20% of the iron in red meat. In many developing countries, the common vegetarian diets contribute to high rates of iron deficiency. Parasitic diseases and abnormal uterine bleeding also promote iron deficiency. Iron therapy in anemic children can often, but not always, improve behavior and cognitive performance. Iron deficiency during pregnancy often contributes to maternal and perinatal mortality. Yet treatment, if given to a child in time, can lead to normal growth and hinder infections. However, excess iron can be damaging. Too much supplemental iron in a malnourished child promotes fatal infections since the excess iron is available for the pathogens use. Many countries do not have an effective system for diagnosing, treating, and preventing iron deficiency. Therefore a concerted international effort is needed to eliminate iron deficiency in the world.

  12. Cholesterol is essential for mitosis progression and its deficiency induces polyploid cell formation.

    Science.gov (United States)

    Fernández, Carlos; Lobo Md, María del Val T; Gómez-Coronado, Diego; Lasunción, Miguel A

    2004-10-15

    As an essential component of mammalian cell membranes, cells require cholesterol for proliferation, which is either obtained from plasma lipoproteins or synthesized intracellularly from acetyl-CoA. In addition to cholesterol, other non-sterol mevalonate derivatives are necessary for DNA synthesis, such as the phosphorylated forms of isopentane, farnesol, geranylgeraniol, and dolichol. The aim of the present study was to elucidate the role of cholesterol in mitosis. For this, human leukemia cells (HL-60) were incubated in a cholesterol-free medium and treated with SKF 104976, which inhibits cholesterol biosynthesis by blocking sterol 14alpha-demethylase, and the expression of relevant cyclins in the different phases of the cell cycle was analyzed by flow cytometry. Prolonged cholesterol starvation induced the inhibition of cytokinesis and the formation of polyploid cells, which were multinucleated and had mitotic aberrations. Supplementing the medium with cholesterol completely abolished these effects, demonstrating they were specifically due to cholesterol deficiency. This is the first evidence that cholesterol is essential for mitosis completion and that, in the absence of cholesterol, the cells fail to undergo cytokinesis, entered G1 phase at higher DNA ploidy (tetraploidy), and then progressed through S (rereplication) into G2, generating polyploid cells.

  13. Relationship between Various Chinese Medicine Types and T-cell Subsets in Patients with Ulcerative Colitis

    Institute of Scientific and Technical Information of China (English)

    常廷民; 李秀敏; 赵习德

    2009-01-01

    Objective:To investigate the relationship between various Chinese medicine(CM) types and T-cell subsets(CD4~+ and CD8~+) in the colonic mucous membranes of patients with ulcerative colitis(UC).Methods: Fifty UC patients were enrolled,after differentiation into four types by CM syndromes,i.e.,the internal heat-damp accumulation type(IHDA),the qi-stagnancy with blood stasis type(QSBS),the Pi(脾)-Shen(肾) yang-deficiency type(PSYD) and the yin-blood deficiency type(YBD).From every patient,3-5 pieces of intest...

  14. The Natural History of Children with Severe Combined Immunodeficiency: Baseline Features of the First Fifty Patients of the Primary Immune Deficiency Treatment Consortium Prospective Study 6901

    Science.gov (United States)

    Dvorak, Christopher C.; Cowan, Morton J.; Logan, Brent R.; Notarangelo, Luigi D.; Griffith, Linda M.; Puck, Jennifer M.; Kohn, Donald B.; Shearer, William T.; O'Reilly, Richard J.; Fleisher, Thomas A.; Pai, Sung-Yun; Hanson, I. Celine; Pulsipher, Michael A.; Fuleihan, Ramsay; Filipovich, Alexandra; Goldman, Frederick; Kapoor, Neena; Small, Trudy; Smith, Angela; Chan, Ka-Wah; Cuvelier, Geoff; Heimall, Jennifer; Knutsen, Alan; Loechelt, Brett; Moore, Theodore; Buckley, Rebecca H.

    2013-01-01

    The Primary Immune Deficiency Treatment Consortium (PIDTC) consists of 33 centers in North America. We hypothesized that the analysis of uniform data on patients with severe combined immunodeficiency (SCID) enrolled in a prospective protocol will identify variables that contribute to optimal outcomes following treatment. We report baseline clinical, immunologic, and genetic features of the first 50 patients enrolled, and the initial therapies administered, reflecting current practice in the diagnosis and treatment of both typical (n = 37) and atypical forms (n = 13) of SCID. From August 2010 to May 2012, patients with suspected SCID underwent evaluation and therapy per local center practices. Diagnostic information was reviewed by the PIDTC eligibility review panel, and hematopoietic cell transplantation (HCT) details were obtained from the Center for International Blood and Marrow Transplant Research. Most patients (92%) had mutations in a known SCID gene. Half of the patients were diagnosed by newborn screening or family history, were younger than those diagnosed by clinical signs (median 15 vs. 181 days; P = <0.0001), and went to HCT at a median of 67 days vs. 214 days of life (P = <0.0001). Most patients (92%) were treated with HCT within 1–2 months of diagnosis. Three patients were treated with gene therapy and 1 with enzyme replacement. The PIDTC plans to enroll over 250 such patients and analyze short and long-term outcomes for factors beneficial or deleterious to survival, clinical outcome, and T- and B-cell reconstitution, and which biomarkers are predictive of these outcomes. PMID:23818196

  15. The effect of cholecalciferol supplementation on vitamin D levels and insulin sensitivity is dose related in vitamin D-deficient HIV-1-infected patients.

    NARCIS (Netherlands)

    Beukel, CJ van den Bout-va; Bos, M.; Oyen, W.J.G.; Hermus, A.R.M.M.; Sweep, F.C.; Tack, C.J.J.; Bosch, M.E.; Burger, D.M.; Koopmans, P.P.; Ven, A.J.A.M. van der

    2008-01-01

    OBJECTIVE: The aim of this study was to explore the effects of cholecalciferol supplementation on vitamin D levels, bone mineral density (BMD), body fat distribution and insulin sensitivity in vitamin D-deficient HIV-1-infected patients. METHODS: Twenty vitamin D-deficient HIV-1-infected patients we

  16. Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with inflammatory bowel disease.

    Science.gov (United States)

    Ozgür, Tuba Turul; Asal, Gülten Türkkani; Cetinkaya, D; Orhan, D; Kiliç, S S; Usta, Y; Ozen, H; Tezcan, Ilhan

    2008-12-01

    Partial or total CD3 chain expression defects including CD3 gamma, epsilon, delta, and zeta chain are among the autosomally inherited SCID presenting with T-B+NK+ phenotype with lymphopenia. The clinical findings are generally severe in all except for CD3 gamma deficiency. Here we present a 10-month-old CD3 gamma deficient boy with IBD. The patient had suffered from intractable diarrhea, recurrent pulmonary infections and oral moniliasis since two months of age. Following the first allogeneic HSCT from his HLA-identical (6/6) sister after a reduced intensity regimen, a second transplantation was performed five months later. On day +19 after second transplantation, the CD3 TCR alpha/beta chain expression increased to 66% with development of full donor chimerism (98.6%). A significant improvement in diarrhea, perianal lesions, and rectal fistula was observed suggesting an improvement in inflammatory bowel disease. The patient died at home on day +50 with a sudden respiratory failure secondary to an undetermined infection. The case was interesting being the first reported case with SCID and inflammatory bowel disease who responded very well to HSCT by full recovery of intractable diarrhea, failure to thrive, laboratory findings, and improvement of fistula formation.

  17. Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells

    Energy Technology Data Exchange (ETDEWEB)

    Kinoshita, Taisuke [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Nagamatsu, Go, E-mail: gonag@sc.itc.keio.ac.jp [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012 (Japan); Kosaka, Takeo [Department of Urology, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Takubo, Keiyo [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Hotta, Akitsu [Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012 (Japan); Department of Reprogramming Science, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto (Japan); Ellis, James [Ontario Human iPS Cell Facility, Molecular Genetics, University of Toronto, Developmental and Stem Cell Biology, SickKids, Toronto, Canada MG1L7 (Canada); Suda, Toshio, E-mail: sudato@sc.itc.keio.ac.jp [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan)

    2011-04-08

    Highlights: {yields} iPS cells were induced with a fluorescence monitoring system. {yields} ATM-deficient tail-tip fibroblasts exhibited quite a low reprogramming efficiency. {yields} iPS cells obtained from ATM-deficient cells had pluripotent cell characteristics. {yields} ATM-deficient iPS cells had abnormal chromosomes, which were accumulated in culture. -- Abstract: During cell division, one of the major features of somatic cell reprogramming by defined factors, cells are potentially exposed to DNA damage. Inactivation of the tumor suppressor gene p53 raised reprogramming efficiency but resulted in an increased number of abnormal chromosomes in established iPS cells. Ataxia-telangiectasia mutated (ATM), which is critical in the cellular response to DNA double-strand breaks, may also play an important role during reprogramming. To clarify the function of ATM in somatic cell reprogramming, we investigated reprogramming in ATM-deficient (ATM-KO) tail-tip fibroblasts (TTFs). Although reprogramming efficiency was greatly reduced in ATM-KO TTFs, ATM-KO iPS cells were successfully generated and showed the same proliferation activity as WT iPS cells. ATM-KO iPS cells had a gene expression profile similar to ES cells and WT iPS cells, and had the capacity to differentiate into all three germ layers. On the other hand, ATM-KO iPS cells accumulated abnormal genome structures upon continuous passages. Even with the abnormal karyotype, ATM-KO iPS cells retained pluripotent cell characteristics for at least 20 passages. These data indicate that ATM does participate in the reprogramming process, although its role is not essential.

  18. Effects of aerobic exercise on ectopic lipids in patients with growth hormone deficiency before and after growth hormone replacement therapy

    OpenAIRE

    2016-01-01

    Growth hormone replacement therapy (GHRT) increases exercise capacity and insulin resistance while it decreases fat mass in growth hormone-deficient patients (GHD). Ectopic lipids (intramyocellular (IMCL) and intrahepatocellular lipids (IHCL) are related to insulin resistance. The effect of GHRT on ectopic lipids is unknown. It is hypothesized that exercise-induced utilization of ectopic lipids is significantly decreased in GHD patients and normalized by GHRT. GHD (4 females, 6 males) and age...

  19. Variants of cognitive deficiency depending on the clinical characteristics of the disease in patients with paranoid schizophrenia

    OpenAIRE

    G. G. Lebedeva; E. R. Isaeva

    2015-01-01

    Pecific aspects of cognitive impairments in patients with paranoid schizophrenia depending on the clinical characteristics of the disease have been studied. One hundred and thirty patients were examined. A clinico-psychological, experimental psychological and statistical methods were used. Three main types of cognitive deficiency with paranoid schizophrenia, associated with the onset, disease duration, and severity of psychiatric symptomology : 1) long-term course of the disease accompanied b...

  20. Vitamin D Deficiency and Depressive Symptomatology in Psychiatric Patients Hospitalized with a Current Depressive Episode: A Factor Analytic Study.

    Directory of Open Access Journals (Sweden)

    Roland von Känel

    Full Text Available Low vitamin D levels have been associated with depressive symptoms in population-based studies and non-clinical samples as well as with clinical depression. This study aimed to examine the association of vitamin D levels with the severity and dimensions of depressive symptoms in hospitalized patients with a current episode of depression taking into account confounding variables.We investigated 380 patients (mean age 47 ± 12 years, 70% women who were consecutively hospitalized with a main diagnosis of an ICD-10 depressive episode. All patients self-rated depressive symptom severity with the Hospital Anxiety and Depression Scale (HADS-D, the Beck Depression Inventory-II (BDI-II, and the Brief Symptom Inventory. A principal component analysis was performed with all 34 items of these questionnaires and serum levels of 25-hydroxyvitamin D3 (25-OH D were measured.Vitamin D deficiency ( 75 nmol/l were present in 55.5%, 31.8% and 12.6%, respectively, of patients. Patients with vitamin D deficiency scored higher on the HADS-D scale and on an anhedonia symptom factor than those with insufficient (p-values ≤ 0.023 or sufficient (p-values ≤ 0.008 vitamin D. Vitamin D deficient patients also scored higher on the BDI-II scale than those with sufficient vitamin D (p = 0.007; BDI-II cognitive/affective symptoms, but not somatic/affective symptoms, were higher in patients with vitamin D deficiency (p = 0.005 and insufficiency (p = 0.041 relative to those with sufficient vitamin D. Effect sizes suggested clinically relevant findings.Low vitamin D levels are frequent in hospitalized patients with a current episode of depression. Especially 25-OH D levels < 50 nmol/l were associated with cognitive/affective depressive symptoms, and anhedonia symptoms in particular.

  1. Mitofusin 2 Deficiency Affects Energy Metabolism and Mitochondrial Biogenesis in MEF Cells.

    Directory of Open Access Journals (Sweden)

    Maria Kawalec

    Full Text Available Mitofusin 2 (Mfn2, mitochondrial outer membrane protein which is involved in rearrangement of these organelles, was first described in pathology of hypertension and diabetes, and more recently much attention is paid to its functions in Charcot-Marie-Tooth type 2A neuropathy (CMT2A. Here, cellular energy metabolism was investigated in mouse embryonic fibroblasts (MEF differing in the presence of the Mfn2 gene; control (MEFwt and with Mfn2 gene depleted MEFMfn2-/-. These two cell lines were compared in terms of various parameters characterizing mitochondrial bioenergetics. Here, we have shown that relative rate of proliferation of MEFMfn2-/- cells versus control fibroblasts depend on serum supplementation of the growth media. Moreover, MEFMfn2-/- cells exhibited significantly increased respiration rate in comparison to MEFwt, regardless of serum supplementation of the medium. This effect was correlated with increased level of mitochondrial markers (TOM20 and NAO as well as mitochondrial transcription factor A (TFAM and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α protein levels and unchanged total ATP content. Interestingly, mitochondrial DNA content in MEFMfn2-/- cells was not reduced. Fundamentally, these results are in contrast to a commonly accepted belief that mitofusin 2 deficiency inevitably results in debilitation of mitochondrial energy metabolism. However, we suggest a balance between negative metabolic consequences of mitofusin 2 deficiency and adaptive processes exemplified by increased level of PGC-1α and TFAM transcription factor which prevent an excessive depletion of mtDNA and severe impairment of cell metabolism.

  2. Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.

    Science.gov (United States)

    Meehan, Cristina Adelia; Cochran, Elaine; Kassai, Andrea; Brown, Rebecca J; Gorden, Phillip

    2016-01-01

    The lipodystrophies represent a class of diseases characterized by leptin deficiency. Leptin deficiency is associated with a severe form of the metabolic syndrome characterized by dyslipidemia, insulin resistance, diabetes, and ovarian dysfunction. Metreleptin is the pharmaceutical derived product that has been approved by the Food and Drug Administration (FDA) to treat the severe metabolic abnormalities of the generalized forms of lipodystrophy. Herein we describe the properties of metreleptin, its use in patients, which includes the administration of the drug and how it may be acquired by medical professionals as well as its safety, tolerability, and properties. Finally, we speculate on future uses and development of metreleptin.

  3. Catch-up growth in early treated patients with growth hormone deficiency. Dutch Growth Hormone Working Group.

    OpenAIRE

    Boersma, B.; Rikken, B.; Wit, J.M.

    1995-01-01

    Catch-up growth of 26 children with growth hormone deficiency during four years of growth hormone treatment, which was started young (< 3 years), was compared with that of 16 children with coeliac disease on a gluten free diet. In children with growth hormone deficiency mean (SD) height SD score increased from -4.3 (1.8) to -1.9 (1.4) and in patients with coeliac disease from -1.8 (0.9) to -0.1 (0.8). Height SD score after four years correlated positively with injection frequency and height S...

  4. Stem Cell Transplant Patients and Fungal Infections

    Science.gov (United States)

    ... Foodborne, Waterborne, and Environmental Diseases Mycotic Diseases Branch Stem Cell Transplant Patients and Fungal Infections Recommend on Facebook ... Mold . Top of Page Preventing fungal infections in stem cell transplant patients Fungi are difficult to avoid because ...

  5. A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation.

    Directory of Open Access Journals (Sweden)

    Lihong Zhao

    2011-05-01

    Full Text Available Sphingolipids, lipids with a common sphingoid base (also termed long chain base backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln and toppler (to, with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydroceramide synthase 1 (CerS1, which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases.

  6. A New Fungal Diterpene Induces VDAC1-dependent Apoptosis in Bax/Bak-deficient Cells.

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    Huang, Li; Han, Junjie; Ben-Hail, Danya; He, Luwei; Li, Baowei; Chen, Ziheng; Wang, Yueying; Yang, Yanlei; Liu, Lei; Zhu, Yushan; Shoshan-Barmatz, Varda; Liu, Hongwei; Chen, Quan

    2015-09-25

    The pro-apoptotic Bax and Bak proteins are considered central to apoptosis, yet apoptosis occurs in their absence. Here, we asked whether the mitochondrial protein VDAC1 mediates apoptosis independently of Bax/Bak. Upon screening a fungal secondary metabolite library for compounds inducing apoptosis in Bax/Bak-deficient mouse embryonic fibroblasts, we identified cyathin-R, a new cyathane diterpenoid compound able to activate apoptosis in the absence of Bax/Bak via promotion of the VDAC1 oligomerization that mediates cytochrome c release. Diphenylamine-2-carboxilic acid, an inhibitor of VDAC1 conductance and oligomerization, inhibited cyathin-R-induced VDAC1 oligomerization and apoptosis. Similarly, Bcl-2 overexpression conferred resistance to cyathin-R-induced apoptosis and VDAC1 oligomerization. Silencing of VDAC1 expression prevented cyathin-R-induced apoptosis. Finally, cyathin-R effectively attenuated tumor growth and induced apoptosis in Bax/Bak-deficient cells implanted into a xenograft mouse model. Hence, this study identified a new compound promoting VDAC1-dependent apoptosis as a potential therapeutic option for cancerous cells lacking or presenting inactivated Bax/Bak.

  7. A New Fungal Diterpene Induces VDAC1-dependent Apoptosis in Bax/Bak-deficient Cells*

    Science.gov (United States)

    Huang, Li; Han, Junjie; Ben-Hail, Danya; He, Luwei; Li, Baowei; Chen, Ziheng; Wang, Yueying; Yang, Yanlei; Liu, Lei; Zhu, Yushan; Shoshan-Barmatz, Varda; Liu, Hongwei; Chen, Quan

    2015-01-01

    The pro-apoptotic Bax and Bak proteins are considered central to apoptosis, yet apoptosis occurs in their absence. Here, we asked whether the mitochondrial protein VDAC1 mediates apoptosis independently of Bax/Bak. Upon screening a fungal secondary metabolite library for compounds inducing apoptosis in Bax/Bak-deficient mouse embryonic fibroblasts, we identified cyathin-R, a new cyathane diterpenoid compound able to activate apoptosis in the absence of Bax/Bak via promotion of the VDAC1 oligomerization that mediates cytochrome c release. Diphenylamine-2-carboxilic acid, an inhibitor of VDAC1 conductance and oligomerization, inhibited cyathin-R-induced VDAC1 oligomerization and apoptosis. Similarly, Bcl-2 overexpression conferred resistance to cyathin-R-induced apoptosis and VDAC1 oligomerization. Silencing of VDAC1 expression prevented cyathin-R-induced apoptosis. Finally, cyathin-R effectively attenuated tumor growth and induced apoptosis in Bax/Bak-deficient cells implanted into a xenograft mouse model. Hence, this study identified a new compound promoting VDAC1-dependent apoptosis as a potential therapeutic option for cancerous cells lacking or presenting inactivated Bax/Bak. PMID:26253170

  8. Enhanced Th17-cell responses render CCR2-deficient mice more susceptible for autoimmune arthritis.

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    Rishi R Rampersad

    Full Text Available CCR2 is considered a proinflammatory mediator in many inflammatory diseases such as rheumatoid arthritis. However, mice lacking CCR2 develop exacerbated collagen-induced arthritis. To explore the underlying mechanism, we investigated whether autoimmune-associated Th17 cells were involved in the pathogenesis of the severe phenotype of autoimmune arthritis. We found that Th17 cells were expanded approximately 3-fold in the draining lymph nodes of immunized CCR2(-/- mice compared to WT controls (p = 0.017, whereas the number of Th1 cells and regulatory T cells are similar between these two groups of mice. Consistently, levels of the Th17 cell cytokine IL-17A and Th17 cell-associated cytokines, IL-6 and IL-1β were approximately 2-6-fold elevated in the serum and 22-28-fold increased in the arthritic joints in CCR2(-/- mice compared to WT mice (p = 0.04, 0.0004, and 0.01 for IL-17, IL-6, and IL-1β, respectively, in the serum and p = 0.009, 0.02, and 0.02 in the joints. Furthermore, type II collagen-specific antibodies were significantly increased, which was accompanied by B cell and neutrophil expansion in CCR2(-/- mice. Finally, treatment with an anti-IL-17A antibody modestly reduced the disease severity in CCR2(-/- mice. Therefore, we conclude that while we detect markedly enhanced Th17-cell responses in collagen-induced arthritis in CCR2-deficient mice and IL-17A blockade does have an ameliorating effect, factors additional to Th17 cells and IL-17A also contribute to the severe autoimmune arthritis seen in CCR2 deficiency. CCR2 may have a protective role in the pathogenesis of autoimmune arthritis. Our data that monocytes were missing from the spleen while remained abundant in the bone marrow and joints of immunized CCR2(-/- mice suggest that there is a potential link between CCR2-expressing monocytes and Th17 cells during autoimmunity.

  9. A novel point mutation in CD18 causing leukocyte adhesion deficiency in a Chinese patient

    Institute of Scientific and Technical Information of China (English)

    LI Li; JIN Ying-ying; CAO Rui-ming; CHEN Tong-xin

    2010-01-01

    Background Leukocyte adhesion deficiency type 1 (LAD-1)is a rare, autosomal recessive inherited immunodeficiency disease characterized by recurrent severe bacterial infection, impaired pus formation, poor wound healing, associated with the mutation in the CD18 gene responsible for the ability of the leucocytes to migrate from the blood stream towards the site of inflammation.Correct and early diagnosis of LAD-1 is vital to the success of treatment and prevention of aggressive infections.The purpose of this study was to collect the clinical findings of the disease and to identify the genetic entity.Methods CD18 expression in the peripheral blood leukocytes from the patient, his parents and normal control was measured with flow cytometry.The entire coding regions of the CD18 gene were screened with direct sequencing genomic DNA.Results CD18 expression level on this patient's leukocyte surface was significantly decreased, with normal level in control group, his father and mother.Gene analysis revealed that this patient had a homozygous c.899A>T missense mutation in exon 8 of CD18 gene, causing the substitution of Asp to Val at the 300 amino acid.His parents were both heterozygous carriers while no such mutation was found in 50 normal controls.Conclusion This study disclosed a novel point mutation Asp 300 Val located in a highly conserved region (HCR) of CD18 and confirmed the heterogeneity of the mutations causing LAD-1, indicating it was quite beneficial to establish correct and early diagnosis in children with severe LAD-1.

  10. COPPER AND MAGNESIUM DEFICIENCIES IN PATIENTS WITH SHORT BOWEL SYNDROME RECEIVING PARENTERAL NUTRITION OR ORAL FEEDING

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    Camila Bitu Moreno BRAGA

    2015-06-01

    Full Text Available Background Patients with short bowel syndrome have significant fluid and electrolytes loss. Objective Evaluate the mineral and electrolyte status in short bowel syndrome patients receiving intermittent parenteral nutrition or oral feeding. Methods Twenty two adults with short bowel syndrome, of whom 11 were parenteral nutrition dependent (PN group, and the 11 remaining had been weaned off parenteral nutrition for at least 1 year and received all nutrients by oral feeding (OF group. The study also included 14 healthy volunteers paired by age and gender (control group. Food ingestion, anthropometry, serum or plasma levels of sodium, potassium, phosphorus, magnesium, calcium, zinc, iron and copper were evaluated. PN group subjects were evaluated before starting a new parenteral nutrition cycle. Results The levels of sodium, potassium, phosphorus, calcium and zinc were similar between the groups. The magnesium value was lower in the PN group (1.0 ± 0.4 mEq /L than other groups. Furthermore, this electrolyte was lower in the OF group (1.4 ± 0.3 mEq /L when compared to the Control group (1.8 ± 0.1 mEq/L. Lower values of copper (69±24 vs 73±26 vs 109±16 µg/dL were documented, respectively, for the PN and OF groups when compared to the control group. Conclusion Hypomagnesemia and hypocupremia are electrolyte disturbances commonly observed in short bowel syndrome. Patients with massive intestinal resection require monitoring and supplementation in order to prevent magnesium and copper deficiencies.

  11. A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia.

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    Derman, Richard; Roman, Eloy; Modiano, Manuel R; Achebe, Maureen M; Thomsen, Lars L; Auerbach, Michael

    2017-03-01

    Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open-label, comparative, multi-center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase ≥2 g/dL from baseline at any time between weeks 1-5. Both non-inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase ≥2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.

  12. Iron deficiency and cardiovascular disease.

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    von Haehling, Stephan; Jankowska, Ewa A; van Veldhuisen, Dirk J; Ponikowski, Piotr; Anker, Stefan D

    2015-11-01

    Iron deficiency affects up to one-third of the world's population, and is particularly common in elderly individuals and those with certain chronic diseases. Iron excess can be detrimental in cardiovascular illness, and research has now also brought anaemia and iron deficiency into the focus of cardiovascular medicine. Data indicate that iron deficiency has detrimental effects in patients with coronary artery disease, heart failure (HF), and pulmonary hypertension, and possibly in patients undergoing cardiac surgery. Around one-third of all patients with HF, and more than one-half of patients with pulmonary hypertension, are affected by iron deficiency. Patients with HF and iron deficiency have shown symptomatic improvements from intravenous iron administration, and some evidence suggests that these improvements occur irrespective of the presence of anaemia. Improved exercise capacity has been demonstrated after iron administration in patients with pulmonary hypertension. However, to avoid iron overload and T-cell activation, it seems that recipients of cardiac transplantations should not be treated with intravenous iron preparations.

  13. CCR7 deficient inflammatory Dendritic Cells are retained in the Central Nervous System

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    Clarkson, Benjamin D.; Walker, Alec; Harris, Melissa G.; Rayasam, Aditya; Hsu, Martin; Sandor, Matyas; Fabry, Zsuzsanna

    2017-01-01

    Dendritic cells (DC) accumulate in the CNS during neuroinflammation, yet, how these cells contribute to CNS antigen drainage is still unknown. We have previously shown that after intracerebral injection, antigen-loaded bone marrow DC migrate to deep cervical lymph nodes where they prime antigen-specific T cells and exacerbate experimental autoimmune encephalomyelitis (EAE) in mice. Here, we report that DC migration from brain parenchyma is dependent upon the chemokine receptor CCR7. During EAE, both wild type and CCR7−/− CD11c-eYFP cells infiltrated into the CNS but cells that lacked CCR7 were retained in brain and spinal cord while wild type DC migrated to cervical lymph nodes. Retention of CCR7-deficient CD11c-eYFP cells in the CNS exacerbated EAE. These data are the first to show that CD11chigh DC use CCR7 for migration out of the CNS, and in the absence of this receptor they remain in the CNS in situ and exacerbate EAE. PMID:28216674

  14. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner.

    Science.gov (United States)

    Ablasser, Andrea; Hemmerling, Inga; Schmid-Burgk, Jonathan L; Behrendt, Rayk; Roers, Axel; Hornung, Veit

    2014-06-15

    Cytosolic detection of DNA is crucial for the initiation of antiviral immunity but can also cause autoimmunity in the context of endogenous nucleic acids being sensed. Mutations in the human 3' repair exonuclease 1 (TREX1) have been linked to the type I IFN-associated autoimmune disease Aicardi-Goutières syndrome. The exact mechanisms driving unabated type I IFN responses in the absence of TREX1 are only partly understood, but it appears likely that accumulation of endogenous DNA species triggers a cell-autonomous immune response by activating a cytosolic DNA receptor. In this article, we demonstrate that knocking out the DNA sensor cyclic GMP-AMP synthase completely abrogates spontaneous induction of IFN-stimulated genes in TREX1-deficient cells. These findings indicate a key role of cyclic GMP-AMP synthase for the initiation of self-DNA-induced autoimmune disorders, thus providing important implications for novel therapeutic approaches.

  15. Impact of vitamin D deficiency on the clinical presentation and prognosis of patients with newly diagnosed multiple myeloma.

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    Ng, Alvin C; Kumar, Shaji K; Rajkumar, S Vincent; Drake, Matthew T

    2009-07-01

    Vitamin D is a fundamental mediator of skeletal metabolism. It also has important nonskeletal actions. We hypothesized that vitamin D deficiency may play an important role in skeletal morbidity and clinical outcomes in MM. We studied 148 newly diagnosed MM patients from January 1, 2004 through December 31, 2008 who had a serum 25-hydroxyvitamin D [25(OH)D] obtained within 14 days of diagnosis. Subjects with vitamin D deficiency [25(OH)D level less than 50 nmol/L (20 ng/mL)] had higher mean values of serum C-reactive protein (CRP) (2.40 mg/L vs. 0.84 mg/L, P = 0.02) and creatinine (1.75 mg/dL vs. 1.24 mg/dL, P = 0.03) and lower serum albumin values (3.12 g/dL vs. 3.39 g/dL, P = 0.003) compared to subjects without vitamin D deficiency. The prevalence of vitamin D deficiency increased in parallel with International Staging System (ISS): 16% of subjects in Stage I, 20% in Stage II, and 37% in Stage III (P = 0.03) were vitamin D deficient. No differences were detected between the two groups in terms of skeletal morbidity. Association of vitamin D deficiency with higher serum CRP, serum creatinine and ISS stage at time of diagnosis suggests that vitamin D deficiency may portend poorer outcomes in subjects with MM. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.

  16. A challenging diagnosis of alpha-1-antitrypsin deficiency: identification of a patient with a novel F/Null phenotype

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    Ringenbach Michael R

    2011-11-01

    Full Text Available Abstract Alpha-1-antitrypsin (A1AT deficiency is a genetic disease characterized by low levels and/or function of A1AT protein. A1AT deficiency can result in the development of COPD, liver disease, and certain skin conditions. The disease can be diagnosed by demonstrating a low level of A1AT protein and genotype screening for S and Z mutations, which are the most common. However, there are many genetic variants in A1AT deficiency, and this screening may miss rarer cases, such as those caused by dysfunctional protein. We identified a patient with a previously unreported F/null phenotype that was missed by routine screening. This case highlights the wide variation in possible mutations, limitations in diagnostics, and the importance of combining clinical suspicion with measurement of protein levels, phenotypic analysis, and in appropriate cases expanded genetic analysis.

  17. Granulomatous skin lesions complicating Varicella infection in a patient with Rothmund-Thomson syndrome and immune deficiency: case report

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    Van Den Oord Joost

    2010-12-01

    Full Text Available Abstract Rothmund-Thomson syndrome (RTS(OMIM 268400 is a rare autosomal recessive genodermatosis characterized by poikiloderma, small stature, skeletal and dental abnormalities, cataract and an increased risk of cancer. It is caused by mutations in RECQL4 at 8q24. Immune deficiency is not described as a classical feature of the disease. Here we report the appearance of granulomatous skin lesions complicating primary Varicella Zoster Virus infection in a toddler with Rothmund Thomson syndrome and immune deficiency. Although granulomatous disorders are sometimes seen after Herpes zoster, they are even more rare after Varicella primary infection. Granulomas have hitherto not been described in Rothmund-Thomson syndrome. With this report we aim to stress the importance of screening for immune deficiency in patients with Rothmund-Thomson syndrome.

  18. Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM.

    Science.gov (United States)

    McCabe, Nuala; Hanna, Conor; Walker, Steven M; Gonda, David; Li, Jie; Wikstrom, Katarina; Savage, Kienan I; Butterworth, Karl T; Chen, Clark; Harkin, D Paul; Prise, Kevin M; Kennedy, Richard D

    2015-06-01

    Ataxia te