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Sample records for deficient patient cells

  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. Iron deficiency in sickle cell anaemia patients in Dar es Salaam ...

    African Journals Online (AJOL)

    Iron deficiency in sickle cell anaemia patients in Dar es Salaam, Tanzania. ... Five milliliter of venous blood was taken from all children for serum Ferritin, serum ... of haemoglobin concentration did not significantly influence the body Iron status ...

  3. Polyclonal Expansion of NKG2C+ NK Cells in TAP-deficient Patients

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    vivien eBeziat

    2015-10-01

    Full Text Available Adaptive natural killer (NK cell responses to human cytomegalovirus (CMV infection are characterized by the expansion of NKG2C+ NK cells expressing self-specific inhibitory killer-cell immunoglobulin-like receptors (KIRs. Here, we set out to study the HLA class I-dependency of such NKG2C+ NK cell expansions. We demonstrate expansion of NKG2C+ NK cells in patients with transporter associated with antigen presentation (TAP-deficiency, whom express less than 10% of normal HLA class I levels. In contrast to normal individuals, expanded NKG2C+ NK cell populations in TAP-deficient patients display a polyclonal KIR-profile and remain hyporesponsive to HLA class I-negative target cells. Nonetheless, agonistic stimulation of NKG2C on NK cells from TAP-deficient patients yielded significant responses in terms of degranulation and cytokine production. Thus, while interactions with self-HLA class I molecules likely shape the KIR-repertoire of expanding NKG2C+ NK cells during adaptive NK cell responses in normal individuals, they are not a prerequisite for NKG2C+ NK cell expansions to occur. Thus, the emergence of NKG2C-responsive adaptive NK cells in TAP-deficient patients may contribute to anti-viral immunity and potentially explain these patients’ low incidence of severe viral infections.

  4. Polyclonal Expansion of NKG2C+ NK Cells in TAP-Deficient Patients

    Science.gov (United States)

    Béziat, Vivien; Sleiman, Marwan; Goodridge, Jodie P.; Kaarbø, Mari; Liu, Lisa L.; Rollag, Halvor; Ljunggren, Hans-Gustaf; Zimmer, Jacques; Malmberg, Karl-Johan

    2015-01-01

    Adaptive natural killer (NK) cell responses to human cytomegalovirus infection are characterized by the expansion of NKG2C+ NK cells expressing self-specific inhibitory killer-cell immunoglobulin-like receptors (KIRs). Here, we set out to study the HLA class I dependency of such NKG2C+ NK cell expansions. We demonstrate the expansion of NKG2C+ NK cells in patients with transporter associated with antigen presentation (TAP) deficiency, who express less than 10% of normal HLA class I levels. In contrast to normal individuals, expanded NKG2C+ NK cell populations in TAP-deficient patients display a polyclonal KIR profile and remain hyporesponsive to HLA class I-negative target cells. Nonetheless, agonistic stimulation of NKG2C on NK cells from TAP-deficient patients yielded significant responses in terms of degranulation and cytokine production. Thus, while interactions with self-HLA class I molecules likely shape the KIR repertoire of expanding NKG2C+ NK cells during adaptive NK cell responses in normal individuals, they are not a prerequisite for NKG2C+ NK cell expansions to occur. The emergence of NKG2C-responsive adaptive NK cells in TAP-deficient patients may contribute to antiviral immunity and potentially explain these patients’ low incidence of severe viral infections. PMID:26500647

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

    DEFF Research Database (Denmark)

    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......-stimulated cell proliferation and a decreased LIF-stimulated induction of the proliferation-promoting factors cyclin D1, JunB, and c-myc. SOCS3 protein was upregulated in diabetic myoblasts, and knockdown of SOCS3 rescued LIF-induced gene expression in diabetic myoblasts, whereas neither STAT1 or STAT3 signaling...... nor proliferation rate was affected. In conclusion, although LIF and LIFR proteins were increased in muscle tissue and myoblasts from diabetic patients, LIF signaling and LIF-stimulated cell proliferation were impaired in diabetic myoblasts, suggesting a novel mechanism by which muscle function...

  6. Deficiencies of Circulating Mucosal-associated Invariant T Cells and Natural Killer T Cells in Patients with Multiple Trauma.

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    Jo, Young Goun; Choi, Hyun Jung; Kim, Jung Chul; Cho, Young Nan; Kang, Jeong Hwa; Jin, Hye Mi; Kee, Seung Jung; Park, Yong Wook

    2017-05-01

    Mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells are known to play important roles in autoimmunity, infectious diseases and cancers. However, little is known about the roles of these invariant T cells in multiple trauma. The purposes of this study were to examine MAIT and NKT cell levels in patients with multiple trauma and to investigate potential relationships between these cell levels and clinical parameters. The study cohort was composed of 14 patients with multiple trauma and 22 non-injured healthy controls (HCs). Circulating MAIT and NKT cell levels in the peripheral blood were measured by flow cytometry. The severity of injury was categorised according to the scoring systems, such as Acute Physiology and Chronic Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II, and Injury Severity Score (ISS). Circulating MAIT and NKT cell numbers were significantly lower in multiple trauma patients than in HCs. Linear regression analysis showed that circulating MAIT cell numbers were significantly correlated with age, APACHE II, SAPS II, ISS category, hemoglobin, and platelet count. NKT cell numbers in the peripheral blood were found to be significantly correlated with APACHE II, SAPS II, and ISS category. This study shows numerical deficiencies of circulating MAIT cells and NKT cells in multiple trauma. In addition, these invariant T cell deficiencies were found to be associated with disease severity. These findings provide important information for predicting the prognosis of multiple trauma. © 2017 The Korean Academy of Medical Sciences.

  7. 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 (

  8. Acquired Senescent T-Cell Phenotype Correlates with Clinical Severity in GATA Binding Protein 2-Deficient Patients

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    Raquel Ruiz-García

    2017-07-01

    Full Text Available GATA binding protein 2 (GATA2 deficiency is a rare disorder of hematopoiesis, lymphatics, and immunity caused by spontaneous or autosomal dominant mutations in the GATA2 gene. Clinical manifestations range from neutropenia, lymphedema, deafness, to severe viral and mycobacterial infections, bone marrow failure, and acute myeloid leukemia. Patients also present with monocytopenia, dendritic cell, B- and natural killer (NK-cell deficiency. We studied the T-cell and NK-cell compartments of four GATA2-deficient patients to assess if changes in these lymphocyte populations could be correlated with clinical phenotype. Patients with more severe clinical complications demonstrated a senescent T-cell phenotype whereas patients with lower clinical score had undetectable changes relative to controls. In contrast, patients’ NK-cells demonstrated an immature/activated phenotype that did not correlate with clinical score, suggesting an intrinsic NK-cell defect. These studies will help us to determine the contribution of T- and NK-cell dysregulation to the clinical phenotype of GATA2 patients, and may help to establish the most accurate therapeutic options for these patients. Asymptomatic patients may be taken into consideration for hematopoietic stem cell transplantation when dysregulation of T-cell and NK-cell compartment is present.

  9. 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

  10. 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.

  11. 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

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

    Science.gov (United States)

    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

  13. A study on cytomorphometric analysis of exfoliative buccal cells in iron deficiency anemic patients

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    J Sumanthi

    2012-01-01

    Full Text Available Aim: The aim was to evaluate the quantitative changes in nuclear diameter (ND, cytoplasmic diameter (CD and nuclear/cytoplasmic ratio (N/C in cytological buccal smears of iron deficiency anemic patients by comparing with normal healthy individuals. Materials and Methods: The study group consisted of 40 healthy individuals and 40 iron deficiency anemic patients who were selected on clinical history, hematological investigations, and confirmed by serum ferritin levels. Exfoliative buccal smears stained with PAP stain were evaluated for cytoplasimic, nuclear diameters, and nuclear/cytoplasmic ratios (N/C using Image Proexpress Version 6.0 image analysis system. All the parameters were statistically analyzed by using unpaired ′t′ test. Results: A significant increase is seen in the average nuclear diameter (ND and N/C ratio of the anemic group when compared to the control group. The average cytoplasmic diameter (CD did not show any statistical difference among the two groups. Conclusion: Oral exfoliative cytological techniques could possibly be a noninvasive alternative diagnostic tool for iron deficiency anemia.

  14. A study on cytomorphometric analysis of exfoliative buccal cells in iron deficiency anemic patients.

    Science.gov (United States)

    Sumanthi, J; Reddy, G Sridhar; Anuradha, C H; Sekhar, P Chandhra; Prasad, L Krishna; Reddy, B V Ramana

    2012-09-01

    The aim was to evaluate the quantitative changes in nuclear diameter (ND), cytoplasmic diameter (CD) and nuclear/cytoplasmic ratio (N/C) in cytological buccal smears of iron deficiency anemic patients by comparing with normal healthy individuals. The study group consisted of 40 healthy individuals and 40 iron deficiency anemic patients who were selected on clinical history, hematological investigations, and confirmed by serum ferritin levels. Exfoliative buccal smears stained with PAP stain were evaluated for cytoplasimic, nuclear diameters, and nuclear/cytoplasmic ratios (N/C) using Image Proexpress Version 6.0 image analysis system. All the parameters were statistically analyzed by using unpaired 't' test. A significant increase is seen in the average nuclear diameter (ND) and N/C ratio of the anemic group when compared to the control group. The average cytoplasmic diameter (CD) did not show any statistical difference among the two groups. Oral exfoliative cytological techniques could possibly be a noninvasive alternative diagnostic tool for iron deficiency anemia.

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

    Science.gov (United States)

    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.

  16. 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.

  17. 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.

  18. Deficiency of mast cells in coronary artery endarterectomy of male patients with type 2 diabetes

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    Zorc Metka

    2011-05-01

    Full Text Available Abstract Background Type 2 diabetes is an important risk factor for the development of coronary artery disease (CAD. Focal or diffuse inflammation is often present in the vessels of patients with CAD. Mast cells are frequently present in the plaques as well as in the inflammatory infiltrates in the atherosclerotic vessel wall. In the study we wanted to examine whether there are differences in the morphology, number and distribution of mast cells and in their ability to modify the atherosclerotic process in coronary arteries (CA in the diabetic vs. the hypertensive population of patients with CAD. Methods Coronary artery endarterectomy specimens were obtained from patients with diabetes or hypertension as the only risk factor for CAD. The specimens were stained with haematoxylin-eosin and Sulphated Alcian Blue for mast cells and with immunofluorescent methods for fibrinogen-fibrin and IgG deposits in the vessel wall. Both morphological and stereological assessments were conducted for mast cells and mononuclear cell infiltrates. Results The histological analysis of the vessel wall of diabetic patients in comparison with hypertensive patients showed a damaged endothelial cells layer and deposits of fibrin-fibrinogen and IgG in the tunica intima and media. The stereological count revealed a diminished numerical density of mast cells and a significantly higher volume density of the mononuclear cells. Mast cells displayed cytoplasmic vacuolization, extracellular extrusion of granule and pyknotic nuclei. Conclusion This preliminary study suggests that the impaired mast cells might be the reason for more extensive inflammatory and immunologic atherosclerotic changes in the CA vessel wall of CAD patients with type 2 diabetes. Trial registration 134/88;C3-0564-381-92

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

    Science.gov (United States)

    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.

  20. Blood dendritic cell levels associated with impaired IL-12 production and T-cell deficiency in patients with kidney disease: implications for post-transplant viral infections.

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    Chen, Ping; Sun, Qianmei; Huang, Yanfei; Atta, Mohamed G; Turban, Sharon; Segev, Dorry L; Marr, Kieren A; Naqvi, Fizza F; Alachkar, Nada; Kraus, Edward S; Womer, Karl L

    2014-10-01

    Reduced pretransplant blood myeloid dendritic cell (mDC) levels are associated with post-transplant BK viremia and cytomegalovirus (CMV) disease after kidney transplantation. To elucidate potential mechanisms by which mDC levels might influence these outcomes, we studied the association of mDC levels with mDC IL-12 production and T-cell level/function. Peripheral blood (PB) was studied in three groups: (i) end stage renal disease patients on hemodialysis (HD; n = 81); (ii) chronic kidney disease stage IV-V patients presenting for kidney transplant evaluation or the day of transplantation (Eval/Tx; n = 323); and (iii) healthy controls (HC; n = 22). Along with a statistically significant reduction in mDC levels, reduced CD8(+) T-cell levels were also demonstrated in the kidney disease groups compared with HC. Reduced PB mDC and monocyte-derived DC (MoDC) IL-12 production was observed after in vitro LPS stimulation in the HD versus HC groups. Finally, ELISpot assays demonstrated less robust CD3(+) INF-γ responses by MoDCs pulsed with CMV pp65 peptide from HD patients compared with HC. PB mDC level deficiency in patients with kidney disease is associated with deficient IL-12 production and T-cell level/function, which may explain the known correlation of CD8(+) T-cell lymphopenia with deficient post-transplant antiviral responses. © 2014 Steunstichting ESOT.

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

    Science.gov (United States)

    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.

  2. Mesangial cells from patients with IgA nephropathy have increased susceptibility to galactose-deficient IgA1.

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    Ebefors, Kerstin; Liu, Peidi; Lassén, Emelie; Elvin, Johannes; Candemark, Emma; Levan, Kristina; Haraldsson, Börje; Nyström, Jenny

    2016-04-05

    IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, affecting close to a million people. Circulating galactose-deficient IgA (gd-IgA), present in patients with IgAN, form immune complex deposits in the glomerular mesangium causing local proliferation and matrix expansion. Intriguing though, individuals having gd-IgA deposits in the kidneys do not necessarily have signs of glomerular disease. Recurrence of IgAN only occurs in less than half of transplanted patients with IgAN, indicating that gd-IgA is not the only factor driving the disease. We hypothesize that, in addition to IgA complexes, patients with IgAN possess a subtype of mesangial cells highly susceptible to gd-IgA induced cell proliferation. To test the hypothesis, we designed a technique to culture primary mesangial cells from renal biopsies obtained from IgAN patients and controls. The cell response to gd-IgA treatment was then measured both on gene and protein level and the proliferation rate of the cells in response to PDGF was investigated. When treated with gd-IgA, mesangial cells from patients with IgAN express and release more PDGF compared to controls. In addition, the mesangial cells from patients with IgAN were more responsive to treatment with PDGF resulting in an increased proliferation rate of the cells compared to control. Mesangial cells cultured from patients with IgAN expressed and released more IL-6 than controls and had a higher expression of matrix genes. Both mesangial cells derived from patients with IgAN and controls increased their expressed TGFβ1 and CCL5 when treated with gd-IgA. We conclude that mesangial cells derived from IgAN patients have a mesangioproliferative phenotype with increased reactivity to IgA and that these cellular intrinsic properties may be important for the development of IgA nephropathy.

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Anemia and hematinic deficiencies in gastric parietal cell antibody-positive and -negative oral mucosal disease patients with microcytosis

    Directory of Open Access Journals (Sweden)

    Hung-Pin Lin

    2017-08-01

    Conclusion: We conclude that GPCA in microcytosis patients' sera may have caused significantly lower mean vitamin B12 level as well as significantly higher mean RDW and serum homocysteine level in our GPCA+/microcytosis patients than in GPCA−/microcytosis patients. Herein, iron deficiency anemia was the most common type of anemia in anemic GPCA+/microcytosis and GPCA−/microcytosis patients.

  6. DNA damage and apoptosis in mononuclear cells from glucose-6-phosphate dehydrogenase-deficient patients (G6PD Aachen variant) after UV irradiation.

    Science.gov (United States)

    Efferth, T; Fabry, U; Osieka, R

    2001-03-01

    Patients affected with X chromosome-linked, hereditary glucose-6-phosphate dehydrogenase (G6PD) deficiency suffer from life-threatening hemolytic crises after intake of certain drugs or foods. G6PD deficiency is associated with low levels of reduced glutathione. We analyzed mononuclear white blood cells (MNC) of three males suffering from the German G6PD Aachen variant, four heterozygote females of this family, one G6PD-deficient male from another family coming from Iran, and six healthy male volunteers with respect to their DNA damage in two different genes (G6PD and T-cell receptor-delta) and their propensity to enter apoptosis after UV illumination (0.08-5.28 J/cm2). As determined by PCR stop assays, there was more UV-induced DNA damage in MNC of G6PD-deficient male patients than in those of healthy subjects. MNC of G6PD-deficient patients showed a higher rate of apoptosis after UV irradiation than MNC of healthy donors. MNC of heterozygote females showed intermediate rates of DNA damage and apoptosis. It is concluded that increased DNA damage may be a result of deficient detoxification of reactive oxygen species by glutathione and may ultimately account for the higher rate of apoptosis in G6PD-deficient MNC.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  9. The use of primaquine in malaria infected patients with red cell glucose-6-phosphate dehydrogenase (G6PD) deficiency in Myanmar.

    Science.gov (United States)

    Myat-Phone-Kyaw; Myint-Oo; Aung-Naing; Aye-Lwin-Htwe

    1994-12-01

    32 subjects with Plasmodium falciparum gametocytes, and 31 cases with Plasmodium vivax infection from two military hospitals (Lashio, Mandalay) were treated with quinine 600 mg three times a day for 7 days followed by primaquine 45 mg single dose for gametocytes and 45 mg weekly x 8 weeks for vivax malaria. Although screening of red cell glucose-6-phosphate dehydrogenase (G6PD) was done prior to primaquine treatment, G6PD deficient subjects were not excluded from the trial. 20 patients hemizygous for mild G6PD deficiency (GdB- variant), 2 patients hemizygous for severe deficiency (Gd-Myanmar variant) completed the trial. No case of acute hemolysis was observed in all 22 patients with two genotypes of red cell G6PD deficiency status. Therefore, a single dose of primaquine 45 mg and/or weekly for 8 weeks is adequate for the treatment of patients with P. falciparum gametocytes and/or P. vivax malaria ignoring these red cell G6PD enzyme deficient variants in Myanmar.

  10. CD4+ T-cell deficiency in HIV patients responding to antiretroviral therapy is associated with increased expression of interferon-stimulated genes in CD4+ T cells.

    Science.gov (United States)

    Fernandez, Sonia; Tanaskovic, Sara; Helbig, Karla; Rajasuriar, Reena; Kramski, Marit; Murray, John M; Beard, Michael; Purcell, Damian; Lewin, Sharon R; Price, Patricia; French, Martyn A

    2011-12-15

    Most patients with human immunodeficiency virus (HIV) who remain CD4(+) T-cell deficient on antiretroviral therapy (ART) exhibit marked immune activation. As CD4(+) T-cell activation may be mediated by microbial translocation or interferon-alpha (IFN-α), we examined these factors in HIV patients with good or poor CD4(+) T-cell recovery on long-term ART. Messenger RNA levels for 3 interferon-stimulated genes were increased in CD4(+) T cells of patients with poor CD4(+) T-cell recovery, whereas levels in patients with good recovery did not differ from those in healthy controls. Poor CD4(+) T-cell recovery was also associated with CD4(+) T-cell expression of markers of activation, senescence, and apoptosis, and with increased serum levels of the lipopolysaccharide receptor and soluble CD14, but these were not significantly correlated with expression of the interferon-stimulated genes. Therefore, CD4(+) T-cell recovery may be adversely affected by the effects of IFN-α, which may be amenable to therapeutic intervention.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  17. Dietary recommendations in patients with deficiency anaemia

    Directory of Open Access Journals (Sweden)

    A. Santoyo-Sánchez

    2015-07-01

    Nutritionists should understand deficiency anaemia, and physicians, particularly general practitioners, should be aware of dietary requirements. In this article, therefore, both health care professionals have come together to briefly explain, with examples, the type of diet that should be recommended to patients with deficiency anaemia.

  18. 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.

  19. Generalized verrucosis in a patient with GATA2 deficiency.

    Science.gov (United States)

    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.

  20. Anemia and hematinic deficiencies in gastric parietal cell antibody-positive and antibody-negative erosive oral lichen planus patients with thyroid antibody positivity

    Directory of Open Access Journals (Sweden)

    Julia Y.-F. Chang

    2016-11-01

    Conclusion: We conclude that serum GPCA is the major factor causing vitamin B12 deficiency, macrocytosis and pernicious anemia in GPCA+/TGA/TMA/EOLP patients. ELOP itself but not TGA/TMA positivity plays a significant role in causing anemia and hematinic deficiencies in GPCA−/TGA/TMA/EOLP patients.

  1. 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.

  2. 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.

  3. Vitamin D deficiency in hemodialysis patients

    Directory of Open Access Journals (Sweden)

    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.

  4. Predictor Variables of Developing Anterior Pituitary Deficiencies in a Group of Paediatric Patients with Central Diabetes Insipidus and Langerhans Cell Histiocytosis.

    Science.gov (United States)

    Vaiani, Elisa; Malossetti, Carmen; Vega, Lina Margarita; Zubizarreta, Pedro; Braier, Jorge; Belgorosky, Alicia

    2017-01-01

    Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder of unknown etiopathogenesis. Central diabetes insipidus (CDI) is the most frequent endocrine manifestation and is a known risk factor for the development of further anterior pituitary hormone deficiencies (APD). However, not all CDI patients develop APD, as observed during prolonged periods of follow-up. To find predictors of developing APD in LCH children with CDI followed in our institution. We retrospectively analysed 44 patients over a median period (quartiles) of 12.3 years (8.79-14.24). Patients were subdivided into group 1 and group 2, according to absence or presence of APD, respectively. The main variables studied were: (1) chronological age (CA) at LCH diagnosis, (2) the primary site of LCH at diagnosis: low risk (LR) and multisystemic risk organs, and (3) the presence of reactivation. Multivariate Cox regression analysis showed that APD was positively associated with CA at LCH diagnosis [relative risk (RR) 1.14, p < 0.01], the LR clinical form (RR 8.6, p < 0.03), and negatively associated with the presence of reactivations (RR 0.3, p < 0.01). Patients with older CA at LCH diagnosis, LR clinical forms, and fewer reactivation episodes might represent a subgroup of paediatric LCH CDI patients with a higher risk of developing APD. © 2016 S. Karger AG, Basel.

  5. [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.

  6. 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...

  7. 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.

  8. Obesity in 21-hydroxylase deficient patients

    OpenAIRE

    Cornean, R.; Hindmarsh, P; Brook, C.

    1998-01-01

    OBJECTIVES—To evaluate the natural history and timing of adiposity rebound (nadir of body mass index (BMI)) in children with congenital adrenal hyperplasia 21-hydroxylase deficiency (CYP21). 
STUDY DESIGN—A retrospective mixed longitudinal study.
METHODS—Height and changes in body composition (BMI; weight (kg)/height2 (m)), triceps and subscapular skinfolds) were analysed in 22(14 girls, eight boys) prepubertal patients with CYP21 for whom continuous anthropometric data were ...

  9. Enteroviral Infection in a Patient with BLNK Adaptor Protein Deficiency.

    Science.gov (United States)

    NaserEddin, Adeeb; Shamriz, Oded; Keller, Baerbel; Alzyoud, Raed M; Unger, Susanne; Fisch, Paul; Prus, Evgenia; Berkun, Yakov; Averbuch, Diana; Shaag, Avraham; Wahadneh, Adel M; Conley, Mary Ellen; Warnatz, Klaus; Elpeleg, Orly; Stepensky, Polina

    2015-05-01

    B-cell linker (BLNK) protein is a non-redundant adaptor molecule in the signaling pathway activated by (pre) B-cell antigen receptor signals. We present two siblings with a homozygous deleterious frameshift mutation in BLNK, resulting in a block of B cell development in the bone marrow at the preB1 to preB2 stage, absence of circulating B cells and agammaglobulinemia. This is the first description of an enteroviral infection associated arthritis and dermatitis in a patient with BLNK deficiency.

  10. 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.

  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. 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.

  13. 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

  14. 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.

  15. 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.

  16. p53 deficiency linked to B cell translocation gene 2 (BTG2) loss enhances metastatic potential by promoting tumor growth in primary and metastatic sites in patient-derived xenograft (PDX) models of triple-negative breast cancer.

    Science.gov (United States)

    Powell, Emily; Shao, Jiansu; Yuan, Yuan; Chen, Hsiang-Chun; Cai, Shirong; Echeverria, Gloria V; Mistry, Nipun; Decker, Keith F; Schlosberg, Christopher; Do, Kim-Anh; Edwards, John R; Liang, Han; Piwnica-Worms, David; Piwnica-Worms, Helen

    2016-01-27

    Despite advances in early diagnosis and treatment of cancer patients, metastasis remains the major cause of mortality. TP53 is one of the most frequently mutated genes in human cancer, and these alterations can occur during the early stages of oncogenesis or as later events as tumors progress to more aggressive forms. Previous studies have suggested that p53 plays a role in cellular pathways that govern metastasis. To investigate how p53 deficiency contributes to late-stage tumor growth and metastasis, we developed paired isogenic patient-derived xenograft (PDX) models of triple-negative breast cancer (TNBC) differing only in p53 status for longitudinal analysis. Patient-derived isogenic human tumor lines differing only in p53 status were implanted into mouse mammary glands. Tumor growth and metastasis were monitored with bioluminescence imaging, and circulating tumor cells (CTCs) were quantified by flow cytometry. RNA-Seq was performed on p53-deficient and p53 wild-type tumors, and functional validation of a lead candidate gene was performed in vivo. Isogenic p53 wild-type and p53-deficient tumors metastasized out of mammary glands and colonized distant sites with similar frequency. However, p53-deficient tumors metastasized earlier than p53 wild-type tumors and grew faster in both primary and metastatic sites as a result of increased proliferation and decreased apoptosis. In addition, greater numbers of CTCs were detected in the blood of mice engrafted with p53-deficient tumors. However, when normalized to tumor mass, the number of CTCs isolated from mice bearing parental and p53-deficient tumors was not significantly different. Gene expression profiling followed by functional validation identified B cell translocation gene 2 (BTG2), a downstream effector of p53, as a negative regulator of tumor growth both at primary and metastatic sites. BTG2 expression status correlated with survival of TNBC patients. Using paired isogenic PDX-derived metastatic TNBC cells

  17. 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...

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. Choline Deficiency Causes Colonic Type II Natural Killer T (NKT) Cell Loss and Alleviates Murine Colitis under Type I NKT Cell Deficiency.

    Science.gov (United States)

    Sagami, Shintaro; Ueno, Yoshitaka; Tanaka, Shinji; Fujita, Akira; Niitsu, Hiroaki; Hayashi, Ryohei; Hyogo, Hideyuki; Hinoi, Takao; Kitadai, Yasuhiko; Chayama, Kazuaki

    2017-01-01

    Serum levels of choline and its derivatives are lower in patients with inflammatory bowel disease (IBD) than in healthy individuals. However, the effect of choline deficiency on the severity of colitis has not been investigated. In the present study, we investigated the role of choline deficiency in dextran sulfate sodium (DSS)-induced colitis in mice. Methionine-choline-deficient (MCD) diet lowered the levels of type II natural killer T (NKT) cells in the colonic lamina propria, peritoneal cavity, and mesenteric lymph nodes, and increased the levels of type II NKT cells in the livers of wild-type B6 mice compared with that in mice fed a control (CTR) diet. The gene expression pattern of the chemokine receptor CXCR6, which promotes NKT cell accumulation, varied between colon and liver in a manner dependent on the changes in the type II NKT cell levels. To examine the role of type II NKT cells in colitis under choline-deficient conditions, we assessed the severity of DSS-induced colitis in type I NKT cell-deficient (Jα18-/-) or type I and type II NKT cell-deficient (CD1d-/-) mice fed the MCD or CTR diets. The MCD diet led to amelioration of inflammation, decreases in interferon (IFN)-γ and interleukin (IL)-4 secretion, and a decrease in the number of IFN-γ and IL-4-producing NKT cells in Jα18-/- mice but not in CD1d-/- mice. Finally, adaptive transfer of lymphocytes with type II NKT cells exacerbated DSS-induced colitis in Jα18-/- mice with MCD diet. These results suggest that choline deficiency causes proinflammatory type II NKT cell loss and alleviates DSS-induced colitis. Thus, inflammation in DSS-induced colitis under choline deficiency is caused by type II NKT cell-dependent mechanisms, including decreased type II NKT cell and proinflammatory cytokine levels.

  3. In HepG2 cells, coexisting carnitine deficiency masks important indicators of marginal biotin deficiency.

    Science.gov (United States)

    Bogusiewicz, Anna; Boysen, Gunnar; Mock, Donald M

    2015-01-01

    A large number of birth defects are related to nutrient deficiencies; concern that biotin deficiency is teratogenic in humans is reasonable. Surprisingly, studies indicate that increased urinary 3-hydroxyisovalerylcarnitine (3HIAc), a previously validated marker of biotin deficiency, is not a valid biomarker in pregnancy. In this study we hypothesized that coexisting carnitine deficiency can prevent the increase in 3HIAc due to biotin deficiency. We used a 2-factor nutrient depletion design to induce isolated and combined biotin and carnitine deficiency in HepG2 cells and then repleted cells with carnitine. To elucidate the metabolic pathogenesis, we quantitated intracellular and extracellular free carnitine, acylcarnitines, and acylcarnitine ratios using liquid chromatography-tandem mass spectrometry. Relative to biotin-sufficient, carnitine-sufficient cells, intracellular acetylcarnitine increased by 90%, propionylcarnitine more than doubled, and 3HIAc increased by >10-fold in biotin-deficient, carnitine-sufficient (BDCS) cells, consistent with a defensive mechanism in which biotin-deficient cells transesterify the acyl-coenzyme A (acyl-CoA) substrates of the biotin-dependent carboxylases to the related acylcarnitines. Likewise, in BDCS cells, the ratio of acetylcarnitine to malonylcarnitine and the ratio of propionylcarnitine to methylmalonylcarnitine both more than tripled, and the ratio of 3HIAc to 3-methylglutarylcarnitine (MGc) increased by >10-fold. In biotin-deficient, carnitine-deficient (BDCD) cells, the 3 substrate-derived acylcarnitines changed little, but the substrate:product ratios were masked to a lesser extent. Moreover, carnitine repletion unmasked biotin deficiency in BDCD cells as shown by increases in acetylcarnitine, propionylcarnitine, and 3HIAc (each increased by >50-fold). Likewise, ratios of acetylcarnitine:malonylcarnitine, propionylcarnitine:methylmalonylcarnitine, and 3HIAc:MGc all increased by >8-fold. Our findings provide strong

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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;  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.

  9. 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...

  10. 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

  11. Iron deficiency anemia and megaloblastic anemia in obese patients.

    Science.gov (United States)

    Arshad, Mahmoud; Jaberian, Sara; Pazouki, Abdolreza; Riazi, Sajedeh; Rangraz, Maryam Aghababa; Mokhber, Somayyeh

    2017-03-01

    The association between obesity and different types of anemia remained uncertain. The present study aimed to assess the relation between obesity parameters and the occurrence of iron deficiency anemia and also megaloblastic anemia among Iranian population. This cross-sectional study was performed on 1252 patients with morbid obesity that randomly selected from all patients referred to Clinic of obesity at Rasoul-e-Akram Hospital in 2014. The morbid obesity was defined according to the guideline as body mass index (BMI) equal to or higher than 40 kg/m2. Various laboratory parameters including serum levels of hemoglobin, iron, ferritin, folic acid, and vitamin B12 were assessed using the standard laboratory techniques. BMI was adversely associated with serum vitamin B12, but not associated with other hematologic parameters. The overall prevalence of iron deficiency anemia was 9.8%. The prevalence of iron deficiency anemia was independent to patients' age and also to body mass index. The prevalence of vitamin B12 deficiency was totally 20.9%. According to the multivariable logistic regression model, no association was revealed between BMI and the occurrence of iron deficiency anemia adjusting gender and age. A similar regression model showed that higher BMI could predict occurrence of vitamin B12 deficiency in morbid obese patients. Although iron deficiency is a common finding among obese patients, vitamin B12 deficiency is more frequent so about one-fifth of these patients suffer vitamin B12 deficiency. In fact, the exacerbation of obesity can result in exacerbation of vitamin B12 deficiency.

  12. 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...

  13. 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.

  14. 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.)

  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. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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,...

  1. 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.

  2. The first report of Japanese patients with asparagine synthetase deficiency.

    Science.gov (United States)

    Yamamoto, Takahiro; Endo, Wakaba; Ohnishi, Hidenori; Kubota, Kazuo; Kawamoto, Norio; Inui, Takehiko; Imamura, Atsushi; Takanashi, Jun-Ichi; Shiina, Masaaki; Saitsu, Hirotomo; Ogata, Kazuhiro; Matsumoto, Naomichi; Haginoya, Kazuhiro; Fukao, Toshiyuki

    2017-03-01

    Asparagine synthetase (ASNS) deficiency was recently discovered as a metabolic disorder of non-essential amino acids, and presents as severe progressive microcephaly, intellectual disorder, dyskinetic quadriplegia, and intractable seizures. Two Japanese children with progressive microcephaly born to unrelated patients were analyzed by whole exome sequencing and novel ASNS mutations were identified. The effects of the ASNS mutations were analyzed by structural evaluation and in silico predictions. We describe the first known Japanese patients with ASNS deficiency. Their clinical manifestations were very similar to reported cases of ASNS deficiency. Progressive microcephaly was noted during the prenatal period in patient 1 but only after birth in patient 2. Both patients had novel ASNS mutations: patient 1 had p.L145S transmitted from his mother and p.L247W which was absent from his mother, while patient 2 carried p.V489D and p.W541Cfs*5, which were transmitted from his mother and father, respectively. Three of the four mutations were predicted to affect protein folding, and in silico analyses suggested that they would be pathogenic. We report the first two Japanese patients with ASNS deficiency. Disease severity appears to vary among patients, as is the case for other non-essential amino acid metabolic disorders. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  3. [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.

  4. 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.

  5. 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

  6. Cytokine secretion and NK cell activity in human ADAM17 deficiency.

    Science.gov (United States)

    Tsukerman, Pinchas; Eisenstein, Eli M; Chavkin, Maor; Schmiedel, Dominik; Wong, Eitan; Werner, Marion; Yaacov, Barak; Averbuch, Diana; Molho-Pessach, Vered; Stepensky, Polina; Kaynan, Noa; Bar-On, Yotam; Seidel, Einat; Yamin, Rachel; Sagi, Irit; Elpeleg, Orly; Mandelboim, Ofer

    2015-12-29

    Genetic deficiencies provide insights into gene function in humans. Here we describe a patient with a very rare genetic deficiency of ADAM17. We show that the patient's PBMCs had impaired cytokine secretion in response to LPS stimulation, correlating with the clinical picture of severe bacteremia from which the patient suffered. ADAM17 was shown to cleave CD16, a major NK killer receptor. Functional analysis of patient's NK cells demonstrated that his NK cells express normal levels of activating receptors and maintain high surface levels of CD16 following mAb stimulation. Activation of individual NK cell receptors showed that the patient's NK cells are more potent when activated directly by CD16, albeit no difference was observed in Antibody Depedent Cytotoxicity (ADCC) assays. Our data suggest that ADAM17 inhibitors currently considered for clinical use to boost CD16 activity should be cautiously applied, as they might have severe side effects resulting from impaired cytokine secretion.

  7. 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

  8. 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

  9. Natural killer cells eradicate galectin-1-deficient glioma in the absence of adaptive immunity.

    Science.gov (United States)

    Baker, Gregory J; Chockley, Peter; Yadav, Viveka Nand; Doherty, Robert; Ritt, Michael; Sivaramakrishnan, Sivaraj; Castro, Maria G; Lowenstein, Pedro R

    2014-09-15

    Natural killer (NK) cells safeguard against early tumor formation by destroying transformed target cells in a process referred to as NK immune surveillance. However, the immune escape mechanisms used by malignant brain tumors to subvert this innate type of immune surveillance remain unclear. Here we show that malignant glioma cells suppress NK immune surveillance by overexpressing the β-galactoside-binding lectin galectin-1. Conversely, galectin-1-deficient glioma cells could be eradicated by host NK cells before the initiation of an antitumor T-cell response. In vitro experiments demonstrated that galectin-1-deficient GL26-Cit glioma cells are ∼3-fold more sensitive to NK-mediated tumor lysis than galectin-1-expressing cells. Our findings suggest that galectin-1 suppression in human glioma could improve patient survival by restoring NK immune surveillance that can eradicate glioma cells. Cancer Res; 74(18); 5079-90. ©2014 AACR. ©2014 American Association for Cancer Research.

  10. 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.

  11. 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

  12. 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...

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

    Directory of Open Access Journals (Sweden)

    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.

  14. [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).

  15. 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.

  16. 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.

  17. 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...

  18. 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

  19. Myosin IIA deficient cells migrate efficiently despite reduced traction forces at cell periphery

    Directory of Open Access Journals (Sweden)

    Melissa H. Jorrisch

    2013-02-01

    Cell motility is a cornerstone of embryogenesis, tissue remodeling and repair, and cancer cell invasion. It is generally thought that migrating cells grab and exert traction force onto the extracellular matrix in order to pull the cell body forward. While previous studies have shown that myosin II deficient cells migrate efficiently, whether these cells exert traction forces during cell migration in the absence of the major contractile machinery is currently unknown. Using an array of micron-sized pillars as a force sensor and shRNA specific to each myosin II isoform (A and B, we analyzed how myosin IIA and IIB individually regulate cell migration and traction force generation. Myosin IIA and IIB localized preferentially to the leading edge where traction force was greatest, and the trailing edge, respectively. When individual myosin II isoforms were depleted by shRNA, myosin IIA deficient cells lost actin stress fibers and focal adhesions, whereas myosin IIB deficient cells maintained similar actin organization and focal adhesions as wild-type cells. Interestingly, myosin IIA deficient cells migrated faster than wild-type or myosin IIB deficient cells on both a rigid surface and a pillar array, yet myosin IIA deficient cells exerted significantly less traction force at the leading edge than wild-type or myosin IIB deficient cells. These results suggest that, in the absence of myosin IIA mediated force-generating machinery, cells move with minimal traction forces at the cell periphery, thus demonstrating the remarkable ability of cells to adapt and migrate.

  20. Myosin IIA deficient cells migrate efficiently despite reduced traction forces at cell periphery.

    Science.gov (United States)

    Jorrisch, Melissa H; Shih, Wenting; Yamada, Soichiro

    2013-04-15

    Cell motility is a cornerstone of embryogenesis, tissue remodeling and repair, and cancer cell invasion. It is generally thought that migrating cells grab and exert traction force onto the extracellular matrix in order to pull the cell body forward. While previous studies have shown that myosin II deficient cells migrate efficiently, whether these cells exert traction forces during cell migration in the absence of the major contractile machinery is currently unknown. Using an array of micron-sized pillars as a force sensor and shRNA specific to each myosin II isoform (A and B), we analyzed how myosin IIA and IIB individually regulate cell migration and traction force generation. Myosin IIA and IIB localized preferentially to the leading edge where traction force was greatest, and the trailing edge, respectively. When individual myosin II isoforms were depleted by shRNA, myosin IIA deficient cells lost actin stress fibers and focal adhesions, whereas myosin IIB deficient cells maintained similar actin organization and focal adhesions as wild-type cells. Interestingly, myosin IIA deficient cells migrated faster than wild-type or myosin IIB deficient cells on both a rigid surface and a pillar array, yet myosin IIA deficient cells exerted significantly less traction force at the leading edge than wild-type or myosin IIB deficient cells. These results suggest that, in the absence of myosin IIA mediated force-generating machinery, cells move with minimal traction forces at the cell periphery, thus demonstrating the remarkable ability of cells to adapt and migrate.

  1. 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.

  2. Generation of Peroxisome-Deficient Somatic Animal Cell Mutants.

    Science.gov (United States)

    Okumoto, Kanji; Fujiki, Yukio

    2017-01-01

    Cell mutants with a genetic defect affecting various cellular phenotypes are widely utilized as a powerful tool in genetic, biochemical, and cell biological research. More than a dozen complementation groups of animal somatic mutant cells defective in peroxisome biogenesis have been successfully isolated in Chinese hamster ovary (CHO) cells and used as a model system reflecting fatal human severe genetic disorders named peroxisome biogenesis disorders (PBD). Isolation and characterization of peroxisome-deficient CHO cell mutants has allowed the identification of PEX genes and the gene products peroxins, which directly leads to the accomplishment of isolation of pathogenic genes responsible for human PBDs, as well as elucidation of their functional roles in peroxisome biogenesis. Here, we describe the procedure to isolate peroxisome-deficient mammalian cell mutants from CHO cells, by making use of an effective, photo-sensitized selection method.

  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. Vitamin D deficiency and insufficiency among patients with prostate cancer.

    Science.gov (United States)

    Trump, Donald L; Chadha, Manpreet K; Sunga, Annette Y; Fakih, Marwan G; Ashraf, Umeer; Silliman, Carrie G; Hollis, Bruce W; Nesline, Mary K; Tian, Lili; Tan, Wei; Johnson, Candace S

    2009-10-01

    To assess the frequency of vitamin D deficiency among men with prostate cancer, as considerable epidemiological, in vitro, in vivo and clinical data support an association between vitamin D deficiency and prostate cancer outcome. The study included 120 ambulatory men with recurrent prostate cancer and 50 with clinically localized prostate cancer who were evaluated and serum samples assayed for 25-OH vitamin D levels. Then 100 controls (both sexes), matched for age and season of serum sample, were chosen from a prospective serum banking protocol. The relationship between age, body mass index, disease stage, Eastern Cooperative Oncology Group performance status, season and previous therapy on vitamin D status were evaluated using univariate and multivariate analyses. The mean 25-OH vitamin D level was 25.9 ng/mL in those with recurrent disease, 27.5 ng/mL in men with clinically localized prostate cancer and 24.5 ng/mL in controls. The frequency of vitamin D deficiency (<20 ng/mL) and insufficiency (20-31 ng/mL) was 40% and 32% in men with recurrent prostate; 28% had vitamin D levels that were normal (32-100 ng/mL). Among men with localized prostate cancer, 18% were deficient, 50% were insufficient and 32% were normal. Among controls, 31% were deficient, 40% were insufficient and 29% were normal. Metastatic disease (P = 0.005) and season of blood sampling (winter/spring; P = 0.01) were associated with vitamin D deficiency in patients with prostate cancer, while age, race, performance status and body mass index were not. Vitamin D deficiency and insufficiency were common among men with prostate cancer and apparently normal controls in the western New York region.

  5. 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。

  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. Sirt1 deficiency attenuates spermatogenesis and germ cell function.

    Directory of Open Access Journals (Sweden)

    Matthew Coussens

    Full Text Available In mammals, Sirt1, a member of the sirtuin family of proteins, functions as a nicotinamide adenine dinucleotide-dependent protein deactylase, and has important physiological roles, including the regulation of glucose metabolism, cell survival, and mitochondrial respiration. The initial investigations of Sirt1 deficient mice have revealed a phenotype that includes a reduced lifespan, small size, and an increased frequency of abnormal sperm. We have now performed a detailed analysis of the molecular and functional effects of Sirt1 deficiency in the germ line of Sirt1 knock-out (-/- mice. We find that Sirt1 deficiency markedly attenuates spermatogenesis, but not oogenesis. Numbers of mature sperm and spermatogenic precursors, as early as d15.5 of development, are significantly reduced ( approximately 2-10-fold less; Pdeficiency did not effect the efficiency oocyte production following superovulation of female mice. Furthermore, the proportion of mature sperm with elevated DNA damage ( approximately 7.5% of total epididymal sperm; P = 0.02 was significantly increased in adult Sirt1-/- males. Analysis of global gene expression by microarray analysis in Sirt1 deficient testis revealed dysregulated expression of 85 genes, which were enriched (P<0.05 for genes involved in spermatogenesis and protein sumoylation. To assess the function of Sirt1 deficient germ cells, we compared the efficiency of generating embryos and viable offspring in in vitro fertilization (IVF experiments using gametes from Sirt1-/- and sibling Sirt1+/- mice. While viable animals were derived in both Sirt1-/- X wild type and Sirt1-/- X Sirt1-/- crosses, the efficiency of producing both 2-cell zygotes and viable offspring was diminished when IVF was performed with Sirt1-/- sperm and/or oocytes. Together, these data support an important role for Sirt1 in spermatogenesis, including spermatogenic stem cells, as well as germ cell

  8. 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

  9. 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.

  10. 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.

  11. 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.).

  12. 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.

  13. 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.

  14. Review of succinate dehydrogenase-deficient renal cell carcinoma with focus on clinical and pathobiological aspects

    Directory of Open Access Journals (Sweden)

    Naoto Kuroda

    2016-05-01

    Full Text Available Succinate dehydrogenase (SDH-deficient renal cell carcinoma (RCC was first identified in 2004 and has been integrated into the 2016 WHO classification of RCC. Succinate dehydrogenase (SDH is an enzyme complex composed of four protein subunits (SDHA, SDHB, SDHC and SDHD. The tumor which presents this enzyme mutation accounts for 0.05 to 0.2% of all renal carcinomas. Multiple tumors may occur in approximately 30% of affected patients. SDHB-deficient RCC is the most frequent, and the tumor histologically consists of cuboidal cells with eosinophilic cytoplasm, vacuolization, flocculent intracytoplasmic inclusion and indistinct cell borders. Ultrastructurally, the tumor contains abundant mitochondria. Immunohistochemically, tumor cells are positive for SDHA, but negative for SDHB in SDHB-, SDHC- and SDHD-deficient RCCs. However, SDHA-deficient RCC shows negativity for both SDHA and SDHB. In molecular genetic analyses, a germline mutation in the SDHB , SDHC or SDHD gene (in keeping with most patients having germline mutations in an SDH gene has been identified in patients with or without a family history of renal tumors, paraganglioma/pheochromocytoma or gastrointestinal stromal tumor. While most tumors are low grade, some tumors may behave in an aggressive fashion, particularly if they are high nuclear grade, and have coagulative necrosis or sarcomatoid differentiation.

  15. 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

  16. 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

  17. 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...

  18. Eosinophilic gastroenteritis in a patient with Bruton's tyrosine kinase deficiency.

    Science.gov (United States)

    Yamazaki, Susumu; Ohtsuka, Yoshikazu; Yokokura, Tomoaki; Yokota, Rena; Honjo, Asuka; Inage, Eisuke; Baba, Yosuke; Mori, Mari; Suzuki, Ryuyo; Iwata, Tsutomu; Shimizu, Toshiaki

    2016-05-01

    Eosinophilic gastrointestinal diseases (EGID) are relatively rare diseases characterized by eosinophilic infiltration of the gastrointestinal tract resulting in various gastrointestinal symptoms. EGID are often caused by allergic reactions or systemic eosinophilic disorders, but their comorbidity with Bruton's tyrosine kinase (BTK) deficiency has not been previously documented. Here, we report a case of eosinophilic gastroenteritis (EG) in a patient with BTK deficiency. Despite adequate replacement immunoglobulin (Ig) therapy, trough serum IgG was not maintained. To identify the underlying cause of the low trough level and chronic diarrhea, the intestine was investigated on endoscopy. We also screened for the variable number of tandem repeat polymorphism in FCGRT. Genetic analysis could not explain the low trough IgG, but endoscopy indicated eosinophilic enterocolitis. EG may be an important differential diagnosis when primary immunodeficiency patients have chronic diarrhea or continued low serum IgG. © 2016 Japan Pediatric Society.

  19. 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....

  20. Testosterone deficiency in dialysis patients: Difference between dialysis techniques.

    Science.gov (United States)

    Cigarrán, Secundino; Coronel, Francisco; Florit, Enrique; Calviño, Jesús; Villa, Juan; Gonzalez Tabares, Lourdes; Herrero, José Antonio; Carrero, Juan Jesús

    Testosterone deficiency is a prevalent condition in male patients with chronic kidney disease. However, it is not known whether the type of renal replacement therapy has an impact on testosterone deficiency that accompanies loss of renal function. The cross-sectional study enrolled 79 prevalent male patients on dialysis; 43 on haemodialysis (HD) and 36 on peritoneal dialysis (PD). The median age was 69 years and 31.6% were diabetics. Endogenous testosterone levels were measured by immunoluminescence assay (normal range 3-10.5ng/ml), while nutritional/inflammatory markers, bone and mineral metabolism markers, anaemia, type of dialysis technique and time on dialysis were also assessed. Body composition was evaluated by bioimpedance vector analysis and bioimpedance spectroscopy. Testosterone deficiency was defined as levels below 3ng/ml. Mean testosterone levels were 8.81±6.61ng/ml. Testosterone deficiency affected 39.5% of HD patients and only 5.6% of PD patients. In the univariate analysis, testosterone levels were directly correlated with type of dialysis technique (HD) (Rho Spearman 0.366; P<.001) and time on dialysis (Rho -0.412; P=.036) and only with the HD technique in the multivariate analysis. No other significant correlations were found. Circulating testosterone levels in men on dialysis were independently associated with HD technique. It can be concluded that a new factor -namely the dialysis technique- may be associated with falling testosterone levels and the associated loss of muscle mass and inflammation. Further studies are needed to establish whether the dialysis technique itself triggers testosterone elimination. Copyright © 2017 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  1. 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.

  2. 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.

  3. In HepG2 Cells, Coexisting Carnitine Deficiency Masks Important Indicators of Marginal Biotin Deficiency123

    Science.gov (United States)

    Bogusiewicz, Anna; Boysen, Gunnar; Mock, Donald M

    2015-01-01

    Background: A large number of birth defects are related to nutrient deficiencies; concern that biotin deficiency is teratogenic in humans is reasonable. Surprisingly, studies indicate that increased urinary 3-hydroxyisovalerylcarnitine (3HIAc), a previously validated marker of biotin deficiency, is not a valid biomarker in pregnancy. Objective: In this study we hypothesized that coexisting carnitine deficiency can prevent the increase in 3HIAc due to biotin deficiency. Methods: We used a 2-factor nutrient depletion design to induce isolated and combined biotin and carnitine deficiency in HepG2 cells and then repleted cells with carnitine. To elucidate the metabolic pathogenesis, we quantitated intracellular and extracellular free carnitine, acylcarnitines, and acylcarnitine ratios using liquid chromatography–tandem mass spectrometry. Results: Relative to biotin-sufficient, carnitine-sufficient cells, intracellular acetylcarnitine increased by 90%, propionylcarnitine more than doubled, and 3HIAc increased by >10-fold in biotin-deficient, carnitine-sufficient (BDCS) cells, consistent with a defensive mechanism in which biotin-deficient cells transesterify the acyl-coenzyme A (acyl-CoA) substrates of the biotin-dependent carboxylases to the related acylcarnitines. Likewise, in BDCS cells, the ratio of acetylcarnitine to malonylcarnitine and the ratio of propionylcarnitine to methylmalonylcarnitine both more than tripled, and the ratio of 3HIAc to 3-methylglutarylcarnitine (MGc) increased by >10-fold. In biotin-deficient, carnitine-deficient (BDCD) cells, the 3 substrate-derived acylcarnitines changed little, but the substrate:product ratios were masked to a lesser extent. Moreover, carnitine repletion unmasked biotin deficiency in BDCD cells as shown by increases in acetylcarnitine, propionylcarnitine, and 3HIAc (each increased by >50-fold). Likewise, ratios of acetylcarnitine:malonylcarnitine, propionylcarnitine:methylmalonylcarnitine, and 3HIAc:MGc all increased

  4. Examining the Association between Vitamin B12 Deficiency and Dementia in High-Risk Hospitalized Patients.

    Science.gov (United States)

    Siswanto, O; Smeall, K; Watson, T; Donnelly-Vanderloo, M; O'Connor, C; Foley, N; Madill, J

    2015-12-01

    To explore the association between vitamin B12 deficiency and dementia in patients at high risk for vitamin B12 deficiency. Chart review. Emergency, critical care/ trauma, neurology, medicine, and rehabilitation units of two hospitals in Southwestern Ontario, Canada. Adult patients (n = 666) admitted from 2010 to 2012. Data collection included: reason for admission, gender, age, clinical signs and symptoms of B12 deficiency, serum B12 concentration, and B12 supplementation. Patients with dementia were identified based on their medication profile and medical history. Vitamin B12 deficiency (pmol/L) was defined as serum B12 concentration 220. Comparisons between B12-deficient patients with and without dementia were examined using parametric and non-parametric tests. Serum B12 values were available for 60% (399/666) of the patients, of whom 4% (16/399) were B12-deficient and 14% (57/399) were marginally deficient. Patients with dementia were not more likely to be B12-deficient or marginally deficient [21% (26/121)] compared to those with no dementia [17% (47/278), p=0.27)]. Based on documentation, 34% (25/73) of the B12-deficient and marginally-deficient patients did not receive B12 supplementation, of whom 40% (10/25) had dementia. In this sample of patients, there was no association between B12 deficiency and dementia. However, appropriate B12 screening protocols are necessary for high risk patient to identify deficiency and then receive B12 supplementation as needed.

  5. Apoptosis and signalling in acid sphingomyelinase deficient cells

    Directory of Open Access Journals (Sweden)

    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.

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. Leukocyte adhesion deficiency type III: clinical features and treatment with stem cell transplantation.

    Science.gov (United States)

    Stepensky, Polina Y; Wolach, Baruch; Gavrieli, Ronit; Rousso, Sharon; Ben Ami, Tal; Goldman, Vladimir; Rozovsky, Katya; Hanna, Suhair; Etzioni, Amos; Weintraub, Michael

    2015-05-01

    Leukocyte adhesion deficiency type III (LADIII) is an autosomal recessive disorder that presents with a severe leukocyte adhesion defect and a Glanzmann-type thrombocytopathy. Hematopoietic stem cell transplantation (HSCT)--the only definitive treatment for LADIII--appears to have a high rate of complications. In this study, we describe a new group of patients with LADIII, highlighting further clinical and immunologic aspects of this disease, and reevaluating the effectiveness of HSCT for its treatment. The patients had clinical and laboratory findings consistent with LADIII. Molecular analysis confirmed the presence of a mutation in the kindlin-3 gene. HSCT was carried out in 3 patients and was successful in 2. The diagnosis of LADIII should be considered in all patients who present with recurrent infections and a bleeding diathesis, regardless of the leukocyte count. LADIII is a primary immune deficiency, which can be successfully corrected by bone marrow transplantation if applied early in the course of the disease using appropriate conditioning.

  14. 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

  15. Anesthetic management of patients with ornithine transcarbamylase deficiency.

    Science.gov (United States)

    Schmidt, Joachim; Kroeber, Stefanie; Irouschek, Andrea; Birkholz, Torsten; Schroth, Michael; Albrecht, Sven

    2006-03-01

    Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of the urea cycle. Several specific factors require care during anesthesia in patients with this condition to avoid metabolic decompensation with acute hyperammonemia and encephalopathy. We report monozygous twins with severe neonatal-onset OTCD undergoing general anesthesia twice each, with midazolam, s-ketamine, fentanyl and isoflurane in combination with surgical field infiltration with ropivacaine. Alternative pathway medication and high-caloric diet with 10% glucose solutions were continuously administered during the perioperative course. Both children were extubated within 10 min of the final suture, and their neurological state remained unchanged. Perioperatively, blood ammonia levels remained within the normal range.

  16. 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

  17. Characterization of an adenosine deaminase-deficient human histiocytic lymphoma cell line (DHL-9) and selection of mutants deficient in adenosir kinase and deoxycytidine kinase.

    Science.gov (United States)

    Kubota, M; Kamatani, N; Daddona, P E; Carson, D A

    1983-06-01

    The association of adenosine deaminase (ADA) deficiency with immunodeficiency disease has emphasized the importance of this purine metabolic enzyme for human lymphocyte growth and function. This report describes the natural occurrence of ADA deficiency in a human histiocytic lymphoma cell line, DHL-9. The minimal ADA activity in DHL-9 extracts, 0.028 nmol/min/mg protein, was less than 50% of the activity in two B-lymphoblastoid cell lines from ADA-deficient patients and was resistant to the potent ADA inhibitor deoxycoformycin. A sensitive radioimmunoassay failed to detect immunoreactive ADA in DHL-9 cells. Moreover, in DHL-9 cells, deoxycoformycin did not augment either the growth-inhibitory effects of adenosine and deoxyadenosine or the accumulation of deoxyadenosine triphosphate from deoxyadenosine. When compared to six other human hematopoietic cell lines, DHL-9 had 5.6-fold-higher levels of adenosylhomocysteinase. Chromosome 20, which bears the structural gene for ADA and adenosylhomocysteinase, was diploid and had a normal Giemsa banding pattern. The parental DHL-9 cell line was used for the selection and cloning of secondary mutants deficient in deoxycytidine kinase and adenosine kinase.

  18. 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......: group 1, 50% (n = 15). Fecal fat was measured by the method of Van de Kamer the last 2 of 5 d of a 75-g fat diet. Serum fatty acids in the phospholipid fraction were measured by gas-liquid chromatography after separation...... by thin-layer chromatography and expressed as a percentage of total fatty acids. The concentration of linoleic acid in groups 1, 2, 3, and 4 was 21.7%, 19.4%, 16.4%, and 13.4% respectively (P acid in groups 1, 2, 3, and 4 was 0.4%, 0.4%, 0.3% and 0.3%, respectively...

  19. Bone marrow transplantation for CVID-like humoral immune deficiency associated with red cell aplasia.

    Science.gov (United States)

    Sayour, Elias J; Mousallem, Talal; Van Mater, David; Wang, Endi; Martin, Paul; Buckley, Rebecca H; Barfield, Raymond C

    2016-10-01

    Patients with common variable immunodeficiency (CVID) have a higher incidence of autoimmune disease, which may mark the disease onset; however, anemia secondary to pure red cell aplasia is an uncommon presenting feature. Here, we describe a case of CVID-like humoral immune deficiency in a child who initially presented with red cell aplasia and ultimately developed progressive bone marrow failure. Although bone marrow transplantation (BMT) has been associated with high mortality in CVID, our patient was successfully treated with a matched sibling BMT and engrafted with >98% donor chimerism and the development of normal antibody titers to diphtheria and tetanus toxoids. © 2016 Wiley Periodicals, Inc.

  20. Immune deficiency in Ataxia-Telangiectasia: a longitudinal study of 44 patients.

    Science.gov (United States)

    Chopra, C; Davies, G; Taylor, M; Anderson, M; Bainbridge, S; Tighe, P; McDermott, E M

    2014-05-01

    Ataxia-Telangiectasia (A-T) is a genetic condition leading to neurological defects and immune deficiency. The nature of the immune deficiency is highly variable, and in some cases causes significant morbidity and mortality due to recurrent sinopulmonary infections. Although the neurological defects in A-T are progressive, the natural history of the immune deficiency in A-T has not been evaluated formally. In this study we analyse the clinical history and immunological data in 44 patients with A-T who attended the National Ataxia-Telangiectasia clinic in Nottingham between 2001 and 2011. Using patient medical records and Nottingham University Hospitals (NUH) National Health Service Trust medical IT systems, data regarding clinical history, use of immunoglobulin replacement therapy, total immunoglobulin levels, specific antibody levels and lymphocyte subset counts were obtained. T cell receptor spectratyping results in some patients were already available and, where possible, repeat blood samples were collected for analysis. This study shows that subtle quantitative changes in certain immunological parameters such as lymphocyte subset counts may occur in patients with A-T over time. However, in general, for the majority of patients the severity of immune deficiency (both clinically and in terms of immunological blood markers) does not seem to deteriorate significantly with time. This finding serves to inform the long-term management of this cohort of patients because, if recurrent respiratory tract infections present later in life, then other contributory factors (e.g. cough/swallowing difficulties, underlying lung disease) should be investigated aggressively. Our findings also offer some form of reassurance for parents of children with A-T, which is otherwise a progressively severely debilitating condition. © 2014 British Society for Immunology.

  1. 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.

  2. 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.

  3. 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

  4. Cytidine-5'-monophosphate-N-acetylneuraminic acid. Asialoglycoprotein sialic acid transferase activity in liver and serum of patients with juvenile hepatic cirrhosis and alpha-1-antitrypsin deficiency.

    Science.gov (United States)

    Kuhlenschmidt, M S; Peters, S P; Pinkard, O D; Glew, R H; Sharp, H

    1976-04-08

    The molecular basis for the accumulation of a substance which displays the immunological reactivity of alpha-1-antitrypsin within vesicles of liver parenchymal cells of individuals with hepatic cirrhosis and serum alpha-1-antitrypsin deficiency remains unclear. We recently reported that serum from a patient with alpha-1-antitrypsin deficiency and hepatic cirrhosis was substantially deficient in sialyltransferease (EC 2.4.99.1) an enzyme which transfers sialic acid from cytidine 5'-monophosphate-N-acetylneuraminic acid to a variety of asialoglycoprotein acceptors. In the present report we have extended these studies to include serum from five additional patients with alpha-1-antitrypsin deficiency and juvenile hepatic cirrhosis as well as a liver specimen obtained at autopsy of one of these patients. We find the sialytransferase activity in serum from six patients with alpha-1-antitrypsin deficiency and hepatic cirrhosis to be 50% of healthy pediatric control values and 30% of pediatric patients with liver disease. However, serum from family members homozygous for alpha-1-antitrypsin deficiency but without hepatic cirrhosis, and serum from patients with a variety of other kinds of liver disease, failed to exhibit the marked sialytransferase deficiency. Similar assays carried out on a homogenate of a liver sample from one patient with alpha-1-antitrypsin deficiency and hepatic cirrhosis indicated that the deficiency of sialyltransferase activity was not demonstrable in liver. Furthermore, a comparative kinetic analysis of serum and liver sialytransferase in normal and afflicted individuals failed to detect differences in substrate affinities which might account for a decrease in functional sialyltransferase capacity in individuals with alpha-1-antitrypsin deficiency and hepatic cirrhosis. These observations suggest that the serum sialyltransferase deficiency in such patients probably arises after chronic and extensive liver disease involving hepatic accumulation of

  5. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers.

    Science.gov (United States)

    Aguilar, Claire; Lenoir, Christelle; Lambert, Nathalie; Bègue, Bernadette; Brousse, Nicole; Canioni, Danielle; Berrebi, Dominique; Roy, Maryline; Gérart, Stéphane; Chapel, Helen; Schwerd, Tobias; Siproudhis, Laurent; Schäppi, Michela; Al-Ahmari, Ali; Mori, Masaaki; Yamaide, Akiko; Galicier, Lionel; Neven, Bénédicte; Routes, John; Uhlig, Holm H; Koletzko, Sibylle; Patel, Smita; Kanegane, Hirokazu; Picard, Capucine; Fischer, Alain; Bensussan, Nadine Cerf; Ruemmele, Frank; Hugot, Jean-Pierre; Latour, Sylvain

    2014-11-01

    Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients

  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. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach.

    Science.gov (United States)

    Stepensky, Polina; Weintraub, Michael; Yanir, Asaf; Revel-Vilk, Shoshana; Krux, Frank; Huck, Kirsten; Linka, Rene M; Shaag, Avraham; Elpeleg, Orly; Borkhardt, Arndt; Resnick, Igor B

    2011-03-01

    Mutations in the IL-2-inducible T-cell kinase gene have recently been shown to cause an autosomal recessive fatal Epstein Barr virus (EBV) associated lymphoproliferation. We report 3 cases from a single family who presented with EBV-positive B-cell proliferation diagnosed as Hodgkin's lymphoma. Single nucleotide polymorphism array-based genome-wide linkage analysis revealed IL-2-inducible T-cell kinase as a candidate gene for this disorder. All 3 patients harbored the same novel homozygous nonsense mutation C1764G which causes a premature stop-codon in the kinase domain. All cases were initially treated with chemotherapy. One patient remains in durable remission, the second patient subsequently developed severe hemophagocytic lymphohistiocytosis with multi-organ failure and died, and the third patient underwent a successful allogeneic bone marrow transplantation. IL-2-inducible T-cell kinase deficiency underlies a new primary immune deficiency which may account for part of the spectrum of Epstein Barr virus related lymphoproliferative disorders which can be successfully corrected by bone marrow transplantation.

  13. Methylthioadenosine phosphorylase gene is silenced by promoter hypermethylation in human lymphoma cell line DHL-9: another mechanism of enzyme deficiency.

    Science.gov (United States)

    Ishii, Masaaki; Nakazawa, Keiko; Wada, Hideo; Nishioka, Junji; Nakatani, Kaname; Yamada, Yasuaki; Kamihira, Shimeru; Kusunoki, Masato; Nobori, Tsutomu

    2005-04-01

    Methylthioadenosine phosphorylase (MTAP) involved in the metabolism of purine and polyamine has been known to be deficient in a variety of tumors. Although this enzyme deficiency was reportedly caused by partial or total deletion of the MTAP gene, human MTAP-deficient lymphoma cell line DHL-9 has the intact MTAP gene. In order to determine the mechanism of MTAP deficiency in DHL-9, we carried out methylation-specific PCR analysis of sodium bisulfite-treated genomic DNA followed by DNA sequence analysis. Following incubation with various concentrations of 5-Aza-2'-deoxycytidine, DHL-9 cells were subjected to RT-PCR and an immunoblot analysis for MTAP expression. MTAP promoter in DHL-9 cells was methylated at cytosine of all CpG dinucleotides analyzed. Moreover, 5-Aza-2'-deoxycytidine treatment induced DHL-9 cells to express MTAP mRNA and protein. Taken together, MTAP deficiency in DHL-9 was caused by transcriptional silencing due to promoter methylation. Promoter methylation of the MTAP gene was also found in DNA samples from adult T-cell leukemia patients. These results indicated that promoter hypermethylation is another mechanism of MTAP deficiency in human malignancy. Thus, immunological diagnostics will be needed for an accurate evaluation of MTAP expression at the protein level.

  14. 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.

  15. 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.

  16. 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

  17. 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.

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

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    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

  19. 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.

  20. [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.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Early biochemical and hematological response to intramuscular cyanocobalamin therapy in vitamin B(12)-deficient patients.

    Science.gov (United States)

    Mansoor, M Azam; Stea, Tonje Holte; Schneede, Jørn; Reine, Andreas

    2013-01-01

    Data on early biochemical and hematological responses to cobalamin therapy in vitamin B12-deficient patients are scarce. Therefore, we investigated whether cobalamin injections would include prompt biochemical and hematological responses in vitamin B12-deficient patients. Seven female patients (mean age: 69.4 years, range: 61-78) with a mean serum cobalamin level of 104 ± 38 pmol/l mean ± SD and 7 male patients (mean age: 67.0 years, range: 53-78) with a mean serum cobalamin level of 84 ± 40 (±SD) participated in the study. They were administered 1 mg i.m. cyanocobalamin per week for 3 weeks. Blood samples were collected before and 1, 3, 7, 14 and 21 days after cobalamin injection. The concentrations of plasma aminothiols and serum methylmalonic acid (MMA) were measured with high-performance liquid chromatography and gas chromatography/mass spectrometry, respectively, and hematological parameters were determined with a hematological analyzer. Already 1 day after intramuscular Cobalamin injections, the concentrations of serum vitamin B12 and plasma total cysteine were significantly increased while the concentrations of serum folate, plasma total homocysteine and serum MMA were decreased. Mean cell volume was also significantly decreased first after 14 days of therapy. Intramuscular cobalamin administration causes swift and significant changes in plasma aminothiols, whereas the first change in hematological parameters was detected only after 14 days. Copyright © 2013 S. Karger AG, Basel.

  3. Possible contribution of taurine to distorted glucagon secretion in intra-islet insulin deficiency: a metabolome analysis using a novel α-cell model of insulin-deficient diabetes.

    Directory of Open Access Journals (Sweden)

    Megumi Bessho

    Full Text Available Glycemic instability is a serious problem in patients with insulin-deficient diabetes, and it may be due in part to abnormal endogenous glucagon secretion. However, the intracellular metabolic mechanism(s involved in the aberrant glucagon response under the condition of insulin deficiency has not yet been elucidated. To investigate the metabolic traits that underlie the distortion of glucagon secretion under insulin deficient conditions, we generated an αTC1-6 cell line with stable knockdown of the insulin receptor (IRKD, i.e., an in vitro α-cell model for insulin-deficient diabetes, which exhibits an abnormal glucagon response to glucose. A comprehensive metabolomic analysis of the IRKD αTC1-6 cells (IRKD cells revealed some candidate metabolites whose levels differed markedly compared to those in control αTC1-6 cells, but also which could affect the glucagon release in IRKD cells. Of these candidates, taurine was remarkably increased in the IRKD cells and was identified as a stimulator of glucagon in αTC1-6 cells. Taurine also paradoxically exaggerated the glucagon secretion at a high glucose concentration in IRKD cells and islets with IRKD. These results indicate that the metabolic alterations induced by IRKD in α-cells, especially the increase of taurine, may lead to the distorted glucagon response in IRKD cells, suggesting the importance of taurine in the paradoxical glucagon response and the resultant glucose instability in insulin-deficient diabetes.

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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...

  11. Rhoh deficiency reduces peripheral T-cell function and attenuates allogenic transplant rejection

    DEFF Research Database (Denmark)

    Porubsky, Stefan; Wang, Shijun; Kiss, Eva

    2011-01-01

    Rhoh is a hematopoietic system-specific GTPase. Rhoh-deficient T cells have been shown to have a defect in TCR signaling manifested during their thymic development. Our aims were to investigate the phenotype of peripheral Rhoh-deficient T cells and to explore in vivo the potential benefit of Rhoh...

  12. Association between functional iron deficiency and reactive thrombocytosis in hospitalised patients: a case-control study.

    Science.gov (United States)

    Nicola, H; Ho, K M; Cordingley, F

    2016-11-01

    The association of deficiency in total body iron with an increased risk of reactive thrombocytosis is well known, but whether 'functional iron deficiency' is also associated with reactive thrombocytosis is unknown. This retrospective case-control study assessed the relationships between functional iron deficiency, reactive thrombocytosis and risk of thromboembolism. A total of 150 patients with reactive thrombocytosis (platelet count >400 x 10(9)/l) and 343 controls (platelet count thrombocytosis, infection, and an elevated C-reactive protein (CRP) concentration were all significantly more common in patients with functional iron deficiency than in those without functional iron deficiency (all P thrombocytosis (odds ratio 1.66, 95% confidence interval 1.10-2.75; P=0.048). Thromboembolic events occurred in 32 patients (6.6%). This was not significantly associated with functional iron deficiency. Our results suggest that in patients without haematological malignancy or recent chemotherapy there might be a link between functional iron deficiency and reactive thrombocytosis. Whether treating patients with functional iron deficiency with intravenous iron corrects reactive thrombocytosis without inducing infection remains uncertain, but merits further investigation.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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...

  18. 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

  19. 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.

  20. 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

  1. Implications of vitamin D deficiency in lithiasic patient and in general population.

    Science.gov (United States)

    Millán-Rodríguez, F; Gavrilov, P; Gracia-García, S; Angerri-Feu, O; Sánchez-Martín, F M; Villavicencio-Mavrich, H

    2015-05-01

    Vitamin D deficiency causes problems in mineral metabolism but also overall health. In first place a review of the topic was carried out. Then, in order to contextualize it in lithiasic patient, a study on Vitamin D deficiency and its possible relationship with impaired PTH levels is performed. A review of topics such as metabolism, epidemiology and the relationship of vitamin D deficiency with several pathologies was performed. Besides a multivariate analysis and a correlation study between vitamin D and PTH levels was conducted in 100 lithiasic patients. We present a review of Vitamin D metabolism, receptors and functions, as well as about its valuation methodology and the treatment of its deficiency. Lithiasic patients show a higher vitamin D deficiency than general population. Vitamin D deficiency has been significantly associated with increased PTH levels. In addition, there is enough literature showing a relationship between vitamin D deficiency not only with bone disease, but also with multiple diseases. vitamin D levels should be measured in all lithiasic patients, and those with vitamin D deficiency should be treated. Copyright © 2014 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. 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

  3. Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease.

    Science.gov (United States)

    Magalhaes, Joana; Gegg, Matthew E; Migdalska-Richards, Anna; Doherty, Mary K; Whitfield, Phillip D; Schapira, Anthony H V

    2016-08-15

    Glucocerebrosidase (GBA1) gene mutations increase the risk of Parkinson disease (PD). While the cellular mechanisms associating GBA1 mutations and PD are unknown, loss of the glucocerebrosidase enzyme (GCase) activity, inhibition of autophagy and increased α-synuclein levels have been implicated. Here we show that autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase. ALR is a cellular process controlled by mTOR which regenerates functional lysosomes from autolysosomes formed during macroautophagy. A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of GCase deficiency, including primary mouse neurons and the PD patient derived fibroblasts with GBA1 mutations, suggesting that ALR is compromised. Importantly Rab7, a GTPase crucial for endosome-lysosome trafficking and ALR, accumulated in GCase deficient cells, supporting the notion that lysosomal recycling is impaired. Recombinant GCase treatment reversed ALR inhibition and lysosomal dysfunction. Moreover, ALR dysfunction was accompanied by impairment of macroautophagy and chaperone-mediated autophagy, increased levels of total and phosphorylated (S129) monomeric α-synuclein, evidence of amyloid oligomers and increased α-synuclein release. Concurrently, we found increased cholesterol and altered glucosylceramide homeostasis which could compromise ALR. We propose that GCase deficiency in PD inhibits lysosomal recycling. Consequently neurons are unable to maintain the pool of mature and functional lysosomes required for the autophagic clearance of α-synuclein, leading to the accumulation and spread of pathogenic α-synuclein species in the brain. Since GCase deficiency and lysosomal dysfunction occur with ageing and sporadic PD pathology, the decrease in lysosomal reformation may be a common feature in PD. © The Author 2016. Published by Oxford University Press.

  4. 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.

  5. 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.

  6. Successful Interferon–alpha 2b Therapy for Unremitting Warts in a Patient with DOCK8 Deficiency

    Science.gov (United States)

    Al-Zahrani, Daifulah; Raddadi, Ali; Massaad, Michel; Keles, Sevgi; Jabara, Haifa H.

    2014-01-01

    The autosomal recessive form of the Hyper IgE syndrome (AR-HIES) with dedicator of cytokinesis 8 (DOCK8) deficiency is associated with difficult to treat persistent viral skin infections, including papilloma virus infection. Type I interferons play an important role in the defense against viruses. We examined the effect of therapy with IFN–α 2b in an 11-year old boy with DOCK8 deficiency due to a homozygous splice donor site mutation in DOCK8 intron 40. His unremitting warts showed dramatic response to IFN–α 2b therapy. Immunological studies revealed decreased circulating plasmacytoid dendritic cells (pDCs) and profound deficiency of IFN-α production by his peripheral blood mononuclear cells in response to treatment with CpG oligonucleotides. These findings indicate that underlying pDC deficiency and impaired IFN-α production may predispose to chronic viral infections in DOCk8 deficiency. IFN–α 2b therapy maybe useful in controlling recalcitrant viral infections in these patients. PMID:24743019

  7. Successful interferon-alpha 2b therapy for unremitting warts in a patient with DOCK8 deficiency.

    Science.gov (United States)

    Al-Zahrani, Daifulah; Raddadi, Ali; Massaad, Michel; Keles, Sevgi; Jabara, Haifa H; Chatila, Talal A; Geha, Raif

    2014-07-01

    The autosomal recessive form of the Hyper IgE syndrome (AR-HIES) with dedicator of cytokinesis 8 (DOCK8) deficiency is associated with difficult to treat persistent viral skin infections, including papilloma virus infection. Type I interferons play an important role in the defense against viruses. We examined the effect of therapy with IFN-α 2b in an 11-year old boy with DOCK8 deficiency due to a homozygous splice donor site mutation in DOCK8 intron 40. His unremitting warts showed dramatic response to IFN-α 2b therapy. Immunological studies revealed decreased circulating plasmacytoid dendritic cells (pDCs) and profound deficiency of IFN-α production by his peripheral blood mononuclear cells in response to treatment with CpG oligonucleotides. These findings indicate that underlying pDC deficiency and impaired IFN-α production may predispose to chronic viral infections in DOCK8 deficiency. IFN-α 2b therapy maybe useful in controlling recalcitrant viral infections in these patients. Copyright © 2014. Published by Elsevier Inc.

  8. 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.

  9. 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.

  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. 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.

  12. 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.

  13. [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.

  14. 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.

  15. In vitro fertilization as a diagnostic and therapeutic tool in a patient with partial 17,20-desmolase deficiency.

    Science.gov (United States)

    Pellicer, A; Miró, F; Sampaio, M; Gómez, E; Bonilla-Musoles, F M

    1991-05-01

    To present a case with 17,20-desmolase activity deficiency in which in vitro fertilization (IVF) served not only as a therapeutic approach but also as a diagnostic tool for the specificity of the enzymatic deficiency. IVF in the patient under study compared with a control group. All women treated with pure follicle-stimulating hormone (FSH). IVF program at the Instituto Valenciano de Infertilidad. A patient with primary amenorrhea, who was the subject under study, and seven normally cycling control patients undergoing IVF in the same series. IVF, steroidogenesis in vitro of granulosa-luteal cell obtained at ovum pick-up. Oocyte fertilization and embryo cleavage. Serum and follicular fluid (FF) levels of estradiol (E2), progesterone (P), testosterone (T), androstendione (A), 17 alpha-hydroxyprogesterone (17-OHP). In vitro accumulation of E2 and P. Ovulation induction with FSH was successful in achieving follicular development despite low circulating E2. Fertilization and cleavage rates were similar to the control subjects. The patient developed ovarian hyperstimulation. The lack of 17,20-desmolase activity was detected by normal P levels in serum and FF, high 17-OHP, and low T, A, and E2 levels in serum and FF. Granulosaluteal cell cultures in the presence of T restored normal E2 and P production in response to gonadotropins. In patients with 17,20-desmolase deficiency, follicular development, oocyte maturation, and fertilization can take place in a low estrogenic environment.

  16. 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.

  17. 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

  18. Compensatory T cell responses in IRG-deficient mice prevent sustained Chlamydia trachomatis infections.

    Directory of Open Access Journals (Sweden)

    Jörn Coers

    2011-06-01

    Full Text Available The obligate intracellular pathogen Chlamydia trachomatis is the most common cause of bacterial sexually transmitted diseases in the United States. In women C. trachomatis can establish persistent genital infections that lead to pelvic inflammatory disease and sterility. In contrast to natural infections in humans, experimentally induced infections with C. trachomatis in mice are rapidly cleared. The cytokine interferon-γ (IFNγ plays a critical role in the clearance of C. trachomatis infections in mice. Because IFNγ induces an antimicrobial defense system in mice but not in humans that is composed of a large family of Immunity Related GTPases (IRGs, we questioned whether mice deficient in IRG immunity would develop persistent infections with C. trachomatis as observed in human patients. We found that IRG-deficient Irgm1/m3((-/- mice transiently develop high bacterial burden post intrauterine infection, but subsequently clear the infection more efficiently than wildtype mice. We show that the delayed but highly effective clearance of intrauterine C. trachomatis infections in Irgm1/m3((-/- mice is dependent on an exacerbated CD4(+ T cell response. These findings indicate that the absence of the predominant murine innate effector mechanism restricting C. trachomatis growth inside epithelial cells results in a compensatory adaptive immune response, which is at least in part driven by CD4(+ T cells and prevents the establishment of a persistent infection in mice.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. Iron and Ferritin Levels in Saliva of Patients with Thalassemia and Iron Deficiency Anemia

    OpenAIRE

    Canatan, Duran; Akdeniz, Sevgi Kosaci

    2012-01-01

    Most of the techniques for measuring iron stores such as serum iron concentration, iron binding capacity, serum ferritin level, liver biopsy can be troublesome or invasive for patients with thalassemia. The salivary iron measurement could be of potential advantage being an easy and non invasive approach for diagnosis of iron deficiency and iron overload . The aim of this study was to compare the levels of iron and ferritin in saliva and serum of patients affected by thalassemia or iron defici...

  4. 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 ...

  5. 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.

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

    Science.gov (United States)

    Unal, Ozlem; Orhan, Diclehan; Ostergaard, Elsebet; Tokatli, Aysegul; Dursun, Ali; Ozturk-Hismi, Burcu; Coskun, Turgay; Wibrand, Flemming; Kalkanoglu-Sivri, H Serap

    2013-11-01

    Nemaline rods are the pathologic hallmark of nemaline myopathy, but they have also been described as a secondary phenomenon in a variety of other disorders. Nemaline rods have not been reported in pyruvate carboxylase deficiency before. Here we present a patient with pyruvate carboxylase deficiency 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 carboxylase in cellular energy pathways.

  7. 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

    Nemaline rods are the pathologic hallmark of nemaline myopathy, but they have also been described as a secondary phenomenon in a variety of other disorders. Nemaline rods have not been reported in pyruvate carboxylase deficiency before. Here we present a patient with pyruvate carboxylase deficiency...... 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...

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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

  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. 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.

  18. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.

    Science.gov (United States)

    Lo, Bernice; Zhang, Kejian; Lu, Wei; Zheng, Lixin; Zhang, Qian; Kanellopoulou, Chrysi; Zhang, Yu; Liu, Zhiduo; Fritz, Jill M; Marsh, Rebecca; Husami, Ammar; Kissell, Diane; Nortman, Shannon; Chaturvedi, Vijaya; Haines, Hilary; Young, Lisa R; Mo, Jun; Filipovich, Alexandra H; Bleesing, Jack J; Mustillo, Peter; Stephens, Michael; Rueda, Cesar M; Chougnet, Claire A; Hoebe, Kasper; McElwee, Joshua; Hughes, Jason D; Karakoc-Aydiner, Elif; Matthews, Helen F; Price, Susan; Su, Helen C; Rao, V Koneti; Lenardo, Michael J; Jordan, Michael B

    2015-07-24

    Mutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. The biological role of LRBA in immunologic disease is unknown. We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)-immunoglobulin fusion drug. Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor. We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3(+) regulatory and activated conventional T cells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway. Copyright © 2015, American Association for the Advancement of Science.

  19. 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.

  20. Mycobacterium simiae infection in two unrelated patients with different forms of inherited IFN-γR2 deficiency.

    Science.gov (United States)

    Martínez-Barricarte, Rubén; Megged, Orli; Stepensky, Polina; Casimir, Pierre; Moncada-Velez, Marcela; Averbuch, Diana; Assous, Marc Victor; Abuzaitoun, Omar; Kong, Xiao-Fei; Pedergnana, Vincent; Deswarte, Caroline; Migaud, Mélanie; Rose-John, Stefan; Itan, Yuval; Boisson, Bertrand; Belkadi, Aziz; Conti, Francesca; Abel, Laurent; Vogt, Guillaume; Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent; Bustamante, Jacinta

    2014-11-01

    Interferon-γ receptor 2 (IFN-γR2) deficiency is a rare primary immunodeficiency characterized by predisposition to infections with weakly virulent mycobacteria, such as environmental mycobacteria and BCG vaccines. We describe here two children with IFN-γR2 deficiency, from unrelated, consanguineous kindreds of Arab and Israeli descent. The first patient was a boy who died at the age of 4.5 years, from recurrent, disseminated disease caused by Mycobacterium simiae. His IFN-γR2 defect was autosomal recessive and complete. The second patient was a girl with multiple disseminated mycobacterial infections, including infection with M. simiae. She died at the age of 5 years, a short time after the transplantation of umbilical cord blood cells from an unrelated donor. Her IFN-γR2 defect was autosomal recessive and partial. Autosomal recessive IFN-γR2 deficiency is life-threatening, even in its partial form, and genetic diagnosis and familial counseling are therefore particularly important for this condition. These two cases are the first of IFN-γR2 deficiency associated with M. simiae infection to be described.

  1. 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.

  2. 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...

  3. 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.

  4. 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....

  5. 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.

  6. 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...

  7. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients.

    Science.gov (United States)

    Singh, A K; Kumar, A; Karmakar, D; Jha, R K

    2013-01-01

    Long-term metformin use has been hypothesized to cause B12 deficiency and neuropathy in Type 2 diabetes patients. However, there is a paucity of Indian data regarding the same. To compare the prevalence of B12 deficiency and peripheral neuropathy in patients with Type 2 diabetes mellitus treated with or without metformin. We recruited patients with Type 2 diabetes and divided them into metformin exposed and nonmetformin exposed groups. We measured baseline demographic variables like age, sex, vegetarian status, and HbA1c levels in both groups. We compared vitamin B12 levels and severity of peripheral neuropathy (using Toronto Clinical Scoring System (TCSS)) in both groups. Definite B12 deficiency was defined as B12 diabetes patients.

  8. 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

  9. 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.

  10. New therapeutic approach by sirolimus for enteropathy treatment in patients with LRBA deficiency.

    Science.gov (United States)

    Azizi, G; Abolhassani, H; Yazdani, R; Mohammadikhajehdehi, S; Parvaneh, N; Negahdari, B; Mohammadi, J; Aghamohammadi, A

    2017-09-01

    Purpose. To report the successful use of sirolimus for management of enteropathy in four patients with LPS-responsive beige-like anchor protein (LRBA) deficiency. Methods. Case series. Results. sirolimus therapy led to a complete improvement of symptoms including decrease in frequency and severity of diarrhea, as well as patients' weight gain. No signs of abdominal cramps and anorexia were also detected during the follow up period after treatment. Conclusions. sirolimus with its potential efficacy and immunomodulatory properties may be recommended for the treatment of severe enteropathy refractory to conventional therapy in patients with LRBA deficiency.

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. 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

  6. 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...

  7. 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

  8. 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...

  9. 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.

  10. 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.

  11. 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.

  12. Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice

    DEFF Research Database (Denmark)

    Thomsen, Allan Randrup; Johansen, J; Marker, O

    1996-01-01

    To study the contribution of CD4+ T cells and B cells to antiviral immunity and long term virus control, MHC class II-deficient and B cell-deficient mice were infected with lymphocytic choriomeningitis virus. In class II-deficient mice, which lack CD4+ T cells, the primary CTL response is virtually...... this phenomenon could reflect participation of B cells and/or Abs in long term virus control, similar experiments were performed with mice that do not have mature B cells because of a disrupted membrane exon of the mu chain gene. In these mice, the cell-mediated immune response was slightly delayed, but transient...... and that in their absence, the virus-specific CTL potential becomes exhausted. Together our results indicate that while CD8+ cells play a dominant role in acute virus control, all three major components of the immune system are required for long term virus control....

  13. Unilateral partial limbal stem cell deficiency: contralateral versus ipsilateral autologous cultivated limbal epithelial transplantation.

    Science.gov (United States)

    Vazirani, Jayesh; Basu, Sayan; Kenia, Hemal; Ali, Md Hasnat; Kacham, Santhosh; Mariappan, Indumathi; Sangwan, Virender

    2014-03-01

    To report the outcomes of autologous cultivated limbal epithelial transplantation using the healthy part of the affected eye or the fellow eye as a source of limbal stem cells in patients with unilateral, partial limbal stem cell deficiency (LSCD). Retrospective, nonrandomized, interventional case series. setting: L. V. Prasad Eye Institute, Hyderabad, India. study population: Patients with unilateral, partial LSCD who underwent autologous cultivated limbal epithelial transplantation between 2001 and 2011. intervention: The limbal biopsy was taken either from the healthy part of the limbus of the same eye (ipsilateral group) or from the healthy fellow eye (contralateral group). Cells were cultivated using a xeno-free explant culture technique, and cultivated cells were transplanted onto the affected surface. primary outcome measure: Success of cultivated limbal epithelial transplantation, defined as a completely epithelialized, avascular, and clinically stable corneal surface. Seventy eyes of 70 patients were studied. The mean follow up was 17.5 ± 7 months. In 34 eyes the limbal biopsy was taken from the ipsilateral eye and in the remaining 36 eyes from the contralateral eye. Clinical success was achieved in 70.59% of eyes in the ipsilateral group and 75% of eyes in the contralateral group (P = .79). Limbal transplant survival rates at the final follow-up visit were 65.1% ± 0.09% in the ipsilateral group and 53.6% ± 0.12% in the contralateral group (P = .74). Ocular surface restoration in partial LSCD is possible with cell-based therapy. Outcomes are similar irrespective of whether the limbal biopsy is taken from the healthy part of the ipsilateral eye or the contralateral eye. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. 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

  15. 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.

  16. 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...

  17. Chemotherapy is linked to severe vitamin D deficiency in patients with colorectal cancer

    Science.gov (United States)

    Fakih, Marwan G.; Trump, Donald L.; Johnson, Candace S.; Tian, Lili; Muindi, Josephia; Sunga, Annette Y.

    2009-01-01

    Background Preclinical and clinical evidence support an association between vitamin D deficiency and an increased risk of colorectal cancer. Normal vitamin D status has been linked to favorable health outcomes ranging from decreased risk of osteoporosis to improved cancer mortality. We performed a retrospective study to assess the impact of metastatic disease and chemotherapy treatment on vitamin D status in patients with colorectal cancer residing in Western New York. Materials and methods Patients, 315, with colorectal cancer treated in a single institute were assayed for 25-OH vitamin D. The association of age, gender, primary disease site and stage, body mass index, and chemotherapy with vitamin D status was investigated. Results Vitamin D deficiency was common among participants with a median 25-OH vitamin D level of 21.3 ng/ml (optimal range 32–100 ng/ml). Primary site of disease and chemotherapy status were associated with very low 25-OH vitamin D levels (≤15 ng/ml) on multivariate analysis. Patients receiving chemotherapy and patients with a rectal primary were fourfold and 2.6-fold more likely to have severe vitamin D deficiency on multivariate analysis than nonchemotherapy patients and colon cancer primary patients, respectively. Conclusions Chemotherapy is associated with a significant increase in the risk of severe vitamin D deficiency. Patients with colorectal cancer, especially those receiving chemotherapy, should be considered for aggressive vitamin D replacement strategies. PMID:18830610

  18. Heart failure in patients with kidney disease and iron deficiency; the role of iron therapy.

    Science.gov (United States)

    Cases Amenós, Aleix; Ojeda López, Raquel; Portolés Pérez, José María

    2017-06-10

    Chronic kidney disease and anaemia are common in heart failure (HF) and are associated with a worse prognosis in these patients. Iron deficiency is also common in patients with HF and increases the risk of morbidity and mortality, regardless of the presence or absence of anaemia. While the treatment of anaemia with erythropoiesis-stimulating agents in patients with HF have failed to show a benefit in terms of morbidity and mortality, treatment with IV iron in patients with HF and reduced ejection fraction and iron deficiency is associated with clinical improvement. In a posthoc analysis of a clinical trial, iron therapy improved kidney function in patients with HF and iron deficiency. In fact, the European Society of Cardiology's recent clinical guidelines on HF suggest that in symptomatic patients with reduced ejection fraction and iron deficiency, treatment with IV ferric carboxymaltose should be considered to improve symptoms, the ability to exercise and quality of life. Iron plays a key role in oxygen storage (myoglobin) and in energy metabolism, and there are pathophysiological bases that explain the beneficial effect of IV iron therapy in patients with HF. All these aspects are reviewed in this article. Copyright © 2017 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  19. Merosin-deficient congenital muscular dystrophy (CMD): a study of 25 Brazilian patients using MRI

    Energy Technology Data Exchange (ETDEWEB)

    Leite, Claudia C.; Lucato, Leandro T.; Martin, Maria G.M. [School of Medicine of the University of Sao Paulo, Department of Radiology, Sao Paulo, SP (Brazil); Ferreira, Lucio G.; Resende, Maria B.D.; Carvalho, Mary S.; Marie, Suely K.N.; Reed, Umbertina C. [School of Medicine of the University of Sao Paulo, Department of Neurology, Sao Paulo, SP (Brazil); Jinkins, J.Randy [Downstate Medical Center, State University of New York, Department of Radiology, Brooklyn, NY (United States)

    2005-06-01

    Merosin-deficient congenital muscular dystrophy (CMD) is characterized clinically by hypotonia and muscular weakness and, on imaging studies, by white matter (WM) abnormality. To evaluate MRI findings in Brazilian patients with merosin-deficient CMD. Twenty-five patients were evaluated using MRI. Three patients presented with partial merosin deficiency and 22 with total merosin deficiency. Follow-up examinations were done in 7 cases. T1- and T2-weighted images were performed in all examinations, and fluid-attenuated inversion recovery (FLAIR) was performed in 15. Enhanced images were done in 11 cases. The WM involvement was classified according to location and severity. From 1991 to 2004, 32 MRI examinations were performed. Severe involvement was found in 23 patients in the frontal and temporal lobes, in 18 patients in the parietal lobes, and in 7 patients in the occipital lobes. The brain stem (n=5), cerebellum (n=6), internal capsules (n=1), and external capsules (n=5) were also affected. One patient had occipital pachygyria, and one had cerebellar vermian hypoplasia. No gadolinium enhancement was noted. Follow-up MRI showed no interval change (n=4), progression (n=1), or improvement of the findings (n=2). (orig.)

  20. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients

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    A K Singh

    2013-01-01

    Full Text Available Context: Long-term metformin use has been hypothesized to cause B12 deficiency and neuropathy in Type 2 diabetes patients. However, there is a paucity of Indian data regarding the same. Aim: To compare the prevalence of B12 deficiency and peripheral neuropathy in patients with Type 2 diabetes mellitus treated with or without metformin. Materials and Methods: We recruited patients with Type 2 diabetes and divided them into metformin exposed and nonmetformin exposed groups. We measured baseline demographic variables like age, sex, vegetarian status, and HbA1c levels in both groups. We compared vitamin B12 levels and severity of peripheral neuropathy (using Toronto Clinical Scoring System (TCSS in both groups. Definite B12 deficiency was defined as B12 <150 pg/ml and possible B12 deficiency as <220 pg/ml. The difference in vitamin B12 levels and TCSS was calculated in both groups using independent samples t-test. Spearman′s rank correlation between cumulative metformin use and B12 level was calculated. Odds ratio of vitamin B12 deficiency in metformin exposed group was also estimated. Results: Mean serum B12 levels was significantly lower in metformin exposed group (n=84 compared with nonmetformin exposed group (n=52 (410±230.7 versus 549.2±244.7, P=0.0011. Mean neuropathy score was significantly higher in metformin exposed group. (5.72±2.04 versus 4.62±2.12, P=0.0064. Odds ratio for possible B12 deficiency was 4.45 (95% CI 1.24-15.97. There was significant negative correlation between cumulative metformin dose and vitamin B12 level (r=−0.68, P<0.0001. Conclusion: Metformin use is associated with vitamin B12 deficiency and clinical neuropathy in Type 2 diabetes patients.

  1. Ccr5 deficiency regulates the proliferation and trafficking of natural killer cells under physiological conditions.

    Science.gov (United States)

    Weiss, Ido D; Shoham, Hadas; Wald, Ori; Wald, Hanna; Beider, Katia; Abraham, Michal; Barashi, Neta; Galun, Eithan; Nagler, Arnon; Peled, Amnon

    2011-06-01

    Chemokines were shown to govern the trafficking of immune cells and may also play important roles in the survival and activation of these cells. We report here that under physiological conditions, the bone marrow (BM), spleen, blood and liver of Ccr5, but not of Ccr1-deficient mice, contain reduced numbers of NK cells. NK cells in the BM of Ccr5-deficient mice proliferate to a lesser extent compared to WT mice. Furthermore, spleen NK cells derived from Ccr5-deficient mice that were transplanted into irradiated recipients failed to proliferate in the host. Ccr5, but not Ccr1-deficient NK cells, failed to migrate in vitro in response to RANTES and MIP-1β but not MIP-1β or SDF-1 and had reduced activation, lower expression levels of NK cell markers and a slightly reduced capacity to adhere to target cells and stimulate their killing. Using the polyI:C mouse model for NK trafficking, we found that in the absence of Ccr5, but not Ccr1, NK cells failed to accumulate in the liver. In contrast, using the influenza viral infection as a model to evaluate NK cell proliferation, we found that Ccr5-deficient NK cells in the BM had a higher proliferation rate than WT NK cells. These results suggest a role for Ccr5 in NK cell proliferation and circulation under physiological conditions and a complex role for Ccr5 in determining the fate of NK cells under pathological conditions. Copyright © 2011. Published by Elsevier Ltd.

  2. 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.

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

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    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.

  4. 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

  5. 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.

  6. 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

  7. 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-

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

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    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.

  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. Study of gastrointestinal polypeptides controlling gastric acid secretion in patients with primary antibody deficiency.

    Science.gov (United States)

    Alonso Falcón F; Codoceo Alquinta R; Polanco Allué I; Aguado Gil A; Fontán Casariego G

    1999-01-01

    BACKGROUND: gastric abnormalities are a common feature in patients with primary antibody deficiency. The most important problem is the high incidence of stomach cancer found in these patients. Chronic atrophic gastritis with pernicious anemia is also a common finding that predisposes to gastric adenocarcinoma. The aim of the present study was to identify factors predictive of high risk for developing gastric cancer in patients with primary antibody deficiency. PATIENTS AND METHODS: we studied gastric hormones (gastrin, somatostatin and gastrin-releasing peptide, GRP) in 47 patients (23 children and 24 adults) with primary antibody deficiency. In accordance with the World Health Organization (WHO) classification, patients were diagnosed as having X-linked agammaglobulinemia (Bruton disease) in 13 cases, common variable immunodeficiency in 28, and hypogammaglobulinemia with hyperIgM in 6. Gastric biopsy was performed in 22 patients (16 children and 6 adults). Hormone determinations were carried out by radioimmunoassay. RESULTS: baseline serum gastrin levels were normal or increased compared with controls, but the response to stimulation with a hyperproteic diet was delayed in 18 patients and lower than in controls in 7. In 4 adult patients, all with pernicious anemia, gastric biopsy revealed chronic atrophic gastritis involving the stomach corpus and antrum (type B gastritis). The absence of a normal response of gastrin secretion to stimulation with a hyperproteic diet may be explained by this finding. Serum somatostatin and GRP levels were higher than in controls. No correlations were found between these findings and patient age, type of immunodeficiency or duration of clinical manifestations.

  11. Critical appraisal of discriminant formulas for distinguishing thalassemia from iron deficiency in patients with microcytic anemia.

    Science.gov (United States)

    Urrechaga, Eloísa; Hoffmann, Johannes J M L

    2017-08-28

    Many discriminant formulas have been reported for distinguishing thalassemia trait from iron deficiency in patients with microcytic anemia. Independent verification of several discriminant formulas is deficient or even lacking. Therefore, we have retrospectively investigated discriminant formulas in a large, well-characterized patient population. The investigational population consisted of 2664 patients with microcytic anemia: 1259 had iron deficiency, 1196 'pure' thalassemia trait (877 β- and 319 α-thalassemia), 150 had thalassemia trait with concomitant iron deficiency or anemia of chronic disease, and 36 had other diseases. We investigated 25 discriminant formulas that only use hematologic parameters available on all analyzers; formulas with more advanced parameters were disregarded. The diagnostic performance was investigated using ROC analysis. The three best performing formulas were the Jayabose (RDW index), Janel (11T), and Green and King formulas. The differences between them were not statistically significant (p>0.333), but each of them had significantly higher area under the ROC curve than any other formula. The Jayabose and Green and King formulas had the highest sensitivities: 0.917 both. The highest specificity, 0.925, was found for the Janel formula, which is a composite score of 11 other formulas. All investigated formulas performed significantly better in distinguishing β- than α-thalassemia from iron deficiency. In our patient population, the Jayabose RDW index, the Green and King formula and the Janel 11T score are superior to all other formulas examined for distinguishing between thalassemia trait and iron deficiency anemia. We confirmed that all formulas perform much better in β- than in α-thalassemia carriers and also that they incorrectly classify approximately 30% of thalassemia carriers with concomitant other anemia as not having thalassemia. The diagnostic performance of even the best formulas is not high enough for making a final

  12. 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...

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

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    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.

  14. Culture of Oral Mucosal Epithelial Cells for the Purpose of Treating Limbal Stem Cell Deficiency

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    Tor Paaske Utheim

    2016-03-01

    Full Text Available The cornea is critical for normal vision as it allows allowing light transmission to the retina. The corneal epithelium is renewed by limbal epithelial cells (LEC, which are located in the periphery of the cornea, the limbus. Damage or disease involving LEC may lead to various clinical presentations of limbal stem cell deficiency (LSCD. Both severe pain and blindness may result. Transplantation of cultured autologous oral mucosal epithelial cell sheet (CAOMECS represents the first use of a cultured non-limbal autologous cell type to treat this disease. Among non-limbal cell types, CAOMECS and conjunctival epithelial cells are the only laboratory cultured cell sources that have been explored in humans. Thus far, the expression of p63 is the only predictor of clinical outcome following transplantation to correct LSCD. The optimal culture method and substrate for CAOMECS is not established. The present review focuses on cell culture methods, with particular emphasis on substrates. Most culture protocols for CAOMECS used amniotic membrane as a substrate and included the xenogeneic components fetal bovine serum and murine 3T3 fibroblasts. However, it has been demonstrated that tissue-engineered epithelial cell sheet grafts can be successfully fabricated using temperature-responsive culture surfaces and autologous serum. In the studies using different substrates for culture of CAOMECS, the quantitative expression of p63 was generally poorly reported; thus, more research is warranted with quantification of phenotypic data. Further research is required to develop a culture system for CAOMECS that mimics the natural environment of oral/limbal/corneal epithelial cells without the need for undefined foreign materials such as serum and feeder cells.

  15. Culture of Oral Mucosal Epithelial Cells for the Purpose of Treating Limbal Stem Cell Deficiency.

    Science.gov (United States)

    Utheim, Tor Paaske; Utheim, Øygunn Aass; Khan, Qalb-E-Saleem; Sehic, Amer

    2016-03-01

    The cornea is critical for normal vision as it allows allowing light transmission to the retina. The corneal epithelium is renewed by limbal epithelial cells (LEC), which are located in the periphery of the cornea, the limbus. Damage or disease involving LEC may lead to various clinical presentations of limbal stem cell deficiency (LSCD). Both severe pain and blindness may result. Transplantation of cultured autologous oral mucosal epithelial cell sheet (CAOMECS) represents the first use of a cultured non-limbal autologous cell type to treat this disease. Among non-limbal cell types, CAOMECS and conjunctival epithelial cells are the only laboratory cultured cell sources that have been explored in humans. Thus far, the expression of p63 is the only predictor of clinical outcome following transplantation to correct LSCD. The optimal culture method and substrate for CAOMECS is not established. The present review focuses on cell culture methods, with particular emphasis on substrates. Most culture protocols for CAOMECS used amniotic membrane as a substrate and included the xenogeneic components fetal bovine serum and murine 3T3 fibroblasts. However, it has been demonstrated that tissue-engineered epithelial cell sheet grafts can be successfully fabricated using temperature-responsive culture surfaces and autologous serum. In the studies using different substrates for culture of CAOMECS, the quantitative expression of p63 was generally poorly reported; thus, more research is warranted with quantification of phenotypic data. Further research is required to develop a culture system for CAOMECS that mimics the natural environment of oral/limbal/corneal epithelial cells without the need for undefined foreign materials such as serum and feeder cells.

  16. 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.

  17. 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.

  18. [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.

  19. High prevalence of vitamin D deficiency and insufficiency in patients with manifest Huntington disease

    Science.gov (United States)

    Chel, Victor GM; Ooms, Marcel E; van der Bent, Jessie; Veldkamp, Fleur; Roos, Raymund AC; Achterberg, Wilco P; Lips, Paul

    2013-01-01

    Vitamin D deficiency and insufficiency are common in older institutionalized people and known to be associated with muscle weakness, impaired balance and increased fall risk. Falls and balance problems are common in people with Huntington disease (HD). Despite this, the prevalence of vitamin D deficiency in patients with manifest HD has never been investigated. Serum 25(OH)D levels were measured in routinely drawn blood samples from 28 Dutch institutionalized patients with manifest Huntington disease. Mean serum 25(OH)D level was 33 nmol/l (SD 15). Twenty-five subjects (89%) were vitamin D deficient or insufficient (25(OH)D < 50 nmol/L). A positive association was found between serum 25(OH)D levels and Functional Ambulation Classification (FAC) scores (p = 0.023). PMID:24516688

  20. Suboptimal response to ferrous sulfate in iron-deficient patients taking omeprazole.

    Science.gov (United States)

    Ajmera, Akash V; Shastri, Ghanshyam S; Gajera, Mithil J; Judge, Thomas A

    2012-05-01

    Iron deficiency anemia is commonly encountered in outpatient practice. Gastric acid is one of the important factors for optimum absorption of iron. Proton pump inhibitors are very commonly prescribed medications. One of the debated effects of proton pump inhibitors is on oral iron absorption. Their effect on absorption of oral iron supplementation in iron-deficient patients has not been studied. At the Cooper Hematology Outpatient office, we reviewed charts of iron-deficient anemic patients who were on omeprazole for the last 4 years. Fifty patients having no apparent ongoing blood loss, having other causes of anemia especially that of chronic diseases ruled out, and on omeprazole while starting ferrous sulfate therapy for iron deficiency were selected for chart review. The iron-study results at the start of oral ferrous sulfate therapy and at 3 months follow-up were compared to evaluate the response of ferrous sulfate. The mean hemoglobin change was 0.8 ± 1.2 g/L. The mean change in ferrtin values was 10.2 ± 7.8 μg/L. Only 16% of the patients had a normal response to hemoglobin levels (rise of >2 g/dL), and only 40% had a normal response to ferritin levels (rise of >20 μg/dL). The average age of patients having a suboptimal response to both hemoglobin and ferritin was significantly higher compared with that of the patients with an optimal response. Omeprazole and possibly all proton pump inhibitors decrease the absorption of oral iron supplementation. Iron-deficient patients taking proton pump inhibitors may have to be treated with high dose iron therapy for a longer duration or with intravenous iron therapy.

  1. Cobalamin deficiency.

    Science.gov (United States)

    Herrmann, Wolfgang; Obeid, Rima

    2012-01-01

    Cobalamin (Cbl, vitamin B12) consists of a corrinoid structure with cobalt in the centre of the molecule. Neither humans nor animals are able to synthesize this vitamin. Foods of animal source are the only natural source of cobalamin in human diet. There are only two enzymatic reactions in mammalian cells that require cobalamin as cofactor. Methylcobolamin is a cofactor for methionine synthase. The enzyme methylmalonyl-CoA-mutase requires adenosylcobalamin as a cofactor. Therefore, serum concentrations of homocysteine (tHcy) and methylmalonic acid (MMA) will increase in cobalamin deficiency. The cobalamin absorption from diet is a complex process that involves different proteins: haptocorrin, intrinsic factor and transcobalamin (TC). Cobalamin that is bound to TC is called holotranscobalamin (holoTC) which is the metabolically active vitamin B12 fraction. HoloTC consists 6 and 20% of total cobalamin whereas 80% of total serum cobalamin is bound to another binding protein, haptocorrin. Cobalamin deficiency is common worldwide. Cobalamin malabsorption is common in elderly subjects which might explain low vitamin status. Subjects who ingest low amount of cobalamin like vegetarians develop vitamin deficiency. No single parameter can be used to diagnose cobalamin deficiency. Total serum cobalamin is neither sensitive nor it is specific for cobalamin deficiency. This might explain why many deficient subjects would be overlooked by utilizing total cobalamin as status marker. Concentration of holotranscobalamin (holoTC) in serum is an earlier marker that becomes decreased before total serum cobalamin. Concentrations of MMA and tHcy increase in blood of cobalamin deficient subjects. Despite limitations of these markers in patients with renal dysfunction, concentrations of MMA and tHcy are useful functional markers of cobalamin status. The combined use of holoTC and MMA assays may better indicate cobalamin status than either of them. Because Cbl deficiency is a risk factor

  2. 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. [Impending Coumarin-necrosis in a patient with heterozygous protein C deficiency type I].

    Science.gov (United States)

    Schulze, R; Behr, W; Wittwer, H; Harwix, S; Murmann, K; V Scheidt, W; Ehret, W; Schlimok, G

    2008-05-01

    Painful pink or magenta colored skin lesions characterized by a clear line of demarcation between the affected area and surrounding tissue appearing under therapy with coumarins may be a sign for evolving coumarin-necrosis. Immediate treatment with a protein C preparation in patients with protein C deficiency can prevent necrosis.

  2. Nocturnal Rapid Eye Movement Sleep Latency for Identifying Patients With Narcolepsy/Hypocretin Deficiency

    Science.gov (United States)

    Andlauer, Olivier; Moore, Hyatt; Jouhier, Laura; Drake, Christopher; Peppard, Paul E.; Han, Fang; Hong, Seung-Chul; Poli, Francesca; Plazzi, Giuseppe; O’Hara, Ruth; Haffen, Emmanuel; Roth, Thomas; Young, Terry; Mignot, Emmanuel

    2014-01-01

    IMPORTANCE Narcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically. OBJECTIVE To determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency. DESIGN, SETTING, AND PARTICIPANTS Observational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels. MAIN OUTCOME AND MEASURES Sensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal

  3. 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.

  4. Clinical and immunological correction of DOCK8 deficiency by allogeneic hematopoietic stem cell transplantation following a reduced toxicity conditioning regimen.

    Science.gov (United States)

    Boztug, Heidrun; Karitnig-Weiß, Cäcilia; Ausserer, Bernd; Renner, Ellen D; Albert, Michael H; Sawalle-Belohradsky, Julie; Belohradsky, Bernd H; Mann, Georg; Horcher, Ernst; Rümmele-Waibel, Alexandra; Geyeregger, Rene; Lakatos, Karoly; Peters, Christina; Lawitschka, Anita; Matthes-Martin, Susanne

    2012-10-01

    Dedicator of cytokinesis 8 protein (DOCK8) deficiency is a combined immunodeficiency disorder characterized by an expanding clinical picture with typical features of recurrent respiratory or gastrointestinal tract infections, atopic eczema, food allergies, chronic viral infections of the skin, and blood eosinophilia often accompanied by elevated serum IgE levels. The only definitive treatment option is allogeneic hematopoietic stem cell transplantation (HSCT). We report a patient with early severe manifestation of DOCK8 deficiency, who underwent unrelated allogeneic HSCT at the age of 3 years following a reduced toxicity conditioning regimen. The transplant course was complicated by pulmonary aspergilloma pretransplantation, adenovirus (ADV) reactivation, and cytomegalovirus (CMV) pneumonitis 4 weeks after transplantation. With antifungal and antiviral treatment the patient recovered. Seven months after transplantation the patient is in excellent clinical condition. Eczematous rash, chronic viral skin infections, and food allergies have subsided, associated with normalization of IgE levels and absolute numbers of eosinophils. Chimerism analysis shows stable full donor chimerism. DOCK8 deficiency can be successfully cured by allogeneic HSCT. This treatment option should be considered early after diagnosis, as opportunistic infections and malignancies that occur more frequently during the natural course of the disease are associated with higher morbidity and mortality.

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

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    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.

  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. A Metabolomics Approach to Stratify Patients Diagnosed with Diabetes Mellitus into Excess or Deficiency Syndromes

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    Tao Wu

    2015-01-01

    Full Text Available The prevalence of type 2 diabetes continuously increases globally. The traditional Chinese medicine (TCM can stratify the diabetic patients based on their different TCM syndromes and, thus, allow a personalized treatment. Metabolomics is able to provide metabolite biomarkers for disease subtypes. In this study, we applied a metabolomics approach using an ultraperformance liquid chromatography (UPLC coupled with quadruple-time-of-flight (QTOF mass spectrometry system to characterize the metabolic alterations of different TCM syndromes including excess and deficiency in patients diagnosed with diabetes mellitus (DM. We obtained a snapshot of the distinct metabolic changes of DM patients with different TCM syndromes. DM patients with excess syndrome have higher serum 2-indolecarboxylic acid, hypotaurine, pipecolic acid, and progesterone in comparison to those patients with deficiency syndrome. The excess patients have more oxidative stress as demonstrated by unique metabolite signatures than the deficiency subjects. The results provide an improved understanding of the systemic alteration of metabolites in different syndromes of DM. The identified serum metabolites may be of clinical relevance for subtyping of diabetic patients, leading to a personalized DM treatment.

  8. NK and B cell deficiency in a MPS type II family with novel mutation in the IDS gene.

    Science.gov (United States)

    Torres, Leuridan Cavalcante; Soares, Diogo Cordeiro de Queiroz; Kulikowski, Leslie Domenici; Franco, Jose Francisco; Kim, Chong Ae

    2014-10-01

    The mucopolysaccharidoses (MPSs) are a group of rare, inherited lysosomal storage disorders that are clinically characterized by abnormalities in multiple organ systems and reduced life expectancy. Whereas the lysosome is essential to the functioning of the immune system, some authors suggest that the MPS patients have abnormalities in the immune system similar to the patients with primary immunodeficiency. In this study, we evaluated 8 male MPS type II patients of the same family with novel mutation in the IDS gene. We found in this MPS family a quantitative deficiency of NK and B cells with normal values of IgG, IgM and IgA serum antibodies and normal response to polysaccharide antigens. Interestingly, abnormalities found in these patients were not observed in other MPS patients, suggesting that the type of mutation found in the IDS gene can be implicated in the immunodeficiency. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. 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.

  10. 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.

  11. Congenital muscular dystrophy with merosin deficiency: MRI findings in five patients

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    Farina, L.; Milanesi, I.; Ciceri, E.; Savoiardo, M. [Dept. of Neuroradiology, Ist. Nazionale Neurologico C. Besta, Milan (Italy); Morandi, L.; Mora, M. [Dept. of Neuromuscular Disorders, Ist. Nazionale Neurologico C. Besta, Milan (Italy); Moroni, I.; Pantaleoni, C. [Dept. of Child Neurology, Ist. Nazionale Neurologico C. Besta, Milan (Italy)

    1998-12-01

    We present the MRI findings in five patients with congenital muscular dystrophy (CMD) and merosin (laminin {alpha} 2) deficiency, which was total in one and partial in four. In one patient with partial merosin deficiency, MRI was normal. The other four patients had supratentorial white matter abnormalities. In three, T2-weighted images revealed subcortical, deep lobar and periventricular high signal in white matter, while in the other there were only small peritrigonal areas of increased signal. On T1-weighted images, there was slightly low signal. Cortical abnormalities were absent. None of these changes were accompanied by symptoms or signs of central nervous system involvement. White matter abnormalities in a patient with CMD should prompt investigation of merosin. (orig.) With 4 figs., 11 refs.

  12. 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.

  13. 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.

  14. Novel CFI mutation in a patient with leukocytoclastic vasculitis may redefine the clinical spectrum of Complement Factor I deficiency

    DEFF Research Database (Denmark)

    Bay, Jakob Thaning; Katzenstein, Terese Lea; Kofoed, Kristian

    2015-01-01

    presentation of Factor I deficiency varies and includes severe recurrent bacterial infections, glomerulonephritis and autoimmune diseases. The patient, a 28-years old woman with consanguineous parents, presented with recurrent leukocytoclastic vasculitis in the lower extremities with no associated systemic...... mutations vary among patients sole association with leukocytoclastic vasculitis redefines the clinical spectrum of complete Factor I deficiency....

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

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    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.

  16. Iron deficiency decreases hemolysis in sickle cell anemia Anemia ferropriva diminui hemólise em anemia falciforme

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    Oswaldo Castro

    2009-02-01

    Full Text Available A woman with homozygous sickle cell disease developed severe iron deficiency due to long-standing uterine bleeding. At this point, the serum lactic dehydrogenase level was normal and the reticulocyte count was only minimally elevated. This suggested that the low red cell hemoglobin concentration that resulted from iron deficiency also decreased Hb S polymerization and lowered the hemolytic rate. Iron replacement led first to a substantially improved hemoglobin concentration with only a minimal increase in the hemolytic rate and secondarily to a modest further improvement in the hemoglobin concentration and a marked increase in the hemolytic rate. The hematologic changes observed in this patient, and those in other iron deficient sickle cell patients reported in the literature, suggest that it may be appropriate to consider the induction of an intermediate iron deficient stage as experimental treatment in adult sickle cell patients.Uma mulher com anemia falciforme homozigose para a Hb S evoluiu com anemia ferropriva grave devido a sangramento uterino prolongado. A dosagem de dehidrogenase lática era normal e a contagem de reticulócitos estava levemente aumentada. Isto sugere que concentrações baixas de hemoglobina, que resulta de anemia ferropriva, também diminuem a polimeração de Hb S e reduz a taxa de hemólise. O complemento de ferro levou, primeiramente, a uma concentração substancialmente maior de hemoglobina com apenas um aumento mínimo na taxa hemolítica e subsequentemente a um aumento leve adicional na concentração da hemoglobina e um aumento notável na taxa hemolítica. As mudanças hematológicas observadas nesta paciente e aquelas em outras pacientes com anemia falciforme e também deficientes de ferro relatadas na literatura sugerem que pode ser interessante considerar a indução de deficiência de ferro como tratamento experimental em pacientes adultos com anemia falciforme.

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

    Directory of Open Access Journals (Sweden)

    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

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

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    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. Iron deficiency anemia as initial presentation of a non-small cell lung carcinoma: A case report

    Science.gov (United States)

    Linsen, Philip V.M.; Linsen, Victor M.J.; Buunk, Gerba; Arnold, Dorothee E.; Aerts, Joachim G.J.V.

    2015-01-01

    Duodenal metastases secondary to lung cancer are very rare and most of the time asymptomatic. When symptomatic they usually present with bowel obstruction or perforation. We here describe the case of a 68 year-old man with a solitary metastasis in the duodenum from a non-small cell lung carcinoma (NSCLC). The patient presented with reduced exercise tolerance and iron deficiency anemia without clinical gastrointestinal blood loss. Further investigation showed a tumor in the left upper lung lobe and a duodenal metastasis for which he received chemotherapy. To the best of our knowledge this is the first case report of iron deficiency anemia as initial presentation of a duodenal metastasis from a NSCLC. PMID:26744672

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Ocular Surface Reconstruction with Cultivated Limbal Epithelial Cells in Limbal Stem Cell Deficiency: One-year Follow-up Results

    Directory of Open Access Journals (Sweden)

    İsmet Durak

    2012-05-01

    Full Text Available Pur po se: To evaluate the 1-year follow-up results of cultivated limbal epithelial cell (CLEC transplantation in unilateral limbal stem cell deficiency (LSCD. Ma te ri al and Met hod: One-year follow-up results of five unilateral LSCD patients who had undergone CLEC transplantation were evaluated. Parameters for this evaluation were: fluorescein staining of ocular surface, corneal vascularization and status of epithelium with slit lamp, and visual acuity. 1.5-mm limbal biopsy was performed from the superior limbus of the healthy eyes, broke into two equal pieces, expanded on human amniotic membrane (hAM and inserts for 14 days until getting 20 mm in size. CLECs on hAMs were used directly, and cells on inserts were usedafter detachment procedure. The symblepharon and pannus tissues were removed, superficial keratectomy was performed. CLEC on hAMs were transplanted with the epithelial side up onto the bare corneal stroma, sutured to the conjunctiva with 10-0 nylon sutures. Free CLEC layer from insert was placed on hAM as a second layer, additional hAM was used as a protective layer all over other tissues. Re sults: Median age was 44.4 years (14-71. The etiology was chemical burn in all patients. Median duration of symptoms was 10 years (2-18, median follow-up period was 12.6 (12-12.5 months. Preoperative best corrected visual acuities (BCVA were light perception in three patients, counting fingers at 50 cm in one patient and 3/10 in one patient. Visions were improved in all patients. Postoperative BCVA 12 months after the surgery were between counting fingers at 3 meters to 6/10. There was a temporary hemorrhage between the two layers of hAMs in one patient at the early postoperative period. Peripheral corneal vascularization has occurred in three patients, in patient corneal vascularization has reached to the paracentral area. Dis cus si on: CLEC transplantation is an efficient treatment option for unilateral LSCD in mid-long term. (Turk J

  2. Complex regional pain syndrome treated with intravenous immunoglobulin in a patient with common variable immune deficiency.

    Science.gov (United States)

    Tachdjian, Raffi

    2013-12-01

    Common variable immunodeficiency (CVID) represents a large heterogeneous group of antibody-deficiency syndromes associated with a wide range of clinical features and a lack of defined causes in the realm of primary immunodeficiencies. Here, we present a case of CVID in a 62-year-old white male patient with a history of longstanding complex regional pain syndrome (CRPS). His medical history included multiple sinus infections per year and several pneumonias requiring antibiotics. He has had various back surgeries, including a laminectomy at the L4 level 1 year prior to his diagnosis. Thereafter, he underwent four sympathetic nerve blocks with minimal pain relief. Blood chemistries showed a normal white blood cell count with a normal differential, but increased erythrocyte sedimentation rate and C-reactive protein levels. Total Ig (Immunoglobulin)G was 611 mg/dL (normal 700-1,600), IgG1 was 425 mg/dL (341-894), IgG2 was 114 mg/dL (171-632), IgG3 was 14.4 mg/dL (18.4-106), and IgG4 was 7.4 mg/dL (2.4-121). IgA was 47 mg/dL (normal 70-400), IgM was 131 mg/dL (40-230), and IgE was 4.5 kU/L (<4.0). He only had 10 of 23 pneumococcal titers in the protective range post-vaccination. Upon treatment of the CVID with intravenous immunoglobulin, the patient's pain levels were significantly decreased and have been maintained for more than 2 years. Therefore, immunoglobulin therapy appears to have been beneficial in the treatment of the patient's symptoms of CRPS, including pain. Additional studies investigating the mechanism by which immunoglobulin therapy may reduce the inflammation and pain of CRPS are needed.

  3. 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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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.

  7. 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.

  8. Vitamin D Deficiency Reduces the Immune Response, Phagocytosis Rate, and Intracellular Killing Rate of Microglial Cells

    Science.gov (United States)

    Onken, Marie Luise; Schütze, Sandra; Redlich, Sandra; Götz, Alexander; Hanisch, Uwe-Karsten; Bertsch, Thomas; Ribes, Sandra; Hanenberg, Andrea; Schneider, Simon; Bollheimer, Cornelius; Sieber, Cornel; Nau, Roland

    2014-01-01

    Meningitis and meningoencephalitis caused by Escherichia coli are associated with high rates of mortality and neurological sequelae. A high prevalence of neurological disorders has been observed in geriatric populations at risk of hypovitaminosis D. Vitamin D has potent effects on human immunity, including induction of antimicrobial peptides (AMPs) and suppression of T-cell proliferation, but its influence on microglial cells is unknown. The purpose of the present study was to determine the effects of vitamin D deficiency on the phagocytosis rate, intracellular killing, and immune response of murine microglial cultures after stimulation with the Toll-like receptor (TLR) agonists tripalmitoyl-S-glyceryl-cysteine (TLR1/2), poly(I·C) (TLR3), lipopolysaccharide (TLR4), and CpG oligodeoxynucleotide (TLR9). Upon stimulation with high concentrations of TLR agonists, the release of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was decreased in vitamin D-deficient compared to that in vitamin D-sufficient microglial cultures. Phagocytosis of E. coli K1 after stimulation of microglial cells with high concentrations of TLR3, -4, and -9 agonists and intracellular killing of E. coli K1 after stimulation with high concentrations of all TLR agonists were lower in vitamin D-deficient microglial cells than in the respective control cells. Our observations suggest that vitamin D deficiency may impair the resistance of the brain against bacterial infections. PMID:24686054

  9. 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.

  10. 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.

  11. 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

  12. Treatment of confirmed B12 deficiency in hemodialysis patients improves Epogen® requirements

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    Saifan C

    2013-06-01

    Full Text Available Chadi Saifan, Mark Samarneh, Norbert Shtaynberg, Rabih Nasr, Elie El-Charabaty, Suzanne El-Sayegh Division of Nephrology, Staten Island University Hospital, Staten Island, NY, USA Background: Vitamin B12 deficiency may have deleterious effects on end stage renal disease (ESRD patients on maintenance hemodialysis, and may increase erythropoietin stimulating agent (ESA resistance, yet little is known about its prevalence in this population. Methods: Serum Vitamin B12 and methylmalonic acid (MMA levels were drawn from ESRD patients prior to hemodialysis. All patients with MMA levels greater than 800 nmol/L had peripheral smears evaluated for B12 deficiency. Those with confirmatory smears were considered to be deficient and received intramuscular vitamin B12 injections for 4 months. Post-treatment MMA levels and smears were obtained. Erythropoietin dosages were monitored throughout the treatment period. Results: There was a 58% (60/103 prevalence of vitamin B12 deficiency as defined by a positive MMA level and a positive blood smear. Out of 52 patients with positive smears, 36 (69.2% were negative on repeat analysis after B12 treatment. Mean Epogen® (EPO dosages significantly decreased by 16,572 ± 41,902 units per month from baseline to the post-B12 treatment period (P = 0.0082, Wilcoxon signed-rank test. Three months prior to treatment, the mean monthly EPO dose was 82,067 ± 47,906 and post, the mean EPO usage was 65,495 ± 39,691. Post treatment hemoglobin levels were not significantly different from baseline. Conclusion: Vitamin B12 supplementation was associated with a decrease in the mean dose of ESA administration while maintaining a stable hemoglobin level. Maintaining serum vitamin B12 levels improves functionality, and may allow a decrease in the use of ESA’s, avoiding their toxicities and significant costs. Keywords: ESRD, end stage renal disease, chronic kidney disease, anemia, vitamin deficiency, erythropoietin, dialysis

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

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    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. 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.

  15. 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.

  16. Vitamin B12 deficiency is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Hansen, Christian S; Jensen, Jan S; Ridderstråle, Martin

    2017-01-01

    AIMS: Vitamin B12 deficiency could be associated with cardiovascular autonomic neuropathy (CAN) in diabetes patients. We aim to investigate the association between serum levels of vitamin B12 and CAN in type 2 diabetes patients. METHODS: 469 ambulatory type 2 diabetes patients (mean diabetes.......01; 0.43, p=0.038), and a decrease in 5min RHR of 0.25 beats per minute (95% CI -0.47; -0.03, p=0.025). CONCLUSION: Vitamin B12 may be inversely associated with CAN in patients with type 2 diabetes. Confirmatory studies investigating a causal role of vitamin B12 for the development of diabetic CAN...

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. Prevalence of factor VII deficiency and molecular characterization of the F7 gene in Brazilian patients.

    Science.gov (United States)

    Rodrigues, Dalva N; Siqueira, Lucia H; Galizoni, Andréa M; Arruda, Valder R; Annichino-Bizzacchi, Joyce M

    2003-04-01

    The prevalence of factor VII (FVII) deficiency in 267 Brazilian patients was estimated to be 4.1%, including one patient with significant bleeding, five with minor bleeding and five patients asymptomatic. Only one novel mutation 8926G F7 polymorphisms and FVII activity were found in these patients, as those with higher levels of FVII activity presented the genotype described in the literature as related to reduced FVII activity. As the R304Q mutation was the most frequent in these patients, and may be associated with an asymptomatic form of the disease, particularly in Blacks, we examined this mutation and FVII activity in 49 Blacks and 49 Caucasian blood donors with no clinical bleeding. None of the individuals showed the R304Q mutation, and FVII activity was normal in all of them, thus indicating that FVII deficiency is not common in normal individuals of these two ethnic groups in Brazil. This is the first study in South America to examine the prevalence and molecular basis of FVII deficiency, including the description of a novel mutation.

  5. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Vitamin D Deficiency in Patients with Central Retinal Vein Occlusion: A Case Control Study.

    Science.gov (United States)

    Epstein, David; Kvanta, Anders; Lindqvist, Pelle G

    2017-03-01

    Central retinal vein occlusion (CRVO) has been shown to occur more often in winter/spring season. We aimed to evaluate if patients with CRVO have more vitamin D deficiency compared to matched controls. Prospective match controlled study of 72 patients with CRVO and 144 matched controls. All new CRVO cases presenting at St. Erik Eye Hospital, Stockholm, Sweden during the study period were approached to participate. Statistics Sweden provided randomly selected controls matched for age, gender, and season. The first 18 cases of CRVO and 36 controls for each of the four seasons were included and blood was drawn for 25-OH vitamin D analysis (25(OH)D). About half of the patients (51.4%) in the CRVO group had vitamin D deficiency [25(OH)D D were 55.3 nmol/l (95% CI 48.4-62.2) in the study group and 59.8 nmol/l (95% CI 55.4-64.2) in the control group (p = 0.28). In stratified analysis, the CRVO patients under 75 years had significantly lower 25(OH)D levels than the matched controls (47.8 nmol/l vs. 59.0 nmol/l, p = 0.02). Vitamin D deficiency is common in patients with CRVO. No significant differences in vitamin deficiency or 25(OH)D levels were found in comparison to the control group. However, the CRVO patients under 75 years had significantly lower 25(OH)D levels as compared to the control group.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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...

  13. Maternal vitamin B12 deficiency and abnormal cell-free DNA results in pregnancy

    NARCIS (Netherlands)

    Schuring-Blom, Heleen; Lichtenbelt, Klaske; van Galen, Karin; Elferink, Martin; Weiss, Marjan; Vermeesch, Joris Robert; Page-Christiaens, Lieve

    2016-01-01

    What's Already Known about this Topic? Prenatal testing with cell-free DNA may incidentally identify maternal genetic anomalies and malignancies. What does this Study Add? Profound vitamin B12 deficiency with intramedullary hemolysis may cause abnormal genomic patterns that can be detected by

  14. Induction of protective CTL immunity against peptide transporter TAP-deficient tumors through dendritic cell vaccination.

    Science.gov (United States)

    Chambers, Benedict; Grufman, Per; Fredriksson, Vanoohi; Andersson, Kenth; Roseboom, Marjet; Laban, Sandra; Camps, Marcel; Wolpert, Elisabeth Z; Wiertz, Emmanuel J H J; Offringa, Rienk; Ljunggren, Hans-Gustaf; van Hall, Thorbald

    2007-09-15

    A large proportion of human cancers show deficiencies in the MHC class I antigen-processing machinery. Such defects render tumors resistant to immune eradication by tumoricidal CTLs. We recently identified a unique population of CTL that selectively targets tumor immune-escape variants through recognition of MHC-presented peptides, termed TEIPP (T cell epitopes associated with impaired peptide processing), expressed on cells lacking functional TAP-peptide transporters. Previously, we showed that vaccination with TEIPP peptides mediates protection against TAP-deficient tumors. Here, we further explored the concept of TEIPP-targeted therapy using a dendritic cell (DC)-based cellular vaccine. Impairment of TAP function in DC induced the presentation of endogenous TEIPP antigens by MHC class I molecules, and immunization with these DCs protected mice against the outgrowth of TAP-deficient lymphomas and fibrosarcomas. Immune analysis of vaccinated mice revealed strong TEIPP-specific CTL responses, and a crucial role for CD8(+) cells in tumor resistance. Finally, we show that TEIPP antigens could be successfully induced in wild-type DC by introducing the viral TAP inhibitor UL49.5. Our results imply that immune intervention strategies with TAP-inhibited DC could be developed for the treatment of antigen processing-deficient cancers in humans.

  15. 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

  16. Gastric emptying in patients with vitamin B{sub 12} deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Yagci, Muenci; Yamac, Kadri; Acar, Kadir; Haznedar, Rauf [Department of Hematology, Gazi Medical School (Turkey); Cingi, Elif; Kitapci, Mehmet [Department of Nuclear Medicine, Gazi Medical School (Turkey)

    2002-09-01

    The clinical presentation of patients with vitamin B{sub 12} deficiency varies in a spectrum ranging from haematological disorders to neuropsychiatric diseases. In rare cases, orthostatic hypotension, impotence, constipation and urinary retention have been attributed to autonomic nervous system dysfunction due to vitamin B{sub 12} deficiency. The aim of this study was to evaluate the effect of vitamin B{sub 12} deficiency on autonomic nervous system function by studying gastric emptying times (T{sub 1/2}). Twenty patients with newly diagnosed vitamin B{sub 12} deficiency and 12 control patients with gastritis and normal vitamin B{sub 12} levels were enrolled in this study. Gastroduodenoscopy, endoscopic biopsy, histopathological evaluation of the biopsy specimens and radionuclide gastric emptying studies were performed. After vitamin B{sub 12} replacement therapy for 3 months, radionuclide gastric emptying studies were repeated. Mean gastric emptying T{sub 1/2} in patients before and after treatment and in controls were 103.83{+-}48.80 min, 90.00{+-}17.29 min and 74.55{+-}8.52 min, respectively. The difference in mean gastric emptying T{sub 1/2} between patients before treatment and controls was statistically significant (P<0.01). The statistically significant difference persisted after vitamin B{sub 12} treatment (P<0.05), though mean gastric emptying T{sub 1/2} was somewhat shorter. There were no positive or negative correlations between gastric emptying T{sub 1/2} and the following parameters: haemoglobin, vitamin B{sub 12} level and Helicobacter pylori positivity. In conclusion, gastric emptying T{sub 1/2} was prolonged in patients with vitamin B{sub 12} deficiency and this prolongation was not corrected after vitamin B{sub 12} replacement therapy. Although autonomic nervous system dysfunction due to vitamin B{sub 12} deficiency rarely gives rise to clinical manifestations, latent dysfunction demonstrated by laboratory tests seems to be a frequent phenomenon

  17. [Characteristics and Outcomes of Treatment in Patients with Stage IV Colorectal Cancer with Mismatch Repair Deficiency].

    Science.gov (United States)

    Ishibashi, Keiichiro; Chika, Noriyasu; Suzuki, Okihide; Ito, Tetsuya; Amano, Kunihiko; Kumamoto, Kensuke; Fukuchi, Minoru; Kumagai, Youichi; Mochiki, Erito; Ishida, Hideyuki

    2016-11-01

    Mismatch repair(MMR)protein deficiency in colorectal cancer is well correlated with high-level microsatellite instability (MSI-H). There are little data on mismatch repair deficiency(dMMR)colorectal cancers in Japan. In addition, we have no available data on the therapeutic efficacy of oxaliplatin(oxa)-based chemotherapy, one of the standard treatment regimens for metastatic colorectal cancer, for patients with dMMR colorectal cancer. The subjects were 254 patients with Stage IV colorectal cancer whose tumors were immunohistochemically stained for MMR proteins, MLH1, MSH2, MSH6, and PMS2. Patients who underwent R0 resection were excluded. Clinicopathologic factors and the efficacy of oxa-based chemotherapy were compared between patients with dMMR colorectal cancer and those with mismatch repair proficient(pMMR)colorectal cancer. There were 7(2.8%)patients with dMMR. Four patients demonstrated both MLH1 and PMS2 loss, while 3 patients demonstrated both MSH2 and MSH6 loss. Though the dMMR had a higher frequency in female patients(p=0.02) and a lower frequency in those with liver metastasis(pcolorectal cancers was lower than those(4-11%)reported in Western countries. Therefore, the clinical significance of universal screeningfor dMMR in all colorectal cancer samples may not be valid. Concerningsurvival benefit, oxa-based chemotherapy seems to be an effective alternative in clinical practice for metastatic colorectal cancer patients with dMMR.

  18. Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis.

    Science.gov (United States)

    Wright, Aaron T; Magnaldo, Thierry; Sontag, Ryan L; Anderson, Lindsey N; Sadler, Natalie C; Piehowski, Paul D; Gache, Yannick; Weber, Thomas J

    2015-06-01

    Human phenotypes that are highly susceptible to radiation carcinogenesis have been identified. Sensitive phenotypes often display robust regulation of molecular features that modify biological response, which can facilitate identification of the pathways/networks that contribute to pathophysiological outcomes. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced inducible tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol reactive probes to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent Gorlin syndrome patients, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and ALDH1A1 protein deficiency in GDFs was confirmed by Western blot. A number of additional protein thiol differences in GDFs were identified, including radiation responsive annexin family members and lamin A/C. Collectively, candidates identified in our study have plausible implications for radiation health effects and cancer susceptibility.

  19. 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.

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    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

  2. 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

    invariably succumb to i.c. infection with LCMV strain Armstrong, although a few days later than matched wild-type mice. Upon further investigation, we found that this delay correlates with the delayed recruitment of inflammatory cells to the central nervous system (CNS). However, CD8(+) effector T cells were......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......, recent studies have revealed additional functional defects within the effector T cells of LCMV-infected perforin-deficient mice, raising the possibility that perforin may not be directly involved in mediating lethal disease. For this reason, we decided to reevaluate the role of perforin in determining...

  3. SALIVA IRON AND FERRITIN LEVELS IN PATIENTS WITH THALASSEMIA AND IRON DEFICIENCY ANEMIA

    Directory of Open Access Journals (Sweden)

    Duran Canatan

    2012-01-01

    Full Text Available

    Most of the  techniques for measuring iron accumulation such as serum iron concentration, iron binding capacity, serum ferritin level, liver biopsy are invasive and hard methods for patients. The changes in trace element concentrations in saliva at different systemic diseases shows the quantity of the element at the body. The aim of this study was to compare the levels of iron and ferritin in saliva and serum in patients  with thalassemia and iron deficiency anemia. For this purpose, 35 healthy children as control group and 71 thalassemia major, 10 thalassemia intermedia and 15 thalassemia trait patients were involved. Their saliva  and serum iron and ferritin levels were measured.  There was no statistically difference between age and gender in all groups and control group (p>0.05.  In all groups saliva iron levels are higher than serum iron levels(p<0.05. Furthermore there was a positive correlation betwen serum and saliva  iron levels in thalassemia major, intermedia and trait groups ( p=0.000, r=0.972, r=0.720, r=0.955 and also there was a positive correlation between serum and saliva iron levels in control and iron deficiency group (p= 0.000, r= 0.885, r= 0.368.  In conclusion,  Saliva iron and ferritin levels increase  as well as serum in patients with thalassemia and decrease in patients with iron deficiency anemia. Saliva can be used for diagnosis routinely  to shows the iron overload  and deficiency of the body and its easy applicability and also a non-invasive procedure is important advantage.

  4. SALIVA IRON AND FERRITIN LEVELS IN PATIENTS WITH THALASSEMIA AND IRON DEFICIENCY ANEMIA

    Directory of Open Access Journals (Sweden)

    Duran Canatan

    2012-08-01

    Full Text Available Most of the  techniques for measuring iron accumulation such as serum iron concentration, iron binding capacity, serum ferritin level, liver biopsy are invasive and hard methods for patients. The changes in trace element concentrations in saliva at different systemic diseases shows the quantity of the element at the body. The aim of this study was to compare the levels of iron and ferritin in saliva and serum in patients  with thalassemia and iron deficiency anemia. For this purpose, 35 healthy children as control group and 71 thalassemia major, 10 thalassemia intermedia and 15 thalassemia trait patients were involved. Their saliva  and serum iron and ferritin levels were measured.  There was no statistically difference between age and gender in all groups and control group (p>0.05.  In all groups saliva iron levels are higher than serum iron levels(p<0.05. Furthermore there was a positive correlation betwen serum and saliva  iron levels in thalassemia major, intermedia and trait groups ( p=0.000, r=0.972, r=0.720, r=0.955 and also there was a positive correlation between serum and saliva iron levels in control and iron deficiency group (p= 0.000, r= 0.885, r= 0.368.  In conclusion,  Saliva iron and ferritin levels increase  as well as serum in patients with thalassemia and decrease in patients with iron deficiency anemia. Saliva can be used for diagnosis routinely  to shows the iron overload  and deficiency of the body and its easy applicability and also a non-invasive procedure is important advantage.

  5. Vitamin D deficiency is associated with inflammatory cytokine concentrations in patients with diabetic foot infection.

    Science.gov (United States)

    Tiwari, Shalbha; Pratyush, Daliparthy Devi; Gupta, Sanjeev Kumar; Singh, Surya Kumar

    2014-12-28

    Vitamin D has been recognised as a potent immunomodulator and its deficiency is common in different population groups including patients with diabetic foot infection. Diabetic foot infection reflects the altered immune status of the host. As cytokine regulation plays a significant role in infection and wound-healing processes, the present study aimed to evaluate the association between vitamin D status and inflammatory cytokine profiles in patients with diabetic foot infection. The serum concentrations of vitamin D (25-hydroxyvitamin D), IL-1β, IL-6, TNF-α and interferon-γ (IFN-γ) were measured in 112 diabetic foot infection cases and 109 diabetic controls. Severe vitamin D deficiency (25-hydroxyvitamin D concentration diabetes, HbA1C (glycosylated Hb) concentration and BMI were similar, cases had significantly higher concentrations of IL-6 (P≤ 0.001), IL-1β (P≤ 0.02) and TNF-α (P≤ 0.006) than controls. A significant negative correlation was also observed between 25-hydroxyvitamin D concentration and circulating concentrations of IL-1β (r -0.323; P≤ 0.001) as well as IL-6 (r -0.154; P≤ 0.04), but not between 25-hydroxyvitamin D and TNF-α and IFN-γ concentrations. Furthermore, a significant difference in IL-1β (P≤ 0.007) and IL-6 (P≤ 0.02) concentrations was observed in patients with severe 25-hydroxyvitamin D deficiency compared with patients with 25-hydroxyvitamin D concentration ≥ 25 nmol/l, and this difference was remarkable for TNF-α. In conclusion, severe vitamin D deficiency is associated with elevated inflammatory cytokine concentrations in diabetic patients, particularly in those with foot infection. A 25-hydroxyvitamin D concentration value diabetes mellitus.

  6. Metaxin deficiency alters mitochondrial membrane permeability and leads to resistance to TNF-induced cell killing.

    Science.gov (United States)

    Ono, Koh; Wang, Xiaofei; Kim, Sung Ouk; Armstrong, Lucas C; Bornstein, Paul; Han, Jiahuai

    2010-02-01

    Metaxin, a mitochondrial outer membrane protein, is critical for TNF-induced cell death in L929 cells. Its deficiency, caused by retroviral insertion-mediated mutagenesis, renders L929 cells resistance to TNF killing. In this study, we further characterized metaxin deficiency-caused TNF resistance in parallel with Bcl-X(L) overexpression-mediated death resistance. We did not find obvious change in mitochondria membrane potential in metaxin-deficient (Met(mut)) and Bcl-X(L)-overexpressing cells, but we did find an increase in the release rate of the mitochondrial membrane potential probe rhodamine 123 (Rh123) that was preloaded into mitochondria. In addition, overexpression of a function-interfering mutant of metaxin (MetaΔTM/C) or Bcl-X(L) in MCF-7.3.28 cells also resulted in an acquired resistance to TNF killing and a faster rate of Rh123 release, indicating a close correlation between TNF resistance and higher rates of the dye release from the mitochondria. The release of Rh123 can be controlled by the mitochondrial membrane permeability transition (PT) pore, as targeting an inner membrane component of the PT pore by cyclosporin A (CsA) inhibited Rh123 release. However, metaxin deficiency and Bcl-X(L) overexpression apparently affect Rh123 release from a site(s) different from that of CsA, as CsA can overcome their effect. Though both metaxin and Bcl-X(L) appear to function on the outer mitochondrial membrane, they do not interact with each other. They may use different mechanisms to increase the permeability of Rh123, since previous studies have suggested that metaxin may influence certain outer membrane porins while Bcl-X(L) may form pores on the outer membrane. The alteration of the mitochondrial outer membrane properties by metaxin deficiency and Bcl-X(L) overexpression, as indicated by a quicker Rh123 release, may be helpful in maintaining mitochondrial integrity.

  7. 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.

  8. 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.

  9. Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients.

    Science.gov (United States)

    Hollak, C E M; de Sonnaville, E S V; Cassiman, D; Linthorst, G E; Groener, J E; Morava, E; Wevers, R A; Mannens, M; Aerts, J M F G; Meersseman, W; Akkerman, E; Niezen-Koning, K E; Mulder, M F; Visser, G; Wijburg, F A; Lefeber, D; Poorthuis, B J H M

    2012-11-01

    Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NPD-B], with a more variable spectrum of manifestations. Enzyme replacement therapy (ERT) with recombinant sphingomyelinase is currently studied as potential treatment for NPD-B patients. The objective of this study is to characterize the clinical features of patients with ASM deficiency in the Netherlands and Belgium with focus on the natural disease course of NPD-B patients. Prospective and retrospective data on ASM deficient patients were collected in The Netherlands and part of Belgium. Patients with NPD-B that could be followed prospectively were evaluated every 6-12 months for pulmonary function tests, 6 minute walk test (6 MWT), imaging (bone marrow infiltration measured by QCSI, organ volumes by MRI and CT scan of the lungs) and biochemical markers. Twenty-five patients with ASM deficiency were identified (13 males, 12 females, median age 13years, range 1-59 years). Nine patients had died at the time of the study, including four NPD-A patients at the age of 1,1, 2, 3 and five NPDB patents at the age of 5, 6, 43, 56 and 60 years. There was a high prevalence of homozygosity and compound heterozygosity for the common p.Arg608del mutation in 43% and 19% of NPD-B patients, respectively. In NPD-B patients, thrombocytopenia was present in most, while anemia and leucopenia were less common (33% and 6 % respectively). HDL cholesterol was reduced in most patients. Pulmonary disease was severe in several patients. Follow-up up to 11 years revealed a gradual decrease in platelet count. Detailed investigations in 6 NPD-B patients with follow-up in 4 patients revealed remarkable stable disease parameters up to 6 years, with some decline in pulmonary function and 6 MWT. Bone

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

    LENUS (Irish Health Repository)

    Haroon, Muhammad

    2012-02-01

    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.

  13. 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.

  14. PREVALENCE OF VITAMIN D DEFICIENCY IN DIFFERENT GROUPS OF CHRONIC RENAL FAILURE PATIENTS.

    Directory of Open Access Journals (Sweden)

    Bistra T. Galunska

    2015-09-01

    Full Text Available Purpose: To determine and compare the vitamin D status of different groups CKD patients on hemodialysis, peritoneal dialysis, or no renal replacement therapy and to evaluate the effect of vitamin D therapy. Patients and Methods: This pilot study enrolled 40 consecutive CKD patients (21 men, 19 women divided into three groups: 15 CKD patients in 1,2,3,4 stage of the disease without renal replacement therapy (RRT; 10CKD patients on hemodialysis (HD and 15 CKD patients on peritoneal dialysis (PD, ten of which were on vitamin D therapy. Vitamin D status was determined by serum 25-xydroxyvitamin D (25OHD. Results: Ninety percent of patients were in vitamin D deficiency/insufficiency; and only 4 patients (10.0% reached 25OHD levels above 75nmol/L. The median 25OHD level was 31.15nmol/L (interquartile range: 16.67-48.33nmol/L.Tendency of worse vitamin D status in women than in men was observed. Higher 25OHD levels were found in pre-dialysis patients (median 44.81nmol/L, 25%-75% percentile 16.24-52.21nmol/L and lower in HD (median 31.15nmol/L, 25%-75% percentile 13.04-64.45nmol/L and PD patients (median 33.38nmol/L, 25%-75% percentile 23.15-48.49nmol/L, but the difference did not reach statistical significance. Better vitamin D status was found in the PD group of patients receiving vitamin D preparations (p<0.05. Conclusions: 25OHD deficiency/insufficiency is prevalent in renal failure patients with or without renal replacement therapy. It seems that vitamin D therapy improves the vitamin D status of PD patients. Further larger studies are needed to clarify the effect of specific type vitamin D therapy on serum 25OHD levels and clinical outcome in different groups of CKD patients.

  15. 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...

  16. 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.

  17. Combined immune deficiency in a patient with a novel NFKB2 mutation.

    Science.gov (United States)

    Lindsley, Andrew W; Qian, Yaping; Valencia, C Alexander; Shah, Kara; Zhang, Kejian; Assa'ad, Amal

    2014-11-01

    NFKB2 encodes the p100/p52 protein, a critical mediator of the canonical and noncanonical NFkB signaling pathways. Here we report the comprehensive immune evaluation of a child with a novel NFKB2 mutation and provide evidence that aberrant NFKB2 signaling not only causes humoral immune deficiency, but also interferes with the TCR-mediated proliferation of T cells. These observations expand the known phenotype associated with NFKB2 mutations.

  18. 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".

  19. 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.

  20. PKK deficiency in B cells prevents lupus development in Sle lupus mice.

    Science.gov (United States)

    Oleksyn, D; Zhao, J; Vosoughi, A; Zhao, J C; Misra, R; Pentland, A P; Ryan, D; Anolik, J; Ritchlin, C; Looney, J; Anandarajah, A P; Schwartz, G; Calvi, L M; Georger, M; Mohan, C; Sanz, I; Chen, L

    2017-05-01

    Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can result in damage to multiple organs. It is well documented that B cells play a critical role in the development of the disease. We previously showed that protein kinase C associated kinase (PKK) is required for B1 cell development as well as for the survival of recirculating mature B cells and B-lymphoma cells. Here, we investigated the role of PKK in lupus development in a lupus mouse model. We demonstrate that the conditional deletion of PKK in B cells prevents lupus development in Sle1Sle3 mice. The loss of PKK in Sle mice resulted in the amelioration of multiple classical lupus-associated phenotypes and histologic features of lupus nephritis, including marked reduction in the levels of serum autoantibodies, proteinuria, spleen size, peritoneal B-1 cell population and the number of activated CD4 T cells. In addition, the abundance of autoreactive plasma cells normally seen in Sle lupus mice was also significantly decreased in the PKK-deficient Sle mice. Sle B cells deficient in PKK display defective proliferation responses to BCR and LPS stimulation. Consistently, B cell receptor-mediated NF-κB activation, which is required for the survival of activated B cells, was impaired in the PKK-deficient B cells. Taken together, our work uncovers a critical role of PKK in lupus development and suggests that targeting the PKK-mediated pathway may represent a promising therapeutic strategy for lupus treatment. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  1. 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...

  2. 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...... or placebo; and after a 12-month open phase of GH therapy. In the placebo group, insulin sensitivity and fat mass increased and lipid oxidation decreased, whereas glucose oxidation increased (p...

  3. [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.

  4. 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 ...

  5. Do PT and APTT sensitivities to factors' deficiencies calculated by the H47-A2 2008 CLSI guideline reflect the deficiencies found in plasmas from patients?

    Science.gov (United States)

    Martinuzzo, M; Barrera, L; Rodriguez, M; D'Adamo, M A; López, M S; Otaso, J C

    2015-12-01

    Prothrombin time (PT) and activated partial thromboplastin time (APTT) sensitivity for detecting isolated factor deficiencies varies with different reagents and coagulometers. The Clinical and Laboratory Standards Institute (CLSI) H47A2 guideline proposed a method to calculate these sensitivities, but some inconsistency has been reported. This study aimed to calculate factor sensitivities using CLSI guideline and to compare them with those obtained from single factor-deficient patients' data. Different mixtures of normal pooled and deficient plasmas were prepared (CLSI H47A2 guideline. PT with rabbit brain (RB) and human recombinant (HR) thromboplastins, APTT and factors' activities were measured in an ACL TOP coagulometer. Sensitivities (maximum factor concentration that produces PT or APTT values out of the reference range) were calculated from mixtures and from patients with single-factor deficiencies: 17 factor FV, 36 FVII, 19 FX, 39 FVIII, 15 FIX 15 FXI and 24 FXII. PT sensitivity with RB was as follows: FV 38 and 59, FVII 35 and 58, FX 56 and 64 IU/dL; PT sensitivity with HR was as follows: FV 39 and 45, FVII 51 and 50, FX 33 and 61 IU/dL; and APTT sensitivity was as follows: FV 39 and 45, FX 32 and 38, FVIII 47 and 60, FIX 35 and 44, FXI 33 and 43, FXII 37 and 46 IU/dL, respectively. Reagent-coagulometer combination has adequate sensitivities to factor deficiencies according to guideline recommendations (>30 IU/dL). These should not be considered as actual sensitivities because those obtained by analysing patients' plasmas with single-factor deficiencies were higher for most factors and could induce misinterpretation of the basic coagulation test results. © 2015 John Wiley & Sons Ltd.

  6. 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.

  7. 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...

  8. 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...

  9. 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.

  10. 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.

  11. [Effects of silicone punctal plugs for tear deficiency dry eye patients].

    Science.gov (United States)

    Shi, Shuai; Chen, Wei; Zhang, Xin; Ma, Hui-xiang; Sun, Li

    2013-02-01

    To evaluate the efficacy of silicone punctual plug for treating aqueous tear deficiency dry eye patients. Prospective consecutive cases study. Silicone punctal plugs (France Chirurgie Instrumentation) were inserted into lower canaliculus in 65 tear deficiency dry eye patients (65 eyes). The clinical data collected included sex and age of the patients, frequency of lubricant use, the Ocular Surface Disease Index (OSDI) scores, slit lamp microscope examination, Schirmer I test (SIT) (with anesthesia), tear break-up time (TBUT), and ocular surface staining with fluoresce in sodium. All examinations were recorded at baseline, 6 weeks and 6 months after punctal occlusion. There were 41 women and 24 men in this study, and their average age was 41.77 years old. The dry eye symptoms improved in 57 (87.69%) of 65 eyes at 6 months follow-up. The frequency of lubricant use was significantly decreased in these eyes (χ(2) = 81.97, P eyes, which did not need lubricant any more. At baseline, 6 weeks and 6 months after punctal occlusion, OSDI mean score was 37.32 ± 2.41, 19.60 ± 8.07 and 18.17 ± 7.93, respectively (F = 344.10, P eyes, 18.46%). Epiphora (4 eyes, 6.15%), partial extrusion (3 eyes, 4.62%), and total extrusion (3 eyes, 4.62%) were the other complications encountered. Silicone punctal plug insertion is a stable, effective and safety method for the treatment of tear deficiency dry eye.

  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. 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.

  14. 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. Copyright © 2013 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

  15. 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

  16. 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.

  17. Vitamin D deficiency in patients admitted to the general ward with breast, lung, and colorectal cancer in Buenos Aires, Argentina.

    Science.gov (United States)

    Aguirre, Marina; Manzano, Natalia; Salas, Yésica; Angel, Martín; Díaz-Couselo, Fernando A; Zylberman, Marcelo

    2016-01-01

    A high prevalence of hypovitaminosis D has been reported in cancer patients. Low levels of 25-(OH)-vitamin D were found in 158 of 162 (97.5%) inpatients with breast, lung, and colorectal cancer under active treatment, with severe deficiency (prevalence of vitamin D deficiency has been reported in cancer patients. Nevertheless, vitamin D serum levels have been checked in few patients. Information about the frequency of hypovitaminosis D in cancer patients in Argentina is unknown. The aim of the study was to assess the frequency of vitamin D deficiency in patients with breast, lung, and colorectal cancer. A prospective observational study was designed for cancer patients admitted to the general ward in 2014. The patients included had breast, lung, and colorectal cancer. All of them were under active treatment. The serum level of 25-(OH)-vitamin D [25-(OH)-D] was measured and categorized as sufficiency (>30 ng/ml), mild deficiency (20-30 ng/ml), and severe deficiency (colorectal cancer patients. The study found a high prevalence of vitamin D deficiency in hospitalized cancer patients under active treatment. Many authors have recommended dosing vitamin D levels in this population; normalizing serum levels is difficult.

  18. 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...

  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. 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.

  1. 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

  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. Characterizing T cells in SCID patients presenting with reactive or residual T lymphocytes.

    Science.gov (United States)

    Lev, Atar; Simon, Amos J; Trakhtenbrot, Luba; Goldstein, Itamar; Nagar, Meital; Stepensky, Polina; Rechavi, Gideon; Amariglio, Ninette; Somech, Raz

    2012-01-01

    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. 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. 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. 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.

  4. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.

    Directory of Open Access Journals (Sweden)

    Tim F Cloughesy

    2008-01-01

    Full Text Available BACKGROUND: There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. METHODS AND FINDINGS: Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR, we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation varied substantially. Tumor cell proliferation (measured by Ki-67 staining was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin

  5. Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency: The Karolinska Experience.

    Science.gov (United States)

    Olsson, Richard F; Hagelberg, Stefan; Schiller, Bodil; Ringdén, Olle; Truedsson, Lennart; Åhlin, Anders

    2016-06-01

    Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder. We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m) and fludarabine (30 mg/m) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate. A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved. Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy.

  6. 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,

  7. Antioxidant enzymes and oxidative stress in the erythrocytes of iron deficiency anemic patients supplemented with vitamins.

    Science.gov (United States)

    Madhikarmi, Nirjala Laxmi; Murthy, Kora Rudraiah Siddalinga

    2014-01-01

    Iron deficiency anemia is one of the major causes of morbidity and mortality worldwide. Evidences from epidemiological and clinical studies suggest a possible correlation between antioxidant levels and the anemic disease risk. The present work is to investigate antioxidant levels and lipid peroxidation in anemic patients. A number of 30 patients (15 males and 15 females) were selected for the study. Likewise, 30 age- and gender-matched healthy volunteers (15 males and 15 females) were selected with their informed consent. Patients and healthy subjects were supplemented with vitamins C and E for 15 days. The lipid peroxidation both in plasma and erythrocyte lysates was determined by thiobarbituric acid reactive substances and lipid peroxides. The antioxidant vitamins A, C, and E and total antioxidant activity were also analyzed. The antioxidant enzyme superoxide dismutase, catalase, and glutathione peroxidase were also determined. Based on analysis, we found that the increase in lipid peroxidation was higher in the anemic subjects before vitamin supplementation, which was statistically significant at Pantioxidant enzymes were higher in the patients before antioxidant supplementation when compared with patients after vitamin supplementation. Our data revealed higher oxidative stress before vitamin supplementation in iron deficiency anemic patients and after supplementation, lower lipid peroxidation and increased antioxidant vitamins were achieved.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. Essential fatty acid deficiency in patients receiving home parenteral nutrition 1,2

    DEFF Research Database (Denmark)

    Jeppesen, P. B.; Høy, Carl-Erik; Mortensen, Per B

    1998-01-01

    Home parenteral nutrition (HPN), initiated in patients with severe malabsorption or decreased oral intake, may exhaust stores of essential fatty acids and cause clinical manifestations, mainly dermatitis. Plasma fatty acid profiles were measured by gas-liquid chromatography in 37 healthy control...... of essential fatty acid deficiency (EFAD). The effect of parenteral lipid on plasma phospholipids was evaluated in subgroups of patients. In patients with > 200 cm of remaining small intestine, those receiving parenteral lipids had only minor changes in the fatty acids of plasma phospholipids compared...... with patients not receiving parenteral lipids. In patients with parenteral lipids had increased concentrations of total n-6 fatty acids; however, these did not reach the concentrations in control subjects. No differences were seen in n-3 fatty acids. Twenty...

  14. 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.

  15. 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

  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. Antioxidant dietary deficiency induces caspase activation in chick skeletal muscle cells

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    V.A. Nunes

    2003-08-01

    Full Text Available Apoptosis and necrosis are two distinct forms of cell death that can occur in response to different agents and stress conditions. In order to verify if the oxidative stress induced by dietary selenium and vitamin E deficiencies can lead muscle cells to apoptosis, one-day-old chicks were reared using diets differing in their vitamin E (0 or 10 IU/kg and selenium (0 or 0.15 ppm supplementation. Chick skeletal muscle tissue was obtained from 28-day-old animals and used to verify apoptosis occurrence based on caspase activity detection and DNA fragmentation. Antioxidant deficiency significantly increased caspase-like activity assessed by the hydrolysis of fluorogenic peptide substrates (Abz-peptidyl-EDDnp at lambdaexc = 320 nm and lambdaem = 420 nm. Proteolytic activation was not accompanied by typical internucleosomal DNA fragmentation detected by field inversion gel electrophoresis. Although the general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(O-Me fluoromethyl ketone (Z-VAD-fmk (0 to 80 muM did not block caspase-like activity when preincubated for 30 min with muscle homogenates, the hydrolyzed substrates presented the same cleavage profile in HPLC (at the aspartic acid residue when incubated with the purified recombinant enzyme caspase-3. These data indicate that oxidative stress causes caspase-like activation in muscle cells and suggest that cell death associated with exudative diathesis (dietary deficiency of selenium and vitamin E can follow the apoptotic pathway.

  19. 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.

  20. 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

  1. GAA Deficiency in Pompe Disease Is Alleviated by Exon Inclusion in iPSC-Derived Skeletal Muscle Cells

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    Erik van der Wal

    2017-06-01

    Full Text Available Pompe disease is a metabolic myopathy caused by deficiency of the acid α-glucosidase (GAA enzyme and results in progressive wasting of skeletal muscle cells. The c.-32-13T>G (IVS1 GAA variant promotes exon 2 skipping during pre-mRNA splicing and is the most common variant for the childhood/adult disease form. We previously identified antisense oligonucleotides (AONs that promoted GAA exon 2 inclusion in patient-derived fibroblasts. It was unknown how these AONs would affect GAA splicing in skeletal muscle cells. To test this, we expanded induced pluripotent stem cell (iPSC-derived myogenic progenitors and differentiated these to multinucleated myotubes. AONs restored splicing in myotubes to a similar extent as in fibroblasts, suggesting that they act by modulating the action of shared splicing regulators. AONs targeted the putative polypyrimidine tract of a cryptic splice acceptor site that was part of a pseudo exon in GAA intron 1. Blocking of the cryptic splice donor of the pseudo exon with AONs likewise promoted GAA exon 2 inclusion. The simultaneous blocking of the cryptic acceptor and cryptic donor sites restored the majority of canonical splicing and alleviated GAA enzyme deficiency. These results highlight the relevance of cryptic splicing in human disease and its potential as therapeutic target for splicing modulation using AONs.

  2. 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.

  3. 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

    variables were analysed in relation to cataplexy and hypocretin deficiency with uni- and multivariate logistic/linear regression models, controlling for possible rapid eye movement sleep behaviour disorder biasing factors (age, gender, disease duration, previous anti-cataplexy medication). Only hypocretin......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...

  4. Sustainability of Endovenous Iron Deficiency Anaemia Treatment: Hospital-Based Health Technology Assessment in IBD Patients

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    A. Poscia

    2017-01-01

    Full Text Available Iron deficiency anaemia (IDA is the main extraintestinal manifestation affecting patients with inflammatory bowel disease (IBD. The Health Technology Assessment approach was applied to evaluate the sustainability of intravenous (IV iron formulations in the Italian hospital setting, with particular focus on ferric carboxymaltose. Data on the epidemiology of IBD and associated IDA, in addition to the efficacy and safety of IV iron formulations currently used in Italy, were retrieved from scientific literature. A hospital-based cost-analysis of the outpatient delivery of IV iron treatments was performed. Organizational and ethical implications were discussed. IDA prevalence in IBD patients varies markedly from 9 to 73%. IV iron preparations were proven to have good efficacy and safety profiles, and ferric carboxymaltose provided a fast correction of haemoglobin and serum ferritin levels in iron-deficient patients. Despite a higher price, ferric carboxymaltose would confer a beneficial effect to the hospital, in terms of reduced cost related to individual patient management and additionally to the patient by reducing the number of infusions and admissions to healthcare facilities. Ethically, the evaluation is appropriate due to its efficacy and compliance. This assessment supports the introduction of ferric carboxymaltose in the Italian outpatient setting.

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

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    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

  6. Boron deficiency inhibits root cell elongation via an ethylene/auxin/ROS-dependent pathway in Arabidopsis seedlings

    Science.gov (United States)

    Camacho-Cristóbal, Juan J.; Martín-Rejano, Esperanza M.; Herrera-Rodríguez, M. Begoña; Navarro-Gochicoa, M. Teresa; Rexach, Jesús; González-Fontes, Agustín

    2015-01-01

    One of the earliest symptoms of boron (B) deficiency is the inhibition of root elongation which can reasonably be attributed to the damaging effects of B deprivation on cell wall integrity. It is shown here that exposure of wild-type Arabidopsis thaliana seedlings to B deficiency for 4h led to a drastic inhibition of root cell length in the transition between the elongation and differentiation zones. To investigate the possible mediation of ethylene, auxin, and reactive oxygen species (ROS) in the effect of B deficiency on root cell elongation, B deficiency was applied together with aminoethoxyvinylglycine (AVG, a chemical inhibitor of ethylene biosynthesis), silver ions (Ag+, an antagonist of ethylene perception), α-(phenylethyl-2‐oxo)‐indoleacetic acid (PEO-IAA, a synthetic antagonist of TIR1 receptor function), and diphenylene iodonium (DPI, an inhibitor of ROS production). Interestingly, all these chemicals partially or fully restored cell elongation in B-deficient roots. To further explore the possible role of ethylene and auxin in the inhibition of root cell elongation under B deficiency, a genetic approach was performed by using Arabidopsis mutants defective in the ethylene (ein2‐1) or auxin (eir1-4 and aux1-22) response. Root cell elongation in these mutants was less sensitive to B-deficient treatment than that in wild-type plants. Altogether, these results demonstrated that a signalling pathway involving ethylene, auxin, and ROS participates in the reduction of root cell elongation when Arabidopsis seedlings are subjected to B deficiency. A similar signalling process has been described to reduce root elongation rapidly under various types of cell wall stress which supports the idea that this signalling pathway is triggered by the impaired cell wall integrity caused by B deficiency. PMID:25922480

  7. 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.

  8. Iron Deficiency in Pediatric Patients in Long-Term Risperidone Treatment

    Science.gov (United States)

    Ziegler, Ekhard E.

    2013-01-01

    Abstract Objective Atypical antipsychotics, increasingly used in children and adolescents, modulate brain dopamine. Iron plays a critical role in dopaminergic signaling. Therefore, we explored whether body iron status is related to psychiatric symptom severity, treatment response, and tolerability following extended antipsychotic therapy. Methods Between November 2005 and August 2009, medically healthy 7–17-year-old risperidone-treated participants enrolled in a cross-sectional study examining the long-term safety of this antipsychotic. Anthropometric measurements were obtained. Psychiatric symptom severity and dietary intake were assessed. Serum ferritin, transferrin receptor, and prolactin concentrations were measured. Linear multivariable regression analysis tested the association among body iron, symptom severity, the dose of risperidone and psychostimulants, and serum prolactin concentration. Results The sample consisted of 115 patients (87% males) with a mean (±SD) age of 11.6 (±2.8) years. The majority had externalizing disorders, and they had taken risperidone for 2.4 (±1.7) years. Body iron was low, with 45% having iron depletion and 14% having iron deficiency. Iron status was inversely associated with weight gain during risperidone treatment and with interleukin-6. Body iron was neither associated with psychiatric symptom severity nor with the daily dose of risperidone and psychostimulants. It was, however, inversely associated with prolactin concentration, which was nearly 50% higher in the iron-deficient group. Conclusions Iron depletion and deficiency are prevalent in children and adolescents chronically treated with risperidone. Iron deficiency accentuates the antipsychotic-induced elevation in prolactin. Future studies should confirm this finding and investigate the potential benefit of iron supplementation in antipsychotic-treated patients. PMID:23480322

  9. 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...

  10. 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…

  11. 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

  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. Mutator Phenotype and DNA Double-Strand Break Repair in BLM Helicase-Deficient Human Cells.

    Science.gov (United States)

    Suzuki, Tetsuya; Yasui, Manabu; Honma, Masamitsu

    2016-12-01

    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. Copyright © 2016 Suzuki et al.

  14. A deficiency of uPAR alters endothelial angiogenic function and cell morphology

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    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.

  15. 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.

  16. The Cardiac effect of Rapid Maxillary expansion Patients with Maxillary Deficiency

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    Oral Sökücü

    2014-05-01

    Full Text Available Background: The aim of this study is to evaluate the affect of rapid maxillary expansion (RME on cardiologic parameter.Methods: 12 patients (4 male and 8 females with maxillary deficiency and bilateral cross-bite were selected to this study group. Before RME 24 h Holter monitoring of electrocardiography was used on patients. The prevalence analysis of arrhythmias, mean heart rate (MHR and ventricular premature contraction (VPC analysis was assessed over a 24-h period. Six months after achieving successfully expansion the Holter procedure was repeated again on patients.Results: VPC count per day and MHR, detected on 24 h ambulatory electrocardiography, showed significant statistical difference was present in pre and post-treatment periods. (VPC; 54.25±69.56/day, 6.50±5.98/day p<0.05; MHR; 108±12/day, 82±8/day p<0.05: respectivelyConclusion: The patients with maxillary deficiency may have been a potential with cardiologic abnormalities. The expansion may improve the cardiac problems by expansion.

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

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    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.

  18. Incidence of adverse drug reactions in human immune deficiency virus-positive patients using highly active antiretroviral therapy

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    B Akshaya Srikanth

    2012-01-01

    Full Text Available To estimate the incidence of adverse drug reactions (ADRs in Human immune deficiency virus (HIV patients on highly active antiretroviral therapy (HAART. To identify the risk factors associated with ADRs in HIV patients. To analyze reported ADRs based on various parameters like causality, severity, predictability, and preventability. Retrospective case-control study. An 18-month retrospective case-control study of 208 patients newly registered in ART center, RIMS hospital, Kadapa, were intensively monitored for ADRs to HAART. Predictability was calculated based on the history of previous exposure to drug. Multivariate logistic regressions were used to identify the risk factors for ADRs. Data were analyzed using the chi-square test for estimating the correlation between ADRs and different variables. All statistical calculations were performed using EpiInfo version 3.5.3. Monitoring of 208 retrospective patients by active Pharmacovigilance identified 105 ADRs that were identified in 71 patients. Skin rash and anemia were the most commonly observed ADRs. The organ system commonly affected by ADR was skin and appendages (31.57%. The ADRs that were moderate were 90.14% of cases. The incidence of ADRs (53.52% was higher with Zidovudine + Lamivudine + Nevirapine combination. CD4 cell count less than <250 cells/μl were 80.28%, male gender were observed to be the risk factors for ADRs. Our study finding showed that there is a need of active pharmaceutical care with intensive monitoring for ADRs in Indian HIV-positive patients who are illiterate, of male and female gender, with CD4 count ≤250 cells/mm 3 with comorbid conditions.

  19. Restoring Ureagenesis in Hepatocytes by CRISPR/Cas9-mediated Genomic Addition to Arginase-deficient Induced Pluripotent Stem Cells

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    Patrick C Lee

    2016-01-01

    Full Text Available Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies. In this study, we demonstrate a universally-applicable CRISPR/Cas9-based strategy utilizing exon 1 of the hypoxanthine-guanine phosphoribosyltransferase locus to genetically modify and restore arginase activity, and thus ureagenesis, in genetically distinct patient-specific human induced pluripotent stem cells and hepatocyte-like derivatives. Successful strategies restoring gene function in patient-specific human induced pluripotent stem cells may advance applications of genetically modified cell therapy to treat urea cycle and other inborn errors of metabolism.

  20. Effects of PARP-1 Deficiency on Th1 and Th2 Cell Differentiation

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    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.

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

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    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. Safeguarding of Fetal Growth by Mast Cells and Natural Killer Cells: Deficiency of One Is Counterbalanced by the Other

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    Nicole Meyer

    2017-06-01

    Full Text Available Uterine natural killer cells (uNKs and mast cells (uMCs are of crucial importance for spiral artery (SA remodeling and placentation. Mice deficient for both NKs and MCs including uNKs and uMCs show markedly impaired SA remodeling and their fetuses are growth-retarded. In contrast, the absence of either NKs or MCs results in only minor impairment. This suggests that uNKs can compensate for the effects of uMCs on SA remodeling and vice versa. To test this hypothesis, we assessed uNK numbers in uMC-deficient mice as well as uMC numbers in uNK-depleted mice. Notably, uMC-deficient C57BL/6J-KitW-sh/W-sh (W-sh mice showed markedly increased numbers of uNKs in contrast to wild type, and the transfer of bone marrow-derived MCs reverted this phenotype. Vice versa, uNK-deficient C57BL/6NTac-IL15tm1ImxN5 (IL-15−/− mice had significantly increased numbers of uMCs and MC-specific proteases. Our results suggest that uNKs and uMCs can counterbalance their effects at the feto–maternal interface and jointly promote SA remodeling and placentation.

  3. T cells from Programmed Death-1 deficient mice respond poorly to Mycobacterium tuberculosis infection.

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    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.

  4. Establishment of HeLa cell mutants deficient in sphingolipid-related genes using TALENs.

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    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.

  5. Excretion of laccase by sycamore (Acer pseudoplatanus L.) cells. Effects of a copper deficiency.

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    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.

  6. Estrogen deficiency leads to telomerase inhibition,telomere shortening and reduced cell proliferation in the adrenal gland of mice

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    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.

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

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    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.

  8. RAD51AP1-deficiency in vertebrate cells impairs DNA replication.

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    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.

  9. Investigation of iron deficiency in patients with congestive heart failure: A medical practice that requires greater attention.

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    Belmar Vega, Lara; de Francisco, Alm; Albines Fiestas, Zoila; Serrano Soto, Mara; Kislikova, María; Seras Mozas, Miguel; Unzueta, Mayte García; Arias Rodríguez, Manuel

    2016-01-01

    Iron deficiency in congestive heart failure (CHF), with or without concomitant anaemia, is associated with health-related quality of life, NYHA functional class, and exercise capacity. Prospective, randomised studies have demonstrated that correcting iron deficiency improves the quality of life and functional status of patients with CHF, including those who do not have anaemia. The aim of this study was to analyse how frequently these iron parameters are tested and thus determine the extent to which this quality improvement tool has been implemented in patients admitted with CHF. Retrospective observational study of patients from a university hospital diagnosed with CHF on admission between 01/01/2012 and 11/06/2013. Iron parameters were tested in 39% (324) of the 824 patients analysed. There was no significant difference in age between the patients whose iron was tested and those whose iron was not tested, but the difference in terms of gender was significant (P=.007). Glomerular filtration rate and haemoglobin, were significantly lower in the group of patients whose iron was tested (P<.001). The proportion of patients with anaemia, renal failure or both was significantly higher in the group of patients who had iron tests (P<.001). Of the 324 patients whose iron parameters were tested, 164 (51%) had iron deficiency. There were no differences between patients with and without iron deficiency in terms of age or gender. The iron parameters in both groups, ferritin and transferrin saturation index were significantly lower among the patients with iron deficiency (P<.001). The glomerular filtration rate values were significantly lower in patients with no iron deficiency (P<.001). Significant differences were also observed between those with and without iron deficiency in the proportion of patients with renal failure (79 vs. 66%, respectively, P=.013), but not in terms of haemoglobin concentration. Congestive heart failure is very frequently associated with anaemia, iron

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

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    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)