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Sample records for immunodeficieny disease scid

  1. The use of SCID mice in biotechnology and as a model for human disease

    SciTech Connect

    Sandhu, J.S. |; Boynton, E.; Gorczynski, R.; Hozumi, N.

    1996-05-01

    The use of SCID (severe combined immunodeficient) mice in medical research and biotechnology has increased tremendously in recent years. This review outlines the major characteristics of these animals and the impediments that they poise to the engraftment of human cells and tissues. The development of the SCID mice pretreatment protocol (anti-asialo GM 1 antisera and radiation) is described, and the results of xenotransplantation studies of human cells and tissues in these pretreated animals are outlined. Wherever possible, data from transplantation studies (of human tissues and cells) in pretreated and nonpretreated animals are compared. The potential of the pretreated SCID mice for medical research and biotechnology is discussed.

  2. Eliminating SCID row: new approaches to SCID.

    PubMed

    Kohn, Donald B

    2014-12-01

    Treatments for patients with SCID by hematopoietic stem cell transplantation (HSCT) have changed this otherwise lethal primary immune deficiency disorder into one with an increasingly good prognosis. SCID has been the paradigm disorder supporting many key advances in the field of HSCT, with first-in-human successes with matched sibling, haploidentical, and matched unrelated donor allogeneic transplantations. Nevertheless, the optimal approaches for HSCT are still being defined, including determining the optimal stem cell sources, the use and types of pretransplantation conditioning, and applications for SCID subtypes associated with radiosensitivity, for patients with active viral infections and for neonates. Alternatively, autologous transplantation after ex vivo gene correction (gene therapy) has been applied successfully to the treatment of adenosine deaminase-deficient SCID and X-linked SCID by vector-mediated gene addition. Gene therapy holds the prospect of avoiding risks of GVHD and would allow each patient to be their own donor. New approaches to gene therapy by gene correction in autologous HSCs using site-specific endonuclease-mediated homology-driven gene repair are under development. With newborn screening becoming more widely adopted to detect SCID patients before they develop complications, the prognosis for SCID is expected to improve further. This chapter reviews recent advances and ongoing controversies in allogeneic and autologous HSCT for SCID.

  3. Development of autoimmune disease in SCID mice populated with long-term "in vitro" proliferating (NZB x NZW)F1 pre-B cells

    PubMed Central

    1992-01-01

    Pre-B cell lines proliferating for several months on stromal cells in the presence of interleukin 7 (IL-7) were established from fetal liver of (NZB x NZW)F1 mice. They express the B lineage-specific markers PB76, B220, and VpreB, but do not express surface immunoglobulin (sIg). Upon removal of IL-7 from the culture, they differentiate to sIg+ B cells that can then be stimulated by lipopolysaccharide to become IgM- secreting cells. Transfer of these pre-B cell lines into SCID mice leads to hypergammaglobulinemia of IgM (600-900 micrograms/ml), IgG2a (1-3 mg/ml), and IgG3 (300-500 micrograms/ml) for the next 3-5 mo. The spleen appears populated with (NZB x NZW)F1-derived pre-B cells, few B cells, and many IgM and/or IgG-producing plasma cells. In contrast, SCID mice populated with pre-B cell lines of normal (C57BL/6 x DBA/2)F1 mouse fetal liver develop normal levels of serum IgM (approximately 100- 300 micrograms/ml), almost no detectable levels of IgG, and no plasma cell hyperplasia. The (NZB x NZW)F1 pre-B cell-populated SCID mice contain elevated serum titers of IgG antinuclear autoantibodies, but no retroviral gp70-specific nor erythrocyte-specific autoantibodies. Up to 20% of the SCID mice develop proteinuria as a consequence of IgG deposits in the kidney glomeruli during a 7-mo period of observation. All signs of autoimmune disease seen in these mice are independent of the sex of the SCID host. This experimental system provides a distinction between the disease-determining (NZB x NZW)F1 genes, which are expressed in the B lymphocyte lineage and cause the development of the disease, from those expressed in other cell lineages which only modulate its progression. PMID:1402680

  4. NOD/SCID-GAMMA mice are an ideal strain to assess the efficacy of therapeutic agents used in the treatment of myeloma bone disease.

    PubMed

    Lawson, Michelle A; Paton-Hough, Julia M; Evans, Holly R; Walker, Rebecca E; Harris, William; Ratnabalan, Dharshi; Snowden, John A; Chantry, Andrew D

    2015-01-01

    Animal models of multiple myeloma vary in terms of consistency of onset, degree of tumour burden and degree of myeloma bone disease. Here we describe five pre-clinical models of myeloma in NOD/SCID-GAMMA mice to specifically study the effects of therapeutic agents on myeloma bone disease. Groups of 7-8 week old female irradiated NOD/SCID-GAMMA mice were injected intravenously via the tail vein with either 1x106 JJN3, U266, XG-1 or OPM-2 human myeloma cell lines or patient-derived myeloma cells. At the first signs of morbidity in each tumour group all animals were sacrificed. Tumour load was measured by histological analysis, and bone disease was assessed by micro-CT and standard histomorphometric methods. Mice injected with JJN3, U266 or OPM-2 cells showed high tumour bone marrow infiltration of the long bones with low variability, resulting in osteolytic lesions. In contrast, mice injected with XG-1 or patient-derived myeloma cells showed lower tumour bone marrow infiltration and less bone disease with high variability. Injection of JJN3 cells into NOD/SCID-GAMMA mice resulted in an aggressive, short-term model of myeloma with mice exhibiting signs of morbidity 3 weeks later. Treating these mice with zoledronic acid at the time of tumour cell injection or once tumour was established prevented JJN3-induced bone disease but did not reduce tumour burden, whereas, carfilzomib treatment given once tumour was established significantly reduced tumour burden. Injection of U266, XG-1, OPM-2 and patient-derived myeloma cells resulted in less aggressive longer-term models of myeloma with mice exhibiting signs of morbidity 8 weeks later. Treating U266-induced disease with zoledronic acid prevented the formation of osteolytic lesions and trabecular bone loss as well as reducing tumour burden whereas, carfilzomib treatment only reduced tumour burden. In summary, JJN3, U266 or OPM-2 cells injected into NOD/SCID-GAMMA mice provide robust models to study anti-myeloma therapies

  5. Development of novel major histocompatibility complex class I and class II-deficient NOD-SCID IL2R gamma chain knockout mice for modeling human xenogeneic graft-versus-host disease.

    PubMed

    Pino, Steve; Brehm, Michael A; Covassin-Barberis, Laurence; King, Marie; Gott, Bruce; Chase, Thomas H; Wagner, Jennifer; Burzenski, Lisa; Foreman, Oded; Greiner, Dale L; Shultz, Leonard D

    2010-01-01

    Immunodeficient mice have been used as recipients of human peripheral blood mononuclear cells (PBMC) for in vivo analyses of human xeno-graft-versus-host disease (GVHD). This xeno-GVHD model system in many ways mimics the human disease. The model system is established by intravenous or intraperitoneal injection of human PBMC or spleen cells into unconditioned or irradiated immunodeficient recipient mice. Recently, the development of several stocks of immunodeficient Prkdc ( scid ) (scid) and recombination activating 1 or 2 gene (Rag1 or Rag2) knockout mice bearing a targeted mutation in the gene encoding the IL2 receptor gamma chain (IL2rgamma) have been reported. The addition of the mutated IL2rgamma gene onto an immunodeficient mouse stock facilitates heightened engraftment with human PBMC. Stocks of mice with mutations in the IL2rgamma gene have been studied in several laboratories on NOD-scid, NOD-Rag1 ( null ), BALB/c-Rag1 ( null ), BALB/c-Rag2 ( null ), and Stock-H2(d)-Rag2 ( null ) strain backgrounds. Parameters to induce human xeno-GVHD in H2(d)-Rag2 ( null ) IL2rgamma ( null ) mice have been published, but variability in the frequency of disease and kinetics of GVHD were observed. The availability of the NOD-scid IL2rgamma ( null ) stock that engrafts more readily with human PBMC than does the Stock-H2(d)-Rag2 ( null ) IL2rgamma ( null ) stock should lead to a more reproducible humanized mouse model of GVHD and for the use in drug evaluation and validation. Furthermore, GVHD in human PBMC-engrafted scid mice has been postulated to result predominately from a human anti-mouse major histocompatibility complex (MHC) class II reactivity. Our recent development of NOD-scid IL2rgamma ( null ) beta2m ( null ) and NOD-scid IL2rgamma ( null ) Ab ( null ) stocks of mice now make it possible to investigate directly the role of host MHC class I and class II in the pathogenesis of GVHD in humanized mice using NOD-scid IL2rgamma ( null ) stocks that engraft at high

  6. Attenuation of graft-versus-host-disease in NOD scid IL-2Rγ(-/-) (NSG) mice by ex vivo modulation of human CD4(+) T cells.

    PubMed

    Hilger, Nadja; Glaser, Jakob; Müller, Claudia; Halbich, Christoph; Müller, Anne; Schwertassek, Ulla; Lehmann, Jörg; Ruschpler, Peter; Lange, Franziska; Boldt, Andreas; Stahl, Lilly; Sack, Ulrich; Oelkrug, Christopher; Emmrich, Frank; Fricke, Stephan

    2016-09-01

    NOD.Cg-Prkdc(scid) IL-2rg(tm1Wjl) /SzJ (NSG) mice are a valuable tool for studying Graft-versus-Host-Disease (GvHD) induced by human immune cells. We used a model of acute GvHD by transfer of human peripheral blood mononuclear cells (PBMCs) into NSG mice. The severity of GvHD was reflected by weight loss and was associated with engraftment of human cells and the expansion of leukocytes, particularly granulocytes and monocytes. Pre-treatment of PBMCs with the anti-human CD4 antibody MAX.16H5 IgG1 or IgG4 attenuated GvHD. The transplantation of 2 × 10(7) PBMCs without anti-human CD4 pre-treatment induced a severe GvHD (0% survival). In animals receiving 2 × 10(7) PBMCs pre-incubated with MAX.16H5 IgG1 or IgG4, GvHD development was reduced and survival was increased. Immune reconstitution was measured by flow cytometry and confirmed for human leukocytes (CD45), CD3(+) /CD8(+) cytotoxic T cells and CD3(+) /CD4(+) T helper cells. Human B cells (CD19) and monocytes (CD14) could not be detected. Histopathological analysis (TUNEL assay) of the gut of recipient animals showed significantly less apoptotic crypt cells in animals receiving a MAX.16H5 IgG1 pre-incubated graft. These findings indicate that pre-incubation of an allogeneic graft with an anti-human CD4 antibody may decrease the frequency and severity of GvHD after hematopoietic stem cell transplantation (HSCT) and the need of conventional immunosuppressive drugs. Moreover, this approach most probably provides a safer HSCT that must be confirmed in appropriate clinical trials in the future. © 2016 International Society for Advancement of Cytometry. PMID:27560708

  7. Improved Engraftment of Human Spleen Cells in NOD/LtSz-scid/scid Mice as Compared with C.B-17-scid/scid Mice

    PubMed Central

    Greiner, Dale L.; Shultz, Leonard D.; Yates, Jon; Appel, Michael C.; Perdrizet, George; Hesselton, RuthAnn M.; Schweitzer, Isabelle; Beamer, Wes G.; Shultz, Kathryn L.; Pelsue, Stephen C.; Leif, Jean H.; Rajan, Thiruchandurai V.

    1995-01-01

    T and B lymphocyte-deficient mice homozygous for the severe combined immunodeficiency (SCID) mutation can be immunologically engrafted with human lymphocytes. However, low levels of human peripheral blood mononuclear cell engraftment are commonly observed, impeding full use of this model We now demonstrate that strain background in mice homozygous for the scid mutation is a strong determinant of levels of human lymphocyte engraftment. NOD/LtSz-scid/scid mice support higher levels of engraftment of both human spleen and peripheral blood mononuclear cells than do C.B-17-scid/scid mice. We observed, using human spleen cell injected scid mice, 1), high levels of engraftment of the host peripheral lymphoid tissues with human CD45+ (leukocytes), CD3+ (T cells), CD4+ (helper/inducer), and CD8+ (suppressor/cytotoxic) lymphoid cells for up to 24 weeks in NOD/LtSz-scid/scid mice; 2), migration of high numbers of human lymphocytes to peripheral lymphoid and nonlymphoid organs in NOD/LtSz-scid/scid, but not in C.B-17-scid/scid mice; 3), higher levels of serum immunoglobulin of human origin in NOD/LtSz-scid/scid mice than in C.B-17-scid/scid mice; 4), histological lesions character-istic of human anti-mouse xenoreactivity in NOD/LtSz-scid/scid mice; and 5), human origin antibodies against filarial antigens after engraftment with naive human spleen cells. The use of NOD/LtSz-scid/scid mice as recipients to achieve significantly enhanced human lymphopoietic cell engraftment will now enable human immunity to be more easily studied in animal models. ImagesFigure 5Figure 6Figure 7Figure 8Figure 9Figure 10Figure 12 PMID:7717456

  8. Suppression of dsDNA-specific B lymphocytes reduces disease symptoms in SCID model of mouse lupus.

    PubMed

    Gesheva, Vera; Kerekov, Nikola; Nikolova, Kalina; Mihaylova, Nikolina; Todorov, Todor; Nikolova, Maria; Tchorbanov, Andrey

    2014-05-01

    Self-specific B cells play a main role in the pathogenesis of lupus. This autoimmune disease is characterized by the generation of autoantibodies against self antigens, and the elimination of B and T cells involved in the pathological immune response is a logical approach for effective therapy. We have previously constructed a chimeric molecule by coupling a DNA-mimotope peptides to an anti-CD32 antibody. Using this protein molecule for the treatment of lupus-prone MRL/lpr mice, we suppressed selectively the autoreactive B-lymphocytes by cross-linking B cell receptors with the inhibitory FcγRIIb receptors. This approach was limited by the development of anti-chimeric antibodies in MRL mice. In order to avoid this problem, we established a murine severe combined immunodeficiency lupus model, allowing a long-term chimera therapy. Elimination of the double-stranded DNA-specific B cells by chimera therapy in MRL-transferred immunodeficient mice resulted in inhibition of T cell proliferation and prevented the appearance of IgG anti-DNA antibodies and of proteinuria.

  9. Differentiation of uterine natural killer cells in pregnant SCID (scid/scid) mice.

    PubMed

    Hiyama, Masato; Kusakabe, Ken Takeshi; Kuwahara, Ai; Wakitani, Shoichi; Khan, Hamayun; Kiso, Yasuo

    2011-10-01

    To determine whether functional T- and B-cells can affect differentiation and/or proliferation of uterine natural killer (uNK) cells, their numbers in SCID mice (genotype, C.B.-17/Icr-scid/scid) were compared with those of control mice (genotype, C.B.-17/Icr-+/+) on days 8, 12 and 16 of pregnancy. Using biotinylated-Dolichos biflorus agglutinin (DBA) lectin staining, uNK cells can be readily classified into 4 subtypes, I to IV, from immature to mature types. The number of uNK cells was significantly lower in the decidua basalis of SCID mice than in that of control mice on day 8 of pregnancy. Particularly, the number of uNK cells of immature subtype II was significantly lower in SCID mice than in the control mice. By day 12, however, the uNK cell number in the SCID mice reached the same level as that of the control mice. It is likely that uNK cell differentiation in SCID mice was delayed during the early placentation period due to a lack of functional T and B cells.

  10. Severe combined immunodeficiency (SCID): from molecular basis to clinical management.

    PubMed

    Sponzilli, Ivonne; Notarangelo, Luigi D

    2011-04-01

    Primary immune deficiency diseases (PID) comprise a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, as well as T and B lymphocytes. Severe combined immunodeficiency (SCID) is a group of disorders characterized by increased susceptibility to severe infections and early death. The diagnosis of SCID is supported by the demonstration of low absolute lymphocyte count and T cell lymphopenia (variably associated with numerical defects of B and NK cells). In the last two decades, advances in the characterization of the molecular pathophysiology of SCID, have permitted the development of novel diagnostic assays based on analysis of the expression of the disease-associated proteins and mutation analysis. More recently, pilot newborn screening programs for the identification of infants with SCID have been initiated in the United States. Prompt and aggressive treatment of infections, antimicrobial prophylaxis (in particular against Pneumocystis jiroveci) and regular administration of immunoglobulins are essential to reduce the risk of early death. However, survival ultimately depends on reconstitution of immune function, that is usually achieved by means of hematopoietic cell transplantation (HCT). Gene therapy and enzyme replacement therapy have also been used successfully is selected forms of SCID. Here we review the molecular and cellular pathophysiology and the mainstay of treatment of SCID.

  11. Validation of the NetSCID: an automated web-based adaptive version of the SCID.

    PubMed

    Brodey, Benjamin B; First, Michael; Linthicum, Jared; Haman, Kirsten; Sasiela, Jordan W; Ayer, David

    2016-04-01

    The present study developed and validated a configurable, adaptive, web-based version of the Structured Clinical Interview for DSM, the NetSCID. The validation included 24 clinicians who administered the SCID and 230 participants who completed the paper SCID and/or the NetSCID. Data-entry errors, branching errors, and clinician satisfaction were quantified. Relative to the paper SCID, the NetSCID resulted in far fewer data-entry and branching errors. Clinicians 'preferred' using the NetSCID and found that the NetSCID was easier to administer. PMID:26995238

  12. Impaired Lymphocytes Development and Xenotransplantation of Gastrointestinal Tumor Cells in Prkdc-Null SCID Zebrafish Model.

    PubMed

    Jung, In Hye; Chung, Yong-Yoon; Jung, Dawoon E; Kim, Young Jin; Kim, Do Hee; Kim, Kyung-Sik; Park, Seung Woo

    2016-08-01

    Severe combined immunodeficiency (SCID) mice have widely been used as hosts for human tumor cell xenograft study. This animal model, however, is labor intensive. As zebrafish is largely emerging as a promising model system for studying human diseases including cancer, developing efficient immunocompromised strains for tumor xenograft study are also demanded in zebrafish. Here, we have created the Prkdc-null SCID zebrafish model which provides the stable immune-deficient background required for xenotransplantation of tumor cell. In this study, the two transcription activator-like effector nucleases that specifically target the exon3 of the zebrafish Prkdc gene were used to induce a frame shift mutation, causing a complete knockout of the gene function. The SCID zebrafish showed susceptibility to spontaneous infection, a well-known phenotype found in the SCID mutation. Further characterization revealed that the SCID zebrafish contained no functional T and B lymphocytes which reflected the phenotypes identified in the mice SCID model. Intraperitoneal injection of human cancer cells into the adult SCID zebrafish clearly showed tumor cell growth forming into a solid mass. Our present data show the suitability of using the SCID zebrafish strain for xenotransplantation experiments, and in vivo monitoring of the tumor cell growth in the zebrafish demonstrates use of the animal model as a new platform of tumor xenograft study.

  13. Impaired Lymphocytes Development and Xenotransplantation of Gastrointestinal Tumor Cells in Prkdc-Null SCID Zebrafish Model.

    PubMed

    Jung, In Hye; Chung, Yong-Yoon; Jung, Dawoon E; Kim, Young Jin; Kim, Do Hee; Kim, Kyung-Sik; Park, Seung Woo

    2016-08-01

    Severe combined immunodeficiency (SCID) mice have widely been used as hosts for human tumor cell xenograft study. This animal model, however, is labor intensive. As zebrafish is largely emerging as a promising model system for studying human diseases including cancer, developing efficient immunocompromised strains for tumor xenograft study are also demanded in zebrafish. Here, we have created the Prkdc-null SCID zebrafish model which provides the stable immune-deficient background required for xenotransplantation of tumor cell. In this study, the two transcription activator-like effector nucleases that specifically target the exon3 of the zebrafish Prkdc gene were used to induce a frame shift mutation, causing a complete knockout of the gene function. The SCID zebrafish showed susceptibility to spontaneous infection, a well-known phenotype found in the SCID mutation. Further characterization revealed that the SCID zebrafish contained no functional T and B lymphocytes which reflected the phenotypes identified in the mice SCID model. Intraperitoneal injection of human cancer cells into the adult SCID zebrafish clearly showed tumor cell growth forming into a solid mass. Our present data show the suitability of using the SCID zebrafish strain for xenotransplantation experiments, and in vivo monitoring of the tumor cell growth in the zebrafish demonstrates use of the animal model as a new platform of tumor xenograft study. PMID:27566103

  14. Spontaneous nonthymic tumors in SCID mice.

    PubMed

    Huang, Peigen; Westmoreland, Susan V; Jain, Rakesh K; Fukumura, Dai

    2011-06-01

    SCID mice provide an excellent platform for cancer research. Because of their lack of immunity, SCID mice readily succumb to infectious pathogens and therefore must be maintained in an SPF, barrier-protected environment. Although SPF and barrier facilities prevent infection, SCID mice remain prone to premature death due in part to a high prevalence of spontaneous thymic lymphomas. However, little is known about spontaneous nonthymic tumors in SCID mice. We therefore analyzed the incidence of nonthymic tumor in our defined-flora C.B-17/Icr-SCID/Sed mice and examined their histopathologic characteristics. We necropsied 1060 retired SCID breeders (506 males, 554 females; average ages of 325 and 320 d, respectively) and found that 24 mice had developed nonthymic tumors, yielding an incidence of 2.26% (1.78% in males; 2.71% in females). The incidence of nonthymic tumors was substantially lower than that of thymic lymphomas in our retired SCID breeders (12.3% in males; 4.15% in females). Based on histopathology, 9 nonthymic tumors in male SCID mice consisted of 4 salivary gland myoepiteliomas, 2 rhabdomyosarcomas, and 3 cases of leukemia involving multiple organs. Female SCID mice had 15 nonthymic tumors consisting of 8 mammary adenocarcinomas, 4 salivary gland myoepitheliomas, and 1 case each of leukemia, rhabdomyosarcoma, and fibrosarcoma. In addition, we tested in vivo transplantability and characterized the growth behavior of several of these tumors. To our knowledge, this report is the first comprehensive description of spontaneous nonthymic tumors, including 8 myoepitheliomas and 3 rhabdomyosarcomas, from the same SCID mouse colony.

  15. Learning about Severe Combined Immunodeficiency (SCID)

    MedlinePlus

    ... of page What do we know about the immune system and SCID? Lymphocytes, a type of white blood ... compensate for the mutation. Thus, they have normal immune systems. However, since males have only one X chromosome ...

  16. Guidelines for Screening, Early Diagnosis and Management of Severe Combined Immunodeficiency (SCID) in India.

    PubMed

    Madkaikar, Manisha; Aluri, Jahnavi; Gupta, Sudhir

    2016-05-01

    Severe combined immunodeficiency (SCID) is one of the most severe and fatal forms of inherited primary immunodeficiency. Early diagnosis of SCID improves the outcome of life before and after hematopoietic stem cell transplant (HSCT). SCID fulfills the internationally-established criteria for a condition to be screened for at birth. T cell receptor excision circle (TREC) assay is commonly used in western countries as part of newborn blood spot screening (NBS) program as the assay has high sensitivity and specificity to identify SCID infants, allowing early intervention and curative bone marrow (BM) transplantation. In India, the blood spot based screening programs are yet to mature into a full-fledged national program. Moreover, TREC assay, a PCR based test, is not widely available and may cost USD 5-7 per test; thus limiting its applicability for screening newborns in Indian scenario. Most of the SCID patients have lymphopenia at birth and routine evaluation for absolute lymphocyte count (ALC) on cord blood samples can help in pre-symptomatic detection and early intervention for neonates with SCID. Although ALC count lacks the sensitivity and specificity of TREC assay; its lower cost and widespread availability makes it an attractive option for identifying newborns with lymphopenia during the post-partum hospital stay. BCG vaccine and other live attenuated vaccines (e.g., oral polio vaccine) should be withheld in lymphopenic infants until SCID is excluded by clinical and/or immunological work-up. A diagnosis of SCID warrants immediate care to prevent and treat infections and wherever feasible, early stem cell transplantation for disease free survival.

  17. Guidelines for Screening, Early Diagnosis and Management of Severe Combined Immunodeficiency (SCID) in India.

    PubMed

    Madkaikar, Manisha; Aluri, Jahnavi; Gupta, Sudhir

    2016-05-01

    Severe combined immunodeficiency (SCID) is one of the most severe and fatal forms of inherited primary immunodeficiency. Early diagnosis of SCID improves the outcome of life before and after hematopoietic stem cell transplant (HSCT). SCID fulfills the internationally-established criteria for a condition to be screened for at birth. T cell receptor excision circle (TREC) assay is commonly used in western countries as part of newborn blood spot screening (NBS) program as the assay has high sensitivity and specificity to identify SCID infants, allowing early intervention and curative bone marrow (BM) transplantation. In India, the blood spot based screening programs are yet to mature into a full-fledged national program. Moreover, TREC assay, a PCR based test, is not widely available and may cost USD 5-7 per test; thus limiting its applicability for screening newborns in Indian scenario. Most of the SCID patients have lymphopenia at birth and routine evaluation for absolute lymphocyte count (ALC) on cord blood samples can help in pre-symptomatic detection and early intervention for neonates with SCID. Although ALC count lacks the sensitivity and specificity of TREC assay; its lower cost and widespread availability makes it an attractive option for identifying newborns with lymphopenia during the post-partum hospital stay. BCG vaccine and other live attenuated vaccines (e.g., oral polio vaccine) should be withheld in lymphopenic infants until SCID is excluded by clinical and/or immunological work-up. A diagnosis of SCID warrants immediate care to prevent and treat infections and wherever feasible, early stem cell transplantation for disease free survival. PMID:26920398

  18. Atypical radiation response of SCID cells

    NASA Astrophysics Data System (ADS)

    Chawapun, Nisa

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

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

    PubMed Central

    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.

    2014-01-01

    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. PMID:24144642

  20. Humanized Chronic Graft-versus-Host Disease in NOD-SCID il2rγ-/- (NSG) Mice with G-CSF-Mobilized Peripheral Blood Mononuclear Cells following Cyclophosphamide and Total Body Irradiation.

    PubMed

    Fujii, Hisaki; Luo, Zhi-Juan; Kim, Hye Jin; Newbigging, Susan; Gassas, Adam; Keating, Armand; Egeler, R Maarten

    2015-01-01

    Chronic graft-versus-host disease (cGvHD) is the major source of late phase morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Humanized acute GvHD (aGvHD) in vivo models using NOD-SCID il2rγ-/- (NSG) mice are well described and are important tools for investigating pathogenicity of human cells in vivo. However, there have been only few reported humanized cGvHD mouse models. We evaluated if prolonged inflammation driven by low dose G-CSF-mobilized human PBMCs (G-hPBMCs) would lead to cGvHD following cyclophosphamide (CTX) administration and total body irradiation (TBI) in NSG mice. Engraftment was assessed in peripheral blood (PB) and in specific target organs by either flow cytometry or immunohistochemistry (IHC). Tissue samples were harvested 56 days post transplantation and were evaluated by a pathologist. Some mice were kept for up to 84 days to evaluate the degree of fibrosis. Mice that received CTX at 20mg/kg did not show aGvHD with stable expansion of human CD45+ CD3+ T-cells in PB (mean; 5.8 to 23.2%). The pathology and fibrosis scores in the lung and the liver were significantly increased with aggregation of T-cells and hCD68+ macrophages. There was a correlation between liver pathology score and the percentage of hCD68+ cells, suggesting the role of macrophage in fibrogenesis in NSG mice. In order to study long-term survival, 6/9 mice who survived more than 56 days showed increased fibrosis in the lung and liver at the endpoint, which suggests the infiltrating hCD68+ macrophages may be pathogenic. It was shown that the combination of CTX and TBI with a low number of G-hPBMCs (1x106) leads to chronic lung and liver inflammation driven by a high infiltration of human macrophage and mature human T cells from the graft, resulting in fibrosis of lung and liver in NSG mice. In conclusion this model may serve as an important pre-clinical model to further current understanding of the roles of human macrophages in cGvHD.

  1. SCID: Model for Effective Instructional Development.

    ERIC Educational Resources Information Center

    Norton, Robert E.

    The Systematic Curriculum and Instructional Development (SCID) model provides a tested procedure for developing high-quality, low-cost competency-based education and tech prep curriculum and instructional materials. It consists of 5 phases--analysis, design, development, implementation, and evaluation--and 23 components. The analysis phase…

  2. Web Pages Created Via SCID Process.

    ERIC Educational Resources Information Center

    Stammen, Ronald M.

    This paper describes the use of a management process, Systematic Curriculum and Instructional Development (SCID), for developing online multimedia modules. The project, "Collaboratively Creating Multimedia Modules for Teachers and Professors," was funded by the USWEST Foundation. The curriculum development process involved teams of experts in…

  3. Treatment of severe combined immunodeficiency disease (SCID) due to adenosine deaminase deficiency with CD34+ selected autologous peripheral blood cells transduced with a human ADA gene. Amendment to clinical research project, Project 90-C-195, January 10, 1992.

    PubMed

    Blaese, R M; Culver, K W; Chang, L; Anderson, W F; Mullen, C; Nienhuis, A; Carter, C; Dunbar, C; Leitman, S; Berger, M

    1993-08-01

    Significant increases in lymphocyte adenosine deaminase activity, T cell numbers and immune function have been achieved in the two children with SCID thus far treated with autologous T cells genetically-corrected by retroviral-mediated insertion of a normal ADA gene. Although the data obtained to date demonstrate that the use of ADA gene corrected peripheral T cells appears to be an effective treatment for ADA(-)SCID, it is theoretically preferable to try to develop a treatment for these children that will result in stem cell gene correction. The genetic correction of T cell progenitors with long-term immune reconstituting ability would be more desirable because repeated infusions of genetically altered cells should not be necessary and the generation of a more complete repertoire of T cell specificities might also be possible. Furthermore, the present treatment protocol involves indefinite continuation of enzyme replacement treatment with PEG-ADA. The demonstration of ADA gene expression in the progeny of transduced stem cells may simplify the decision concerning cessation of this very costly enzyme treatment (approximately $250,000/yr./patient). Recent evidence suggests that a small fraction of bone marrow or peripheral blood mononuclear cells bearing the CD34 antigen contains hematopoietic stem cells with both lymphoid and myeloid reconstituting ability. We propose in this amendment to supplement the infusion of human ADA gene-transduced autologous T cells in children with ADA(-)SCID with autologous peripheral blood CD34+ cells transduced with a second, readily distinguishable ADA vector.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Not All SCID Pigs Are Created Equally: Two Independent Mutations in the Artemis Gene Cause SCID in Pigs.

    PubMed

    Waide, Emily H; Dekkers, Jack C M; Ross, Jason W; Rowland, Raymond R R; Wyatt, Carol R; Ewen, Catherine L; Evans, Alyssa B; Thekkoot, Dinesh M; Boddicker, Nicholas J; Serão, Nick V L; Ellinwood, N Matthew; Tuggle, Christopher K

    2015-10-01

    Mutations in >30 genes are known to result in impairment of the adaptive immune system, causing a group of disorders collectively known as SCID. SCID disorders are split into groups based on their presence and/or functionality of B, T, and NK cells. Piglets from a line of Yorkshire pigs at Iowa State University were shown to be affected by T(-)B(-)NK(+) SCID, representing, to our knowledge, the first example of naturally occurring SCID in pigs. In this study, we present evidence for two spontaneous mutations as the molecular basis for this SCID phenotype. Flow cytometry analysis of thymocytes showed an increased frequency of immature T cells in SCID pigs. Fibroblasts from these pigs were more sensitive to ionizing radiation than non-SCID piglets, eliminating the RAG1 and RAG2 genes. Genetic and molecular analyses showed that two mutations were present in the Artemis gene, which in the homozygous or compound heterozygous state cause the immunodeficient phenotype. Rescue of SCID fibroblast radiosensitivity by human Artemis protein demonstrated that the identified Artemis mutations are the direct cause of this cellular phenotype. The work presented in the present study reveals two mutations in the Artemis gene that cause T(-)B(-)NK(+) SCID in pigs. The SCID pig can be an important biomedical model, but these mutations would be undesirable in commercial pig populations. The identified mutations and associated genetic tests can be used to address both of these issues.

  5. Infection of SCID mice with Montana Myotis leukoencephalitis virus as a model for flavivirus encephalitis.

    PubMed

    Charlier, Nathalie; Leyssen, Pieter; Paeshuyse, Jan; Drosten, Christian; Schmitz, Herbert; Van Lommel, Alfons; De Clercq, Erik; Neyts, Johan

    2002-08-01

    We have established a convenient animal model for flavivirus encephalitis using Montana Myotis leukoencephalitis virus (MMLV), a bat flavivirus. This virus has the same genomic organization, and contains the same conserved motifs in genes that encode potential antiviral targets, as flaviviruses that cause disease in man (N. Charlier et al., accompanying paper), and has a similar particle size (approximately 40 nm). MMLV replicates well in Vero cells and appears to be equally as sensitive as yellow fever virus and dengue fever virus to a selection of experimental antiviral agents. Cells infected with MMLV show dilation of the endoplasmic reticulum, a characteristic of flavivirus infection. Intraperitoneal, intranasal or direct intracerebral inoculation of SCID mice with MMLV resulted in encephalitis ultimately leading to death, whereas immunocompetent mice were refractory to either intranasal or intraperitoneal infection with MMLV. Viral RNA and/or antigens were detected in the brain and serum of MMLV-infected SCID mice, but not in any other organ examined: MMLV was detected in the olfactory lobes, the cerebral cortex, the limbic structures, the midbrain, cerebellum and medulla oblongata. Infection was confined to neurons. Treatment with the interferon-alpha/beta inducer poly(I).poly(C) protected SCID mice against MMLV-induced morbidity and mortality, and this protection correlated with a reduction in infectious virus titre and viral RNA load. This validates the MMLV model for use in antiviral drug studies. The MMLV SCID model may, therefore, be attractive for the study of chemoprophylactic or chemotherapeutic strategies against flavivirus infections causing encephalitis.

  6. SCID: A Competency-Based Curriculum Development Model.

    ERIC Educational Resources Information Center

    Norton, Robert E.

    To provide structure for developing curriculum for Competency Based Education (CBE), an effective and efficient model, Systematic Curriculum and Instructional Development (SCID), has been devised. SCID has five phases: analysis, design, development, implementation, and evaluation. Each of 23 components involves several steps, some optional. Phase…

  7. Severe combined immunodeficiency (SCID) presenting with neonatal aplastic anemia.

    PubMed

    Scott, Angela; Glover, Jason; Skoda-Smith, Suzanne; Torgerson, Troy R; Xu, Min; Burroughs, Lauri M; Woolfrey, Ann E; Fleming, Mark D; Shimamura, Akiko

    2015-11-01

    Aplastic anemia in the neonate is rare. We report a case of severe combined immunodeficiency (SCID) presenting with neonatal aplastic anemia. This report highlights the importance of considering SCID early in the evaluation of neonatal aplastic anemia prior to the development of infectious complications.

  8. Pathogenicity of Helicobacter rodentium in A/JCr and SCID mice.

    PubMed

    Myles, Matthew H; Livingston, Robert S; Franklin, Craig L

    2004-10-01

    Helicobacter rodentium was first recognized as a potential pathogen when it was isolated, along with Helicobacter bilis, from a colony of scid/Trp53 knockout mice with diarrhea. Clinical disease in these mice was more severe than that previously reported in mice infected with H. bilis alone, thus suggesting that H. rodentium contributed to the pathogenesis of enteritis. The purpose of the study reported here was to address two questions: is H. rodentium pathogenic in mice, and when co-infection with a pathogenic helicobacter occurs, does H. rodentium augment disease? To this end, A/JCr and C.B-17/IcrCrl-scidBr mice were inoculated with H. rodentium and/or H. hepaticus. Twelve weeks after inoculation, mice were euthanized. The cecum and liver were evaluated microscopically for evidence of disease. Cecal interferon-inducible protein 10 (IP-10), macrophage inflammatory protein 1alpha (MIP-1alpha), interleukin 10 (IL-10), and interferon gamma (IFN-gamma) mRNA values were measured as an indicator of mucosal immune response. Hepatic lesions were not identified in mice mono-infected with H. rodentium; likewise, cecal lesion scores were not significantly different from those of uninfected controls. With the exception of an increased IL-10 mRNA value in SCID mice, mean immune-related gene expression in H. rodentium mono-infected and uninfected control mice was not significantly different. In contrast, all mice infected with H. hepaticus developed moderate to severe hepatitis, significant increase in cecal lesion scores, and increased immune-related gene expression. The C.B-17/IcrCrl-scidBr mice co-infected with H. hepaticus and H. rodentium had liquid cecal contents and low terminal body weight. Further, compared with mice infected with H. hepaticus alone, co-infection was associated with significant increases of IL-10, MIP-1alpha, and IP-10 mRNA values in C.B-17/IcrCrl-scidBr and IFN-gamma and MIP-1alpha mRNA values in A/JCr mice. These results suggested that H. rodentium

  9. Differential Secondary Reconstitution of In Vivo-Selected Human SCID-Repopulating Cells in NOD/SCID versus NOD/SCID/γ chain Mice.

    PubMed

    Cai, Shanbao; Wang, Haiyan; Bailey, Barbara; Hartwell, Jennifer R; Silver, Jayne M; Juliar, Beth E; Sinn, Anthony L; Baluyut, Arthur R; Pollok, Karen E

    2011-01-01

    Humanized bone-marrow xenograft models that can monitor the long-term impact of gene-therapy strategies will help facilitate evaluation of clinical utility. The ability of the murine bone-marrow microenvironment in NOD/SCID versus NOD/SCID/γ chain(null) mice to support long-term engraftment of MGMT(P140K)-transduced human-hematopoietic cells following alkylator-mediated in vivo selection was investigated. Mice were transplanted with MGMT(P140K)-transduced CD34(+) cells and transduced cells selected in vivo. At 4 months after transplantation, levels of human-cell engraftment, and MGMT(P140K)-transduced cells in the bone marrow of NOD/SCID versus NSG mice varied slightly in vehicle- and drug-treated mice. In secondary transplants, although equal numbers of MGMT(P140K)-transduced human cells were transplanted, engraftment was significantly higher in NOD/SCID/γ chain(null) mice compared to NOD/SCID mice at 2 months after transplantation. These data indicate that reconstitution of NOD/SCID/γ chain(null) mice with human-hematopoietic cells represents a more promising model in which to test for genotoxicity and efficacy of strategies that focus on manipulation of long-term repopulating cells of human origin.

  10. Successful newborn screening for SCID in the Navajo Nation.

    PubMed

    Kwan, Antonia; Hu, Diana; Song, Miran; Gomes, Heidi; Brown, Denise R; Bourque, Trudy; Gonzalez-Espinosa, Diana; Lin, Zhili; Cowan, Morton J; Puck, Jennifer M

    2015-05-01

    Newborn screening (NBS) for severe combined immunodeficiency (SCID) identifies affected infants before the onset of life-threatening infections, permitting optimal treatment. Navajo Native Americans have a founder mutation in the DNA repair enzyme Artemis, resulting in frequent Artemis SCID (SCID-A). A pilot study at 2 Navajo hospitals assessed the feasibility of SCID NBS in this population. Dried blood spots from 1800 infants were assayed by PCR for T-cell receptor excision circles (TRECs), a biomarker for naïve T cells. Starting in February 2012, TREC testing transitioned to standard care throughout the Navajo Area Indian Health Service, and a total of 7900 infants were screened through July 2014. One infant had low TRECs and was diagnosed with non-SCID T lymphopenia, while 4 had undetectable TRECs due to SCID-A, all of whom were referred for hematopoietic cell transplantation. This report establishes the incidence of SCID-A and demonstrates effectiveness of TREC NBS in the Navajo.

  11. Successful Newborn Screening for SCID in the Navajo Nation

    PubMed Central

    Kwan, Antonia; Hu, Diana; Song, Miran; Gomes, Heidi; Brown, Denise R.; Bourque, Trudy; Gonzalez-Espinosa, Diana; Lin, Zhili; Cowan, Morton J.; Puck, Jennifer M.

    2015-01-01

    Newborn screening (NBS) for severe combined immunodeficiency (SCID) identifies affected infants before the onset of life-threatening infections, permitting optimal treatment. Navajo Native Americans have a founder mutation in the DNA repair enzyme Artemis, resulting in frequent Artemis SCID (SCID-A). A pilot study at 2 Navajo hospitals assessed the feasibility of SCID NBS in this population. Dried blood spots from 1,800 infants were assayed by PCR for T-cell receptor excision circles (TRECs), a biomarker for naïve T cells. Starting in February 2012, TREC testing transitioned to standard care throughout the Navajo Area Indian Health Service, and a total of 7,900 infants were screened through July 2014. One infant had low TRECs and was diagnosed with non-SCID T lymphopenia, while 4 had undetectable TRECs due to SCID-A, all of whom were referred for hematopoietic cell transplantation. This report establishes the incidence of SCID-A and demonstrates effectiveness of TREC NBS in the Navajo. PMID:25762520

  12. Successful newborn screening for SCID in the Navajo Nation.

    PubMed

    Kwan, Antonia; Hu, Diana; Song, Miran; Gomes, Heidi; Brown, Denise R; Bourque, Trudy; Gonzalez-Espinosa, Diana; Lin, Zhili; Cowan, Morton J; Puck, Jennifer M

    2015-05-01

    Newborn screening (NBS) for severe combined immunodeficiency (SCID) identifies affected infants before the onset of life-threatening infections, permitting optimal treatment. Navajo Native Americans have a founder mutation in the DNA repair enzyme Artemis, resulting in frequent Artemis SCID (SCID-A). A pilot study at 2 Navajo hospitals assessed the feasibility of SCID NBS in this population. Dried blood spots from 1800 infants were assayed by PCR for T-cell receptor excision circles (TRECs), a biomarker for naïve T cells. Starting in February 2012, TREC testing transitioned to standard care throughout the Navajo Area Indian Health Service, and a total of 7900 infants were screened through July 2014. One infant had low TRECs and was diagnosed with non-SCID T lymphopenia, while 4 had undetectable TRECs due to SCID-A, all of whom were referred for hematopoietic cell transplantation. This report establishes the incidence of SCID-A and demonstrates effectiveness of TREC NBS in the Navajo. PMID:25762520

  13. Complementation analysis of the murine scid cell line

    SciTech Connect

    Zdzienicka, M.Z. |; Priestly, A.; Jeggo, P.A.

    1995-09-01

    It has been shown that several X-ray-sensitive Chinese hamster cell mutants defective in repair of DNA double-strand breaks (DSBs) are also impaired in the process of V(D)J recombination. The hamster mutants with this phenotype represent three distinct complementation groups, represented by the xrs series, XR-1 and V-3. The murine scid cell line also shows the same phenotype, and therefore we examined whether the scid mutant represents a new complementation group or belongs to one of the existing groups. Scid cells were fused with hamster cell mutants representing the three complementation groups. Hybrids between V-3 and scid cells were only partially complemented for X-ray sensitivity, whereas hybrids derived from fusions with the other mutants were resistant to X rays. These results suggest that V-3 and scid cells are defective in the same gene. To confirm this finding, a single human chromosome 8, which is known to carry the scid gene, was introduced into V-3 cells by microcell-mediated chromosome transfer. Nine hybrid clones derived from V-3 and carrying human chromosome 8 were obtained, and seven were found to be partially complemented for X-ray sensitivity. When human chromosome 8 was introduced into scid cells, seven of eight hybrid clones became resistant to X rays. The results indicate that the defective genes in V-3 and scid are both localized on human chromosome 8. This supports the results from the fusion analysis that V-3 and scid cells are defective in the same gene. 53 refs., 4 figs., 1 tab.

  14. Data in support of the bone analysis of NOD-SCID mice treated with zoledronic acid and prednisolone.

    PubMed

    Hori, Naoko; Abe, Takahiro; Sato, Tsuyoshi; Kokabu, Shoichiro; Shimamura, Yumiko; Sato, Tomoya; Yoda, Tetsuya

    2016-06-01

    This paper reports data on the bone, specifically the tibia and mandible, of nonobese diabetic mice with severe combined immunodeficiency disease (NOD-SCID mice) treated with zoledronic acid (ZA) and prednisolone (PSL). The data described here are related to the research article titled "Zoledronic acid basically increases circulating soluble RANKL level in mice, and in glucocorticoid-administrated mice, more increases lymphocytes derived sRANKL by bacterial endotoxic stimuli" [1]. The present data and the NOD-SCID mice experiments described contain insights into the role of bone-remodeling factors induced by ZA treatment.

  15. E2f1-deficient NOD/SCID mice have dry mouth due to a change of acinar/duct structure and the down-regulation of AQP5 in the salivary gland.

    PubMed

    Satoh, Keitaro; Narita, Takanori; Matsuki-Fukushima, Miwako; Okabayashi, Ken; Ito, Tatsuro; Senpuku, Hidenobu; Sugiya, Hiroshi

    2013-02-01

    Non-obese diabetic (NOD) mice have been used as a model for dry mouth. NOD mice lacking the gene encoding E2f1, a transcription factor, develop hyposalivation more rapidly progressively than control NOD mice. However, the model mice are associated with an underlying disease such as diabetes. We have now established E2f1-deficient NOD/severe combined immunodeficiency disease (NOD/SCID.E2f1(-/-)) mice to avoid the development of diabetes (Matsui-Inohara et al., Exp Biol Med (Maywood) 234(12):1525-1536, 2009). In this study, we investigated the pathophysiological features of dry mouth using NOD/SCID.E2f1(-/-) mice. In NOD/SCID.E2f1(-/-) mice, the volume of secreted saliva stimulated with pilocarpine is about one third that of control NOD/SCID mice. In behavioral analysis, NOD/SCID.E2f1(-/-) mice drank plenty of water when they ate dry food, and the frequency and time of water intake were almost double compared with control NOD/SCID mice. Histological analysis of submandibular glands with hematoxylin-eosin stain revealed that NOD/SCID.E2f1(-/-) mice have more ducts than NOD/SCID mice. In western blot analysis, the expression of aquaporin 5 (AQP5), a marker of acinar cells, in parotid and in submandibular glands of NOD/SCID.E2f1(-/-) mice was lower than in NOD/SCID mice. Immunohistochemical analysis of parotid and submandibular acini revealed that the localization of AQP5 in NOD/SCID.E2f1(-/-) mice differs from that in NOD/SCID mice; AQP5 was leaky and diffusively localized from the apical membrane to the cytosol in NOD/SCID.E2f1(-/-) mice. The ubiquitination of AQP5 was detected in submandibular glands of NOD/SCID.E2f1(-/-) mice. These findings suggest that the change of acinar/duct structure and the down-regulation of AQP5 in the salivary gland cause the pathogenesis of hyposalivation in NOD/SCID.E2f1(-/-) mice.

  16. Clinical characteristics and genetic profiles of 44 patients with severe combined immunodeficiency (SCID): report from Shanghai, China (2004-2011).

    PubMed

    Yao, Chun-Mei; Han, Xiao-Hua; Zhang, Yi-Dan; Zhang, Hui; Jin, Ying-Ying; Cao, Rui-Ming; Wang, Xi; Liu, Quan-Hua; Zhao, Wei; Chen, Tong-Xin

    2013-04-01

    Severe combined immunodeficiency (SCID), a rare type of genetic associated immune disorder, is poorly characterized in mainland China. We retrospectively reviewed 44 patients with SCID who received treatment from 2004 to 2011 in Shanghai, China, and herein summarize their clinical manifestations and immunological and preliminary genetic features. The male-to-female ratio was 10:1. Twenty five patients presented with X-SCID symptoms. Only one patient was diagnosed before the onset of symptoms due to positive family history. The mean time of delay in the diagnosis of X-SCID was 2.69 months (range, 0.5-8.67). Thirty-seven of the 44 patients died by the end of 2011 with the mean age of death being 7.87 months (range, 1.33-31). Six patients received hematopoietic stem cell transplantation (HSCT); only one of them survived, who was transplanted twice. The time between onset and death was shorter in the HSCT-treated group compared with the untreated group (2.87 ± 1.28 and 3.34 ± 0.59 months, respectively), probably due to active infections during transplantation. Bacillus Calmette-Guérin (BCG) complications occurred in 14 of the 34 patients who received BCG vaccination. Transfusion-induced graft-versus-host disease occurred in 5 patients. Total 20 mutations in interleukin-2 receptor subunit gamma (IL2RG) were identified in 22 patients, including 11 novel mutations. Most patients were misdiagnosed before referred to our SCID Center. Therefore, establishing more diagnostic centers dedicated to the care of PID and accessible by primary immunodeficiency patients will facilitate early, correct diagnosis and better care of SCID in China.

  17. Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy.

    PubMed

    Titova, Ksenya A; Sergeev, Alexander A; Zamedyanskaya, Alena S; Galahova, Darya O; Kabanov, Alexey S; Morozova, Anastasia A; Bulychev, Leonid E; Sergeev, Artemiy A; Glotova, Tanyana I; Shishkina, Larisa N; Taranov, Oleg S; Omigov, Vladimir V; Zavjalov, Evgenii L; Agafonov, Alexander P; Sergeev, Alexander N

    2015-09-01

    The possibility of using immunocompetent ICR mice and immunodeficient SCID mice as model animals for smallpox to assess antiviral drug efficacy was investigated. Clinical signs of the disease did not appear following intranasal (i.n.) challenge of mice with strain Ind-3a of variola virus (VARV), even when using the highest possible dose of the virus (5.2 log10 p.f.u.). The 50 % infective doses (ID50) of VARV, estimated by the virus presence or absence in the lungs 3 and 4 days post-infection, were 2.7 ± 0.4 log10 p.f.u. for ICR mice and 3.5 ± 0.7 log10 p.f.u. for SCID mice. After i.n. challenge of ICR and SCID mice with VARV 30 and 50 ID50, respectively, steady reproduction of the virus occurred only in the respiratory tract (lungs and nose). Pathological inflammatory destructive changes were revealed in the respiratory tract and the primary target cells for VARV (macrophages and epithelial cells) in mice, similar to those in humans and cynomolgus macaques. The use of mice to assess antiviral efficacies of NIOCH-14 and ST-246 demonstrated the compliance of results with those described in scientific literature, which opens up the prospect of their use as an animal model for smallpox to develop anti-smallpox drugs intended for humans. PMID:26067292

  18. Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy.

    PubMed

    Titova, Ksenya A; Sergeev, Alexander A; Zamedyanskaya, Alena S; Galahova, Darya O; Kabanov, Alexey S; Morozova, Anastasia A; Bulychev, Leonid E; Sergeev, Artemiy A; Glotova, Tanyana I; Shishkina, Larisa N; Taranov, Oleg S; Omigov, Vladimir V; Zavjalov, Evgenii L; Agafonov, Alexander P; Sergeev, Alexander N

    2015-09-01

    The possibility of using immunocompetent ICR mice and immunodeficient SCID mice as model animals for smallpox to assess antiviral drug efficacy was investigated. Clinical signs of the disease did not appear following intranasal (i.n.) challenge of mice with strain Ind-3a of variola virus (VARV), even when using the highest possible dose of the virus (5.2 log10 p.f.u.). The 50 % infective doses (ID50) of VARV, estimated by the virus presence or absence in the lungs 3 and 4 days post-infection, were 2.7 ± 0.4 log10 p.f.u. for ICR mice and 3.5 ± 0.7 log10 p.f.u. for SCID mice. After i.n. challenge of ICR and SCID mice with VARV 30 and 50 ID50, respectively, steady reproduction of the virus occurred only in the respiratory tract (lungs and nose). Pathological inflammatory destructive changes were revealed in the respiratory tract and the primary target cells for VARV (macrophages and epithelial cells) in mice, similar to those in humans and cynomolgus macaques. The use of mice to assess antiviral efficacies of NIOCH-14 and ST-246 demonstrated the compliance of results with those described in scientific literature, which opens up the prospect of their use as an animal model for smallpox to develop anti-smallpox drugs intended for humans.

  19. Breast cancer metastasis in a human bone NOD/SCID mouse model.

    PubMed

    Yang, Wenyi; Lam, Pearl; Kitching, Richard; Kahn, Harriette J; Yee, Albert; Aubin, Jane E; Seth, Arun

    2007-08-01

    A major dilemma facing patients with breast cancer is how to decide between over treating indolent tumors and failing to adequately treat aggressive, potentially lethal cancers. Determination of the metastatic potential of a patient's breast cancer would clearly help guide those treatment decisions. Breast cancer commonly spreads to bone in 70% of women with advanced disease. However, the mechanism of bone metastasis is not well understood. One possibility is that the microenvironment within bone marrow, highly rich in growth factors and cytokines, is suitable for the proliferation of breast cancer cells. In this study, we developed a method for implanting human bone in NOD/SCID mice and show that the human bone implants are viable for more than 20 weeks. This human bone NOD/SCID mouse model provides an opportunity to functionally characterize human breast cancer cell behavior in an in vivo human microenvironment. Several breast tumor cell lines have been shown to grow in the human-bone-NOD/SCID model system, however each line has a different functional profile. Here we show that cotransplantation of GFP-MDA-MB-231 breast cancer cells with morcellized human bone allows for tissue specific metastasis to an initially tumor free bone implant. Furthermore, metastasis of breast tumor cells to implanted tumor-free human bone was seen when patient bone containing a metastatic breast tumor was implanted in the host mouse. With this model, we can distinguish between primary invasive breast tumors with and without bone metastatic potential. PMID:17704641

  20. An intrinsic BM hematopoietic niche occupancy defect of HSC in scid mice facilitates exogenous HSC engraftment.

    PubMed

    Qing, Yulan; Lin, Yuan; Gerson, Stanton L

    2012-02-16

    Although scid mice have been widely used for human HSC engraftment studies, the function of HSCs of scid mice has not been characterized. We hypothesized that the DNA repair defect of scid mice results in a stem cell defect that facilitates HSC engraftment. scid BM cells showed severely impaired repopulation potentials in the competitive repopulation assay. To assess the BM hematopoietic niche occupancy ability of scid HSC, WT BM cells were transplanted into scid mice without any conditioning and observed to achieve long-term engraftment. Furthermore, the defects of scid HSCs are independent of their inability to perform lymphopoiesis because a similar defect in hematopoietic niche occupancy was not observed with Rag1(-/-) recipients. These results demonstrate that scid HSCs are impaired in maintenance within the niche, which may explain the nature of the conducive marrow niche environment of scid mice for xenotransplantation.

  1. Faster T-cell development following gene therapy compared with haploidentical HSCT in the treatment of SCID-X1.

    PubMed

    Touzot, Fabien; Moshous, Despina; Creidy, Rita; Neven, Bénédicte; Frange, Pierre; Cros, Guilhem; Caccavelli, Laure; Blondeau, Johanna; Magnani, Alessandra; Luby, Jean-Marc; Ternaux, Brigitte; Picard, Capucine; Blanche, Stéphane; Fischer, Alain; Hacein-Bey-Abina, Salima; Cavazzana, Marina

    2015-06-01

    During the last decade, gene therapy via ex vivo gene transfer into autologous hematopoietic stem cells has emerged as a convincing therapy for severe combined immunodeficiency caused by ILR2G mutation (SCID-X1) despite the occurrence of genotoxicity caused by the integration of first-generation retroviral vectors. However, the place of gene therapy among the therapeutic armamentarium remains to be defined. We retrospectively analyze and compare clinical outcomes and immune reconstitution in 13 consecutive SCID-X1 patients having undergone haploidentical hematopoietic stem cell transplantation (HSCT) and 14 SCID-X1 patients treated with gene therapy over the same period at a single center level: the Necker Children's Hospital (Paris, France). Our results show a clear advantage in terms of T-cell development of gene therapy over HSCT with a mismatched donor. Patients treated with gene therapy display a faster T-cell reconstitution and a better long-term thymic output. Interestingly, this advantage of gene therapy vs haploidentical HSCT seems to be independent of the existence of clinical graft-versus-host disease in the latter condition. If data of safety are confirmed over the long term, gene therapy for SCID-X1 appears to be an equal, if not superior, alternative to haploidentical HSCT.

  2. Lymphoid Regeneration from Gene Corrected SCID-X1 Patient Derived iPSC

    PubMed Central

    Menon, T; Firth, AL; Scripture-Adams, D.D.; Galic, Z; Qualls, SJ; Gilmore, WB; Ke, E; Singer, O; Anderson, LS; Bornzin, AR; Alexander, IE; Zack, JA; Verma, IM

    2015-01-01

    Summary X-Linked severe combined immunodeficiency (SCID-X1) is a genetic disease that leaves newborns at high risk of serious infection and a predicted lifespan of less than one year in the absence of a matched bone marrow donor. The disease pathogenesis is due to mutations in the gene encoding the Interleukin-2 receptor gamma chain (IL-2Rγ) leading to a lack of functional lymphocytes. With the leukemogenic concerns of viral gene therapy there is a need to explore alternative therapeutic options. We have utilized induced pluripotent stem cell (iPSC) technology and genome editing mediated by TALENs to generate isogenic patient-specific mutant and gene corrected iPSC lines. While the patient-derived mutant iPSC have the capacity to generate hematopoietic precursors and myeloid cells, only wild-type and gene-corrected iPSC can additionally generate mature NK-cells and T-cell precursors expressing the correctly spliced IL-2Rγ. This study highlights the potential for the development of autologous cell therapy for SCID-X1 patients. PMID:25772073

  3. Lymphoid regeneration from gene-corrected SCID-X1 subject-derived iPSCs.

    PubMed

    Menon, Tushar; Firth, Amy L; Scripture-Adams, Deirdre D; Galic, Zoran; Qualls, Susan J; Gilmore, William B; Ke, Eugene; Singer, Oded; Anderson, Leif S; Bornzin, Alexander R; Alexander, Ian E; Zack, Jerome A; Verma, Inder M

    2015-04-01

    X-linked Severe Combined Immunodeficiency (SCID-X1) is a genetic disease that leaves newborns at high risk of serious infection and a predicted life span of less than 1 year in the absence of a matched bone marrow donor. The disease pathogenesis is due to mutations in the gene encoding the Interleukin-2 receptor gamma chain (IL-2Rγ), leading to a lack of functional lymphocytes. With the leukemogenic concerns of viral gene therapy there is a need to explore alternative therapeutic options. We have utilized induced pluripotent stem cell (iPSC) technology and genome editing mediated by TALENs to generate isogenic subject-specific mutant and gene-corrected iPSC lines. While the subject-derived mutant iPSCs have the capacity to generate hematopoietic precursors and myeloid cells, only wild-type and gene-corrected iPSCs can additionally generate mature NK cells and T cell precursors expressing the correctly spliced IL-2Rγ. This study highlights the potential for the development of autologous cell therapy for SCID-X1 subjects. PMID:25772073

  4. NK cells are intrinsically functional in pigs with Severe Combined Immunodeficiency (SCID) caused by spontaneous mutations in the Artemis gene.

    PubMed

    Powell, Ellis J; Cunnick, Joan E; Knetter, Susan M; Loving, Crystal L; Waide, Emily H; Dekkers, Jack C M; Tuggle, Christopher K

    2016-07-01

    We have identified Severe Combined Immunodeficiency (SCID) in a line of Yorkshire pigs at Iowa State University. These SCID pigs lack B-cells and T-cells, but possess Natural Killer (NK) cells. This SCID phenotype is caused by recessive mutations in the Artemis gene. Interestingly, two human tumor cell lines, PANC-1 and A375-SM, survived after injection into these SCID pigs, but, as we demonstrate here, these cells, as well as K562 tumor cells, can be lysed in vitro by NK cells from SCID and non-SCID pigs. NK cells from both SCID and non-SCID pigs required activation in vitro with either recombinant human IL-2 or the combination of recombinant porcine IL-12 and IL-18 to kill tumor targets. We also showed that SCID NK cells could be activated to produce perforin, and perforin production was greatly enhanced in NK cells from both SCID and non-SCID pigs after IL-2 cytokine treatment. While CD16+, CD172- NK cells constituted an average of only 4% in non-SCID pigs, NK cells averaged 27% of the peripheral blood mononuclear cell population in SCID pigs. We found no significant differences in killing activity per NK cell between SCID and non-SCID pigs. We conclude that survival of human cancer cells in these SCID pigs is not due to an intrinsic defect in NK cell killing ability.

  5. Hyperbilirubinemia and rapid fatal hepatic failure in severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID).

    PubMed

    Kühl, J S; Schwarz, K; Münch, A; Schmugge, M; Pekrun, A; Meisel, C; Wahn, V; Ebell, W; von Bernuth, H

    2011-03-01

    Adenosin deaminase (ADA) deficiency is the cause for Severe Combined Immunodeficiency (SCID) in about 15% of patients with SCID, often presenting as T (-)B (-)NK (-)SCID. Treatment options for ADA-SCID are enzyme replacement, bone marrow transplantation or gene therapy. We here describe the first patient with ADA-SCID and fatal hepatic failure despite bone marrow transplantation from a 10/10 HLA identical related donor. As patients with ADA-SCID may be at yet underestimated increased risk for rapid hepatic failure we speculate whether hepatitis in ADA-SCID should lead to the immediate treatment with enzyme replacement by pegylated ADA.

  6. Reduction of human anti-tetanus toxoid antibody in hu-PBL-SCID mice by immunodominant peptides of tetanus toxoid

    PubMed Central

    Jackson, D J; Elson, C J; Kumpel, B M

    2004-01-01

    Immunotherapy of murine autoimmune and allergic diseases by administration of peptides corresponding to the dominant T cell epitope is a reality. However, problems remain in applying this therapy to reduce antibody responses in humans. To overcome these difficulties, a preclinical system was developed to test the effect of immunodominant peptides from a common antigen, tetanus toxoid (TT), on the long-term human anti-TT response. Individuals whose T cells proliferated against dominant TT peptides were identified. Peripheral blood leucocytes (PBL) from these donors were injected intraperitoneally (i.p.) into mice with severe combined immunodeficiency (SCID) that had been depleted of murine natural killer (NK) cells (hu-PBL-SCID mice). Peptides or PBS were injected i.p. before a further injection of PBL and immunization with TT. The concentration of human IgG and anti-TT in murine plasma was followed for 10 weeks. The total IgG was similar in both groups. By contrast, there was a statistically significant reduction in IgG anti-TT from eight weeks onwards. It is considered that the hu-PBL-SCID model system may provide a means by which the efficacy of peptide immunotherapy for reduction of pathological antibodies in humans can be examined. PMID:15270840

  7. The case for mandatory newborn screening for severe combined immunodeficiency (SCID).

    PubMed

    Gaspar, H B; Hammarström, L; Mahlaoui, N; Borte, M; Borte, S

    2014-05-01

    Severe combined immunodeficiency (SCID) is the most severe form of inherited primary immunodeficiency and is a paediatric emergency. Delay in recognising and detecting SCID can have fatal consequences and also reduces the chances of a successful haematopoietic stem cell transplant (HSCT). Screening for SCID at birth would prevent children from dying before HSCT can be attempted and would increase the success of HSCT. There is strong evidence to show that SCID fulfills the internationally-established criteria for a condition to be screened for at birth. There is also a test (the T-cell receptor excision circle (TREC) assay) that is now being successfully used in an increasing number of US states to screen for SCID in routine newborn Guthrie samples. Concerted lobbying efforts have highlighted the need for newborn screening (NBS) for SCID, and its implementation is being discussed in Europe both at EU and individual country level, but as yet there is no global mandate to screen for this rare and frequently lethal condition. This paper summarizes the current evidence for, and the success of SCID NBS, together with a review of the practical aspects of SCID testing and the arguments in favour of adding SCID to the conditions screened for at birth.

  8. Establishment of xenotransplantation model of human CN-AML with FLT3-ITD (mut) /NPM1 (-) in NOD/SCID mice.

    PubMed

    Shang, Zhen; Wang, Jue; Wang, Di; Xiao, Min; Li, Tong-juan; Wang, Na; Huang, Liang; Zhou, Jian-feng

    2013-06-01

    Patients with FLT3-ITD (mut) /NPM1 (-) cytogenetically normal acute myeloid leukemia (CN-AML), as high-risk molecular group in CN-AML, are associated with a worse prognosis than other CN-AML patients. It is beneficial to generate xenotransplantation model of FLT3-ITD (mut) /NPM1 (-) CN-AML to better understand the pathogenesis and therapeutic strategies of such AML subtype. The purpose of present study was to establish the xenotransplantation model in NOD/SCID mice with FLT3-ITD (mut) /NPM1 (-) CN-AML primary cells. The FLT3-ITD (mut) /NPM1 (-) CN-AML primary cells from 3 of 7 cases were successfully transplanted into NOD/SCID mice, and human CD45 positive cells were detected in the peripheral blood, spleen and bone marrow of mice by using flow cytometry. Infiltration of human leukemia cells in various organs of mice was observed by using immunohistochemistry. Gene analysis confirmed sustained FLT3/ITD mutation without NPM1 mutation in mice. By performing serial transplantation, it was found that characteristics of the leukemia cells in secondary and tertiary generation models remained unchanged. Moreover, in vivo cytarabine administration could extend survival of NOD/SCID mice, which was consistent with clinical observation. In conclusion, we successfully established xenotransplantation model of human FLT3-ITD (mut) /NPM1 (-) CN-AML in NOD/SCID mice. The model was able to present primary disease and suitable to evaluate the curative effects of new drugs or therapy strategies.

  9. Human Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes home preferentially to and induce selective regressions of autologous EBV- induced B cell lymphoproliferations in xenografted C.B-17 scid/scid mice [published erratum appears in J Exp Med 1996 Sep 1;184(3):1199

    PubMed Central

    1996-01-01

    autologous but not to HLA-mismatched EBV+ tumors as early as 24 h after intravenous adoptive transfer. Immunophenotypic analyses also demonstrated preferential infiltration of T cells into the autologous EBV+ tumor in SCID mice bearing both the autologous and either fully HLA-mismatched or genotypically related haplotype-sharing EBV+ tumors. The human T cells infiltrating EBV+ tumors were CD3+ and, predominantly, CD8+CD4-. Our results indicate that EBV-specific CTL preferentially localize to and infiltrate EBV+ tumors bearing the appropriate HLA antigens and thereafter induce targeted regressions of disease. PMID:8642263

  10. Induction and repair of chromosome aberrations in scid cells measured by premature chromosome condensation

    SciTech Connect

    Evans, J.W.; Kirchgessner, C.U.; Brown, J.M.; X.F. Liu

    1996-01-01

    Severe combined immunodeficient (scid) murine cells, which are defective in both repair of DNA double-strand breaks and V(D)J recombination, are deficient in DNA-dependent protein kinase (DNA-PK), a protein which forms an activated complex with the DNA end-binding Ku proteins (p80 and p70) upon association with damaged DNA. Xrs 5 cells are deficient in the Ku p80 protein and also fail to form an active DNA-PK repair complex. Since both scid and xrs cells are defective in the same protein complex, we compared the kinetics of chromosome repair in scid cells to results published previously for xrs 5 cells. C.B-17 cells, scid cells and scid cells complemented with a single human chromosome 8 were irradiated with 6 Gy and allowed to repair from 0-24 h before fusion to HeLa cells for chromosome condensation. Breaks and dicentrics were visualized by fluorescence in situ hybridization. All cells had the same initial amount of chromosome damage, but scid cells had a slower rate of rejoining, more unrejoined breaks and more dicentrics than C.B-17 and scid cells with human chromosome 8. The scid cells appear to respond differently than xrs 5 cells, despite both cells lacking an essential component of the same DNA repair complex. 40 refs., 6 figs., 3 tabs.

  11. Saquinavir-mediated inhibition of human immunodeficiency virus (HIV) infection in SCID mice implanted with human fetal thymus and liver tissue: an in vivo model for evaluating the effect of drug therapy on HIV infection in lymphoid tissues.

    PubMed Central

    Pettoello-Mantovani, M; Kollmann, T R; Raker, C; Kim, A; Yurasov, S; Tudor, R; Wiltshire, H; Goldstein, H

    1997-01-01

    Treatment with protease inhibitors alone or in combination with inhibitors of reverse transcriptase potently suppresses levels of human immunodeficiency virus (HIV) RNA in plasma and thereby may significantly delay the progression of HIV-mediated disease. To investigate the effect of treatment with the protease inhibitor saquinavir on HIV replication in the lymphoid tissues, we used a SCID-hu mouse model that we developed, in which human thymic and liver tissues (hu-thy/liv) were implanted under both kidney capsules in SCID mice (thy/liv-SCID-hu mice). These mice are populated in the periphery with large numbers of human T cells and develop disseminated HIV infection after intraimplant injection. thy/liv-SCID-hu mice with established HIV infection that were treated for 1 month with saquinavir had a significantly lower viral load present in the implanted hu-thy/liv and mouse spleen than did the untreated HIV-infected thy/liv-SCID-hu mice. To examine the capacity of acute treatment with saquinavir to prevent HIV infection, some thy/liv-SCID-hu mice were inoculated with HIV and then immediately started on saquinavir. Although treated mice had markedly lower viral loads in the thy/liv implants and spleens, HIV infection was not completely prevented. Thus, the effect of antiviral therapy on HIV infection in the major site of HIV replication, the lymphoid tissues, can be readily evaluated in our thy/liv-SCID-hu mice. These mice should prove to be a useful model for determining the in vivo effectiveness of different therapeutic interventions on acute and chronic HIV infection. PMID:9303378

  12. A novel missense RAG-1 mutation results in T-B-NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories.

    PubMed

    Xiao, Zheng; Yannone, Steven M; Dunn, Elizabeth; Cowan, Morton J

    2009-02-01

    DNA double-strand repair factors in the non-homologous end joining (NHEJ) pathway resolve DNA double-strand breaks introduced by the recombination-activating gene (RAG) proteins during V(D)J recombination of T and B lymphocyte receptor genes. Defective NHEJ and subsequent failure of V(D)J recombination leads to severe combined immunodeficiency disease (SCID). We originally linked T(-)B(-)NK(+) SCID in Athabascan-speaking Native Americans in the Southwestern US and Northwest Territories of Canada to chromosome 10. However, despite a common ancestry, the null mutation in the Artemis gene that we found to be causal in the SCID among the Navajo and Apache Indians was not present in the Dine Indians in the Northwest Territories. We now report a novel homozygous missense mutation (R776W) in RAG-1 in three children with T(-)B(-)NK(+) SCID from two related families of Athabascan-speaking Dine Indians in the Canadian Northwest Territories. As expected, we found no increased sensitivity to ionizing radiation in patient fibroblasts. The impaired activity of this RAG-1 mutant in V(D)J recombination was confirmed by the EGFP-based V(D)J recombination assays. Overexpression of wild type RAG-1 in patient fibroblasts complemented V(D)J recombination, with recovery of both coding and signal joint formation. Our results indicate that the novel R776W missense mutation in RAG-1 is causal in the T(-)B(-)NK(+) SCID phenotype in Athabascan-speaking Dine Indians from the Canadian Northwest Territories. PMID:18701881

  13. Biochemical and genetic defects in the DNA-dependent protein kinase in murine scid lymphocytes.

    PubMed Central

    Danska, J S; Holland, D P; Mariathasan, S; Williams, K M; Guidos, C J

    1996-01-01

    The scid gene product has been identified as the 460-kDa catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs p460), a member of the phosphatidylinositol 3-kinase family. DNA-PK activity is undetectable in scid cells, but the molecular basis for this defect has not been identified. Here we report that expression of p460 in scid lymphocyte precursors is detectable but is reduced at least 10-fold relative to that in wild-type lymphocytes. In addition, we show that the scid mutation disturbs p460 nuclear association, presumably affecting its role in DNA repair pathways. To examine the molecular basis for our observations, we used a degenerate PCR strategy to clone the C-terminal p460 kinase domain from wild-type and scid thymocytes. Northern (RNA) analysis with these probes revealed normal steady-state p460 mRNA levels in scid cells, suggesting that the reduced abundance of p460 protein is due to a posttranscriptional defect. Sequence comparisons identified a single-base-pair alteration in the scid C-terminal p460 kinase domain, resulting in a premature stop codon. This mutation is predicted to truncate p460 by approximately 8 kDa, but it preserves the conserved motifs required for kinase activity in members of the phosphoinositidyl 3-kinase family. Despite a computed molecular weight alteration of less than 2%, we were able to visualize this difference by Western blot (immunoblot) analysis of wild-type and scid p460. These data demonstrate that the scid DNA-PKes mutation is not a null allele and suggest a molecular rationale for the well-described leakiness of the scid phenotype. PMID:8816463

  14. Expanded conserved linkage group between human 16p13 and the Scid region of the mouse chromosome 16

    SciTech Connect

    Deng, Z.M.; Siciliano, M.J.; Davisson, M.T.

    1994-09-01

    Knowledge of homologies between human and mouse chromosomes is essential for understanding chromosomal evolution and the development of experimental models for human disease. We have reported the identification of a conserved linkage group between human 16p13 and the centromeric portion of the mouse 16. Defining the extent of this linkage conservation has significant biomedical implications since that region of mouse genome contains the Scid mutation and the human 16p13 contains genes that are involved in DNA repair and certain types of human leukemia as well as other diseases such as Rubinstein-Taybi Syndrome. Here, this conserved linkage group has been defined and expanded. It now contains 5 genetic loci and spans more than 3 Mb in human and 23 cM in mouse. The 5 loci are PRM1,2 (protamine 1 and 2), NOP3 (a subclone of D16S237), GSPT1 (a gene involved in the regulation of G1 to S phase transition), MYH11 (a human smooth muscle myosin heavy chain gene) and MRP (multi-drug resistant-associated protein gene). Using a panel of human-rodent hybrids that are informative for different portions of human 16, we have established the following order on human 16p: telomere-NOP3-PRM1,2-GSPT1-(MYH11,MRP)-centromere. The genes were assigned to the mouse chromosome 16 by a mouse-Chinese hamster somatic cell hybrid panel informative for mouse chromosomes. Linkage analysis using backcross mice informative for the Scid mutation indicated the following order and genetic distance (in cM) in mouse: centromere-Nop3-11.7-Prm1-1.4-Gspt1-8.2-(Myh11,Mrp)-1.4-Scid-telomere.

  15. NK cells are intrinsically functional in pigs with Severe Combined Immunodeficiency (SCID) caused by spontaneous mutations in the Artemis gene

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have identified Severe Combined Immunodeficiency (SCID) in a line of Yorkshire pigs at Iowa State University. These SCID pigs lack B-cells and T-cells, but possess Natural Killer (NK) cells. This SCID phenotype is caused by recessive mutations in the Artemis gene. Interestingly, two human tumor c...

  16. Severe combined immunodeficiency (SCID) in the mouse. Pathology, reconstitution, neoplasms.

    PubMed Central

    Custer, R. P.; Bosma, G. C.; Bosma, M. J.

    1985-01-01

    Histologic findings in mice with severe combined immunodeficiency (SCID) were remarkably uniform, consisting of lymphopenia, a rudimentary thymic medulla without cortex, relatively empty splenic follicles and lymph nodes, and undeveloped bronchial and gastrointestinal lymphocytic foci. Fluorescence-activated cell sorter studies revealed a few T cells (apparently nonfunctional) in thymus and spleen; interestingly, these cells seemed highly disposed to neoplasia, because thymic T-cell lymphomas were observed in 41 of 269 mice. No pre-B or B cells could be identified. Cells of the myeloid lineage appeared normal. Reconstitution of lymphoid tissues was achieved after intravenous injection of histocompatible bone marrow cells. Images Figure 1 p467-a Figure 5 Figure 6 Figure 7 PMID:2412448

  17. Gene Therapy for "Bubble Boy" Disease.

    PubMed

    Hoggatt, Jonathan

    2016-07-14

    Adenosine deaminase (ADA) deficiency results in the accumulation of toxic metabolites that destroy the immune system, causing severe combined immunodeficiency (ADA-SCID), often referred to as the "bubble boy" disease. Strimvelis is a European Medicines Agency approved gene therapy for ADA-SCID patients without a suitable bone marrow donor.

  18. Impact of stromal sensitivity on radiation response of tumors implanted in SCID hosts revisited.

    PubMed

    García-Barros, Mónica; Thin, Tin Htwe; Maj, Jerzy; Cordon-Cardo, Carlos; Haimovitz-Friedman, Adriana; Fuks, Zvi; Kolesnick, Richard

    2010-10-15

    Severe combined immunodeficient (SCID) mice carry a germ-line mutation in DNA-PK, associated with deficiency in recognition and repair DNA double-strand breaks. Thus, SCID cells and tissues display increased sensitivity to radiation-induced postmitotic (clonogenic) cell death. Nonetheless, the single-radiation doses required for 50% permanent local control (TCD(50)) of tumors implanted in SCID mice are not significantly different from the TCD(50) values of the same tumors in wild-type hosts. Whereas the tumor stroma is derived from the host, the observation that tumors implanted in SCID mice do not exhibit hypersensitivity to radiation might imply that stromal endothelial elements do not contribute substantially to tumor cure by ionizing radiation. Here, we challenge this notion, testing the hypothesis that ASMase-mediated endothelial apoptosis, which results from plasma membrane alterations, not DNA damage, is a crucial element in the cure of tumors in SCID mice by single-dose radiotherapy (SDRT). We show that the endothelium in MCA/129 fibrosarcomas and B16 melanomas exhibits a wild-type apoptotic phenotype in SCID hosts, abrogated in tumors in SCID(asmase-/-) littermates, which also acquire resistance to SDRT. Conversion into a radioresistant tumor phenotype when implanted in SCID(asmase-/-) hosts provides compelling evidence that cell membrane ASMase-mediated microvascular dysfunction, rather than DNA damage-mediated endothelial clonogenic lethality, plays a mandatory role in the complex pathophysiologic mechanism of tumor cure by SDRT, and provides an explanation for the wild-type SDRT responses reported in tumors implanted in SCID mice.

  19. Differential post-surgical metastasis and survival in SCID, NOD-SCID and NOD-SCID-IL-2Rγ(null) mice with parental and subline variants of human breast cancer: implications for host defense mechanisms regulating metastasis.

    PubMed

    Milsom, Chloe C; Lee, Christina R; Hackl, Christina; Man, Shan; Kerbel, Robert S

    2013-01-01

    We compare for the first time, the metastatic aggressiveness of the parental MDA-MB-231 breast cancer cell line and two luciferase-tagged in vivo-derived and selected pro-metastatic variants (LM2-4/luc⁺ and 164/8-1B/luc⁺ in SCID, NOD-SCID and NOD-SCID-IL-2Rγ(null) (NSG) mice following orthotopic implantation and primary tumour resection. The variants are known to be more aggressively metastatic in SCID mice, compared to the parental line which has limited spontaneous metastatic competence in these mice. When 2×10⁶ cells were injected into the mammary fat pad, the growth of the resultant primary tumours was identical for the various cell lines in the three strains of mice. However, metastatic spread of all three cell lines, including the MDA-MB-231 parental cell line, was strikingly more aggressive in the highly immunocompromised NSG mice compared to both NOD-SCID and SCID mice, resulting in extensive multi-organ metastases and a significant reduction in overall survival. While these studies were facilitated by monitoring post-surgical spontaneous metastases using whole body bioluminescence imaging, we observed that the luciferase-tagged parental line showed altered growth and diminished metastatic properties compared to its untagged counterpart. Our results are the first to show that host immunity can have a profound impact on the spread of spontaneous visceral metastases and survival following resection of a primary tumour in circumstances where the growth of primary tumours is not similarly affected; as such they highlight the importance of immunity in the metastatic process, and by extension, suggest certain therapeutic strategies that may have a significant impact on reducing metastasis.

  20. Intratibial Injection of Human Multiple Myeloma Cells in NOD/SCID IL-2Rγ(Null) Mice Mimics Human Myeloma and Serves as a Valuable Tool for the Development of Anticancer Strategies

    PubMed Central

    Schueler, Julia; Wider, Dagmar; Klingner, Kerstin; Siegers, Gabrielle M.; May, Annette M.; Wäsch, Ralph; Fiebig, Heinz-Herbert; Engelhardt, Monika

    2013-01-01

    Background We systematically analyzed multiple myeloma (MM) cell lines and patient bone marrow cells for their engraftment capacity in immunodeficient mice and validated the response of the resulting xenografts to antimyeloma agents. Design and Methods Using flow cytometry and near infrared fluorescence in-vivo-imaging, growth kinetics of MM cell lines L363 and RPMI8226 and patient bone marrow cells were investigated with use of a murine subcutaneous bone implant, intratibial and intravenous approach in NOD/SCID, NOD/SCID treated with CD122 antibody and NOD/SCID IL-2Rγ(null) mice (NSG). Results Myeloma growth was significantly increased in the absence of natural killer cell activity (NSG or αCD122-treated NOD/SCID). Comparison of NSG and αCD122-treated NOD/SCID revealed enhanced growth kinetics in the former, especially with respect to metastatic tumor sites which were exclusively observed therein. In NSG, MM cells were more tumorigenic when injected intratibially than intravenously. In NOD/SCID in contrast, the use of juvenile long bone implants was superior to intratibial or intravenous cancer cell injection. Using the intratibial NSG model, mice developed typical disease symptoms exclusively when implanted with human MM cell lines or patient-derived bone marrow cells, but not with healthy bone marrow cells nor in mock-injected animals. Bortezomib and dexamethasone delayed myeloma progression in L363- as well as patient-derived MM cell bearing NSG. Antitumor activity could be quantified via flow cytometry and in vivo imaging analyses. Conclusions Our results suggest that the intratibial NSG MM model mimics the clinical situation of the disseminated disease and serves as a valuable tool in the development of novel anticancer strategies. PMID:24223204

  1. Generation of Pediatric Leukemia Xenograft Models in NSG-B2m Mice: Comparison with NOD/SCID Mice.

    PubMed

    Gopalakrishnapillai, Anilkumar; Kolb, E Anders; Dhanan, Priyanka; Bojja, Aruna Sri; Mason, Robert W; Corao, Diana; Barwe, Sonali P

    2016-01-01

    Generation of orthotopic xenograft mouse models of leukemia is important to understand the mechanisms of leukemogenesis, cancer progression, its cross talk with the bone marrow microenvironment, and for preclinical evaluation of drugs. In these models, following intravenous injection, leukemic cells home to the bone marrow and proliferate there before infiltrating other organs, such as spleen, liver, and the central nervous system. Moreover, such models have been shown to accurately recapitulate the human disease and correlate with patient response to therapy and prognosis. Thus, various immune-deficient mice strains have been used with or without recipient preconditioning to increase engraftment efficiency. Mice homozygous for the severe combined immune deficiency (SCID) mutation and with non-obese diabetic background (NOD/SCID) have been used in the majority of leukemia xenograft studies. Later, NOD/SCID mice deficient for interleukin 2 receptor gamma chain (IL2Rγ) gene called NSG mice became the model of choice for leukemia xenografts. However, engraftment of leukemia cells without irradiation preconditioning still remained a challenge. In this study, we used NSG mice with null alleles for major histocompatibility complex class I beta2-microglobulin (β2m) called NSG-B2m. This is a first report describing the 100% engraftment efficiency of pediatric leukemia cell lines and primary samples in NSG-B2m mice in the absence of host preconditioning by sublethal irradiation. We also show direct comparison of the engraftment efficiency and growth rate of pediatric acute leukemia cells in NSG-B2m and NOD/SCID mice, which showed 80-90% engraftment efficiency. Secondary and tertiary xenografts in NSG-B2m mice generated by injection of cells isolated from the spleens of leukemia-bearing mice also behaved similar to the primary patient sample. We have successfully engrafted 25 acute lymphoblastic leukemia (ALL) and 5 acute myeloid leukemia (AML) patient samples with

  2. Generation of Pediatric Leukemia Xenograft Models in NSG-B2m Mice: Comparison with NOD/SCID Mice.

    PubMed

    Gopalakrishnapillai, Anilkumar; Kolb, E Anders; Dhanan, Priyanka; Bojja, Aruna Sri; Mason, Robert W; Corao, Diana; Barwe, Sonali P

    2016-01-01

    Generation of orthotopic xenograft mouse models of leukemia is important to understand the mechanisms of leukemogenesis, cancer progression, its cross talk with the bone marrow microenvironment, and for preclinical evaluation of drugs. In these models, following intravenous injection, leukemic cells home to the bone marrow and proliferate there before infiltrating other organs, such as spleen, liver, and the central nervous system. Moreover, such models have been shown to accurately recapitulate the human disease and correlate with patient response to therapy and prognosis. Thus, various immune-deficient mice strains have been used with or without recipient preconditioning to increase engraftment efficiency. Mice homozygous for the severe combined immune deficiency (SCID) mutation and with non-obese diabetic background (NOD/SCID) have been used in the majority of leukemia xenograft studies. Later, NOD/SCID mice deficient for interleukin 2 receptor gamma chain (IL2Rγ) gene called NSG mice became the model of choice for leukemia xenografts. However, engraftment of leukemia cells without irradiation preconditioning still remained a challenge. In this study, we used NSG mice with null alleles for major histocompatibility complex class I beta2-microglobulin (β2m) called NSG-B2m. This is a first report describing the 100% engraftment efficiency of pediatric leukemia cell lines and primary samples in NSG-B2m mice in the absence of host preconditioning by sublethal irradiation. We also show direct comparison of the engraftment efficiency and growth rate of pediatric acute leukemia cells in NSG-B2m and NOD/SCID mice, which showed 80-90% engraftment efficiency. Secondary and tertiary xenografts in NSG-B2m mice generated by injection of cells isolated from the spleens of leukemia-bearing mice also behaved similar to the primary patient sample. We have successfully engrafted 25 acute lymphoblastic leukemia (ALL) and 5 acute myeloid leukemia (AML) patient samples with

  3. Generation of Pediatric Leukemia Xenograft Models in NSG-B2m Mice: Comparison with NOD/SCID Mice

    PubMed Central

    Gopalakrishnapillai, Anilkumar; Kolb, E. Anders; Dhanan, Priyanka; Bojja, Aruna Sri; Mason, Robert W.; Corao, Diana; Barwe, Sonali P.

    2016-01-01

    Generation of orthotopic xenograft mouse models of leukemia is important to understand the mechanisms of leukemogenesis, cancer progression, its cross talk with the bone marrow microenvironment, and for preclinical evaluation of drugs. In these models, following intravenous injection, leukemic cells home to the bone marrow and proliferate there before infiltrating other organs, such as spleen, liver, and the central nervous system. Moreover, such models have been shown to accurately recapitulate the human disease and correlate with patient response to therapy and prognosis. Thus, various immune-deficient mice strains have been used with or without recipient preconditioning to increase engraftment efficiency. Mice homozygous for the severe combined immune deficiency (SCID) mutation and with non-obese diabetic background (NOD/SCID) have been used in the majority of leukemia xenograft studies. Later, NOD/SCID mice deficient for interleukin 2 receptor gamma chain (IL2Rγ) gene called NSG mice became the model of choice for leukemia xenografts. However, engraftment of leukemia cells without irradiation preconditioning still remained a challenge. In this study, we used NSG mice with null alleles for major histocompatibility complex class I beta2-microglobulin (β2m) called NSG-B2m. This is a first report describing the 100% engraftment efficiency of pediatric leukemia cell lines and primary samples in NSG-B2m mice in the absence of host preconditioning by sublethal irradiation. We also show direct comparison of the engraftment efficiency and growth rate of pediatric acute leukemia cells in NSG-B2m and NOD/SCID mice, which showed 80–90% engraftment efficiency. Secondary and tertiary xenografts in NSG-B2m mice generated by injection of cells isolated from the spleens of leukemia-bearing mice also behaved similar to the primary patient sample. We have successfully engrafted 25 acute lymphoblastic leukemia (ALL) and 5 acute myeloid leukemia (AML) patient samples with

  4. A severe combined immunodeficient (SCID) mouse model for infection with Entamoeba histolytica

    PubMed Central

    1992-01-01

    We used severe combined immunodeficient (SCID) mice to study resistance to invasive infection with Entamoeba histolytica. Seven of seven SCID mice developed liver abscesses when challenged intrahepatically with virulent HM1:IMSS strain E. histolytica trophozoites. Only one of seven similarly challenged immunocompetent congenic C.B-17 mice developed an abscess. Adoptive transfer of polyclonal rabbit anti-E. histolytica antiserum, but not preimmune rabbit serum, completely protected 7 of 12 SCID mice from intrahepatic challenge with ameba. These results demonstrate that lymphocyte-based immunity is important in protection against amebic liver abscess, and that anti-E. histolytica antibody can protect against amebic infection in this system. The SCID mouse may provide a powerful model for studying the components of protective immunity to invasive amebiasis. PMID:1460420

  5. Using the SCID-D to assess dissociative identity disorder in adolescents: three case studies.

    PubMed

    Steinberg, M; Steinberg, A

    1995-01-01

    The authors report on the diagnostic assessment of dissociative identity disorder in three adolescents using the Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D; Steinberg, 1993b), a semistructured instrument for the diagnosis and assessment of dissociative symptoms and disorders. Although the SCID-D has received good-to-excellent ratings for reliability and validity in the adult population, these three cases are the first reports of the results of its administration to younger patients. Comparison of the three adolescent SCID-D interviews with findings in adults indicates that the profiles of the five dissociative symptoms measured by the SCID-D are virtually identical in adolescents and adults. The authors conclude with suggestions for future research regarding dissociative symptomatology in adolescents and outcome studies.

  6. From Murine to Human Nude/SCID: The Thymus, T-Cell Development and the Missing Link

    PubMed Central

    Romano, Rosa; Palamaro, Loredana; Fusco, Anna; Iannace, Leucio; Maio, Stefano; Vigliano, Ilaria; Giardino, Giuliana; Pignata, Claudio

    2012-01-01

    Primary immunodeficiencies (PIDs) are disorders of the immune system, which lead to increased susceptibility to infections. T-cell defects, which may affect T-cell development/function, are approximately 11% of reported PIDs. The pathogenic mechanisms are related to molecular alterations not only of genes selectively expressed in hematopoietic cells but also of the stromal component of the thymus that represents the primary lymphoid organ for T-cell differentiation. With this regard, the prototype of athymic disorders due to abnormal stroma is the Nude/SCID syndrome, first described in mice in 1966. In man, the DiGeorge Syndrome (DGS) has long been considered the human prototype of a severe T-cell differentiation defect. More recently, the human equivalent of the murine Nude/SCID has been described, contributing to unravel important issues of the T-cell ontogeny in humans. Both mice and human diseases are due to alterations of the FOXN1, a developmentally regulated transcription factor selectively expressed in skin and thymic epithelia. PMID:22474479

  7. Impaired human responses to tetanus toxoid in vitamin A-deficient SCID mice reconstituted with human peripheral blood lymphocytes.

    PubMed

    Molrine, D C; Polk, D B; Ciamarra, A; Phillips, N; Ambrosino, D M

    1995-08-01

    Vitamin A deficiency is associated with increased childhood morbidity and mortality from respiratory and diarrheal diseases. In order to evaluate the effect of vitamin A on human antibody responses, we developed a vitamin A-deficient severe combined immunodeficient (SCID) mouse model. Vitamin A-deficient mice were produced by depriving them of vitamin A at day 7 of gestation. Mice were reconstituted with human peripheral blood lymphocytes (huPBL) from tetanus toxoid immune donors at 6 weeks of age and immunized with tetanus toxoid at 6 and 8 weeks of age. Secondary human antibody responses were determined 10 days later. The geometric mean human anti-tetanus toxoid immunoglobulin G concentrations were 3.75 micrograms/ml for the deficient mice and 148 micrograms/ml for controls (P = 0.0005). Vitamin A-deficient mice had only a 2.9-fold increase in human anti-tetanus toxoid antibody compared with a 74-fold increase in controls (P < 0.01). Supplementation with vitamin A prior to reconstitution restored human antibody responses to normal. These data suggest that vitamin A deficiency impairs human antibody responses. We speculate that impaired responses could increase susceptibility to certain infections. Furthermore, we propose that effects of other nutritional deficiencies on the human immune system could be evaluated in the SCID-huPBL model.

  8. Genotype, phenotype, and outcomes of nine patients with T-B+NK+ SCID.

    PubMed

    Yu, Grace P; Nadeau, Kari C; Berk, David R; de Saint Basile, Geneviève; Lambert, Nathalie; Knapnougel, Perrine; Roberts, Joseph; Kavanau, Kristina; Dunn, Elizabeth; Stiehm, E Richard; Lewis, David B; Umetsu, Dale T; Puck, Jennifer M; Cowan, Morton J

    2011-11-01

    There are few reports of clinical presentation, genotype, and HCT outcomes for patients with T-B+NK+ SCID. Between 1981 and 2007, eight of 84 patients with SCID who received and/or were followed after HCT at UCSF had the T-B+NK+ phenotype. One additional patient with T-B+NK+ SCID was identified as the sibling of a patient treated at UCSF. Chart reviews were performed. Molecular analyses of IL7R, IL2RG, JAK3, and the genes encoding the CD3 T-cell receptor components δ (CD3D), ε (CD3E), and ζ (CD3Z) were carried out. IL7R mutations were documented in four patients and CD3D mutations in two others. Three patients had no defects found. Only two of nine patients had an HLA-matched related HCT donor. Both survived, and neither developed GVHD. Five of seven recipients of haploidentical grafts survived. Although the majority of reported cases of T-B+NK+ SCID are caused by defects in IL7R, CD3 complex defects were also found in this series and should be considered when evaluating patients with T-B+NK+ SCID. Additional genes, mutations in which account for T-B+NK+ SCID, remain to be found. Better approaches to early diagnosis and HCT treatment are needed for patients lacking an HLA-matched related donor.

  9. SCID: full reference spatial color image quality metric

    NASA Astrophysics Data System (ADS)

    Ouni, S.; Chambah, M.; Herbin, M.; Zagrouba, E.

    2009-01-01

    The most used full reference image quality assessments are error-based methods. Thus, these measures are performed by pixel based difference metrics like Delta E ( E), MSE, PSNR, etc. Therefore, a local fidelity of the color is defined. However, these metrics does not correlate well with the perceived image quality. Indeed, they omit the properties of the HVS. Thus, they cannot be a reliable predictor of the perceived visual quality. All this metrics compute the differences pixel to pixel. Therefore, a local fidelity of the color is defined. However, the human visual system is rather sensitive to a global quality. In this paper, we present a novel full reference color metric that is based on characteristics of the human visual system by considering the notion of adjacency. This metric called SCID for Spatial Color Image Difference, is more perceptually correlated than other color differences such as Delta E. The suggested full reference metric is generic and independent of image distortion type. It can be used in different application such as: compression, restoration, etc.

  10. The presence and preferential activation of Tregs diminishes adoptive transfer of autoimmune diabetes by polyclonal NOD T cell effectors into NSG versus NOD-scid mice1

    PubMed Central

    Presa, Maximiliano; Chen, Yi-Guang; Grier, Alexandra E.; Leiter, Edward H.; Brehm, Michael A.; Greiner, Dale L.; Shultz, Leonard D.; Serreze, David V.

    2015-01-01

    NOD-scid.Il2rgnull (NSG) mice are currently being used as recipients to screen for pathogenic autoreactive T-cells in Type 1 Diabetes (T1D) patients. We questioned whether the restriction of IL-2 receptor gamma chain (Il-2rγ) dependent cytokine signaling only to donor cells in NSG recipients differently influenced the activities of transferred diabetogenic T-cells when they were introduced as a monoclonal/oligoclonal population versus being part of a polyclonal repertoire. Unexpectedly, a significantly decreased T1D transfer by splenocytes from prediabetic NOD donors was observed in Il2rγnull -NSG versus Il2rγ-intact standard NOD-scid recipients. In contrast, NOD-derived monoclonal/oligoclonal TCR transgenic ß-cell autoreactive T-cells in either the CD8 (AI4, NY8.3) or CD4 (BDC2.5) compartments transferred disease significantly more rapidly to NSG than to NOD-scid recipients. The reduced diabetes transfer efficiency by polyclonal T cells in NSG recipients was associated with enhanced activation of regulatory T-cells (Tregs) mediated by NSG myeloid APC. This enhanced suppressor activity was associated with higher levels of Treg GITR expression in the presence of NSG than NOD-scid APC. These collective results indicate NSG recipients might be efficiently employed to test the activity of T1D patient-derived ß-cell autoreactive T-cell clones and lines, but when screening for pathogenic effectors within polyclonal populations, Tregs should be removed from the transfer inoculum to avoid false negative results. PMID:26283479

  11. Raman spectroscopy for in situ- evaluation of high-grade malignant gliomas induced in SCID mice

    NASA Astrophysics Data System (ADS)

    Clary, Candace E.; Dergachev, Alex Y.; Mirov, Sergey B.; Gillespie, G. Yancey

    1997-05-01

    Each year, more people at younger ages are diagnosed with primary brain tumors. Current histological discrimination between normal and diseased tissue occurs after tissue excision. A reliable optical biopsy for open craniotomy would optimize the amount and types of tissue removal by making an accurate evaluation before excision. The presented work is part of a study investigating the clinical diagnostic potential of Raman spectroscopy for gliomas. It has been shown that the optical properties of in vitro tissue are strongly dependent upon sample preparation. The investigation of the effects of time latency, paraformalin tissue fixation, and tissue perfusion with carbogen-bubbled cortical transport solution on their respective Raman spectra of brain tissue and tumors will be discussed, as well as their implications on the study of neurological tissue. The studies are conducted with in situ tissue samples from scid mice and 785 nm pulsed alexandrite laser excitation. Results illustrating positive qualitative and quantitative variations between Raman spectra of normal and malignant brain tissue will be presented.

  12. Impact of Stromal Sensitivity on Radiation Response of Tumors Implanted in SCID Hosts Revisited

    PubMed Central

    García-Barros, Mónica; Thin, Tin Htwe; Maj, Jerzy; Cordon-Cardo, Carlos; Haimovitz-Friedman, Adriana; Fuks, Zvi; Kolesnick, Richard

    2010-01-01

    Severe combined immunodeficient (SCID) mice carry a germ-line mutation in DNA-PK, associated with deficiency in recognition and repair DNA double strand breaks. Thus, SCID cells and tissues display increased sensitivity to radiation-induced post-mitotic (clonogenic) cell death. Nonetheless, the single radiation doses required for 50% permanent local control (TCD50) of tumors implanted in SCID mice are not significantly different from the TCD50 values of the same tumors in wild-type hosts. Whereas the tumor stroma is derived from the host, the observation that tumors implanted in SCID mice do not exhibit hypersensitivity to radiation might imply that stromal endothelial elements do not contribute substantially to tumor cure by ionizing radiation. Here we challenge this notion, testing the hypothesis that acid sphingomyelinase (ASMase)-mediated endothelial apoptosis, which results from plasma membrane alterations, not DNA damage, is a crucial element in the cure of tumors in SCID mice by single dose radiotherapy (SDRT). We show that endothelium in MCA/129 fibrosarcomas and B16 melanomas exhibit a wild-type apoptotic phenotype in SCID hosts, abrogated in tumors in SCIDasmase−/− littermates, which also acquire resistance to SDRT. Conversion into a radioresistant tumor phenotype when implanted in SCIDasmase−/− hosts provides compelling evidence that cell membrane ASMase-mediated microvascular dysfunction, rather than DNA damage-mediated endothelial clonogenic lethality, plays a mandatory role in the complex pathophysiologic mechanism of tumor cure by SDRT, and provides an explanation for the wild-type SDRT responses reported in tumors implanted in SCID mice. PMID:20924105

  13. Spectrum of mutations in a cohort of UK patients with ADA deficient SCID: Segregation of genotypes with specific ethnicities.

    PubMed

    Adams, Stuart P; Wilson, Melanie; Harb, Elissar; Fairbanks, Lynette; Xu-Bayford, Jinhua; Brown, Lucie; Kearney, Laura; Madkaikar, Manisha; Bobby Gaspar, H

    2015-12-01

    Severe combined immunodeficiency (SCID) arises from a number of different genetic defects, one of the most common being mutations in the gene encoding adenosine deaminase (ADA). In the UK, ADA deficient SCID compromises approximately 20% of all known cases of SCID. We carried out a retrospective analysis of the ADA gene in 46 known ADA deficient SCID patients on whom DNA had been stored. Here, we report a high frequency of two previously reported mutations and provide a link between the mutations and patient ethnicity within our patient cohort. We also report on 9 novel mutations that have been previously unreported.

  14. [Transplantation of genetically modified cells in the treatment of children with SCID: great hopes and recent disappointments].

    PubMed

    Smogorzewska, Elzbieta Monika; Weinberg, Kenneth I; Kohn, Donald B

    2003-01-01

    Children with severe combined immunodeficiency (SCID) die within 2 years of age if untreated. The only effective treatment for SCID since 1968 is a hematopoetic stem cells (HSC) transplantation. Only 25% of patients have an HLA matched related donor, while the rest have to be transplanted with T cells depleted haploidentical parental bone marrow, unrelated bone marrow or unrelated umbilical cord blood. In many cases, however, despite a positive outcome, children are not achieving B cell reconstitution and require regular IV Ig infusion. Gene therapy with genetically modified autologous cells offers a cure with no immunological complications such as graft rejection, graft versus host disease (GVHD) or post-transplantation immunosuppressive therapy. The first gene therapy trials were introduced in 1990 for adenosine deaminase (ADA) deficient patients who had failed to respond to PEG-ADA. Since then, three clinical trials have evaluated the transplantation of ex-vivo transduced autologous haematopoietic stem cells (HSC) to treat ADA deficiency. One trial used only bone marrow HSC, a second used bone marrow plus peripheral blood T lymphocytes, and a third used umbilical cord blood HSC. These trials give promise but also define the present limitations of gene therapy. Future protocols might be adjusted according to the new observations that ADA-expressing T cells have a strong selective advantage over ADA-deficient T cells. PEG-ADA enzyme therapy might be therefore contraindicated. Another new strategy might involve moderate conditioning prior to the reinfusion of genetically modified CD34+ cells, "making space" for transplanted HSC. The first successful gene therapy was reported for treatment of X-linked severe combined immunodeficiency (SCID-X1) in Science 2000. Since then, the group at the Hopital Necker in Paris has treated 11 patients with ex-vivo gene therapy for the deficiency of the common g chain. All eleven boys are alive, however, one of them recently

  15. Herpes simplex virus type 1 infection in mice with severe combined immunodeficiency (SCID).

    PubMed

    Minagawa, H; Sakuma, S; Mohri, S; Mori, R; Watanabe, T

    1988-01-01

    Herpes simplex virus type 1 (HSV-1) infection in mutant mice with severe combined immunodeficiency (SCID mice), i.e., mice in which the differentiation of both T and B lymphocytes is severely impaired, was studied. All control (infected and not treated with antibodies or with immune spleen cells) SCID mice were dead by 17 days after intracutaneous injection in the right midflank with 1 x 10(5) PFU of a virulent HSV-1 strain, Hayashida. Immunization with an avirulent strain of HSV-1 (SKa) did not protect them from death or prolong the survival time. Tissue virus titration of infected mice killed at various times after inoculation detected infectious virus in various organs, dorsal root ganglia, spinal cord, brain, kidney and adrenal gland in addition to the inoculation site of the skin in SCID mice, whereas virus could be detected only in the inoculation site and the nervous tissues in euthymic BALB/c mice, and in the adrenal gland from only one out of 17 nude mice. Human gamma globulin containing neutralizing antibody against HSV-1 prolonged the survival time but did not protect SCID mice from death. Transfer of spleen cells from immunized BALB/c mice protected the infected SCID mice from death. Treatment of spleen cells with anti-Thy 1.2 monoclonal antibody and complement abolished the protection.

  16. Xeno-repopulation of Fah -/- Nod/Scid mice livers by human hepatocytes.

    PubMed

    Su, Baoliang; Liu, Changcheng; Xiang, Dao; Zhang, Haibin; Yuan, Siming; Wang, Minjun; Chen, Fei; Zhu, Haiying; He, Zhiying; Wang, Xin; Hu, Yiping

    2011-03-01

    Functional human hepatocytes xenografted into the liver of mice can be used as a model system to study pharmacokinetics, infection of hepatitis viruses, and the efficacy of hepatitis vaccines. Significant levels of liver xeno-repopulation have been reported in Fah (-/-) Rag2 (-/-) Il2rg (-/-) mice. However, A new model, termed Fah (-/-) Nod/Scid mice, which combines the advantages of liver repopulation in Fah (-/-) mice with the ease of xenotransplantation in Nod/Scid mice was obtained by gradual cross-breeding. Fah (-/-) Nod/Scid mice were easily maintained in breeding colonies and in adult animal care facilities. FK506 treatment combined with gradual withdrawal of NTBC before cell transplantation ensured that Fah (-/-) Nod/Scid mice were susceptible to liver xeno-repopulation by human hepatocytes; the proportion of engrafted human hepatocytes reached 33.6%. The function of the expanded human hepatocytes within the chimeric liver was confirmed by weight curve analysis, the expression of characteristic proteins, and the biochemical analysis of liver function. These results show that Fah (-/-) Nod/Scid mice are an ideal humanized liver mouse model with many useful applications.

  17. Severe Leukopenia and Dysregulated Erythropoiesis in SCID Mice Persistently Infected with the Parvovirus Minute Virus of Mice

    PubMed Central

    Segovia, José C.; Gallego, Jesús M.; Bueren, Juan A.; Almendral, José M.

    1999-01-01

    Parvovirus minute virus of mice strain i (MVMi) infects committed granulocyte-macrophage CFU and erythroid burst-forming unit (CFU-GM and BFU-E, respectively) and pluripotent (CFU-S) mouse hematopoietic progenitors in vitro. To study the effects of MVMi infection on mouse hemopoiesis in the absence of a specific immune response, adult SCID mice were inoculated by the natural intranasal route of infection and monitored for hematopoietic and viral multiplication parameters. Infected animals developed a very severe viral-dose-dependent leukopenia by 30 days postinfection (d.p.i.) that led to death within 100 days, even though the number of circulating platelets and erythrocytes remained unaltered throughout the disease. In the bone marrow of every lethally inoculated mouse, a deep suppression of CFU-GM and BFU-E clonogenic progenitors occurring during the 20- to 35-d.p.i. interval corresponded with the maximal MVMi production, as determined by the accumulation of virus DNA replicative intermediates and the yield of infectious virus. Viral productive infection was limited to a small subset of primitive cells expressing the major replicative viral antigen (NS-1 protein), the numbers of which declined with the disease. However, the infection induced a sharp and lasting unbalance of the marrow hemopoiesis, denoted by a marked depletion of granulomacrophagic cells (GR-1+ and MAC-1+) concomitant with a twofold absolute increase in erythroid cells (TER-119+). A stimulated definitive erythropoiesis in the infected mice was further evidenced by a 12-fold increase per femur of recognizable proerythroblasts, a quantitative apoptosis confined to uninfected TER-119+ cells, as well as by a 4-fold elevation in the number of circulating reticulocytes. Therefore, MVMi targets and suppresses primitive hemopoietic progenitors leading to a very severe leukopenia, but compensatory mechanisms are mounted specifically by the erythroid lineage that maintain an effective erythropoiesis. The

  18. Prednisolone reduces experimental arthritis, and inflammatory tissue destruction in SCID mice infected with Borrelia burgdorferi.

    PubMed

    Hurtenbach, U; Böggemeyer, E; Stehle, T; Museteanu, C; Del Pozo, E; Simon, M M

    1996-05-01

    Glucocorticosteroids (GC) are widely used as anti-inflammatory agents. The effects of Prednisolone on the development of Borrelia (B.) burgdorferi-induced clinical arthritis and organ inflammation was studied in severe combined immunodeficiency (SCID) mice. The drug was administered orally at a dose of 3, 10 and 30 mg/kg, starting shortly before experimental infection of the mice. A dose dependent inhibition of arthritic joint swelling was observed. Full protection was obtained with 30 mg/kg until 21 days after infection, subsequently, mild joint swelling developed but progression and severity of the disease was considerably less than in the other treated as well as in the untreated mice. Inhibition of clinical arthritis coincided with reduction of inflammatory cell infiltration in the joints, liver and muscle. Prednisolone was ineffective when application was initiated after arthritis was fully developed, i.e., 22 days after infection. Since the activated endothelium plays a critical role in development of inflammatory lesions, the expression of the cellular adhesion molecules (CAMs) E-selectin, P-selectin, ICAM-1 and VCAM-1 was determined in vitro using the bEnd3 endothelial cell line. Stimulation with a sonicated B. burgdorferi preparation in the presence of the water-soluble compound Prednisolone-21-hemisuccinate considerably reduced expression of ICAM-1, and marginally also of E-selectin, whereas the level of P-selectin and VCAM-1 remained unaltered. Thus, downregulation of ICAM-1 might be a critical factor in Prednisolone-mediated inhibition of B. burgdorferi-induced inflammation; the flare up of the disease after the initial protection indicates that additional therapy, e.g. with antibiotics, is necessary.

  19. Prednisolone reduces experimental arthritis, and inflammatory tissue destruction in SCID mice infected with Borrelia burgdorferi.

    PubMed

    Hurtenbach, U; Böggemeyer, E; Stehle, T; Museteanu, C; Del Pozo, E; Simon, M M

    1996-05-01

    Glucocorticosteroids (GC) are widely used as anti-inflammatory agents. The effects of Prednisolone on the development of Borrelia (B.) burgdorferi-induced clinical arthritis and organ inflammation was studied in severe combined immunodeficiency (SCID) mice. The drug was administered orally at a dose of 3, 10 and 30 mg/kg, starting shortly before experimental infection of the mice. A dose dependent inhibition of arthritic joint swelling was observed. Full protection was obtained with 30 mg/kg until 21 days after infection, subsequently, mild joint swelling developed but progression and severity of the disease was considerably less than in the other treated as well as in the untreated mice. Inhibition of clinical arthritis coincided with reduction of inflammatory cell infiltration in the joints, liver and muscle. Prednisolone was ineffective when application was initiated after arthritis was fully developed, i.e., 22 days after infection. Since the activated endothelium plays a critical role in development of inflammatory lesions, the expression of the cellular adhesion molecules (CAMs) E-selectin, P-selectin, ICAM-1 and VCAM-1 was determined in vitro using the bEnd3 endothelial cell line. Stimulation with a sonicated B. burgdorferi preparation in the presence of the water-soluble compound Prednisolone-21-hemisuccinate considerably reduced expression of ICAM-1, and marginally also of E-selectin, whereas the level of P-selectin and VCAM-1 remained unaltered. Thus, downregulation of ICAM-1 might be a critical factor in Prednisolone-mediated inhibition of B. burgdorferi-induced inflammation; the flare up of the disease after the initial protection indicates that additional therapy, e.g. with antibiotics, is necessary. PMID:8933206

  20. Gene Therapy for Diseases and Genetic Disorders

    MedlinePlus

    ... notable advancements are the following: Gene Therapy for Genetic Disorders Severe Combined Immune Deficiency (ADA-SCID) ADA- ... in preclinical animal models of this disease. Other genetic disorders After many years of laboratory and preclinical ...

  1. Simple and reliable genotyping protocol for mouse Prkdc(SCID) mutation.

    PubMed

    Quadros, Rolen M; Poluektova, Larisa Y; Gurumurthy, Channabasavaiah B

    2016-04-01

    Mutant mouse models, genetically-engineered or spontaneous-mutations, serve as valuable tools for biomedical research. Genotyping of mutant mice is a critical requirement for maintaining the colony, to breed with other mutants and to match the phenotypic observations. The SCID (Severe Combine Immuno Deficiency) mouse model has been extensively used as a common background-strain in many immunology and transplantation studies. Many different types of assays, including Restriction Fragment Length Polymorphism (RFLP), confronting two primer pairs PCR and end-point methods have been attempted for establishing a genotyping protocol for the SCID mutation. However, the best method that is thought to be reliable is sequencing, which requires additional time and resources to perform on a routine basis. In this report, we describe a novel RFLP assay that is simple and reliable. The method is validated by sequencing analysis, and this novel method can be adapted for routine genotyping of SCID model. PMID:26851521

  2. Simple and reliable genotyping protocol for mouse Prkdc(SCID) mutation.

    PubMed

    Quadros, Rolen M; Poluektova, Larisa Y; Gurumurthy, Channabasavaiah B

    2016-04-01

    Mutant mouse models, genetically-engineered or spontaneous-mutations, serve as valuable tools for biomedical research. Genotyping of mutant mice is a critical requirement for maintaining the colony, to breed with other mutants and to match the phenotypic observations. The SCID (Severe Combine Immuno Deficiency) mouse model has been extensively used as a common background-strain in many immunology and transplantation studies. Many different types of assays, including Restriction Fragment Length Polymorphism (RFLP), confronting two primer pairs PCR and end-point methods have been attempted for establishing a genotyping protocol for the SCID mutation. However, the best method that is thought to be reliable is sequencing, which requires additional time and resources to perform on a routine basis. In this report, we describe a novel RFLP assay that is simple and reliable. The method is validated by sequencing analysis, and this novel method can be adapted for routine genotyping of SCID model.

  3. Inhibition of Human Colon Cancer Growth by Antibody-Directed Human LAK Cells in SCID Mice

    NASA Astrophysics Data System (ADS)

    Takahashi, Hiroshi; Nakada, Tetsuya; Puisieux, Isabelle

    1993-03-01

    Advanced human colon cancer does not respond to lymphokine-activated killer (LAK) cells. In order to direct cytotoxic cells to the tumor, human LAK cells linked with antibodies to a tumor cell surface antigen were tested with established hepatic metastases in severe combined immunodeficient (SCID) mice. These cells had increased uptake into the tumor and suppression of tumor growth as compared with LAK cells alone, thereby improving the survival of tumor-bearing mice. Thus, tumor growth can be inhibited by targeted LAK cells, and SCID mice can be used to test the antitumor properties of human effector cells.

  4. Immunodeficient NOD-scid IL-2Rγ(null) mice do not display T and B cell leakiness.

    PubMed

    Katano, Ikumi; Ito, Ryoji; Eto, Tomoo; Aiso, Sadakazu; Ito, Mamoru

    2011-01-01

    NOD/Shi-scid IL-2Rγ(null) (NOG) mice established by introducing the IL-2Rγ(null) gene of IL-2Rγ KO mice into NOD/Shi-scid mice by backcross-mating show a high xenograft engraftment level and are therefore well suited as a humanized mouse model. SCID mice bearing the Prkdc(scid) gene show a high incidence of thymic lymphoma and a leaky phenomenon in which a few clonal T and B cells develop in aged mice. In the present study, NOG mice were assessed for the presence of a leaky phenomenon such as the one observed in C.B-17-scid and NOD-scid mice. Serum immunoglobulin analysis did not detect IgG or IgM in NOG mice, unlike the findings in C.B-17-scid and NOD-scid mice. Flow cytometry analysis revealed the absence of T and B cells in the peripheral blood and spleens of NOG mice. These results reflect the suppression of the leaky phenomenon in NOG mice through the inactivation of the IL-2Rγ gene, which is commonly expressed in T and B cell growth factor receptors to IL-2, IL-4 and IL-7.

  5. Influence of human myasthenia gravis thymus on the differentiation of human cord blood stem cells in SCID mice.

    PubMed

    Li, Qian Ru; Liu, Ping Ping; Xuan, Xiao Yan; Guan, Sha Sha; Du, Ying; Gao, Feng; Zhang, Qing Yong

    2014-02-01

    The normal thymus contributes to T lymphocytes differentiation and induction of tolerance to self-antigens. Myasthenia gravis (MG) is characterized by abnormal thymic hyperplasia. To assess the potential influence of MG-thymus on the differentiation of T lymphocytes differentiation, we used the MG-thymus transplanted severe combined immunodeficiency (SCID) mice model to evaluate the human cord blood stem cells differentiation. Thymus fragments from MG patient and human cord blood stem cells were transplanted into SCID mice successively. SCID mice were observed to develop sustained human T lymphocytes and a functional anti-tumor immune. The levels of various T cell subsets in SCID mice with MG-thymus were different from that of control group. Among that, the frequency of CD4(+)CD25(+) T cells was significant lower in SCID mice with MG-thymus. The deficiency of CD4(+)CD25(+) T cells seens to contribute to the pathogenesis of MG.

  6. Efficient xenoengraftment in severe immunodeficient NOD/Shi-scid IL2rγnull mice is attributed to a lack of CD11c+B220+CD122+ cells.

    PubMed

    Ito, Ryoji; Katano, Ikumi; Ida-Tanaka, Miyuki; Kamisako, Tsutomu; Kawai, Kenji; Suemizu, Hiroshi; Aiso, Sadakazu; Ito, Mamoru

    2012-11-01

    Xenograft animal models using immunodeficient mice have been widely applied in medical research on various human diseases. NOD/Shi-scid-IL2rγ(null) (NOG) mice are known to show an extremely high engraftment rate of xenotransplants compared with conventional immunodeficient mice. This high engraftment rate of xenotransplants in NOG mice was substantially suppressed by the transfer of spleen cells from NOD-scid mice that were devoid of NK cells. These results indicate that cell types other than splenic NK cells present in NOD-scid mice but not in NOG mice may be involved in this suppression. To identify the cell types responsible for this effect, we transferred subpopulations of spleen cells from NOD-scid mice into NOG mice and assessed the levels of human cell engraftment after human PBMC (hPBMC) transplantation. These experiments revealed that CD11c(+)B220(+) plasmacytoid dendritic cells (pDCs) from NOD-scid mice markedly inhibited engraftment of human cells. The CD11c(+)B220(+)CD122(+) cells further fractionated from the pDCs based on the expression of CD122, which is an NK cell marker strongly inhibited during hPBMC engraftment in NOG mice. Moreover, the CD122(+) cells in the pDC fraction were morphologically distinguishable from conventional CD122(+) NK cells and showed a higher rejection efficiency. The current results suggest that CD11c(+)B220(+)CD122(+) cells play an important role in xenograft rejection, and their absence in NOG mice may be critical in supporting the successful engraftment of xenotransplants.

  7. Effects of fission neutrons on human thyroid tissues maintained in SCID mice.

    PubMed

    Adachi, Shigeki; Ryo, Haruko; Hongyo, Tadashi; Nakajima, Hiroo; Tsuboi-Kikuya, Rie; Tokita, Yoriko; Matsuzuka, Fumio; Hiramatsu, Keizo; Fujikawa, Kazuo; Itoh, Tetsuo; Nomura, Taisei

    2010-02-01

    Morphology and function (secretion of thyroid hormone) of human thyroid tissues from Graves' disease patients are well maintained in C57BL/6J-scid mice. Serum level of thyroid hormone was reduced by fission neutrons from the nuclear reactor UTR-KINKI, and changes in thyroid hormone by fission neutrons were bigger than those by low LET radiations, X-rays and (137)Cs gamma-rays, suggesting high relative biological effectiveness (RBE; 6.5) of fission neutrons. Microarray analyses revealed that about 3% of genes showed more than 4-fold change in gene expression in the unexposed thyroid tissues against surgically resected thyroid tissues from the same patient, probably due to the difficult oxygen and nutrient supply shortly after transplantation. Dose-dependent changes in gene expression against unexposed concurrent controls were observed with increasing doses of fission neutrons (0.2-0.6Gy) and (137)Cs gamma-rays (1.0-3.0Gy) and showed high RBE (4.2). Furthermore, there were some specific genes which showed more than 4-fold change in gene expression in all the thyroid tissues exposed to higher doses of radiation, especially neutrons (0.4 and 0.6Gy), but none at lower doses (0.2Gy of neutrons and 1.0 and 2.0Gy of gamma-rays). These genes related to degeneration, regeneration, apoptosis, and transcription, respond specifically and very sensitively to neutron injury in human thyroid tissues. This is the first experimental report that fission neutrons can induce some morphological and functional disorders in human tissues, showing high RBE against gamma-ray exposure. These results are useful to evaluate the risks of fission neutrons and cosmic rays to humans.

  8. Highly potent anti-CD20-RLI immunocytokine targeting established human B lymphoma in SCID mouse.

    PubMed

    Vincent, Marie; Teppaz, Géraldine; Lajoie, Laurie; Solé, Véronique; Bessard, Anne; Maillasson, Mike; Loisel, Séverine; Béchard, David; Clémenceau, Béatrice; Thibault, Gilles; Garrigue-Antar, Laure; Jacques, Yannick; Quéméner, Agnès

    2014-01-01

    Rituximab (RTX), a chimeric IgG1 monoclonal antibody directed against the CD20 antigen, has revolutionized the treatment of B-cell malignancies. Nevertheless, the relapsed/refractory rates are still high. One strategy to increase the clinical effectiveness of RTX is based on antibody-cytokine fusion protein (immunocytokine; ICK) vectorizing together at the tumor site the antibody effector activities and the cytokine co-signal required for the generation of cytotoxic cellular immunity. Such ICKs linking various antibody formats to interleukin (IL)-2 are currently being investigated in clinical trials and have shown promising results in cancer therapies. IL-15, a structurally-related cytokine, is now considered as having a better potential than IL-2 in antitumor immunotherapeutic strategies. We have previously engineered the fusion protein RLI, linking a soluble form of human IL-15Rα-sushi+ domain to human IL-15. Compared with IL-15, RLI displayed better biological activities in vitro and higher antitumor effects in vivo in murine and human cancer models. In this study, we investigated the advantages of fusing RLI to RTX. Anti-CD20-RLI kept its binding capacity to CD20, CD16 and IL-15 receptor and therefore fully retained both antibody effector functions (ADCC and CDC), and the cytokine potential of RLI. In a severe combined immunodeficiency (SCID) mouse model of disseminated residual lymphoma, anti-CD20-RLI was found to induce long-term survival of 90% of mice up to at least 120 days whereas RLI and RTX, alone or in combination, just delayed the disease onset (100% of death at 28, 40 and 51 days respectively). These findings suggest that such ICK could improve the clinical efficacy of RTX, particularly in patients with refractory B-cell lymphoma. PMID:25072059

  9. Highly potent anti-CD20-RLI immunocytokine targeting established human B lymphoma in SCID mouse

    PubMed Central

    Vincent, Marie; Teppaz, Géraldine; Lajoie, Laurie; Solé, Véronique; Bessard, Anne; Maillasson, Mike; Loisel, Séverine; Béchard, David; Clémenceau, Béatrice; Thibault, Gilles; Garrigue-Antar, Laure; Jacques, Yannick; Quéméner, Agnès

    2014-01-01

    Rituximab (RTX), a chimeric IgG1 monoclonal antibody directed against the CD20 antigen, has revolutionized the treatment of B-cell malignancies. Nevertheless, the relapsed/refractory rates are still high. One strategy to increase the clinical effectiveness of RTX is based on antibody-cytokine fusion protein (immunocytokine; ICK) vectorizing together at the tumor site the antibody effector activities and the cytokine co-signal required for the generation of cytotoxic cellular immunity. Such ICKs linking various antibody formats to interleukin (IL)-2 are currently being investigated in clinical trials and have shown promising results in cancer therapies. IL-15, a structurally-related cytokine, is now considered as having a better potential than IL-2 in antitumor immunotherapeutic strategies. We have previously engineered the fusion protein RLI, linking a soluble form of human IL-15Rα-sushi+ domain to human IL-15. Compared with IL-15, RLI displayed better biological activities in vitro and higher antitumor effects in vivo in murine and human cancer models. In this study, we investigated the advantages of fusing RLI to RTX. Anti-CD20-RLI kept its binding capacity to CD20, CD16 and IL-15 receptor and therefore fully retained both antibody effector functions (ADCC and CDC), and the cytokine potential of RLI. In a severe combined immunodeficiency (SCID) mouse model of disseminated residual lymphoma, anti-CD20-RLI was found to induce long-term survival of 90% of mice up to at least 120 days whereas RLI and RTX, alone or in combination, just delayed the disease onset (100% of death at 28, 40 and 51 days respectively). These findings suggest that such ICK could improve the clinical efficacy of RTX, particularly in patients with refractory B-cell lymphoma. PMID:25072059

  10. Rapid-high, syncytium-inducing isolates of human immunodeficiency virus type 1 induce cytopathicity in the human thymus of the SCID-hu mouse.

    PubMed Central

    Kaneshima, H; Su, L; Bonyhadi, M L; Connor, R I; Ho, D D; McCune, J M

    1994-01-01

    Clinical deterioration in human immunodeficiency virus type 1 (HIV-1) disease is associated with an increased viral burden in the peripheral blood and a loss of circulating CD4+ T cells. HIV-1 isolates obtained prior to this stage of disease often have a "slow-low," non-syncytium-inducing (NSI) phenotype, whereas those obtained afterwards are often characterized as "rapid-high" and syncytium inducing (SI). Paired NSI and SI isolates from two different patients were inoculated into the human thymus implants of SCID-hu mice. The two slow-low, NSI isolates replicated to minimal levels in the grafts and did not induce thymocyte depletion. In contrast, the two SI isolates from the same patients showed high levels of viral replication and induced a marked degree of thymocyte depletion, accompanied by evidence of programmed cell death. These observations reveal a correlation between the replicative and cytopathic patterns of HIV-1 isolates in vitro and in the SCID-hu mouse in vivo and provide direct evidence that the biological phenotype of HIV-1 switch may be a causal and not a derivative correlate of HIV-1 disease progression. PMID:7966610

  11. Rapid engraftment of human ALL in NOD/SCID mice involves deficient apoptosis signaling.

    PubMed

    Queudeville, M; Seyfried, F; Eckhoff, S M; Trentin, L; Ulrich, S; Schirmer, M; Debatin, K-M; Meyer, L H

    2012-01-01

    Previously, we found that rapid leukemia engraftment (short time to leukemia, TTL(short)) in the NOD/SCID/huALL (non-obese diabetic/severe combined immuno-deficiency/human acute lymphoblastic leukemia) xenograft model is indicative of early patient relapse. As earlier intact apoptosis sensitivity was predictive for good prognosis in patients, we investigated the importance of apoptosis signaling on NOD/SCID/huALL engraftment. Intact apoptosome function as reflected by cytochrome c-related activation of caspase-3 (CRAC-positivity) was strongly associated with prolonged NOD/SCID engraftment (long time to leukemia, TTL(long)) of primary leukemia cells, good treatment response and superior patient survival. Conversely, deficient apoptosome function (CRAC-negativity) was associated with rapid engraftment (TTL(short)) and early relapse. Moreover, an intact apoptosis signaling was associated with high transcript and protein levels of the pro-apoptotic death-associated protein kinase1 (DAPK1). Our data strongly emphasize the impact of intrinsic apoptosis sensitivity of ALL cells on the engraftment phenotype in the NOD/SCID/huALL model, and most importantly also on patient outcome. PMID:22875001

  12. Generation of transgenic mice on an NOD/SCID background using the conventional microinjection technique.

    PubMed

    Kumagai, Katsuyoshi; Kubota, Naoto; Saito, Toshiki I; Sasako, Takayoshi; Takizawa, Rumi; Sudo, Katsuko; Kurokawa, Mineo; Kadowaki, Takashi

    2011-04-01

    Humanized mice, which refers to immunodeficient mice repopulated with the human immune system, are powerful tools for study in the field of immunology. It has been difficult, however, to generate these transgenic (Tg) mice directly from such strains as the NOD/SCID mouse. In this study, we describe a method developed by us for the generation of Tg mice on an NOD/SCID background. First, we obtained fertilized eggs efficiently by means of in vitro fertilization (IVF); then, we attempted to generate CAG-EGFP Tg mice on an NOD/SCID background, finding that delayed timing of the microinjection after the IVF improved the time to development of the two-cell-stage embryos and the obtainment of newborns. We successfully generated Tg mice and confirmed the germ-line transmission in the offspring. In conclusion, we established a novel system for directly generating transgenic mice on an NOD/SCID background. This novel system is expected to allow improved efficiency of the generation of humanized mice.

  13. Autoimmune manifestations in SCID due to IL7R mutations: Omenn syndrome and cytopenias.

    PubMed

    Zago, Claudia Augusta; Jacob, Cristina Miuki Abe; de Albuquerque Diniz, Edna Maria; Lovisolo, Silvana Maria; Zerbini, Maria Claudia Nogueira; Dorna, Mayra; Watanabe, Letícia; Fernandes, Juliana Folloni; Rocha, Vanderson; Oliveira, João Bosco; Carneiro-Sampaio, Magda

    2014-07-01

    B+NK+SCID (severe combined immunodeficiency) due to IL7Rα deficiency represents approximately 10% of American SCID cases. To better understand the spectrum of autoimmune disorders associated with IL7Rα deficiency, we describe two unrelated IL7Rα-deficient female SCID infants whose clinical picture was dominated by autoimmune manifestations: one with intrauterine Omenn syndrome (OS) and another with persistent thrombocytopenic purpura since 4months of age. The OS baby harbored a homozygous p.C118Y mutation in IL7R. She presented dense eosinophilic infiltrates in several organs, including pancarditis, which may have contributed to her death (on the 2nd day of life). B cells were observed in lymph nodes, spleen, bone marrow and thymus. The second patient harbored compound heterozygous p.C118Y and p.I121NfsX8 mutations. She underwent a successful unrelated cord blood transplant. In conclusion, early OS can be observed in patients with IL7R mutations, and autoimmune cytopenias could also complicate the clinical course of SCID babies with this type of defect.

  14. Rapid engraftment of human ALL in NOD/SCID mice involves deficient apoptosis signaling.

    PubMed

    Queudeville, M; Seyfried, F; Eckhoff, S M; Trentin, L; Ulrich, S; Schirmer, M; Debatin, K-M; Meyer, L H

    2012-08-09

    Previously, we found that rapid leukemia engraftment (short time to leukemia, TTL(short)) in the NOD/SCID/huALL (non-obese diabetic/severe combined immuno-deficiency/human acute lymphoblastic leukemia) xenograft model is indicative of early patient relapse. As earlier intact apoptosis sensitivity was predictive for good prognosis in patients, we investigated the importance of apoptosis signaling on NOD/SCID/huALL engraftment. Intact apoptosome function as reflected by cytochrome c-related activation of caspase-3 (CRAC-positivity) was strongly associated with prolonged NOD/SCID engraftment (long time to leukemia, TTL(long)) of primary leukemia cells, good treatment response and superior patient survival. Conversely, deficient apoptosome function (CRAC-negativity) was associated with rapid engraftment (TTL(short)) and early relapse. Moreover, an intact apoptosis signaling was associated with high transcript and protein levels of the pro-apoptotic death-associated protein kinase1 (DAPK1). Our data strongly emphasize the impact of intrinsic apoptosis sensitivity of ALL cells on the engraftment phenotype in the NOD/SCID/huALL model, and most importantly also on patient outcome.

  15. The severe combined immunodeficient (SCID) mouse model of human immunodeficiency virus encephalitis: deficits in cognitive function.

    PubMed

    Griffin, William C; Middaugh, Lawrence D; Cook, Jennifer E; Tyor, William R

    2004-04-01

    The severe combined immunodeficient (SCID) mouse model of human immunodeficiency virus (HIV) encephalitis exhibits many of the histopathological and pathophysiological features of human HIV-associated dementia (HAD). Although deficits that may resemble HAD in humans have been reported for HIV-infected SCID mice, the cognitive deficit aspect of the model has very limited empirical support. Here, the authors report that HIV-infected SCID mice display cognitive deficits on a task requiring the animal to learn and remember the spatial relationship of cues in its environment in order to locate a submerged platform in a Morris water maze. The cognitive deficits manifest as longer latencies to locate the platform on the last day of the maze acquisition period and during a retention test 8 days later. Control experiments indicated that the poor performance by HIV-infected mice in comparison to controls was not due to impaired motor function or swimming ability, impaired visual acuity, or increased susceptibility to fatigue. Thus, the increased times required for HIV-infected mice to locate the submerged platform during the acquisition and memory tests likely reflect a cognitive deficit, rather than sensorimotor or emotional abnormalities. These behavioral deficits are associated with significant increases in astrogliosis and microgliosis in the HIV-infected mice. The results of this study strengthen the SCID mouse model of HIV encephalitis by definitively establishing cognitive deficits for the model in addition to its previously reported neuropathological features.

  16. The inclusion of ADA-SCID in expanded newborn screening by tandem mass spectrometry.

    PubMed

    la Marca, Giancarlo; Giocaliere, Elisa; Malvagia, Sabrina; Funghini, Silvia; Ombrone, Daniela; Della Bona, Maria Luisa; Canessa, Clementina; Lippi, Francesca; Romano, Francesca; Guerrini, Renzo; Resti, Massimo; Azzari, Chiara

    2014-01-01

    Severe combined immunodeficiency due to adenosine-deaminase defect (ADA-SCID) is usually deadly in childhood because of severe recurrent infections. When clinical diagnosis is done, permanent damages due to infections or metabolite accumulation are often present. Gene therapy, bone marrow transplantation or enzyme replacement therapy may be effective if started early. The aim of this study was to set-up a robust method suitable for screening with a minimized preparation process and with inexpensive running costs, for diagnosing ADA-SCID by tandem mass spectrometry. ADA-SCID satisfies all the criteria for inclusion in a newborn screening program. We describe a protocol revised to incorporate adenosine and 2-deoxyadenosine testing into an expanded newborn screening program. We assessed the effectiveness of this approach testing dried blood spots from 4 genetically confirmed early-onset and 5 delayed-onset ADA-SCID patients. Reference values were established on 50,000 healthy newborns (deoxyadenosine <0.09μmol/L, adenosine <1.61μmol/L). We also developed a second tier test to distinguish true positives from false positives and improve the positive predictive value of an initial abnormal result. In the first 18 months, the pilot project has identified a newborn with a genetically confirmed defect in adenosine deaminase (ADA) gene. The results show that the method having great simplicity, low cost and low process preparations can be fully applicable to a mass screening program.

  17. Generation of Novel Chimeric Mice with Humanized Livers by Using Hemizygous cDNA-uPA/SCID Mice.

    PubMed

    Tateno, Chise; Kawase, Yosuke; Tobita, Yoshimi; Hamamura, Satoko; Ohshita, Hiroki; Yokomichi, Hiroshi; Sanada, Harumi; Kakuni, Masakazu; Shiota, Akira; Kojima, Yuha; Ishida, Yuji; Shitara, Hiroshi; Wada, Naoko A; Tateishi, Hiromi; Sudoh, Masayuki; Nagatsuka, Shin-Ichiro; Jishage, Kou-Ichi; Kohara, Michinori

    2015-01-01

    We have used homozygous albumin enhancer/promoter-driven urokinase-type plasminogen activator/severe combined immunodeficient (uPA/SCID) mice as hosts for chimeric mice with humanized livers. However, uPA/SCID mice show four disadvantages: the human hepatocytes (h-heps) replacement index in mouse liver is decreased due to deletion of uPA transgene by homologous recombination, kidney disorders are likely to develop, body size is small, and hemizygotes cannot be used as hosts as more frequent homologous recombination than homozygotes. To solve these disadvantages, we have established a novel host strain that has a transgene containing albumin promoter/enhancer and urokinase-type plasminogen activator cDNA and has a SCID background (cDNA-uPA/SCID). We applied the embryonic stem cell technique to simultaneously generate a number of transgenic lines, and found the line with the most appropriate levels of uPA expression-not detrimental but with a sufficiently damaged liver. We transplanted h-heps into homozygous and hemizygous cDNA-uPA/SCID mice via the spleen, and monitored their human albumin (h-alb) levels and body weight. Blood h-alb levels and body weight gradually increased in the hemizygous cDNA-uPA/SCID mice and were maintained until they were approximately 30 weeks old. By contrast, blood h-alb levels and body weight in uPA/SCID chimeric mice decreased from 16 weeks of age onwards. A similar decrease in body weight was observed in the homozygous cDNA-uPA/SCID genotype, but h-alb levels were maintained until they were approximately 30 weeks old. Microarray analyses revealed identical h-heps gene expression profiles in homozygous and hemizygous cDNA-uPA/SCID mice were identical to that observed in the uPA/SCID mice. Furthermore, like uPA/SCID chimeric mice, homozygous and hemizygous cDNA-uPA/SCID chimeric mice were successfully infected with hepatitis B virus and C virus. These results indicate that hemizygous cDNA-uPA/SCID mice may be novel and useful hosts for

  18. Generation of Novel Chimeric Mice with Humanized Livers by Using Hemizygous cDNA-uPA/SCID Mice.

    PubMed

    Tateno, Chise; Kawase, Yosuke; Tobita, Yoshimi; Hamamura, Satoko; Ohshita, Hiroki; Yokomichi, Hiroshi; Sanada, Harumi; Kakuni, Masakazu; Shiota, Akira; Kojima, Yuha; Ishida, Yuji; Shitara, Hiroshi; Wada, Naoko A; Tateishi, Hiromi; Sudoh, Masayuki; Nagatsuka, Shin-Ichiro; Jishage, Kou-Ichi; Kohara, Michinori

    2015-01-01

    We have used homozygous albumin enhancer/promoter-driven urokinase-type plasminogen activator/severe combined immunodeficient (uPA/SCID) mice as hosts for chimeric mice with humanized livers. However, uPA/SCID mice show four disadvantages: the human hepatocytes (h-heps) replacement index in mouse liver is decreased due to deletion of uPA transgene by homologous recombination, kidney disorders are likely to develop, body size is small, and hemizygotes cannot be used as hosts as more frequent homologous recombination than homozygotes. To solve these disadvantages, we have established a novel host strain that has a transgene containing albumin promoter/enhancer and urokinase-type plasminogen activator cDNA and has a SCID background (cDNA-uPA/SCID). We applied the embryonic stem cell technique to simultaneously generate a number of transgenic lines, and found the line with the most appropriate levels of uPA expression-not detrimental but with a sufficiently damaged liver. We transplanted h-heps into homozygous and hemizygous cDNA-uPA/SCID mice via the spleen, and monitored their human albumin (h-alb) levels and body weight. Blood h-alb levels and body weight gradually increased in the hemizygous cDNA-uPA/SCID mice and were maintained until they were approximately 30 weeks old. By contrast, blood h-alb levels and body weight in uPA/SCID chimeric mice decreased from 16 weeks of age onwards. A similar decrease in body weight was observed in the homozygous cDNA-uPA/SCID genotype, but h-alb levels were maintained until they were approximately 30 weeks old. Microarray analyses revealed identical h-heps gene expression profiles in homozygous and hemizygous cDNA-uPA/SCID mice were identical to that observed in the uPA/SCID mice. Furthermore, like uPA/SCID chimeric mice, homozygous and hemizygous cDNA-uPA/SCID chimeric mice were successfully infected with hepatitis B virus and C virus. These results indicate that hemizygous cDNA-uPA/SCID mice may be novel and useful hosts for

  19. Functional analysis of human cytomegalovirus UL/b' region using SCID-hu mouse model.

    PubMed

    Dulal, Kalpana; Cheng, Tong; Yang, Lianwei; Wang, Wei; Huang, Ying; Silver, Benjamin; Selariu, Anca; Xie, Cynthia; Wang, Dai; Espeseth, Amy; Lin, Yanzhen; Wen, Lanling; Xia, Ningshao; Fu, Tong-Ming; Zhu, Hua

    2016-08-01

    Human cytomegalovirus (HCMV) attenuated strains, Towne, and AD169, differ from prototypic pathogenic strains, such as Toledo, in that they are missing a ∼15-kb segment in the UL/b' region. In contrast to the attenuated strains, Toledo can replicate in human tissue implants in SCID (SCID-hu) mice. Thus, this model provides a unique in vivo system to study the mechanism of viral pathogenesis. Twenty-two ORFs have been annotated in the UL/b' region, including tissue-tropic genes encoded in a pentameric gH/gl complex. To differentiate the role of the pentameric gH/gl complex versus the functions of other ORFs in the 15-kb region in supporting viral growth in vivo, a series of recombinant viral strains were constructed and their ability to replicate in SCID-hu mice was tested. The mutations in the Towne and AD169 strains were repaired to restore their pentameric gH/gl complex and it was found that these changes did not rescue their inability to replicate in the SCID-hu mice. Subsequently four deletion viruses (D1, D2, D3, and D4) in the 15-kb region from the Toledo strain were created. It was demonstrated that D2 and D3 were able to grow in SCID-hu mice, while D1 and D4 were not viable. Interestingly, co-infection of the implant with the D1 and D4 viruses could compensate their respective growth defect in vivo. The results demonstrated that rescuing viral epithelial tropism is not sufficient to revert the attenuation phenotype of AD169 or Towne, and pathogenic genes are located in the segments missing in D1 and D4 viruses. J. Med. Virol. 88:1417-1426, 2016. © 2016 Wiley Periodicals, Inc.

  20. Radiation-induced apoptosis in SCID Mousespleen after a low-dose irration

    NASA Astrophysics Data System (ADS)

    Ohnishi, T.; Takahashi, A.; Ohnishi, K.

    Purpose: To estimate the effects of space radiation on health of space crews, we aimed to clarify whether pre-irradiation at a low-dose interferes in a p53-centered signal transduction pathway induced by radiation. By using a severe combined immunodeficiency (Scid) mouse defective DNA-PK activity, we examined the role of DNA-PK activity in radioadaptation induced by low-dose irradiation. Methodology: Specific pathogen free 5-week-old fe male mice of Scid and the parental mice (CB-17 Icr+/+) were irradiated with X-rays at 3.0 Gy 1, 2, 3 or 4 weeks after conditioning irradiation at 0.15, 0.30, 0.45 or 0.60 Gy. The mice spleens were fixed for immunohistochemistry 12 h after irradiation. Bax on formalin-fixed paraffin-embedded sections were stained by the avidin-biotin peroxidase complex method using HISTOFINE SAB-PO(R) kit (Nichirei Co., Tokyo, Japan). Apoptosis incidence in the sections was measured by staining with HE staining. Results: The frequency of Bax- and apoptosis -positive cells increased up to 12 h after irradiation at 3.0 Gy in the spleen of CB-17 Icr+/+ and Scid mice. However, they were not observed by irradiation with low dose at 0.15-0.60 Gy. When pre-irradiation at 0.45 Gy 2 weeks before challenging acute irradiation at 3.0 Gy was performed, Bax accumulation and apoptosis induced by irradiation at 3.0 Gy was depressed in the spleen of CB-17 Icr+/+ mice, but not Scid mice. Conclusions: These data suggest that DNA-PKcs (expressed in CB-17 Icr+/+, not Scid mice) might play a major role on radioadaptation induced by pre-irradiation at low dose in mice spleen. We expect that the present findings will provide useful information for the care of space crews' health.

  1. Hemopoietic stem-cell compartment of the SCID mouse: Double-exponential survival curve after [gamma] irradiation

    SciTech Connect

    Taniguchi, Satoshi Niigata Univ. ); Hirabayashi, Yoko; Inoue, Tohru; Kanisawa, Masayoshi; Sasaki, Hideki ); Komatsu, Kenshi ); Mori, K.J. )

    1993-05-15

    It has been reported that SCID (severe combined immunodeficiency, scid/scid) mice are more radiosensitive than normal mice. In the present studies, graded doses of radiation were given to bone marrow cells from SCID mice, and double-exponential survival curves were observed for day-9 and day-12 colony-forming units in the spleen (CFU-S). Single-exponential curves were found for SCID CFU in in vitro assays for granulocyte/macrophage-CFUs and erythroid burst-forming units, as reported elsewhere. Since the size of this more resistant fraction seems to decrease with stem-cell maturation, the finding implies that this fraction is a primitive subpopulation of the stem-cell compartment. The mean lethal dose (D[sub 0]), however, of this less sensitive SCID CFU-S is much less than the D[sub 0] of regular CFU-S in normal littermates. Spleen colonies produced by SCID bone marrow were relatively small and abortive. The size of these colonies decreased nearly exponentially with increasing doses of radiation. These colonies produced by the sensitive fraction have disappeared, being killed by a relatively low dose of radiation. This observation might account for the high lymphomagenesis arising from primitive hemopoietic stem cells in SCID mice, because the smallness of the colonies suggests that there is unrepaired or misrepaired damage. Furthermore, this less sensitive fraction might be a source of the [open quotes]leaky[close quotes] change of T and B cells, possibly due to the induction of an equivocal repair system which appears in the later stages of life in the SCID mice. 34 refs., 5 figs., 3 tabs.

  2. Gene for the catalytic subunit of mouse DNA-dependent protein kinase maps to the scid locus.

    PubMed Central

    Miller, R D; Hogg, J; Ozaki, J H; Gell, D; Jackson, S P; Riblet, R

    1995-01-01

    The gene encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) has been proposed recently as a candidate gene for the mouse severe combined immune deficiency (scid) locus. We have used a partial cDNA clone for human DNA-PKcs to map the mouse homologue using a large interspecific backcross panel. We found that the mouse gene for DNA-PKcs does not recombine with scid, consistent with the hypothesis that scid is a mutation in the mouse gene for DNA-PKcs. Images Fig. 3 PMID:7479885

  3. Evaluation of the NOD/SCID xenograft model for glucocorticoid-regulated gene expression in childhood B-cell precursor acute lymphoblastic leukemia

    PubMed Central

    2011-01-01

    Background Glucocorticoids such as prednisolone and dexamethasone are critical drugs used in multi-agent chemotherapy protocols used to treat acute lymphoblastic leukemia (ALL), and response to glucocorticoids is highly predictive of outcome. The NOD/SCID xenograft mouse model of ALL is a clinically relevant model in which the mice develop a systemic leukemia which retains the fundamental biological characteristics of the original disease. Here we report a study evaluating the NOD/SCID xenograft mouse model to investigate glucocorticoid-induced gene expression. Cells from a glucocorticoid-sensitive xenograft derived from a child with B-cell precursor ALL were inoculated into NOD/SCID mice. When highly engrafted the mice were randomized into groups of 4 to receive dexamethasone 15 mg/kg by intraperitoneal injection or vehicle control. Leukemia cells were harvested from mice spleens at 0, 8, 24 or 48 hours thereafter, and gene expression analyzed on Illumina WG-6_V3 chips, comparing all groups to time 0 hours. Results The 8 hour dexamethasone-treated timepoint had the highest number of significantly differentially expressed genes, with fewer observed at the 24 and 48 hour timepoints, and with minimal changes seen across the time-matched controls. When compared to publicly available datasets of glucocorticoid-induced gene expression from an in vitro cell line study and from an in vivo study of patients with ALL, at the level of pathways, expression changes in the 8 hour xenograft samples showed a similar response to patients treated with glucocorticoids. Replicate analysis revealed that at the 8 hour timepoint, a dataset with high signal and differential expression, using data from 3 replicates instead of 4 resulted in excellent recovery scores of > 0.9. However at other timepoints with less signal very poor recovery scores were obtained with 3 replicates. Conclusions The NOD/SCID xenograft mouse model provides a reproducible experimental system in which to

  4. Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/gammac-/-, Balb/c-Rag1-/-gammac-/-, and C.B-17-scid/bg immunodeficient mice.

    PubMed

    Lepus, Christin M; Gibson, Thomas F; Gerber, Scott A; Kawikova, Ivana; Szczepanik, Marian; Hossain, Jaber; Ablamunits, Vitaly; Kirkiles-Smith, Nancy; Herold, Kevan C; Donis, Ruben O; Bothwell, Alfred L; Pober, Jordan S; Harding, Martha J

    2009-10-01

    Immunodeficient mice bearing components of a human immune system present a novel approach for studying human immune responses. We investigated the number, phenotype, developmental kinetics, and function of developing human immune cells following transfer of CD34(+) hematopoietic stem cell (HSC) preparations originating from second trimester human fetal liver (HFL), umbilical cord blood (UCB), or granulocyte colony-stimulating factor-mobilized adult blood (G-CSF-AB) delivered via intrahepatic injection into sublethally irradiated neonatal NOD-scid/gammac(-/-), Balb/c-Rag1(-/-)gammac(-/-), and C.B-17-scid/bg mice. HFL and UCB HSC provided the greatest number and breadth of developing cells. NOD-scid/gammac(-/-) and Balb/c-Rag1(-/-)gammac(-/-) harbored human B and dendritic cells as well as human platelets in peripheral blood, whereas NOD-scid/gammac(-/-) mice harbored higher levels of human T cells. NOD-scid/gammac(-/-) mice engrafted with HFL CD34(+) HSC demonstrated human immunological competence evidenced by white pulp expansion and increases in total human immunoglobulin following immunization with T-dependent antigens and delayed-type hypersensitivity-infiltrating leukocytes in response to antigenic challenge. In conclusion, we describe an encouraging base system for studying human hematopoietic lineage development and function utilizing human HFL or UCB HSC-engrafted NOD-scid/gammac(-/-) mice that is well suited for future studies toward the development of a fully competent humanized mouse model.

  5. Measles virus infection of thymic epithelium in the SCID-hu mouse leads to thymocyte apoptosis.

    PubMed Central

    Auwaerter, P G; Kaneshima, H; McCune, J M; Wiegand, G; Griffin, D E

    1996-01-01

    Mortality from measles is caused mostly by secondary infections associated with the depression of cellular immunity. The mechanism of immune suppression and the role of virus strain differences on the immune system are incompletely understood. SCID-hu mice were used to determine the effects of virulent, wild-type (Chicago-1) and avirulent, vaccine (Moraten) strains of measles virus (MV) on the human thymus in vivo. Chicago-1 replicated rapidly, with a 100-fold decrease in numbers of thymocytes, whereas Moraten replicated slowly, without significant thymocyte death. Productive MV infection occurred not in thymocytes but in thymic epithelial and myelomonocytic cells. Wild-type MV infection of thymic stromata leads to induction of thymocyte apoptosis and may contribute to a long-term alteration of immune responses. The extent of thymic disruption reflects the virulence of the virus, and therefore the SCID-hu mouse may serve as the first small animal model for the study of MV pathogenesis. PMID:8648708

  6. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning.

    PubMed

    Aiuti, Alessandro; Slavin, Shimon; Aker, Memet; Ficara, Francesca; Deola, Sara; Mortellaro, Alessandra; Morecki, Shoshana; Andolfi, Grazia; Tabucchi, Antonella; Carlucci, Filippo; Marinello, Enrico; Cattaneo, Federica; Vai, Sergio; Servida, Paolo; Miniero, Roberto; Roncarolo, Maria Grazia; Bordignon, Claudio

    2002-06-28

    Hematopoietic stem cell (HSC) gene therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) has shown limited clinical efficacy because of the small proportion of engrafted genetically corrected HSCs. We describe an improved protocol for gene transfer into HSCs associated with nonmyeloablative conditioning. This protocol was used in two patients for whom enzyme replacement therapy was not available, which allowed the effect of gene therapy alone to be evaluated. Sustained engraftment of engineered HSCs with differentiation into multiple lineages resulted in increased lymphocyte counts, improved immune functions (including antigen-specific responses), and lower toxic metabolites. Both patients are currently at home and clinically well, with normal growth and development. These results indicate the safety and efficacy of HSC gene therapy combined with nonmyeloablative conditioning for the treatment of SCID. PMID:12089448

  7. Application of HSVtk suicide gene to X-SCID gene therapy: Ganciclovir treatment offsets gene corrected X-SCID B cells

    SciTech Connect

    Uchiyama, Toru; Kumaki, Satoru . E-mail: kumakis@idac.tohoku.ac.jp; Ishikawa, Yoshinori; Onodera, Masafumi; Sato, Miki; Du, Wei; Sasahara, Yoji; Tanaka, Nobuyuki; Sugamura, Kazuo; Tsuchiya, Shigeru

    2006-03-10

    Recently, a serious adverse effect of uncontrolled clonal T cell proliferation due to insertional mutagenesis of retroviral vector was reported in X-SCID gene therapy clinical trial. To offset the side effect, we have incorporated a suicide gene into therapeutic retroviral vector for selective elimination of transduced cells. In this study, B-cell lines from two X-SCID patients were transduced with bicistronic retroviral vector carrying human {gamma}c chain cDNA and Herpes simplex virus thymidine kinase gene. After confirmation of functional reconstitution of the {gamma}c chain, the cells were treated with ganciclovir (GCV). The {gamma}c chain positive cells were eliminated under low concentration without cytotoxicity on untransduced cells and have not reappeared at least for 5 months. Furthermore, the {gamma}c chain transduced cells were still sensitive to GCV after five months. These results demonstrated the efficacy of the suicide gene therapy although further in vivo studies are required to assess feasibility of this approach in clinical trial.

  8. Insertional activation of myb by F-MuLV in SCID mice induces myeloid leukemia.

    PubMed

    Haeri, Mehran; Li, Youjun; Li, Yanmei; Li, Qi; Spaner, David E; Ben-David, Yaacov

    2013-07-01

    Identification of retrovirus integration sites is a powerful method to identify cancer-related genes. This approach led to the discovery of the Friend murine leukemia virus (F-MuLV) integration site-1 (fli-1). Viral insertion at the fli-1 locus induces erythroleukemia in susceptible strains of mice. Our recent data demonstrated that, F-MuLV-infected SCID mice, in contrast to wt CB17 controls, developed a non‑erythroleukemic leukemia without viral integration at the fli-1 locus. Using ligation-mediated polymerase chain reaction (LM-PCR) approach we identified a total of 15 viral integration sites in F-MuLV-infected SCID mice. One of the identified insertion sites was located about 62 kb upstream of the myeloblastosis (myb) gene. While integration within or surrounding the myb gene has been reported before for murine leukemia viruses, the location of the viral integration site identified in F-MuLV‑infected SCID mice is novel and has never been reported. Using PCR analysis we showed that viral integration at the myb locus occurs with a frequency of 35% and therefore is considered as a common integration site. Integration of F-MuLV in this locus resulted in upregulation of the MYB protein. Flow cytometry analysis and methylcellulose culture of leukemic cells isolated from tumors with viral integration close to the myb indicated tumors of myeloid origin. Our findings indicate that, in contrast to wt CB17 mice, F-MuLV-infected SCID mice display viral integration within myeloid specific gene loci that result in the development of myelogenous leukemia.

  9. Endogenous and xenobiotic metabolite profiling of liver extracts from SCID and chimeric humanized mice following repeated oral administration of troglitazone.

    PubMed

    Barnes, Alan J; Baker, David R; Hobby, Kirsten; Ashton, Simon; Michopoulos, Filippos; Spagou, Konstantina; Loftus, Neil J; Wilson, Ian D

    2014-01-01

    1. Metabonomic analysis, via a combination of untargeted and targeted liquid chromatography-mass spectrometry (LC-MS) and untargeted (1)H NMR spectroscopy-based metabolite profiling, was performed on aqueous (AQ) and organic liver extracts from control (SCID) and chimeric humanized (PXB) mice dosed with troglitazone at 0, 300 and 600 mg/kg/day for seven days. 2. LC-MS analysis of AQ liver extracts showed a more "human-like" profile for troglitazone metabolites for PXB, compared with SCID, mice. 3. LC-MS detected differences in endogenous metabolites, particularly lipid species in dosed mice, including elevated triacylglycerols and 1-alkyl,2-acylglycerophosphates as well as lowered diacylglycerophosphocholines and 1-alkyl,2-acylglycerophosphocholines for PXB compared with SCID mouse liver extracts. Following drug administration changes in the relative proportions of the ions for various unsaturated fatty acids were observed for both types of mouse, some of which were specific to PXB or SCID mice. 4.  (1)H NMR spectroscopy revealed that AQ PXB mouse liver extracts had elevated amounts of inosine, fumarate, creatine, aspartate, trimethylamine N-oxide, glycerophosphocholine, phosphocholine, choline, glutamine, glutamate, acetate, alanine and lactate relative to SCID mice and decreased histidine, glycogen, α- and β-glucose, taurine, and glutathione. Increased uracil and tyrosine concentrations were detected for PXB mice on troglitazone administration. 5. Metabonomic profiling thus showed clear differences between humanized and SCID mice, including after administration of troglitazone.

  10. The SCID-hu mouse as a model for HIV-1 infection.

    PubMed

    Aldrovandi, G M; Feuer, G; Gao, L; Jamieson, B; Kristeva, M; Chen, I S; Zack, J A

    1993-06-24

    During normal fetal ontogeny, one of the first organs to harbour CD4-positive cells is the thymus. This organ could therefore be one of the earliest targets infected by human immunodeficiency virus type 1 (HIV-1) in utero. HIV-1-infected cells and pathological abnormalities of the thymus have been seen in HIV-1-infected adults and children, and in some fetuses aborted from infected women. Studies of HIV-1 pathogenesis have been hampered by lack of a suitable animal model system. Here we use the SCID-hu mouse as a model to investigate the effect of virus infection on human tissue. The mouse is homozygous for the severe combined immunodeficiency (SCID) defect. The model is constructed by implanting human fetal liver and thymus under the mouse kidney capsule. A conjoint human organ develops, which allows normal maturation of human thymocytes. After direct inoculation of HIV-1 into these implants, we observed severe depletion of human CD4-bearing cells within a few weeks of infection. This correlated with increasing virus load in the implants. Thus the SCID-hu mouse may be a useful in vivo system for the study of HIV-1-induced pathology.

  11. Dynamic Tracking Human Mesenchymal Stem Cells Tropism following Smoke Inhalation Injury in NOD/SCID Mice

    PubMed Central

    Song, MeiJuan; Zhang, XiuWei; Sun, ShuLi; Xiao, PeiXin; Hou, ShiKe; Ding, Hui; Liu, ZiQuan; Dong, WenLong; Wang, JinQiang; Wang, Xue; Sun, ZhiGuang

    2016-01-01

    Multiple preclinical evidences have supported the potential value of mesenchymal stem cells (MSCs) for treatment of acute lung injury (ALI). However, few studies focus on the dynamic tropism of MSCs in animals with acute lung injury. In this study, we track systemically transplanted human bone marrow-derived mesenchymal stem cells (hBMSCs) in NOD/SCID mice with smoke inhalation injury (SII) through bioluminescence imaging (BLI). The results showed that hBMSCs systemically delivered into healthy NOD/SCID mouse initially reside in the lungs and then partially translocate to the abdomen after 24 h. Compared with the uninjured control group treated with hBMSCs, higher numbers of hBMSCs were found in the lungs of the SII NOD/SCID mice. In both the uninjured and SII mice, the BLI signals in the lungs steadily decreased over time and disappeared by 5 days after treatment. hBMSCs significantly attenuated lung injury, elevated the levels of KGF, decreased the levels of TNF-α in BALF, and inhibited inflammatory cell infiltration in the mice with SII. In conclusion, our findings demonstrated that more systemically infused hBMSCs localized to the lungs in mice with SII. hBMSC xenografts repaired smoke inhalation-induced lung injury in mice. This repair was maybe due to the effect of anti-inflammatory and secreting KGF of hMSCs but not associated with the differentiation of the hBMSCs into alveolar epithelial cells. PMID:27725837

  12. The Presence and Preferential Activation of Regulatory T Cells Diminish Adoptive Transfer of Autoimmune Diabetes by Polyclonal Nonobese Diabetic (NOD) T Cell Effectors into NSG versus NOD-scid Mice.

    PubMed

    Presa, Maximiliano; Chen, Yi-Guang; Grier, Alexandra E; Leiter, Edward H; Brehm, Michael A; Greiner, Dale L; Shultz, Leonard D; Serreze, David V

    2015-10-01

    NOD-scid.Il2rg(null) (NSG) mice are currently being used as recipients to screen for pathogenic autoreactive T cells in type 1 diabetes (T1D) patients. We questioned whether the restriction of IL-2R γ-chain (Il-2rγ)-dependent cytokine signaling only to donor cells in NSG recipients differently influenced the activities of transferred diabetogenic T cells when they were introduced as a monoclonal/oligoclonal population versus being part of a polyclonal repertoire. Unexpectedly, a significantly decreased T1D transfer by splenocytes from prediabetic NOD donors was observed in Il-2rγ(null)-NSG versus Il-2rγ-intact standard NOD-scid recipients. In contrast, NOD-derived monoclonal/oligoclonal TCR transgenic β cell-autoreactive T cells in either the CD8 (AI4, NY8.3) or CD4 (BDC2.5) compartments transferred disease significantly more rapidly to NSG than to NOD-scid recipients. The reduced diabetes transfer efficiency by polyclonal T cells in NSG recipients was associated with enhanced activation of regulatory T cells (Tregs) mediated by NSG myeloid APC. This enhanced suppressor activity was associated with higher levels of Treg GITR expression in the presence of NSG than NOD-scid APC. These collective results indicate NSG recipients might be efficiently employed to test the activity of T1D patient-derived β cell-autoreactive T cell clones and lines, but, when screening for pathogenic effectors within polyclonal populations, Tregs should be removed from the transfer inoculum to avoid false-negative results.

  13. Disseminated human immunodeficiency virus 1 (HIV-1) infection in SCID- hu mice after peripheral inoculation with HIV-1

    PubMed Central

    1994-01-01

    A small animal model that could be infected with human immunodeficiency virus 1 (HIV-1) after peripheral inoculation would greatly facilitate the study of the pathophysiology of acute HIV-1 infection. The utility of SCID mice implanted with human fetal thymus and liver (SCID-hu mice) for studying peripheral HIV-1 infection in vivo has been hampered by the requirement for direct intraimplant injection of HIV-1 and the continued restriction of the resultant HIV-1 infection to the human thymus and liver (hu-thy/liv) implant. This may have been due to the very low numbers of human T cells present in the SCID-hu mouse peripheral lymphoid compartment. Since the degree of the peripheral reconstitution of SCID-hu mice with human T cells may be a function of the hu-thy/liv implant size, we increased the quantity of hu-thy/liv tissue implanted under the renal capsule and implanted hu-thy/liv tissue under the capsules of both kidneys. This resulted in SCID-hu mice in which significant numbers of human T cells were detected in the peripheral blood, spleens, and lymph nodes. After intraimplant injection of HIV-1 into these modified SCID-hu mice, significant HIV-1 infection was detected by quantitative coculture not only in the hu- thy/liv implant, but also in the spleen and peripheral blood. This indicated that HIV-1 infection can spread from the thymus to the peripheral lymphoid compartment. More importantly, a similar degree of infection of the hu-thy/liv implant and peripheral lymphoid compartment occurred after peripheral intraperitoneal inoculation with HIV-1. Active viral replication was indicated by the detection of HIV-1 gag DNA, HIV-1 gag RNA, and spliced tat/rev RNA in the hu-thy/liv implants, peripheral blood mononuclear cells (PBMC), spleens, and lymph nodes of these HIV-1-infected SCID-hu mice. As a first step in using our modified SCID-hu mouse model to investigate the pathophysiological consequences of HIV-1 infection, the effect of HIV-1 infection on the

  14. Pharmacokinetics and tissue distribution of inositol hexaphosphate in C.B17 SCID mice bearing human breast cancer xenografts.

    PubMed

    Eiseman, Julie; Lan, Jing; Guo, Jianxia; Joseph, Erin; Vucenik, Ivana

    2011-10-01

    Inositol hexaphosphate (IP(6)) is effective in preclinical cancer prevention and chemotherapy. In addition to cancer, IP(6) has many other beneficial effects for human health, such as reduction in risk of developing cardiovascular disease and diabetes and inhibition of kidney stone formation. Studies presented here describe the pharmacokinetics, tissue distribution, and metabolism of IP(6) following intravenous (IV) or per os (PO) administration to mice. SCID mice bearing MDA-MB-231 xenografts were treated with 20 mg/kg IP(6) (3 μCi per mouse [(14)C]-uniformly ring-labeled IP(6)) and euthanized at various times after IP(6) treatment. Plasma and tissues were analyzed for [(14)C]-IP(6) and metabolites by high-performance liquid chromatography with radioactivity detection. Following IV administration of IP(6), plasma IP(6) concentrations peaked at 5 minutes and were detectable until 45 minutes. Liver IP(6) concentrations were more than 10-fold higher than plasma concentrations, whereas other normal tissue concentrations were similar to plasma. Only inositol was detected in xenografts. After PO administration, IP(6) was detected in liver; but only inositol was detectable in other tissues. After both IV and PO administration, exogenous IP(6) was rapidly dephosphorylated to inositol; however, alterations in endogenous IPs were not examined.

  15. Comparison of polymerase chain reaction and culture for detection of Borrelia burgdorferi in naturally infected Peromyscus leucopus and experimentally infected C.B-17 scid/scid mice.

    PubMed

    Hofmeister, E K; Markham, R B; Childs, J E; Arthur, R R

    1992-10-01

    Culture and the polymerase chain reaction (PCR) were compared for detection of Borrelia burgdorferi infection in wild-caught Peromyscus leucopus and experimentally inoculated C.B-17 scid/scid (severe combined immunodeficient) mice. PCR targeted highly conserved regions of the ospA gene and could detect one to five cultured organisms and 10 to 50 copies of molecularly cloned ospA DNA. Organs (kidney, spleen, and urinary bladder) and/or ear biopsy samples were obtained from 108 captured P. leucopus mice, and tissues were obtained from 7 experimentally inoculated mice. A simple sample-processing procedure with proteinase K and detergent treatment was used in the PCR analysis. Overall, B. burgdorferi was detected in 29 of 108 (27%) P. leucopus mice by culture and in 31 of 108 (29%) mice by PCR. As assessed by the kappa statistic, agreement between PCR and culture was high for ear and bladder (kappa = 0.80 and 0.65, respectively) and low for kidney and spleen (kappa = 0.37 and 0.03, respectively). While concordant results were obtained from 98 animals, PCR detected B. burgdorferi from 6 additional mice for which cultures were negative and culture detected B. burgdorferi from 4 animals which were PCR negative. Further phenol-chloroform extraction of DNA in a limited number of samples improved the sensitivity of PCR compared with that of culture. These results indicate that PCR may be as sensitive as culture for detecting B. burgdorferi in ear samples and that PCR analysis is suitable for establishing the infection status of animals in mark-release-recapture studies.

  16. The SCID-II and DIB-R interviews: diagnostic association with poor outcome risk factors in Borderline Personality Disorder.

    PubMed

    Andión, Óscar; Ferrer, Marc; Di Genova, Andrea; Calvo, Natalia; Gancedo, Beatriz; Matalí, Josep; Valero, Sergi; Torrubia, Rafael; Casas, Miguel

    2012-11-01

    This study assesses whether patients diagnosed with Borderline Personality Disorder (BPD) according to the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) or the Revised Diagnostic Interview for Borderlines (DIB-R) present differences in factors associated with risk of poor outcome. Three hundred fifty-two patients were evaluated with SCID-II and DIB-R. Patients diagnosed as BPD according to one or both instruments were compared in BPD poor outcome risk factors. The analysis was conducted on the participants who were assigned to SCID-II (n = 135) and SCID-II/DIB-R (n = 126) groups. The group diagnosed with BPD according the combined SCID-II/DIB-R interview showed a significantly greater association with risk of poor outcome predictors, such as total number of comorbid Axis II disorders, number of BPD criteria, presence of comorbid paranoid personality disorder, and worse occupational status. No differences between groups were found in the affective instability BPD criterion, self-reported impulsivity, post-traumatic stress disorder, major depressive disorder or presence of any cluster C comorbidity. The observed differences were large enough to advise caution in generalizing findings from studies without considering what measurement was used for the BPD diagnosis.

  17. MicroSPECT/CT imaging of primary human AML engrafted into the bone marrow and spleen of NOD/SCID mice using 111In-DTPA-NLS-CSL360 radioimmunoconjugates recognizing the CD123+ / CD131- epitope expressed by leukemia stem cells.

    PubMed

    Leyton, Jeffrey V; Williams, Brent; Gao, Catherine; Keating, Armand; Minden, Mark; Reilly, Raymond M

    2014-11-01

    Engraftment of primary human acute myeloid leukemia (AML) specimens into the bone marrow (BM) of NOD/SCID mice has been used to study leukemia biology and new treatments for the disease. CSL360 is a chimeric IgG1 monoclonal antibody that recognizes CD123 (IL-3 receptor α-subchain) expressed in the absence of CD131 (β-subchain), an epitope that is displayed by leukemia stem cells (LSCs). We are studying CSL360 modified with diethylenetriaminepentaacetic acid (DTPA) for complexing 111In and 13-mer nuclear translocation sequence (NLS) peptides to enable nuclear importation in LSCs for Auger electron radioimmunotherapy (RIT) of AML. We demonstrate that microSPECT/CT imaging using 111In-DTPA-NLS-CSL360 revealed engraftment of primary human AML specimens into the BM and spleen of NOD/SCID mice. Our results suggest that microSPECT/CT imaging is a powerful tool which enables non-invasive assessment of the engraftment of AML into NOD/SCID mice and in the current study specifically probes an epitope displayed by the LSC subpopulation. The targeting of 111In-DTPA-NLS-CSL360 to sites of AML engraftment in the NOD/SCID mouse model is encouraging for future RIT studies. Ultimately, SPECT imaging could be applied in AML patients to assess the delivery of 111In-DTPA-NLS-CSL360 to sites of leukemia and be combined with Auger electron RIT using the same agent targeting the LSC population as a "theranostic" pair.

  18. Validity of a self-reported diagnosis of depression among participants in a cohort study using the Structured Clinical Interview for DSM-IV (SCID-I)

    PubMed Central

    Sanchez-Villegas, Almudena; Schlatter, Javier; Ortuno, Felipe; Lahortiga, Francisca; Pla, Jorge; Benito, Silvia; Martinez-Gonzalez, Miguel A

    2008-01-01

    Background Depression assessment in population studies is usually based on depressive symptoms scales. However, the use of scales could lead to the choice of an arbitrary cut-off point depending on the sample characteristics and on the patient diagnosis. Thus, the use of a medical diagnosis of depression could be a more appropriate approach. Objective To validate a self-reported physician diagnosis of depression using the Structured Clinical Interview for DSM-IV (SCID-I) as Gold Standard and to assess the factors associated to a valid self-reported diagnosis. Methods The SUN Project is a cohort study based on university graduates followed-up through postal questionnaires. The response to the question included in the questionnaire: Have you ever been diagnosed of depression by a physician? was compared to that obtained through the SCID-I applied by a psychiatrist or a clinical psychologist. The percentages of confirmed depression and non-depression were assessed for the overall sample and according to several characteristics. Logistic regression models were fitted to ascertain the association between different factors and a correct classification regarding depression status. Results The percentage of confirmed depression was 74.2%; 95% confidence interval (95% CI) = 63.3–85.1. Out of 42 participants who did not report a depression diagnosis in the questionnaire, 34 were free of the disease (%confirmed non-depression = 81.1%; 95% CI = 69.1–92.9). The probability of being a true positive was higher among ex-smokers and non-smokers and among those overweight or obese but the differences were not statistically significant. Conclusion The validity of a self-reported diagnosis of depression in the SUN cohort is adequate. Thus, this question about depression diagnosis could be used in further investigations regarding this disease in this graduate cohort study. PMID:18558014

  19. Ethanol affects hepatitis C pathogenesis: humanized SCID Alb-uPA mouse model.

    PubMed

    Osna, Natalia A; Kharbanda, Kusum K; Sun, Yimin; Simpson, Ronda L; Poluektova, Larisa E; Ganesan, Murali; Wisecarver, James L; Mercer, David F

    2014-07-18

    Alcohol consumption exacerbates the course of hepatitis C viral (HCV) infection, worsens outcomes and contributes to the development of chronic infection that exhibits low anti-viral treatment efficiency. The lack of suitable in vivo models makes HCV-ethanol studies very difficult. Here, we examine whether chimeric SCID Alb-uPA mice transplanted with human hepatocytes and infected with HCV develop worsening pathology when fed ethanol. After 5 weeks of feeding, such mice fed chow+water (control) or chow+20% ethanol in water (EtOH) diets mice developed oxidative stress, decreased proteasome activity and increased steatosis. Importantly, HCV(+) mice in the control group cleared HCV RNA after 5 weeks, while the infection persisted in EtOH-fed mice at the same or even higher levels compared with pre-feeding HCV RNA. We conclude that in chimeric SCID Alb-uPA mice, EtOH exposure causes the complex biochemical and histological changes typical for alcoholic liver injury. In addition, ethanol feeding delays the clearance of HCV RNA thereby generating persistent infection and promoting liver injury. Overall, this model is appropriate for conducting HCV-ethanol studies.

  20. Curing genetic disease with gene therapy.

    PubMed

    Williams, David A

    2014-01-01

    Development of viral vectors that allow high efficiency gene transfer into mammalian cells in the early 1980s foresaw the treatment of severe monogenic diseases in humans. The application of gene transfer using viral vectors has been successful in diseases of the blood and immune systems, albeit with several curative studies also showing serious adverse events (SAEs). In children with X-linked severe combined immunodeficiency (SCID-X1), chronic granulomatous disease, and Wiskott-Aldrich syndrome, these SAEs were caused by inappropriate activation of oncogenes. Subsequent studies have defined the vector sequences responsible for these transforming events. Members of the Transatlantic Gene Therapy Consortium [TAGTC] have collaboratively developed new vectors that have proven safer in preclinical studies and used these vectors in new clinical trials in SCID-X1. These trials have shown evidence of early efficacy and preliminary integration analysis data from the SCID-X1 trial suggest an improved safety profile.

  1. Full reconstitution of the immune deficiency in scid mice with normal stem cells requires low-dose irradiation of the recipients

    SciTech Connect

    Fulop, G.M.; Phillips, R.A.

    1986-06-15

    Mice homozygous for an autosomal recessive mutation for the scid gene exhibit a defect that specifically impairs lymphoid differentiation but not myelopoiesis. Such mice can be cured of their lymphoid deficiency by grafts with normal bone marrow, although full reconstitution of lymphoid function is seldom obtained. Long-term bone marrow cultures (LTBMC) are devoid of all mature B and pre-B cells but contain lymphoid stem cells. We therefore reconstituted scid mice with LTBMC cells to study the kinetics of B lymphocyte reconstitution in normal and irradiated (4 Gy) scid recipients and in irradiated (9.5 Gy) co-isogenic C.B-17 mice. Detectable colony-forming B cells rapidly increased in the spleen and bone marrow of irradiated C.B-17 and irradiated scid recipients, reaching normal levels between 4 and 6 wk post-grafting. Unirradiated scid recipients showed limited reconstitution in spleen and very poor reconstitution in bone marrow. Unirradiated scid recipients also had relatively few surface Ig+ cells in spleen or bone marrow, whereas both groups of irradiated recipients had normal numbers between 4 and 6 wk post-reconstitution. Normal levels of cytotoxic T cell activity by 8 wk after reconstitution were observed only in the irradiated C.B-17 and irradiated scid recipients. Analysis of mice reconstituted with cells from LTBMC indicates that these cultures contain lymphoid stem cells with significant proliferative and self-renewal potential, and that full reconstitution of lymphoid function requires prior irradiation of the scid recipient.

  2. Tropism of varicella-zoster virus for human CD4+ and CD8+ T lymphocytes and epidermal cells in SCID-hu mice.

    PubMed Central

    Moffat, J F; Stein, M D; Kaneshima, H; Arvin, A M

    1995-01-01

    To investigate the cell tropism and pathogenicity of varicella-zoster virus (VZV) strains, we analyzed VZV replication by using SCID-hu mice that carry human fetal thymus/liver implants under the kidney capsule or as subcutaneous fetal skin implants. MRC-5 cells infected with wild-type VZV or the Oka strain, used in the live attenuated varicella vaccine, were injected into the implants. The implants were surgically removed 2, 7, 14, and 21 days postinfection. The VZV titer from infected thymus/liver implants peaked on day 7 for the wild-type strain and on day 14 for the Oka strain. Histological analysis showed necrotic areas characterized by thymocyte depletion and fibrosis. VZV protein synthesis was detectable by immunohistochemical staining in the necrotic areas and in distant regions that did not show cytopathic changes, and VZV DNA was detected by in situ hybridization in the same distribution. Fluorescence-activated cell sorting analysis of thymocytes harvested at day 7 postinfection showed that VZV proteins were expressed in CD4+, CD8+, and CD4+ CD8+ T cells; VZV was cultured from each T-cell subpopulation. The Oka strain had tropism for human cell types similar to that of wild-type VZV. T lymphocytes released infectious VZV, which is a novel and important observation about the replication of this otherwise highly cell associated virus. VZV-infected skin implants exhibited microscopic epidermal lesions that were indistinguishable histologically from the characteristic lesions of varicella. These experiments demonstrate a unique tropism of VZV for human T lymphocytes, explaining its capacity to cause viremia in natural disease, and demonstrate the value of the SCID-hu model for studies of VZV pathogenesis. PMID:7636965

  3. Poliomyelitis in MuLV-infected ICR-SCID mice after injection of basement membrane matrix contaminated with lactate dehydrogenase-elevating virus.

    PubMed

    Carlson Scholz, Jodi A; Garg, Rohit; Compton, Susan R; Allore, Heather G; Zeiss, Caroline J; Uchio, Edward M

    2011-10-01

    The arterivirus lactate dehydrogenase-elevating virus (LDV) causes life-long viremia in mice. Although LDV infection generally does not cause disease, infected mice that are homozygous for the Fv1(n) allele are prone to develop poliomyelitis when immunosuppressed, a condition known as age-dependent poliomyelitis. The development of age-dependent poliomyelitis requires coinfection with endogenous murine leukemia virus. Even though LDV is a common contaminant of transplantable tumors, clinical signs of poliomyelitis after inadvertent exposure to LDV have not been described in recent literature. In addition, LDV-induced poliomyelitis has not been reported in SCID or ICR mice. Here we describe the occurrence of poliomyelitis in ICR-SCID mice resulting from injection of LDV-contaminated basement membrane matrix. After exposure to LDV, a subset of mice presented with clinical signs including paresis, which was associated with atrophy of the hindlimb musculature, and tachypnea; in addition, some mice died suddenly with or without premonitory signs. Mice presenting within the first 6 mo after infection had regions of spongiosis, neuronal necrosis and astrocytosis of the ventral spinal cord, and less commonly, brainstem. Axonal degeneration of ventral roots prevailed in more chronically infected mice. LDV was identified by RT-PCR in 12 of 15 mice with typical neuropathology; positive antiLDV immunolabeling was identified in all PCR-positive animals (n = 7) tested. Three of 8 mice with neuropathology but no clinical signs were LDV negative by RT-PCR. RT-PCR yielded murine leukemia virus in spinal cords of all mice tested, regardless of clinical presentation or neuropathology.

  4. Comparison of outcomes of hematopoietic stem cell transplant without chemotherapy conditioning using matched sibling and unrelated donors for treatment of SCID

    PubMed Central

    Dvorak, Christopher C.; Hassan, Amel; Slatter, Mary A.; Hönig, Manfred; Lankester, Arjan C.; Buckley, Rebecca H.; Pulsipher, Michael A.; Davis, Jeffrey H.; Güngör, Tayfun; Gabriel, Melissa; Bleesing, Jacob H.; Bunin, Nancy; Sedlacek, Petr; Connelly, James A.; Crawford, David F.; Notarangelo, Luigi D.; Pai, Sung-Yun; Hassid, Jake; Veys, Paul; Gennery, Andrew R.; Cowan, Morton J.

    2014-01-01

    Background Patients with severe combined immunodeficiency disease (SCID) who have matched sibling donors (MSD) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. Objective To determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URD), either from volunteer adults or umbilical cord blood, are comparable to those from matched sibling donors (MSD). Methods A multicenter survey of SCID transplant centers in North America, Europe, and Australia to compile retrospective data on patients who have undergone unconditioned HCT, from either URDs (n = 37) or MSDs (n = 66). Results Most patients undergoing URD HCT (92%) achieved donor T-cell engraftment, compared to 97% for MSDs, however, estimated 5-year overall and event-free survival were worse for URD recipients (71% and 60%, respectively), compared to MSD recipients (92% and 89%, respectively; P <0.01 for both). URD recipients who received pre-HCT serotherapy had similar 5-year OS (100%) to MSD recipients. The incidences of Grade II-IV acute and chronic GVHD were higher in URD (50% and 39%, respectively), compared to MSD recipients (22% and 5%, respectively; P <0.01 for both). In the surviving patients, there was no difference in T-cell reconstitution at last follow-up between the URD recipients and MSD recipients, however MSD recipients were more likely to achieve B-cell reconstitution (72% vs. 17%; P <0.001). Conclusion Unconditioned URD HCT achieves excellent rates of donor T-cell engraftment similar to MSD recipients, and reconstitution rates are adequate. However, only a minority will develop myeloid and B cell reconstitution and attention must be paid to GVHD prophylaxis. This approach may be safer in children ineligible for intense regimens to spare potential complications of chemotherapy. PMID:25109802

  5. Modulation of tumor response to photodynamic therapy in severe combined immunodeficient (SCID) mice by adoptively transferred lymphoid cells

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Krosl, Gorazd; Krosl, Jana; Dougherty, Graeme J.

    1996-04-01

    Photodynamic treatment, consisting of intravenous injection of PhotofrinR (10 mg/kg) followed by exposure to 110 J/cm2 of 630 plus or minus 10 nm light 24 hours later, cured 100% of EMT6 tumors (murine mammary sarcoma) growing in syngeneic immunocompetent BALB/C mice. In contrast, the same treatment produced no cures of EMT6 tumors growing in either nude or SCID mice (immunodeficient strains). EMT6 tumors growing in BALB/C and SCID mice showed no difference in either the level of PhotofrinR accumulated per gram of tumor tissue, or the extent of tumor cell killing during the first 24 hours post photodynamic therapy (PDT). In an attempt to improve the sensitivity to PDT of EMT6 tumors growing in SCID mice, these hosts were given either splenic T lymphocytes or whole bone marrow from BALB/C mice. The adoptive transfer of lymphocytes 9 days before PDT was successful in delaying tumor recurrence but produced no cures. A better improvement in PDT response was obtained with tumors growing in SCID mice reconstituted with BALB/C bone marrow (tumor cure rate of 63%). The results of this study demonstrate that, at least with the EMT6 tumor model, antitumor immune activity mediated by lymphoid cell populations makes an important contribution to the curative effect of PDT.

  6. Borderline Personality Disorder and Personality Traits: A Comparison of SCID-II BPD and NEO-PI.

    ERIC Educational Resources Information Center

    Clarkin, John F.; And Others

    1993-01-01

    Hospitalized female patients with borderline personality disorder were assessed for Axis II disorders by the Structured Clinical Inventory for the Diagnostic and Statistical Manual of Mental Disorders (SCID-II) and for personality traits with the NEO Personality Inventory. The relationship of results to social adjustment and the utility of…

  7. Clinical, immunologic, and genetic characteristics of RAG mutations in 15 Chinese patients with SCID and Omenn syndrome.

    PubMed

    Bai, Xiaoming; Liu, Jing; Zhang, Zhiyong; Liu, Chaohong; Zhang, Yongjie; Tang, Wenjing; Dai, Rongxin; Wu, Junfeng; Tang, Xuemei; Zhang, Yu; Ding, Yuan; Jiang, Liping; Zhao, Xiaodong

    2016-04-01

    Mutations in Recombination Activating Genes (RAG1 and RAG2) are common genetic causes of severe combined immunodeficiency (SCID) and Omenn syndrome (OS). The clinical, immunologic, and genetic characteristics of RAG mutations in Chinese patients with SCID or OS have not been studied in detail. In this research, 22 RAG mutations were identified in 15 Chinese patients, including 10 novel mutations in RAG1 (R108X, M630T, E510X, S666P, E669K, C730Y, A857V, K847E, L922PfsX7, and L1025FfsX39) and 4 in RAG2 (R73C, I427GfsX12, P432L, and 311insL). L1025FfsX39 is a potential RAG1 hot-spot mutation in the Chinese population. The distribution of RAG1 mutations rather than mutation type seemed to differ between SCID and OS patients. The thymic output of T lymphocytes, TCR rearrangement, and T cell proliferation were severely impaired in RAG mutant patients. These findings will contribute to the early diagnosis and treatment of SCID and OS to a certain extent.

  8. A link between double-strand break-related repair and V(D)J recombination: the scid mutation

    SciTech Connect

    Hendrickson, E.A.; Qin, X.Q.; Bump, E.A.; Schatz, D.G.; Oettinger, M.; Weaver, D.T. )

    1991-05-15

    We show here that mammalian site-specific recombination and DNA-repair pathways share a common factor. The effects of DNA-damaging agents on cell lines derived from mice homozygous for the scid (severe combined immune deficiency) mutation were studied. Surprisingly, all scid cell lines exhibited a profound hypersensitivity to DNA-damaging agents that caused double-strand breaks (x-irradiation and bleomycin) but not to other chemicals that caused single-strand breaks or cross-links. Neutral filter elution assays demonstrated that the x-irradiation hypersensitivity could be correlated with a deficiency in repairing double-strand breaks. These data suggest that the scid gene product is involved in two pathways: DNA repair of random double-strand breaks and the site-specific and lymphoid-restricted variable-(diversity)-joining (V(D)J) DNA rearrangement process. We propose that the scid gene product performs a similar function in both pathways and may be a ubiquitous protein.

  9. Efficacy of gamma interferon and specific antibody for treatment of microsporidiosis caused by Encephalitozoon cuniculi in SCID mice.

    PubMed

    Salát, Jirí; Jelínek, Jirí; Chmelar, Jindrich; Kopecky, Jan

    2008-06-01

    Microsporidia are eukaryotic, obligate, intracellular protists that are emerging pathogens in immunocompromised hosts, including AIDS patients and organ transplant recipients. The efficacy of gamma interferon (IFN-gamma) for the treatment of microsporidiosis caused by Encephalitozoon cuniculi was studied by means of adoptive transfer and IFN-gamma administration in SCID mice. While the adoptive transfer of CD4(+) T cells from immunocompetent mice prolonged survival of SCID mice infected perorally with E. cuniculi, survival was not improved by adoptive transfer of CD4(+) T lymphocytes from IFN-gamma-deficient mice. The protective effect of IFN-gamma was confirmed in cytokine therapy experiments in which SCID mice receiving IFN-gamma survived significantly longer than mice receiving mock injections. The administration of serum containing specific antibodies against E. cuniculi was found to prolong the survival of concurrently IFN-gamma-treated SCID mice. The data presented in this study suggest that IFN-gamma is potentially useful as a cytokine therapy for microsporidiosis, especially in CD4(+) T-cell-deficient patients.

  10. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.

    PubMed

    Peled, A; Petit, I; Kollet, O; Magid, M; Ponomaryov, T; Byk, T; Nagler, A; Ben-Hur, H; Many, A; Shultz, L; Lider, O; Alon, R; Zipori, D; Lapidot, T

    1999-02-01

    Stem cell homing and repopulation are not well understood. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34+CD38-/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34+ cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation. PMID:9933168

  11. [Predictive power on therapy engagement in personality disorders: SWAP- 200 versus SCID-II].

    PubMed

    Löffler-Stastka, Henriette; Blüml, Victor; Jandl-Jager, Elisabeth

    2010-01-01

    The study compares the predictive power of the Shedler-Westen-Assessment Procedure-200 with the Structured Clinical Interview for DSM-IV on engagement in (psychoanalytic) psychotherapy within 297 patients with personality disorders in a 4-year-follow-up. Multinomial logistic regression showed small differences between the prediction rates in the cross-validated data. Both instruments showed clinically useful prediction rates for treatment rejecters: SWAP scales led to correct predictions with dysphoric traits as semi-stable predictors for rejecters, while SCID scales led to correct predictions with Negativistic, Depressive and Schizotypal PD as stable predictors. Results are discussed under the aspect of advantages and disadvantages of the SWAP-200 diagnostic procedure, which includes the assessment of affect-experience, defence-organisation, and object-relation-style. PMID:19790028

  12. scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair

    SciTech Connect

    Biedermann, K.A.; Sun, J.R.; Giaccia, A.J.; Tosto, L.M.; Brown, J.M. )

    1991-02-15

    C.B-17 severe combined immunodeficient (scid) mice carry the scid mutation and are severely deficient in both T cell- and B cell-mediated immunity, apparently as a result of defective V(D)J joining of the immunoglobulin and T-cell receptor gene elements. In the present studies, we have defined the tissue, cellular, and molecular basis of another characteristic of these mice: their hypersensitivity to ionizing radiation. Bone marrow stem cells, intestinal crypt cells, and epithelial skin cells from scid mice are 2- to 3-fold more sensitive when irradiated in situ than are congenic BALB/c or C.B-17 controls. Two independently isolated embryo fibroblastic scid mouse cell lines display similar hypersensitivities to gamma-rays. In addition, these cell lines are sensitive to cell killing by bleomycin, which also produces DNA strand breaks, but not by the DNA crosslinking agent mitomycin C or UV irradiation. Measurement of the rejoining of gamma-ray-induced DNA double-strand breaks by pulsed-field gel electrophoresis indicates that these animals are defective in this repair system. This suggests that the gamma-ray sensitivity of the scid mouse fibroblasts could be the result of reduced repair of DNA double-strand breaks. Therefore, a common factor may participate in both the repair of DNA double-strand breaks as well as V(D)J rejoining during lymphocyte development. This murine autosomal recessive mutation should prove extremely useful in fundamental studies of radiation-induced DNA damage and repair.

  13. The Structured Clinical Interview for DSM-IV Childhood Diagnoses (Kid-SCID): first psychometric evaluation in a Dutch sample of clinically referred youths.

    PubMed

    Roelofs, Jeffrey; Muris, Peter; Braet, Caroline; Arntz, Arnoud; Beelen, Imke

    2015-06-01

    The Structured Clinical Interview for DSM-IV Childhood Disorders (Kid-SCID) is a semi-structured interview for the classification of psychiatric disorders in children and adolescents. This study presents a first evaluation of the psychometric properties of the Kid-SCID in a Dutch sample of children and adolescents who had been referred to an outpatient treatment centre for mental health problems. Results indicated that the inter-rater reliability of the Kid-SCID classifications and the internal consistency of various (dimensional) criteria of the diagnoses were moderate to good. Further, for most Kid-SCID diagnoses, reasonable agreement between children and parents was found. Finally, the correspondence between the Kid-SCID and the final clinical diagnosis as established after the full intake procedure, which included the information as provided by the Kid-SCID, ranged from poor to good. Results are discussed in the light of methodological issues pertaining to the assessment of psychiatric disorders in youths. The Kid-SCID can generally be seen as a reliable and useful tool that can assist clinicians in carrying out clinical evaluations of children and adolescents.

  14. Reconstitution of SCID mice with human lymphoid and myeloid cells after transplantation with human fetal bone marrow without the requirement for exogenous human cytokines.

    PubMed

    Kollmann, T R; Kim, A; Zhuang, X; Hachamovitch, M; Goldstein, H

    1994-08-16

    Investigation of human hematopoietic maturation has been hampered by the lack of in vivo models. Although engraftment of irradiated C.B-17 scid/scid (SCID) mice with human progenitor cells occurred after infusion with human pediatric bone marrow cells, significant engraftment of the mouse bone marrow with human cells was dependent upon continuous treatment with exogenous human cytokines. Furthermore, despite cytokine treatment, only minimal peripheral engraftment of these mice with human cells was observed. In the present study, after infusion of irradiated SCID mice with pre-cultured human fetal bone marrow cells (BM-SCID-hu mice), their bone marrow became significantly engrafted with human precursor cells and their peripheral lymphoid compartment became populated with human B cells and monocytes independently of the administration of extraneous human cytokines. Examination of the bone marrow of the BM-SCID-hu mice for human cytokine mRNA gene expression demonstrated human leukemia inhibitory factor mRNA and interleukin 7 mRNA in nine of nine BM-SCID-hu mice and macrophage-colony-stimulating factor mRNA in seven of eight BM-SCID-hu mice. This was an intriguing observation because these cytokines regulate different stages of human hematopoiesis. Since engraftment occurs in the absence of exogenous cytokine treatment, the BM-SCID-hu mouse model described should provide a useful in vivo system for studying factors important in the maturation of human myeloid and lymphoid cells in the bone marrow and the behavior of the mature human cells after dissemination into the peripheral lymphoid tissue.

  15. Reconstitution of SCID mice with human lymphoid and myeloid cells after transplantation with human fetal bone marrow without the requirement for exogenous human cytokines.

    PubMed Central

    Kollmann, T R; Kim, A; Zhuang, X; Hachamovitch, M; Goldstein, H

    1994-01-01

    Investigation of human hematopoietic maturation has been hampered by the lack of in vivo models. Although engraftment of irradiated C.B-17 scid/scid (SCID) mice with human progenitor cells occurred after infusion with human pediatric bone marrow cells, significant engraftment of the mouse bone marrow with human cells was dependent upon continuous treatment with exogenous human cytokines. Furthermore, despite cytokine treatment, only minimal peripheral engraftment of these mice with human cells was observed. In the present study, after infusion of irradiated SCID mice with pre-cultured human fetal bone marrow cells (BM-SCID-hu mice), their bone marrow became significantly engrafted with human precursor cells and their peripheral lymphoid compartment became populated with human B cells and monocytes independently of the administration of extraneous human cytokines. Examination of the bone marrow of the BM-SCID-hu mice for human cytokine mRNA gene expression demonstrated human leukemia inhibitory factor mRNA and interleukin 7 mRNA in nine of nine BM-SCID-hu mice and macrophage-colony-stimulating factor mRNA in seven of eight BM-SCID-hu mice. This was an intriguing observation because these cytokines regulate different stages of human hematopoiesis. Since engraftment occurs in the absence of exogenous cytokine treatment, the BM-SCID-hu mouse model described should provide a useful in vivo system for studying factors important in the maturation of human myeloid and lymphoid cells in the bone marrow and the behavior of the mature human cells after dissemination into the peripheral lymphoid tissue. Images PMID:7914701

  16. Deletion of nef slows but does not prevent CD4-positive T-cell depletion in human immunodeficiency virus type 1-infected human-PBL-SCID mice.

    PubMed Central

    Gulizia, R J; Collman, R G; Levy, J A; Trono, D; Mosier, D E

    1997-01-01

    The pathogenicity of four human immunodeficiency virus type 1 (HIV-1) isolates with nef deleted for SCID mice repopulated with human peripheral blood leukocytes (hu-PBL-SCID mice) was studied. Deletion of nef led to a substantial reduction in CD4-positive T-cell depletion and delayed kinetics of plasma viremia in infected hu-PBL-SCID mice. Deletion of the nef gene impacts both the efficiency of primary infection and the cytopathicity of virus for infected CD4-positive T cells in this animal model of HIV-1 infection. PMID:9094701

  17. Severe combined immunodeficiency. A model disease for molecular immunology and therapy.

    PubMed

    Fischer, Alain; Le Deist, Françoise; Hacein-Bey-Abina, Salima; André-Schmutz, Isabelle; Basile, Geneviève de Saint; de Villartay, Jean-Pierre; Cavazzana-Calvo, Marina

    2005-02-01

    Severe combined immunodeficiencies (SCIDs) consist of genetically determined arrest of T-cell differentiation. Ten different molecular defects have now been identified, which all lead to early death in the absence of therapy. Transplantation of allogeneic hematopoietic stem cells (HSCT) can restore T-cell development, thus saving the lives of SCID patients. In this review, the different characteristics of HSCT are discussed along with the available data regarding the long-term outcome. Transient thymopoiesis caused by an exhaustion of donor progenitor cells and possibly a progressive loss of thymus function can lead to a progressive decline in T-cell functions. The preliminary results of gene therapy show the correction of two SCID conditions. Based on the assumption that long-lasting pluripotent progenitor cells are transduced, these data suggest that gene therapy could overcome the long-term recurrence of the T-cell immunodeficiency. SCID is thus a disease model for experimental therapy in the hematopoietic system.

  18. Carnosic Acid-combined Arsenic Trioxide Antileukaemia Cells in the Establishment of NB4/SCID Mouse Model.

    PubMed

    Hao, Li; Ran, Wang; Xiang-Xin, Li; Lu-Qun, Wang; Xiao-Ning, Yu

    2016-09-01

    Despite great improvement in the treatment outcome of APL, treatment failure still sometimes occurs due to the toxicity of arsenic trioxide (ATO). Damage to the heart and liver often occurs even when the dose is lower than the therapeutic dose. Based on the results of cell experiments in vitro in this study, we investigated the synergistic activity of carnosic acid (CA) combined with ATO in the SCID mouse model of human promyelocytic leukaemia in vivo. A NB4/SCID mouse model was established in this study. The NB4/SCID mice were randomly divided into three treatment groups (CA alone, ATO alone and CA combined with ATO) and a control group based on factorial design. The evaluation indicators of the curative effect of the drugs included expressions of cleaved caspase-3, PTEN, p27 gene mRNA and proteins by immunohistochemistry, flow cytometry and Western blot analysis. The survival time was compared between the four groups. The results indicated that verification of the NB4/SCID mouse model was confirmed by histopathological examination. Compared with mice treated by CA or ATO alone, the mice in the combination of CA and ATO group had a higher rate of apoptosis, which was linked with expressions of cleaved caspase-3, PTEN, p27 gene mRNA and proteins. Also, the mice with the longest survival time were those treated with the combination of CA and ATO. In conclusion, the results of the present study indicated that CA and ATO in combination have strong synergistic antileukaemic effects on cell activity.

  19. Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting with T-B-SCID or Omenn syndrome.

    PubMed

    Dalal, Ilan; Tasher, Diana; Somech, Raz; Etzioni, Amos; Garti, Ben-Zion; Lev, Dorit; Cohen, Sarit; Somekh, Eli; Leshinsky-Silver, Esther

    2011-09-01

    The relative frequency of the different forms of SCID may vary in different countries. The most frequent form in Israel is the autosomal-recessive T-B- SCID or Omenn syndrome while X-linked SCID is rare. We report our immunological and genetic analyses in multicentre study of patients presenting with either T-B- SCID or Omenn syndrome. Among 16 patients, we identified 7 novel mutations in 6 patients. In the RAG1 gene we detected two novel mutations: L454Q and 469 fs-4bpdel. In the RAG 2 gene: 3 novel mutations: D65Y, G157V, and E480X. One T-B- SCID patient was found to be a compound heterozygote for new mutations in the ADA gene: W264X and R235W. Prenatal diagnosis was performed in 8 families while others refused due to religious reasons. Identification of the new mutations expands our knowledge regarding the unique features of SCID phenotype in Israel and may help the families seeking for genetic counseling.

  20. An analysis and decision tool to measure cost benefit of newborn screening for severe combined immunodeficiency (SCID) and related T-cell lymphopenia.

    PubMed

    Modell, Vicki; Knaus, Megan; Modell, Fred

    2014-10-01

    Severe combined immunodeficiency (SCID) is a group of syndromes resulting from genetic defects causing absence in T-cell and B-cell function, leading to serious and life-threatening infections. SCID is often fatal in the first 2 years of life if not identified and properly treated. While additional laboratory methods are being developed, the current T-cell receptor excision circle assay has proven to have outstanding specificity and sensitivity to accurately identify infants with SCID and other T-cell lymphopenia. The Jeffrey Modell Foundation (JMF) has a long history of advocacy and continues to promote newborn screening for SCID to be implemented in the United States and worldwide. Based on reports provided by California, New York, Texas, and Wisconsin on the results of their population based newborn screening programs, the overall incidence of SCID averaged 1:33,000 and T-cell lymphopenia averaged 1:6,600. JMF has developed a working algorithm or "decision tree", validated by peer-reviewed scientific literature, to be used by Public Health Departments and Health Ministries in states, countries, and regions throughout the world. This decision tool allows for local or regional data to be applied to measure the threshold and economic impact of implementing newborn screening for SCID and T-cell lymphopenia.

  1. Identification of a nonsense mutation in the carboxyl-terminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse.

    PubMed Central

    Blunt, T; Gell, D; Fox, M; Taccioli, G E; Lehmann, A R; Jackson, S P; Jeggo, P A

    1996-01-01

    DNA-dependent protein kinase (DNA-PK) consists of a heterodimeric protein (Ku) and a large catalytic subunit (DNA-PKcs). The Ku protein has double-stranded DNA end-binding activity that serves to recruit the complex to DNA ends. Despite having serine/threonine protein kinase activity, DNA-PKcs falls into the phosphatidylinositol 3-kinase superfamily. DNA-PK functions in DNA double-strand break repair and V(D)J recombination, and recent evidence has shown that mouse scid cells are defective in DNA-PKcs. In this study we have cloned the cDNA for the carboxyl-terminal region of DNA-PKcs in rodent cells and identified the existence of two differently spliced products in human cells. We show that DNA-PKcs maps to the same chromosomal region as the mouse scid gene. scid cells contain approximately wild-type levels of DNA-PKcs transcripts, whereas the V-3 cell line, which is also defective in DNA-PKcs, contains very reduced transcript levels. Sequence comparison of the carboxyl-terminal region of scid and wild-type mouse cells enabled us to identify a nonsense mutation within a highly conserved region of the gene in mouse scid cells. This represents a strong candidate for the inactivating mutation in DNA-PKcs in the scid mouse. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8816792

  2. Persistent colonization of Candida albicans yeast on the tongue in NOD/SCID.e2f1-/- mice.

    PubMed

    Arai, Toshiaki; Kinoshita, Yosuke; Senpuku, Hidenobu

    2015-05-01

    Candida albicans is a commensal fungus that commonly colonizes as opportunistic pathogens human mucosal surfaces. Our aim was to observe persistent infection of C. albicans on the tongue in NOD/SCID.e2f1(-/-) mice, which naturally was decreased saliva and undeveloped T and B cells. Using a cotton swab, a C. albicans suspension was applied to the tongue of wild type and mutant mice after disinfection using 0.2% Chlorhexidine (CHX). In our earlier report, it was found that many times inoculation per day and consecutive day inoculations without disinfection of indigenous microorganisms did not induce significant C. albicans infection for 48 h in the oral cavity. In this study, using inoculation of four sets {one inoculation after disinfection by CHX + interval (3 or 4 d)} induced longer term and higher numbers infection for 4 days on the tongue than results in a previous report in both NOD/SCID.e2f1(+/+) and NOD/SCID.e2f1(-/-) mice. Repeat of disinfection to indigenous microorganisms and inoculation with interval established and realized a new model for persistent infection of C. albicans yeast. However, decreased saliva and consecutive inoculations per day did not contribute to the persistent colonization on the tongue in the mice. It is suggested that the interaction between C. albicans and indigenous microorganisms is important for persistent colonization of C. albicans yeast on the tongue rather than decreased saliva in the oral cavity.

  3. Ability of spleen, peritoneal cavity, and lymph node B cells to reconstitute serum immunoglobulin in SCID mice.

    PubMed Central

    Riggs, J; Stowers, R

    1996-01-01

    The impact of intrinsic B lymphocyte heterogeneity and of microenvironmental influences on serum immunoglobulin production by B cells was examined by intravenous (i.v.) and intraperitoneal (i.p.) transfer of BALB/c and BALB.xid (X-chromosome-linked immunedefective; XID) lymph node (LN), splenic (SP) and peritoneal cavity (PerC) cells into severe-combined immune-defective (SCID) mice. The results indicate that each B-cell source restores all immunoglobulin classes within 5 weeks of transfer, the rates for each isotype, however, differ between the B-cell sources. Serum IgM levels were restored most rapidly by PerC cell transfer, followed by SP and LN cell transfer. In addition, normal immunoglobulin levels were reached in the absence of complete lymphoid reconstitution. Serum immunoglobulin phenotypes characteristic of the donor strain, e.g. reduced IgM and IgG3 production by XID B cells, were maintained after transfer into the SCID recipient. Microenvironmental influences were indicated by reduced immunoglobulin production after i.p. transfer and after i.v. transfer into irradiated SCID recipients. The data show that both B-cell type and microenvironment play significant roles in generating the heterogeneous pool of B cells required for humoral immunity. PMID:8707345

  4. IL-2R{gamma} gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease

    SciTech Connect

    Henthorn, P.S.; Fimiani, V.M.; Patterson, D.F.

    1994-09-01

    X-linked severe combined immunodeficiency (SCID) is characterized by profound defects in cellular and humoral immunity and, in humans, is associated with mutations in the gene for the {gamma} chain of the IL-2 receptor (IL-2R{gamma}). We have examined this gene in a colony of dogs established from a single X-linked SCID carrier female. Affected dogs have a 4-bp deletion in the first exon of the IL-2R{gamma} gene, which precludes the production of a functional protein, demonstrating that the canine disease is a true homologue of human X-linked SCID. 37 refs., 3 figs.

  5. Therapeutic Evaluation of Polyamine Analogue Drug Candidates against Enterocytozoon bieneusi in a SCID Mouse Model▿

    PubMed Central

    Feng, Xiaochuan; Reddy, Venudhar K.; Mayanja-Kizza, Harriet; Weiss, Louis M.; Marton, Laurence J.; Tzipori, Saul

    2009-01-01

    Enterocytozoon bieneusi is the most common cause of chronic diarrhea in individuals with human immunodeficiency virus infection or AIDS, and there is no effective therapy. The inhibitory activities of polyamine analogues (PG-11157, PG-11158, and PG-11302) against E. bieneusi infection were evaluated in SCID mice preconditioned with anti-gamma interferon monoclonal antibody intraperitoneally (i.p.). Mice were challenged orally with 104 E. bieneusi spores, and groups of mice were treated orally or i.p. 14 days later for 7 days. The inhibitory activities of the drugs against infection were determined by enumerating the E. bieneusi spores in feces three times a week by an immunofluorescence assay. Immunohistochemistry staining confirmed the infection within enterocytes. Oral administration of the analogues PG-11157 (at 150 or 75 mg/kg of body weight/day) and PG-11302 (at 250 mg/kg/day) had significant inhibitory activity (96.2 to 99.6%) that was slightly better than that of fumagillin (1 mg/kg/day; 93.7%). The inhibitory activity with i.p. injection was significant only with PG-11302 at 20 mg/kg/day. While the treatments considerably reduced the levels of spore excretion, neither polyamine analogues nor fumagillin was able to completely eliminate E. bieneusi, as excretion reappeared within 7 days after the end of treatment. Drug toxicity was apparent during treatment, but it disappeared at the end of treatment. These results warrant further examination of the analogues PG-11157 and PG-11302. PMID:19289524

  6. MRL/lpr-->severe combined immunodeficiency mouse allografts produce autoantibodies, acute graft-versus-host disease or a wasting syndrome depending on the source of cells.

    PubMed Central

    Ashany, D; Hines, J J; Gharavi, A E; Mouradian, J; Drappa, J; Elkon, K B

    1992-01-01

    MRL/lpr (lpr) mice spontaneously develop a lupus-like illness as well as massive lymphadenopathy. Attempts to transfer autoimmunity by adoptive transfer or radiation bone marrow chimeras have been unsuccessful. Since severe combined immunodeficiency (SCID) mice have been engrafted with human and rat xenografts without apparent graft-versus-host disease (GVHD), we subjected SCID mice to low-dose irradiation and reconstituted the mice with spleen cells from young or old lpr mice or with lpr bone marrow. Fourteen out of twenty (70%) of SCID mice engrafted with spleen cells from old lpr mice produced autoantibodies (anti-DNA and anti-Sm) without evidence of the severe lymphoid atrophy previously described for lpr spleen-->+/+ chimeras. SCID mice engrafted with spleen cells from young lpr mice developed acute GVHD and 5/6 (83%) died within 4 weeks post-transfer. Although 8/11 (73%) of lpr-->SCID bone marrow allografts survived for at least 4 months, these mice developed a wasting disease characterized by lymphoid atrophy and fibrosis without the production of autoantibodies. None of the lpr-->SCID grafts resulted in the transfer of double negative T cells or the lymphoproliferative syndrome characteristic of MRL/lpr mice. These findings indicate that SCID mice can be engrafted with splenocytes from old MRL/lpr mice and that B cells continue to secrete autoantibodies for several months in the SCID recipients. This study also demonstrates that, unlike i.p. transplant of xenogeneic cells, acute GVHD is a consistent feature of i.p. transplants of normal allogeneic mononuclear cells into SCID mice. Images Fig. 5 Fig. 7 Fig. 7 PMID:1458684

  7. The gene for severe combined immunodeficiency disease in Athabascan-speaking Native Americans is located on chromosome 10p.

    PubMed Central

    Li, L; Drayna, D; Hu, D; Hayward, A; Gahagan, S; Pabst, H; Cowan, M J

    1998-01-01

    Severe combined immunodeficiency disease (SCID) consists of a group of heterogeneous genetic disorders. The most severe phenotype, T-B- SCID, is inherited as an autosomal recessive trait and is characterized by a profound deficiency of both T cell and B cell immunity. There is a uniquely high frequency of T-B- SCID among Athabascan-speaking Native Americans (A-SCID). To localize the A-SCID gene, we conducted a genomewide search, using linkage analysis of approximately 300 microsatellite markers in 14 affected Athabascan-speaking Native American families. We obtained conclusive evidence for linkage of the A-SCID locus to markers on chromosome 10p. The maximum pairwise LOD scores 4.53 and 4.60 were obtained from two adjacent markers, D10S191 and D10S1653, respectively, at a recombination fraction of straight theta=.00. Recombination events placed the gene in an interval of approximately 6.5 cM flanked by D10S1664 and D10S674. Multipoint analysis positioned the gene for the A-SCID phenotype between D10S191 and D10S1653, with a peak LOD score of 5.10 at D10S191. Strong linkage disequilibrium was found in five linked markers spanning approximately 6.5 cM in the candidate region, suggesting a founder effect with an ancestral mutation that occurred sometime before 1300 A.D. PMID:9443881

  8. Measures of kidney function by minimally invasive techniques correlate with histological glomerular damage in SCID mice with adriamycin-induced nephropathy

    PubMed Central

    Scarfe, Lauren; Rak-Raszewska, Aleksandra; Geraci, Stefania; Darssan, Darsy; Sharkey, Jack; Huang, Jiaguo; Burton, Neal C.; Mason, David; Ranjzad, Parisa; Kenny, Simon; Gretz, Norbert; Lévy, Raphaël; Kevin Park, B.; García-Fiñana, Marta; Woolf, Adrian S.; Murray, Patricia; Wilm, Bettina

    2015-01-01

    Maximising the use of preclinical murine models of progressive kidney disease as test beds for therapies ideally requires kidney function to be measured repeatedly in a safe, minimally invasive manner. To date, most studies of murine nephropathy depend on unreliable markers of renal physiological function, exemplified by measuring blood levels of creatinine and urea, and on various end points necessitating sacrifice of experimental animals to assess histological damage, thus counteracting the principles of Replacement, Refinement and Reduction. Here, we applied two novel minimally invasive techniques to measure kidney function in SCID mice with adriamycin-induced nephropathy. We employed i) a transcutaneous device that measures the half-life of intravenously administered FITC-sinistrin, a molecule cleared by glomerular filtration; and ii) multispectral optoacoustic tomography, a photoacoustic imaging device that directly visualises the clearance of the near infrared dye, IRDye 800CW carboxylate. Measurements with either technique showed a significant impairment of renal function in experimental animals versus controls, with significant correlations with the proportion of scarred glomeruli five weeks after induction of injury. These technologies provide clinically relevant functional data and should be widely adopted for testing the efficacies of novel therapies. Moreover, their use will also lead to a reduction in experimental animal numbers. PMID:26329825

  9. Development of mature and functional human myeloid subsets in HSC engrafted NOD/SCID/IL2rγKO mice

    PubMed Central

    Tanaka, Satoshi; Saito, Yoriko; Kunisawa, Jun; Kurashima, Yosuke; Wake, Taichi; Suzuki, Nahoko; Shultz, Leonard D.; Kiyono, Hiroshi; Ishikawa, Fumihiko

    2012-01-01

    While physiological development of human lymphoid subsets has become well documented in humanized mice, in vivo development of human myeloid subsets in a xenotransplantation setting has remained unevaluated. Therefore, we investigated in vivo differentiation and function of human myeloid subsets in NOD/SCID/IL2rγnull (NSG) mouse recipients transplanted with purified lineage−CD34+CD38− cord blood hematopoietic stem cells. At four to six months post-transplantation, we identified the development of human neutrophils, basophils, mast cells, monocytes, as well as conventional and plasmacytoid dendritic cells in the recipient hematopoietic organs. The tissue distribution and morphology of these human myeloid cells were similar to those identified in humans. Following cytokine stimulation in vitro, phosphorylation of STAT molecules was observed in neutrophils and monocytes. In vivo administration of human G-CSF resulted in the recruitment of human myeloid cells into the recipient circulation. Flow cytometry and confocal imaging demonstrated that human bone marrow monocytes and alveolar macrophages in the recipients displayed intact phagocytic function. Human BM-derived monocytes/macrophages were further confirmed to exhibit phagocytosis and killing of Salmonella Typhimurium upon the IFN-γ stimulation. These findings demonstrate the development of mature and functionally intact human myeloid subsets in vivo in the NSG recipients. In vivo human myelopoiesis established in the NSG humanized mouse system may facilitate the investigation of human myeloid cell biology including in vivo analyses of infectious diseases and therapeutic interventions. PMID:22611244

  10. Noninvasive Optical Imaging and In Vivo Cell Tracking of Indocyanine Green Labeled Human Stem Cells Transplanted at Superficial or In-Depth Tissue of SCID Mice.

    PubMed

    Sabapathy, Vikram; Mentam, Jyothsna; Jacob, Paul Mazhuvanchary; Kumar, Sanjay

    2015-01-01

    Stem cell based therapies hold great promise for the treatment of human diseases; however results from several recent clinical studies have not shown a level of efficacy required for their use as a first-line therapy, because more often in these studies fate of the transplanted cells is unknown. Thus monitoring the real-time fate of in vivo transplanted cells is essential to validate the full potential of stem cells based therapy. Recent studies have shown how real-time in vivo molecular imaging has helped in identifying hurdles towards clinical translation and designing potential strategies that may contribute to successful transplantation of stem cells and improved outcomes. At present, there are no cost effective and efficient labeling techniques for tracking the cells under in vivo conditions. Indocyanine green (ICG) is a safer, economical, and superior labelling technique for in vivo optical imaging. ICG is a FDA-approved agent and decades of usage have clearly established the effectiveness of ICG for human clinical applications. In this study, we have optimized the ICG labelling conditions that is optimal for noninvasive optical imaging and demonstrated that ICG labelled cells can be successfully used for in vivo cell tracking applications in SCID mice injury models.

  11. Measures of kidney function by minimally invasive techniques correlate with histological glomerular damage in SCID mice with adriamycin-induced nephropathy.

    PubMed

    Scarfe, Lauren; Rak-Raszewska, Aleksandra; Geraci, Stefania; Darssan, Darsy; Sharkey, Jack; Huang, Jiaguo; Burton, Neal C; Mason, David; Ranjzad, Parisa; Kenny, Simon; Gretz, Norbert; Lévy, Raphaël; Kevin Park, B; García-Fiñana, Marta; Woolf, Adrian S; Murray, Patricia; Wilm, Bettina

    2015-09-02

    Maximising the use of preclinical murine models of progressive kidney disease as test beds for therapies ideally requires kidney function to be measured repeatedly in a safe, minimally invasive manner. To date, most studies of murine nephropathy depend on unreliable markers of renal physiological function, exemplified by measuring blood levels of creatinine and urea, and on various end points necessitating sacrifice of experimental animals to assess histological damage, thus counteracting the principles of Replacement, Refinement and Reduction. Here, we applied two novel minimally invasive techniques to measure kidney function in SCID mice with adriamycin-induced nephropathy. We employed i) a transcutaneous device that measures the half-life of intravenously administered FITC-sinistrin, a molecule cleared by glomerular filtration; and ii) multispectral optoacoustic tomography, a photoacoustic imaging device that directly visualises the clearance of the near infrared dye, IRDye 800CW carboxylate. Measurements with either technique showed a significant impairment of renal function in experimental animals versus controls, with significant correlations with the proportion of scarred glomeruli five weeks after induction of injury. These technologies provide clinically relevant functional data and should be widely adopted for testing the efficacies of novel therapies. Moreover, their use will also lead to a reduction in experimental animal numbers.

  12. Comparison of immunopathology and locomotor recovery in C57BL/6, BUB/BnJ, and NOD-SCID mice after contusion spinal cord injury.

    PubMed

    Luchetti, Sabina; Beck, Kevin D; Galvan, Manuel D; Silva, Richard; Cummings, Brian J; Anderson, Aileen J

    2010-02-01

    Studies of cell transplantation therapeutics in animal models of traumatic spinal cord injury (SCI) are often hampered by partial or complete rejection of the graft by the host. Pharmacological immunosuppression is rarely sufficient to prevent rejection. Further, the immunological niche created by both the host immune response and immunosuppressant drugs could hypothetically influence the proliferation, differentiation, and fate of transplanted progenitor/stem cells. To avoid these confounds, we have previously used the constitutively immunodeficient non-obese diabetic severe combined immunodeficient (NOD-SCID) mouse as a model for transplantation studies following SCI. In the current study, we compare behavioral and histological recovery in NOD-SCID, C57BL/6, and BUB/BnJ mice of both sexes to better facilitate interpretation of data from studies using NOD-SCID mice. Of the strains examined, NOD-SCID mice exhibited the greatest locomotor recovery in the open field; no sex differences were detected in locomotor recovery in any of the strains. Stereologic estimation of the number of infiltrated neutrophils showed more cells in C57BL/6 mice than NOD-SCID mice, with BUB/BnJ mice having an intermediate number. The volume of macrophages/microglia did not differ between strains or sexes, though more rostral-caudal spreading was observed in C57BL/6 and BUB/BnJ than NOD-SCID mice. No significant differences were detected in lesion volume. Taken together these findings demonstrate that relative to other strains, NOD-SCID mice have both similar primary lesion volume and cellular inflammatory parameters after SCI, and support the applicability of the model for neurotransplantation studies.

  13. Successful radioimmunotherapy for micro and occult metastases in a SCID mouse model

    SciTech Connect

    Yokoyama, K.; Koshida, K.; Kinuya, S. |

    1996-05-01

    It is often addressed that the most appropriate candidate, theoretically, for radioimmunotherapy (RIT) is not bulky tumor burden but for micro or occult metastatic foci, The major obstacles in the verification for veracious efficacy of RIT had been clinically and preclinically the difficulty in obtaining such a model. We have developed the model of testicular tumor (primary site) with visible small metastases to the lymph nodes (LNs) and non-visible (occult) lesions to distant organs in severe combined immunodeficient (SCID) mice. And thus, the suppression of minute tumor depositions after RIT was evaluated. One week after hemilateral intratesticular injection of 2 million of HELA Hep 2 cells that expressed placental alkaline phosphatase (PLAP), the group of the mice were treated with a single dose of I-131 labeled HPMS-1, anti-PLAP MoAb or with saline control. The I-131 labeled HPMS-1 (5.6 MBq / 150 {mu}g) was intravenously administered and at 2 weeks after, the testis, retroperitoneal and intraperitoneal LNs and other gans were removed. For the control group, the testicular tumor and LNs metastases were found in 100% and 86% of the mice. The metastases in the liver and lung were not observed by histological examination but in all mouse samples, the PCR (polymerase chain reaction) assay could identify the human {beta}-globin gene derived from HeLa cells, indicating the presence of definitive metastases. For the treated group, the average testicular tumor weight was significantly reduced by the factor of 2.4 (132 mg vs 311 mg, p<0.01). The LNs metastases were even more distinctively suppressed by the factor of 45.7 (13 mg vs 599 mg, p,0.05). Remarkably, the PCR products from the occult metastases were almost completely controlled; 97% suppression found for the liver and 81% for the lung. Thus, we conclude that using I-131 as a label, RIT is justified to used for targeting and killing minute tumor foci.

  14. The urokinase inhibitor p-aminobenzamidine inhibits growth of a human prostate tumor in SCID mice.

    PubMed

    Billström, A; Hartley-Asp, B; Lecander, I; Batra, S; Astedt, B

    1995-05-16

    Malignant cells possess a high degree of proteolytic activity in which the plasminogen activator system plays an important role. An increased expression of urokinase type plasminogen activator (uPA) is of significance for degradation of the extracellular tumor matrix, facilitating invasiveness and growth. Inhibition of the active site of uPA makes it possible to evaluate the significance of uPA in tumor growth. We report here experiments on a uPA-producing human prostate xenograft (DU 145) using a competitive inhibitor of uPA, p-aminobenzamidine. In vitro experiments with DU 145 cells showed that p-aminobenzamidine caused a dose-dependent inhibition of uPA activity. DU 145 cells were inoculated s.c. in SCID mice and, once tumors were established, treatment with p-aminobenzamidine added to drinking water was started and lasted for 23 days. Mice receiving 250 mg/kg/day of p-aminobenzamidine showed a clear decrease in tumor-growth rate compared to the non-treated mice, resulting in 64% lower final tumor weight. In addition, uPA-antigen levels in the membrane fractions of DU 145 tumors from p-aminobenzamidine-treated mice were found to be decreased by 59%. We also show that p-aminobenzamidine has an anti-proliferative effect in cell culture at low cell number, correlating with a dose-dependent decrease in uPA production. In conclusion, we show that a low-molecular-weight uPA-inhibitor, p-aminobenzamidine, has a growth-inhibitory effect on a solid uPA-producing tumor. PMID:7759160

  15. Intrahepatic transplantation of CD34+ cord blood stem cells into newborn and adult NOD/SCID mice induce differential organ engraftment.

    PubMed

    Wulf-Goldenberg, Annika; Keil, Marlen; Fichtner, Iduna; Eckert, Klaus

    2012-04-01

    In vivo studies concerning the function of human hematopoietic stem cells (HSC) are limited by relatively low levels of engraftment and the failure of the engrafted HSC preparations to differentiate into functional immune cells after systemic application. In the present paper we describe the effect of intrahepatically transplanted CD34(+) cells from cord blood into the liver of newborn or adult NOD/SCID mice on organ engraftment and differentiation. Analyzing the short and long term time dependency of human cell recruitment into mouse organs after cell transplantation in the liver of newborn and adult NOD/SCID mice by RT-PCR and FACS analysis, a significantly high engraftment was found after transplantation into liver of newborn NOD/SCID mice compared to adult mice, with the highest level of 35% human cells in bone marrow and 4.9% human cells in spleen at day 70. These human cells showed CD19 B-cell, CD34 and CD38 hematopoietic and CD33 myeloid cell differentiation, but lacked any T-cell differentiation. HSC transplantation into liver of adult NOD/SCID mice resulted in minor recruitment of human cells from mouse liver to other mouse organs. The results indicate the usefulness of the intrahepatic application route into the liver of newborn NOD/SCID mice for the investigation of hematopoietic differentiation potential of CD34(+) cord blood stem cell preparations.

  16. T cell engraftment in lymphoid tissues of human peripheral blood lymphocyte reconstituted SCID mice with or without prior activation of cells.

    PubMed

    Olive, C; Cheung, C; Falk, M C

    1998-12-01

    The reconstitution of severe combined immunodeficiency (SCID) mice with human PBL (Hu-PBL-SCID) was assessed using fresh unstimulated PBL and anti-CD3-stimulated PBL. Mice were reconstituted with PBL by intraperitoneal injection of 1-2.5 x 107 PBL in PBS; controls received PBS. Successful engraftment of human PBL in SCID mice was determined by measurement of human IgG in mouse sera, polymerase chain reaction (PCR) detection of human-specific HLA-DRbeta DNA in SCID periphery, and immunohistochemical staining of mouse tissues (spleen, lymph nodes, thymus, liver and lung) with antibodies specific for human CD45 and CD3. Human IgG was detected 1 week after reconstitution in sera of all animals that received at least 1 x 107 PBL and continued to increase for 8 weeks. Human-specific HLA-DRbeta DNA was detected in the majority of mice 3 weeks after reconstitution but not in controls. Moreover, immunohistochemical analysis of Hu-PBL-SCID mouse tissues revealed the presence of human CD45+ cells in all tissues examined. CD3+ T cell engraftment was observed in lymphoid tissues irrespective of whether PBL had been activated prior to transfer or not. PMID:9893029

  17. Tetanus toxoid-specific T cell responses in severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood lymphocytes.

    PubMed Central

    Somasundaram, R; Jacob, L; Herlyn, D

    1995-01-01

    SCID mice reconstituted with human peripheral blood lymphocytes (PBL) have repeatedly been shown to produce antigen-specific B cell responses. We have derived tetanus toxoid (TT)-specific human T cell lines from cells of the peritoneal cavity, spleen and lymph nodes of SCID mice reconstituted with human PBL and boosted with TT. Establishment of these cell lines was dependent on the time interval between reconstitution of the mice with human PBL and initiation of lymphocyte cultures in vitro. When lymphocytes were collected from the mice 8 weeks after reconstitution, human lymphocytes with TT-specific proliferative activity in vitro were isolated from the peritoneal cavity and spleen, but long-term cell lines could not be established after repeated lymphocyte stimulation with TT, IL-2 and autologous Epstein-Barr virus-transformed B cells. In contrast, three long-term (> 10 months) TT-specific human T cell lines were established from lymphocytes collected from two of the eight mice in the group 4 weeks after reconstitution. The T cell lines were either CD4+ (two lines derived from peritoneal cavity and lymph node, respectively) or CD8+ (one line derived from spleen) and all expressed CD3, T cell receptor alpha/beta, and human histocompatibility leucocyte class I antigen. The T cell lines, however, lacked cytotoxic, helper and suppressor activities. Thus, SCID mice can support human T cells that actively migrate to various organs and respond to antigenic stimuli both in vivo and in vitro, but these T cells lack characteristic functions. PMID:7621599

  18. Successful induction of severe destructive arthritis by the transfer of in vitro-activated synovial fluid T cells from patients with rheumatoid arthritis (RA) in severe combined immunodeficient (SCID) mice.

    PubMed

    Sakata, A; Sakata, K; Ping, H; Ohmura, T; Tsukano, M; Kakimoto, K

    1996-05-01

    In order to investigate the role of pathogenic T cells in RA, the establishment of an RA model using patients' T cells is thought to be essential. In this study, multiple and severe destructive arthritis was established by transferring in vitro-stimulated synovial fluid T (SFT) cells from patients with RA through simultaneous injection into knee joint and peritoneal cavity of SCID mice without causing xenogeneic graft-versus-host disease (GVHD). Neither the transfer of unstimulated SFT cells nor sole i.p. injection was sufficient to induce severe arthritis. Interestingly, in contrast with SFT cells, in vitro-activated peripheral blood lymphocytes from RA patients failed to trigger such arthritis, suggesting that pathogenic T cells might be concentrated in synovial fluid of RA patients. This, the first severe arthritis model mimicking RA induced by RA patients' T cells, is expected to provide important information about RA pathogenesis and a possible therapeutic approach.

  19. Identification of newly isolated Babesia parasites from cattle in Korea by using the Bo-RBC-SCID mice

    PubMed Central

    Cho, Shin-Hyeong; Lee, Hyeong-Woo; Tsuji, Masayoshi; Ishihara, Chiaki; Kim, Jong-Taek; Wee, Sung-Hwan; Lee, Chung-Gil

    2002-01-01

    Attempts were made to isolate and identify Korean bovine Babesia parasite. Blood samples were collected from Holstein cows in Korea, and Babesia parasites were propagated in SCID mice with circulating bovine red blood cells for isolation. The isolate was then antigenically and genotypically compared with several Japanese isolates. The Korean parasite was found to be nearly identical to the Oshima strain isolated from Japanese cattle, which was recently designated as Babesia ovata oshimensis n. var. Haemaphysalis longicornis was the most probable tick species that transmited the parasite. PMID:11949211

  20. Experimental Support for the Ecoimmunity Theory: Distinct Phenotypes of Nonlymphocytic Cells in SCID and Wild-Type Mice.

    PubMed

    Ochayon, David E; Baranovski, Boris M; Malkin, Peter; Schuster, Ronen; Kalay, Noa; Ben-Hamo, Rotem; Sloma, Ido; Levinson, Justin; Brazg, Jared; Efroni, Sol; Lewis, Eli C; Nevo, Uri

    2016-01-01

    Immune tolerance toward "self" is critical in multiple immune disorders. While there are several mechanisms to describe the involvement of immune cells in the process, the role of peripheral tissue cells in that context is not yet clear. The theory of ecoimmunity postulates that interactions between immune and tissue cells represent a predator-prey relationship. A lifelong interaction, shaped mainly during early ontogeny, leads to selection of nonimmune cell phenotypes. Normally, therefore, nonimmune cells that evolve alongside an intact immune system would be phenotypically capable of evading immune responses, and cells whose phenotype falls short of satisfying this steady state would expire under hostile immune responses. This view was supported until recently by experimental evidence showing an inferior endurance of severe combined immunodeficiency (SCID)-derived pancreatic islets when engrafted into syngeneic immune-intact wild-type (WT) mice, relative to islets from WT. Here we extend the experimental exploration of ecoimmunity by searching for the presence of the phenotypic changes suggested by the theory. Immune-related phenotypes of islets, spleen, and bone marrow immune cells were determined, as well as SCID and WT nonlymphocytic cells. Islet submass grafting was performed to depict syngeneic graft functionality. Islet cultures were examined under both resting and inflamed conditions for expression of CD40 and major histocompatibility complex (MHC) class I/II and release of interleukin-1α (IL-1α), IL-1β, IL-6, tumor necrosis factor-α (TNF-α), IL-10, and insulin. Results depict multiple pathways that appear to be related to the sculpting of nonimmune cells by immune cells; 59 SCID islet genes displayed relative expression changes compared with WT islets. SCID cells expressed lower tolerability to inflammation and higher levels of immune-related molecules, including MHC class I. Accordingly, islets exhibited a marked increase in insulin release upon

  1. A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals.

    PubMed

    Palamides, Pia; Jodeleit, Henrika; Föhlinger, Michael; Beigel, Florian; Herbach, Nadja; Mueller, Thomas; Wolf, Eckhard; Siebeck, Matthias; Gropp, Roswitha

    2016-09-01

    Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC-affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R γ(null) mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help

  2. A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals

    PubMed Central

    Palamides, Pia; Jodeleit, Henrika; Föhlinger, Michael; Beigel, Florian; Herbach, Nadja; Mueller, Thomas; Wolf, Eckhard; Siebeck, Matthias

    2016-01-01

    ABSTRACT Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC-affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might

  3. Pinworm detection in mice with immunodeficient (NOD SCID) and immunocompetent (CD-1 and Swiss) soiled bedding sentinels in individually ventilated cage systems.

    PubMed

    Eguíluz, C; Rossi, M; Viguera, E

    2015-10-01

    Sentinel exposure to soiled bedding is frequently used for health monitoring of mice housed in individually ventilated cage systems (IVCS). Despite its advantages, the use of soiled bedding sentinels (SBSs) is far for being a reliable method. Two studies were conducted to evaluate the sensitivity of immunodeficient SBSs NOD.CB17-Prkdc(scid)/NCrHsd (NOD SCID) against two immunocompetent outbred strains, Hsd:ICR (CD-1) and RjOr1:Swiss (Swiss) to pinworm detection in IVCS-housing. Four different diagnostic methods were used: perianal tape test, fecal flotation, plate method and histology. Positivity was considered if at least one of the techniques used was positive. In the first study NOD SCID were more sensitive than CD-1 SBSs (P < 0.05), and except for the fecal flotation test performed at week 6, all the diagnostic methods were more sensitive with NOD SCID mice (P < 0.05). In the second study differences between the Swiss and NOD SCID mice were less obvious (P = 0.08). When compared separately, the different diagnostic methods, except for the fecal flotation test, were all more sensitive in the NOD SCID mice (P < 0.05). In addition, the anal tape test in the Swiss SBSs was more sensitive at week 7 than at week 15 (P < 0.05). In conclusion, combining various diagnostic techniques and samplings at week 7 post-exposure with non-invasive methods increases the rate of pinworm detection. Immunodeficient SBSs showed higher sensitivity than immunocompetent ones. Thus, use of immunodeficient SBSs is highly recommended in health control protocols.

  4. Positive Family History, Infection, Low Absolute Lymphocyte Count (ALC) and Absent Thymic Shadow: Diagnostic Clues for all Molecular Forms of Severe Combined Immunodeficiency (SCID)

    PubMed Central

    McWilliams, Laurie M; Railey, Mary Dell; Buckley, Rebecca H

    2015-01-01

    Background Severe Combined Immunodeficiency (SCID) is a syndrome uniformly fatal during infancy unless recognized and treated successfully by bone marrow transplantation or gene therapy. Because SCID infants have no abnormal physical appearance, diagnosis is usually delayed unless newborn screening is performed. Objective In this study, we sought to evaluate the presenting features of all 172 SCID patients transplanted at this institution over the past 31 years. Methods We reviewed original charts from 172 consecutive classic SCID patients who received either T cell-depleted HLA-haploidentical (N=154) or HLA-identical (N=18) non-ablative related marrow transplants at Duke University Medical Center from 1982–2013. Results The mean age at presentation was 4.87 months. When there was a family history of early infant death or known SCID (63/172 or 37%), the mean presentation age was much earlier, 2.0 months compared to 6.6 months. Failure to thrive was common, with 84 patients (50%) having a weight less than the 5th percentile. The leading infections included oral moniliasis (43%), viral infections (61/172 35.5%) and Pneumocystis jiroveci (26%) pneumonia. The group mean ALC was 1454/cmm; 88% of the infants had an ALC less than 3000/cmm. Absent thymic shadow was seen in 92% of infants with electronic radiographic data available. An absence of T cell function was found in all patients. Conclusions SCID infants appear normal at birth but later present with failure to thrive and/or recurrent fungal, viral and bacterial infections. Low ALCs and absent thymic shadow on chest x-ray are key diagnostic clues. The absence of T cell function confirms the diagnosis. PMID:25824440

  5. Inhibition of Acute in vivo Human Immunodeficiency Virus Infection by Human Interleukin 10 Treatment of SCID Mice Implanted with Human Fetal Thymus and Liver

    NASA Astrophysics Data System (ADS)

    Kollmann, Tobias R.; Pettoello-Mantovani, Massimo; Katopodis, Nikos F.; Hachamovitch, Moshe; Rubinstein, Arye; Kim, Ana; Goldstein, Harris

    1996-04-01

    To improve the usefulness of in vivo models for the investigation of the pathophysiology of human immunodeficiency virus (HIV) infection, we modified the construction of SCID mice implanted with human fetal thymus and liver (thy/liv-SCID-hu mice) so that the peripheral blood of the mice contained significant numbers of human monocytes and T cells. After inoculation with HIV-159, a primary patient isolate capable of infecting monocytes and T cells, the modified thy/liv-SCID-hu mice developed disseminated HIV infection that was associated with plasma viremia. The development of plasma viremia and HIV infection in thy/liv-SCID-hu mice inoculated with HIV-159 was inhibited by acute treatment with human interleukin (IL) 10 but not with human IL-12. The human peripheral blood mononuclear cells in these modified thy/liv-SCID-hu mice were responsive in vivo to treatment with exogenous cytokines. Human interferon γ expression in the circulating human peripheral blood mononuclear cells was induced by treatment with IL-12 and inhibited by treatment with IL-10. Thus, these modified thy/liv-SCID-hu mice should prove to be a valuable in vivo model for examining the role of immunomodulatory therapy in modifying HIV infection. Furthermore, our demonstration of the in vivo inhibitory effect of IL-10 on acute HIV infection suggests that further studies may be warranted to evaluate whether there is a role for IL-10 therapy in preventing HIV infection in individuals soon after exposure to HIV such as for children born to HIV-infected mothers.

  6. Inhibition of acute in vivo human immunodeficiency virus infection by human interleukin 10 treatment of SCID mice implanted with human fetal thymus and liver.

    PubMed Central

    Kollmann, T R; Pettoello-Mantovani, M; Katopodis, N F; Hachamovitch, M; Rubinstein, A; Kim, A; Goldstein, H

    1996-01-01

    To improve the usefulness of in vivo mode for the investigation of the pathophysiology of human immunodeficiency virus (HIV) infection, we modified the construction of SCID mice implanted with human fetal thymus and liver (thy/liv-SCID-hu mice) so that the peripheral blood of the mice contained significant numbers of human monocytes and T cells. After inoculation with HIV-1(59), a primary patient isolate capable of infecting monocytes and T cells, the modified thy/liv-SCID-hu mice developed disseminated HIV infection that was associated with plasma viremia. The development of plasma viremia and HIV infection in thy/liv-SCID-hu mice inoculated with HIV-1(59) was inhibited by acute treatment with human interleukin (IL) 10 but not with human IL-12. The human peripheral blood mononuclear cells in these modified thy/liv-SCID-hu mice were responsive to in vivo treatment with exogenous cytokines. Human interferon gamma expression in the circulating human peripheral blood mononuclear cells was induced by treatment with IL-12 and inhibited by treatment with IL-10. Thus, these modified thy/liv-SCID-hu mice should prove to be a valuable in vivo model for examining the role of immunomodulatory therapy in modifying HIV infection. Furthermore, our demonstration of the vivo inhibitory effect of IL-10 on acute HIV infection suggests that further studies may be warranted to evaluate whether there is a role for IL-10 therapy in preventing HIV infection in individuals soon after exposure to HIV such as for children born to HIV-infected mothers. Images Fig. 2 Fig. 3 PMID:8610180

  7. Histopathological and expression profiling studies of early tumor responses to near-infrared PDT treatment in SCID mice

    NASA Astrophysics Data System (ADS)

    Starkey, Jean R.; Rebane, Aleksander; Drobizhev, Mikhail A.; Meng, Fanqin; Gong, Aijun; Elliott, Aleisha; McInnerney, Kate; Pascucci, Elizabeth; Spangler, Charles W.

    2008-02-01

    A novel class of porphyrin-based near-infrared photodynamic therapy (PDT) sensitizers is studied. We achieve regressions of human small cell lung cancer (NCI-H69), non-small cell lung cancer (A 459) and breast cancer (MDAMB- 231) xenografts in SCID mice at significant tissue depth by irradiation with an amplified femtosecond pulsed laser at 800 nm wavelength. Significant tumor regressions were observed during the first 10-14 days post treatment. Tumor histopathology was consistent with known PDT effects, while no significant changes were noted in irradiated normal tissues. In vivo imaging studies using intravenous injections of fluorescent dextran demonstrated an early loss of tumor blood flow. RNA was isolated from NCI-H69 PDT treated SCID mouse xenografts and paired untreated xenografts at 4 hours post laser irradiation. Similarly RNA was isolated from PDT treated and untreated Lewis lung carcinomas growing in C57/Bl6 mice. Expression profiling was carried out using Affymetrix TM human and mouse GeneChips®. Cluster analysis of microarray expression profiling results demonstrated reproducible increases in transcripts associated with apoptosis, stress, oxygen transport and gene regulation in the PDT treated NCI-H69 samples. In addition, PDT treated Lewis lung carcinomas showed reproducible increases in transcripts associated with immune response and lipid biosynthesis. PDT treated C57/Bl6 mice developed cytotoxic T cell activity towards this tumor, while untreated tumor bearing mice failed to do so.

  8. Diagnostic Efficiency among Psychiatric Outpatients of a Self-Report Version of a Subset of Screen Items of the Structured Clinical Interview for DSM-IV-TR Personality Disorders (SCID-II)

    ERIC Educational Resources Information Center

    Germans, Sara; Van Heck, Guus L.; Masthoff, Erik D.; Trompenaars, Fons J. W. M.; Hodiamont, Paul P. G.

    2010-01-01

    This article describes the identification of a 10-item set of the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II) items, which proved to be effective as a self-report assessment instrument in screening personality disorders. The item selection was based on the retrospective analyses of 495 SCID-II interviews. The…

  9. Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases

    ClinicalTrials.gov

    2015-12-01

    Severe Combined Immunodeficiency (SCID); Immunodeficiency With Predominant T-cell Defect, Unspecified; Severe Chronic Neutropenia; Chronic Granulomatous Disease (CGD); Hyper IgE Syndromes; Hyper IgM Deficiencies; Wiskott-Aldrich Syndrome; Mendelian Susceptibility to Mycobacterial Disease; Common Variable Immune Deficiency (CVID)

  10. Expression of LMP and EBNA genes in Epstein-Barr virus-associated lymphomas in Hu-PBL/SCID mice.

    PubMed

    Tang, Yunlian; Lu, Suli; Gan, Xiaoning; Liu, Fang; Zhang, Yang; Luo, Chunyan; Pan, Yuxia; Hong, Li; Gan, Ruliang

    2016-02-01

    Transplantation of peripheral blood lymphocytes (PBLs) from healthy humans with latent Epstein-Barr virus (EBV) infection into severe combined immunodeficiency (SCID) mice results in development of EBV-associated human B-cell lymphoma. However, the expression of EBV genes in relation to lymphoma development has not been reported. We investigated latent membrane protein (LMP) and EBV nuclear antigen (EBNA) gene expression in PBLs from EBV-positive blood donors and induced-lymphoma cells from SCID mice to elucidate the functions and effects of the EBV genome in the occurrence and development of lymphoma. PBLs were isolated from 9 healthy blood donors and transplanted into SCID mice. Gene expression levels of LMP-1, LMP-2A, and LMP-2B and EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C and EBNA-LP were monitored by real-time quantitative-polymerase chain reaction (qRT-PCR) in cells from nine EBV-induced lymphomas and in matched lymphocytes from healthy subjects. LMP-1, EBNA-1 and EBNA-2 protein levels were detected by western blotting. As a result, LMP-1, LMP-2A and LMP-2B mRNA levels were upregulated 256-, 38- and 331-fold, respectively, in the EBV-induced lymphoma cells compared with the controls, while EBNA-1 and EBNA-3A mRNA levels were upregulated 1157- and 1154-fold, respectively. EBNA-2, EBNA-3B, EBNA-3C and EBNA-LP mRNAs were detected in lymphoma cells, but not in lymphocytes from EBV-positive blood donors. LMP-1 and EBNA-2 proteins were not expressed in lymphocytes from EBV-positive blood donors, according to western blotting. Weak EBNA-1 expression was observed in lymphocytes from blood donors with latent EBV infection, while LMP-1, EBNA-1 and EBNA-2 protein levels were significantly upregulated in EBV-induced lymphoma cells, consistent with mRNA expression levels detected by qRT-PCR. In conclusion, LMP-1, LMP-2A, LMP-2B, EBNA-1 and EBNA-3A were upregulated in EBV-induced lymphoma cells, while EBNA-2, EBNA-3B, EBNA-3C and EBNA-LP were absent in lymphocytes from

  11. Reliability and validity of the Turkish version of the Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D): a preliminary study.

    PubMed

    Kundakçi, Turgut; Sar, Vedat; Kiziltan, Emre; Yargiç, Ilhan L; Tutkun, Hamdi

    2014-01-01

    A total of 34 consecutive patients with dissociative identity disorder or dissociative disorder not otherwise specified were evaluated using the Turkish version of the Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D). They were compared with a matched control group composed of 34 patients who had a nondissociative psychiatric disorder. Interrater reliability was evaluated by 3 clinicians who assessed videotaped interviews conducted with 5 dissociative and 5 nondissociative patients. All subjects who were previously diagnosed by clinicians as having a dissociative disorder were identified as positive, and all subjects who were previously diagnosed as not having a dissociative disorder were identified as negative. The scores of the main symptom clusters and the total score of the SCID-D differentiated dissociative patients from the nondissociative group. There were strong correlations between the SCID-D and the Dissociative Experiences Scale total and subscale scores. These results are promising for the validity and reliability of the Turkish version of the SCID-D. However, as the present study was conducted on a predominantly female sample with very severe dissociation, these findings should not be generalized to male patients, to dissociative disorders other than dissociative identity disorder, or to broader clinical or nonclinical populations. PMID:24377970

  12. Reliability and validity of the Turkish version of the Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D): a preliminary study.

    PubMed

    Kundakçi, Turgut; Sar, Vedat; Kiziltan, Emre; Yargiç, Ilhan L; Tutkun, Hamdi

    2014-01-01

    A total of 34 consecutive patients with dissociative identity disorder or dissociative disorder not otherwise specified were evaluated using the Turkish version of the Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D). They were compared with a matched control group composed of 34 patients who had a nondissociative psychiatric disorder. Interrater reliability was evaluated by 3 clinicians who assessed videotaped interviews conducted with 5 dissociative and 5 nondissociative patients. All subjects who were previously diagnosed by clinicians as having a dissociative disorder were identified as positive, and all subjects who were previously diagnosed as not having a dissociative disorder were identified as negative. The scores of the main symptom clusters and the total score of the SCID-D differentiated dissociative patients from the nondissociative group. There were strong correlations between the SCID-D and the Dissociative Experiences Scale total and subscale scores. These results are promising for the validity and reliability of the Turkish version of the SCID-D. However, as the present study was conducted on a predominantly female sample with very severe dissociation, these findings should not be generalized to male patients, to dissociative disorders other than dissociative identity disorder, or to broader clinical or nonclinical populations.

  13. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation.

    PubMed

    Zhang, Cheng Cheng; Kaba, Megan; Iizuka, Satoru; Huynh, HoangDinh; Lodish, Harvey F

    2008-04-01

    Hematopoietic stem cells (HSCs) are the basis of bone marrow transplantation and are attractive target cells for hematopoietic gene therapy, but these important clinical applications have been severely hampered by difficulties in ex vivo expansion of HSCs. In particular, the use of cord blood for adult transplantation is greatly limited by the number of HSCs. Previously we identified angiopoietin-like proteins and IGF-binding protein 2 (IGFBP2) as new hormones that, together with other factors, can expand mouse bone marrow HSCs in culture. Here, we measure the activity of multipotent human severe combined immunodeficient (SCID)-repopulating cells (SRCs) by transplantation into the nonobese diabetic SCID (NOD/SCID) mice; secondary transplantation was performed to evaluate the self-renewal potential of SRCs. A serum-free medium containing SCF, TPO, and FGF-1 or Flt3-L cannot significantly support expansion of the SRCs present in human cord blood CD133+ cells. Addition of either angiopoietin-like 5 or IGF-binding protein 2 to the cultures led to a sizable expansion of HSC numbers, as assayed by NOD/SCID transplantation. A serum-free culture containing SCF, TPO, FGF-1, angiopoietin-like 5, and IGFBP2 supports an approximately 20-fold net expansion of repopulating human cord blood HSCs, a number potentially applicable to several clinical processes including HSC transplantation.

  14. The attenuated nine mile phase II clone 4/RSA439 strain of Coxiella burnetii is highly virulent for severe combined immunodeficient (SCID) mice.

    PubMed

    Islam, Aminul; Lockhart, Michelle; Stenos, John; Graves, Stephen

    2013-10-01

    The Nine Mile phase II clone 4 (NMIIC4) strain of Coxiella burnetii is an attenuated phase II strain that has lost the genes for virulence determinant type 1 lipopolysaccharide. These bacteria were very virulent for severe combined immunodeficient (SCID) mice. The lethal dose 50 (LD50) was ~10 bacteria. Infected SCID mice died between Day 28 and Day 53 post-infection. At termination of the experiment (Day 60) only 5 of 24 mice had survived. The degree of splenomegaly was directly related to the bacterial load in the SCID mice spleens. The NMIIC4 was avirulent in immunocompetent wild mice and bacterial DNA copies in splenic tissue were extremely low. The SCID mice that were inoculated with high doses of heat inactivated NMIIC4 C. burnetii were all alive at Day 60 and without splenomegaly. It appears that the phase I lipopolysaccharide present in virulent Nine Mile phase I but not in attenuated NMIIC4 is not the only virulence factor for C. burnetii.

  15. Foamy viral vector integration sites in SCID-repopulating cells after MGMTP140K-mediated in vivo selection

    PubMed Central

    Olszko, Miles E.; Adair, Jennifer E.; Linde, Ian; Rae, Dustin T.; Trobridge, Patty; Hocum, Jonah D.; Rawlings, David J.; Kiem, Hans-Peter; Trobridge, Grant D.

    2015-01-01

    Foamy virus (FV) vectors are promising for hematopoietic stem cell (HSC) gene therapy but preclinical data on the clonal composition of FV vector transduced human repopulating cells is needed. Human CD34+ human cord blood cells were transduced with an FV vector encoding a methylguanine methyltransferase (MGMT)P140K transgene, transplanted into immunodeficient NOD/SCID IL2Rγnull (NSG) mice, and selected in vivo for gene-modified cells. The retroviral insertion site (RIS) profile of repopulating clones was examined using modified genomic sequencing PCR (MGS-PCR). We observed polyclonal repopulation with no evidence of clonal dominance even with the use of a strong internal spleen focus forming virus (SFFV) promoter known to be genotoxic. Our data supports the use of FV vectors with MGMTP140K for HSC gene therapy, but also suggests additional safety features should be developed and evaluated. PMID:25786870

  16. Establishment of Cloned Anaplasma phagocytophilum and Analysis of p44 Gene Conversion within an Infected Horse and Infected SCID Mice

    PubMed Central

    Lin, Quan; Rikihisa, Yasuko

    2005-01-01

    Diverse p44 alleles at the p44 expression locus (p44Es) encoding surface-exposed major membrane proteins, P44s, of Anaplasma phagocytophilum were hypothesized to be garnered by recombination to enact antigenic variation. However, this hypothesis has not been proven so far, due to inability to clone this obligate intragranulocytic rickettsia. To define the p44E recombination, we developed a novel method to clone A. phagocytophilum. This isogenic cloned population containing a defined p44E was used to infect a naive horse and severe combined immunodeficiency (SCID) mice. During a 58-day infection period in the blood of the horse, p44E conversion was evident in a total of 11 new p44Es, 48% (115/242) of the sequenced p44E population. During a 50-day infection period in the blood of SCID mice, p44E conversion was manifested in a total of 13 new p44Es, 42% (192/460) of the p44E population. Thus, similar levels of p44E convertants were detected in either the presence or absence of an acquired immune system, suggesting that T- and B-cell immune pressure was not essential for recombination and/or selection of the p44E variants. Analysis of sequentially changed p44Es revealed that the entire central hypervariable region of donor p44 pseudogenes or of donor full-length p44s replaced the same region of the resident p44E as a cassette. Putative recombination points were detected within p44 conserved regions flanking the central hypervariable region by the TOPALi analysis. Our results unambiguously demonstrated p44E recombination. The cloning method developed would facilitate precise analysis of the recombination process and the extent of diversity which the recombination creates in the antigenic repertoire. PMID:16041027

  17. Eradication of Human Hepatic and Pulmonary Melanoma Metastases in SCID Mice by Antibody--Interleukin 2 Fusion Proteins

    NASA Astrophysics Data System (ADS)

    Becker, Jurgen C.; Pancook, James D.; Gillies, Stephen D.; Mendelsohn, John; Reisfeld, Ralph A.

    1996-04-01

    Antibody--cytokine fusion proteins combine the unique targeting ability of antibodies with the multifunctional activity of cytokines. Here, we demonstrate the therapeutic efficacy of such constructs for the treatment of hepatic and pulmonary metastases of different melanoma cell lines. Two antibody--interleukin 2 (IL-2) fusion proteins, ch225-IL2 and ch14.18-IL2, constructed by fusion of a synthetic sequence coding for human IL-2 to the carboxyl end of the Cγ 1 gene of the corresponding antibodies, were tested for their therapeutic efficacy against xenografted human melanoma in vivo. Tumorspecific fusion proteins completely inhibited the growth of hepatic and pulmonary metastases in C.B-17 scid/scid mice previously reconstituted with human lymphokine-activated killer cells, whereas treatment with combinations of the corresponding antibodies plus recombinant IL-2 only reduced the tumor load. Even when treatment with fusion proteins was delayed up to 8 days after inoculation of tumor cells, it still resulted in complete eradication of micrometastases that were established at that time point. Selection of tumor cell lines expressing or lacking the targeted antigen of the administered fusion protein proved the specificity of the observed antitumor effect. Biodistribution analysis demonstrated that the tumorspecific fusion protein accumulated not only in subcutaneous tumors but also in lungs and livers affected with micrometastases. Survival times of animals treated with the fusion protein were more than doubled as compared to those treated with the combination of the corresponding antibody plus IL-2. Our data demonstrate that an immunotherapeutic approach using cytokines targeted by antibodies to tumor sites has potent effects against disseminated human melanoma.

  18. Establishment of a retinoic acid-resistant human acute promyelocytic leukaemia (APL) model in human granulocyte-macrophage colony-stimulating factor (hGM-CSF) transgenic severe combined immunodeficiency (SCID) mice.

    PubMed Central

    Fukuchi, Y.; Kizaki, M.; Kinjo, K.; Awaya, N.; Muto, A.; Ito, M.; Kawai, Y.; Umezawa, A.; Hata, J.; Ueyama, Y.; Ikeda, Y.

    1998-01-01

    To understand the mechanisms and identify novel approaches to overcoming retinoic acid (RA) resistance in acute promyelocytic leukaemia (APL), we established the first human RA-resistant APL model in severe combined immunodeficiency (SCID) mice. UF-1 cells, an RA-resistant APL cell line established in our laboratory, were transplanted into human granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing SCID (hGMTg SCID) mice and inoculated cells formed subcutaneous tumours in all hGMTg SCID mice, but not in the non-transgenic control SCID mice. Single-cell suspensions (UF-1/GMTg SCID cells) were similar in morphological, immunological, cytogenetic and molecular genetic features to parental UF-1 cells. All-trans RA did not change the morphological features of cells or their expression of CD11b. RA did not alter the growth curve of cells as determined by MTT assay, suggesting that UF-1/GMTg SCID cells are resistant to RA. These results demonstrate that this is the first RA-resistant APL animal model that may be useful for investigating the biology of this myeloid leukaemia in vivo, as well as for evaluating novel therapeutic approaches including patients with RA-resistant APL. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9764578

  19. Diagnostic efficiency among psychiatric outpatients of a self-report version of a subset of screen items of the Structured Clinical Interview for DSM-IV-TR Personality Disorders (SCID-II).

    PubMed

    Germans, Sara; Van Heck, Guus L; Masthoff, Erik D; Trompenaars, Fons J W M; Hodiamont, Paul P G

    2010-12-01

    This article describes the identification of a 10-item set of the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II) items, which proved to be effective as a self-report assessment instrument in screening personality disorders. The item selection was based on the retrospective analyses of 495 SCID-II interviews. The psychometric properties were studied in a prospective validation study in a random sample of Dutch adult psychiatric outpatients, using the SCID-II interview as the gold standard. First, all patients completed the short questionnaire. One week later, they were interviewed with the full SCID-II. After another week, the short questionnaire was readministered. According to the scores obtained with the full SCID-II, 97 patients (50%) had a personality disorder. The set of 10 SCID-II items correctly classified 78% of all participants. The sensitivity, specificity, and positive and negative power were 0.78, 0.78, 0.78, and 0.78, respectively. The results based on the retrospectively obtained data were rather similar to those obtained in the prospective validation study. Therefore, it is concluded that the set of 10 SCID-II items can be useful as a quick self-report personality disorder screen in a population of psychiatric outpatients.

  20. Comparison of Human Fetal Liver, Umbilical Cord Blood, and Adult Blood Hematopoietic Stem Cell Engraftment in NOD-scid/γc−/−, Balb/c-Rag1−/−γc−/−, and C.B-17-scid/bg Immunodeficient Mice

    PubMed Central

    Lepus, Christin M.; Gibson, Thomas F.; Gerber, Scott A.; Kawikova, Ivana; Szczepanik, Marian; Hossain, Jaber; Ablamunits, Vitaly; Kirkiles-Smith, Nancy; Herold, Kevan C.; Donis, Ruben O.; Bothwell, Alfred L.; Pober, Jordan S.; Harding, Martha J.

    2010-01-01

    Immunodeficient mice bearing components of a human immune system present a novel approach for studying human immune responses. We investigated the number, phenotype, developmental kinetics and function of developing human immune cells following transfer of CD34+ hematopoietic stem cell (HSC) preparations, originating from second trimester human fetal liver (HFL), umbilical cord blood (UCB), or granulocyte colony-stimulating factor-mobilized adult blood (G-CSF-AB) delivered via intrahepatic injection into sublethally irradiated neonatal NOD-scid/γc−/−, Balb/c-Rag1−/−γc−/−, and C.B-17-scid/bg mice. HFL and UCB HSC provided the greatest number and breadth of developing cells. NOD-scid/γc−/− and Balb/c-Rag1−/−γc−/− harbored human B and dendritic cells as well as human platelets in peripheral blood, whereas NOD-scid/γc−/− mice harbored higher levels of human T cells. NOD-scid/γc−/− mice engrafted with HFL CD34+ HSC demonstrated human immunological competence evidenced by white pulp expansion and increases in total human immunoglobulin following immunization with T-dependent antigens, and delayed type hypersensitivity-infiltrating leukocytes in response to antigenic challenge. In conclusion, we describe an encouraging base system for studying human hematopoietic lineage development and function utilizing human HFL or UCB HSC-engrafted NOD-scid/γc−/− mice that is well suited for future studies toward the development of a fully competent humanized mouse model. PMID:19524633

  1. [Effect of combined administration of Angelica polysaccharide and cytarabine on liver of human leukemia NOD/SCID mouse model].

    PubMed

    Zhu, Jia-Hong; Xu, Chun-Yan; Mu, Xin-Yi; Liu, Jun; Zhang, Meng-Si; Jia, Dao-Yong; Zhang, Yan-Yan; Huang, Guo-Ning; Wang, Ya-Ping

    2014-01-01

    Leukemia is a type of malignant tumors of hematopoietic system with the abnormal increased immature leukemia cells showing metastasis and invasion ability. Liver is one of the main targets of the leukemia cells spread to, where they may continue to proliferate and differentiate and cause liver function damage, even liver failure. Our previous studies showed that Angelica polysscharides (APS), the main effective components in Angelica sinensis of Chinese traditional medicine, was able to inhibit the proliferation and induced differentiation of the leukemia cells, however, its effect on the liver during the treatment remains elucidated. In the present study, the human leukemia NOD/SCID mouse model were established by implantation human leukemia K562 cells line, then the leukemia mouse were treated with APS, Ara-c or APS + Ara-c respectively by peritoneal injection for 14 days, to explore the effect and mechanism of the chemicals on the mouse liver. Compared to the human leukemia NOD/SCID mouse model group with the treatments of APS, Ara-c and APS + Ara-c, We found that severe liver damage and pathological changes of the liver were able to alleviate: First, the number of white blood cells in the peripheral blood was significantly lower and with less transplanted K562 leukemia cells; Second, liver function damage was alleviated as liver function tests showed that alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBiL) were significantly reduced, while the albumin (Alb) was notably increased; Third, liver antioxidant ability was improved as the activities of the antioxidant enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were significantly increased, and the contents of GSH and malonaldehyde (MDA) were decreased significantly in the liver; Fourth, the inflammation of the liver was relieved as the level of IL-1beta and IL-6, the inflammatory cytokines, were decreased significantly in the liver. Fifth, liver index

  2. Human platelet antigen (HPA)-1a peptides do not reliably suppress anti-HPA-1a responses using a humanized severe combined immunodeficiency (SCID) mouse model.

    PubMed

    Jackson, D J; Eastlake, J L; Kumpel, B M

    2014-04-01

    Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs most frequently when human platelet antigen (HPA)-1a-positive fetal platelets are destroyed by maternal HPA-1a immunoglobulin (Ig)G antibodies. Pregnancies at risk are treated by administration of high-dose intravenous Ig (IVIG) to women, but this is expensive and often not well tolerated. Peptide immunotherapy may be effective for ameliorating some allergic and autoimmune diseases. The HPA-1a/1b polymorphism is Leu/Pro33 on β3 integrin (CD61), and the anti-HPA-1a response is restricted to HPA-1b1b and HLA-DRB3*0101-positive pregnant women with an HPA-1a-positive fetus. We investigated whether or not HPA-1a antigen-specific peptides that formed the T cell epitope could reduce IgG anti-HPA-1a responses, using a mouse model we had developed previously. Peripheral blood mononuclear cells (PBMC) in blood donations from HPA-1a-immunized women were injected intraperitoneally (i.p.) into severe combined immunodeficient (SCID) mice with peptides and HPA-1a-positive platelets. Human anti-HPA-1a in murine plasma was quantitated at intervals up to 15 weeks. HPA-1a-specific T cells in PBMC were identified by proliferation assays. Using PBMC of three donors who had little T cell reactivity to HPA-1a peptides in vitro, stimulation of anti-HPA-1a responses by these peptides occurred in vivo. However, with a second donation from one of these women which, uniquely, had high HPA-1a-specific T cell proliferation in vitro, marked suppression of the anti-HPA-1a response by HPA-1a peptides occurred in vivo. HPA-1a peptide immunotherapy in this model depended upon reactivation of HPA-1a T cell responses in the donor. For FNAIT, we suggest that administration of antigen-specific peptides to pregnant women might cause either enhancement or reduction of pathogenic antibodies.

  3. Human platelet antigen (HPA)-1a peptides do not reliably suppress anti-HPA-1a responses using a humanized severe combined immunodeficiency (SCID) mouse model

    PubMed Central

    Jackson, D J; Eastlake, J L; Kumpel, B M

    2014-01-01

    Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs most frequently when human platelet antigen (HPA)-1a-positive fetal platelets are destroyed by maternal HPA-1a immunoglobulin (Ig)G antibodies. Pregnancies at risk are treated by administration of high-dose intravenous Ig (IVIG) to women, but this is expensive and often not well tolerated. Peptide immunotherapy may be effective for ameliorating some allergic and autoimmune diseases. The HPA-1a/1b polymorphism is Leu/Pro33 on β3 integrin (CD61), and the anti-HPA-1a response is restricted to HPA-1b1b and HLA-DRB3*0101-positive pregnant women with an HPA-1a-positive fetus. We investigated whether or not HPA-1a antigen-specific peptides that formed the T cell epitope could reduce IgG anti-HPA-1a responses, using a mouse model we had developed previously. Peripheral blood mononuclear cells (PBMC) in blood donations from HPA-1a-immunized women were injected intraperitoneally (i.p.) into severe combined immunodeficient (SCID) mice with peptides and HPA-1a-positive platelets. Human anti-HPA-1a in murine plasma was quantitated at intervals up to 15 weeks. HPA-1a-specific T cells in PBMC were identified by proliferation assays. Using PBMC of three donors who had little T cell reactivity to HPA-1a peptides in vitro, stimulation of anti-HPA-1a responses by these peptides occurred in vivo. However, with a second donation from one of these women which, uniquely, had high HPA-1a-specific T cell proliferation in vitro, marked suppression of the anti-HPA-1a response by HPA-1a peptides occurred in vivo. HPA-1a peptide immunotherapy in this model depended upon reactivation of HPA-1a T cell responses in the donor. For FNAIT, we suggest that administration of antigen-specific peptides to pregnant women might cause either enhancement or reduction of pathogenic antibodies. PMID:24261689

  4. A novel common gamma chain mutation in a Chinese family with X-linked severe combined immunodeficiency (X-SCID; T(-)NK(-)B(+)).

    PubMed

    Tan, Weiping; Yu, Sifei; Lei, Jiaying; Wu, Baojing; Wu, Changyou

    2015-11-01

    X-linked severe combined immunodeficiency (X-SCID) is one of the most common causes of primary immunodeficiencies in humans. A 4-month-old boy with recurrent pulmonary infection had decreased numbers of CD3(+), CD4(+), CD8(+) T lymphocytes, and NK cells and increased levels of CD19(+) B cells but no memory B cells or plasma cells. The production of cytokines by T cells and the activation of T and B cells were either absent or inefficient. While B cell levels were high, they were all IgM-positive, and the secretion of all Ig isotypes by activated B cells in vitro was defective. Genomic DNA sequencing revealed that the patient had missense mutations in the IL2RG (exon 5, 718 T > C) and IL7R genes (exon 2, 197 T > C; exon 4, 412G > A). Although the patient's father and one of his sisters have the same missense homozygous mutations of the IL7R gene, neither of them exhibited the immunological phenotype of SCID. The results indicate that the IL2RG gene mutation or a combination of the IL7R and IL2RG mutations in the sick boy had resulted in T(-)NK(-)B(+) SCID.

  5. Pretransplant Mobilization with Granulocyte Colony-Stimulating Factor Improves B-Cell Reconstitution by Lentiviral Vector Gene Therapy in SCID-X1 Mice

    PubMed Central

    Huston, Marshall W.; Riegman, Adriaan R.A.; Yadak, Rana; van Helsdingen, Yvette; de Boer, Helen; van Til, Niek P.

    2014-01-01

    Abstract Hematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to improve HSC engraftment, but in general it is not considered for SCID-X1 since the poor health of most of these patients at diagnosis and the risk of toxicity preclude the conditioning used in standard bone marrow stem cell transplantation. We hypothesized that mobilization of HSC by granulocyte colony-stimulating factor (G-CSF) should create temporary space in bone marrow niches to improve engraftment and thereby B-cell reconstitution. In the present pilot study supplementing our earlier preclinical evaluation (Huston et al., 2011), Il2rg−/− mice pretreated with G-CSF were transplanted with wild-type lineage negative (Lin−) cells or Il2rg−/− Lin− cells transduced with therapeutic IL2RG lentiviral vectors. Mice were monitored for reconstitution of lymphocyte populations, level of donor cell chimerism, and antibody responses as compared to 2 Gy total body irradiation (TBI), previously found effective in promoting B-cell reconstitution. The results demonstrate that G-CSF promotes B-cell reconstitution similar to low-dose TBI and provides proof of principle for an alternative approach to improve efficacy of gene therapy in SCID patients without adverse effects associated with cytoreductive conditioning. PMID:25222508

  6. Replication and pathogenicity of human immunodeficiency virus type 1 accessory gene mutants in SCID-hu mice.

    PubMed Central

    Aldrovandi, G M; Zack, J A

    1996-01-01

    The functional roles of the human immunodeficiency virus type 1 (HIV-1) accessory genes (nef, vpr, vpu, and vif) are as yet unclear. Using the SCID-hu model system, we have examined the infectivity, replicative capacity, and pathogenicity of strains of the molecular clone HIV-1NL4-3 that contain deletion mutations in these individual accessory genes. We determined that deletion of these genes had differential effects on both infectivity and pathogenicity. Deletion of vpr had little or no effect on viral infectivity, replication, and pathogenicity; however, deletion of vpu or vif had a significant effect on infectivity and moderate effects on pathogenicity. nef-minus strains were the most attenuated in this system, demonstrating significantly lower levels of infectivity and pathogenicity. However, deletion of these individual genes attenuated but did not abrogate the pathogenic properties of HIV-1. Mutant viruses still retained the ability to induce thymocyte depletion to various degrees if implants were infected with higher doses of virus or observed for longer periods of time. The relative contributions of these genes to in vivo pathogenic potential should be taken into consideration when one is contemplating a live attenuated vaccine for HIV-1. PMID:8627668

  7. Biaxial Mechanical Properties of the Inferior Vena Cava in C57BL/6 and CB-17 SCID/bg Mice

    PubMed Central

    Lee, Y.U.; Naito, Y.; Kurobe, H.; Breuer, C.K.; Humphrey, J.D.

    2013-01-01

    Multiple murine models have proven useful in studying the natural history of neovessel development in the tissue engineering of vascular grafts. Nevertheless, to better understand longitudinal changes in the biomechanics of such neovessels, we must first quantify native tissue structure and properties. In this paper, we present the first biaxial mechanical data for, and nonlinear constitutive modeling of, the inferior vena cava from two models used in tissue engineering: wild-type C57BL/6 and immunodeficient CB-17 SCID/bg mice. Results show that inferior vena cava from the latter are significantly stiffer in the circumferential direction, both materially (as assessed by a stored energy function) and structurally (as assessed by the compliance), despite a lower intramural content of fibrillar collagen and similar wall thickness. Quantifying the natural history of neovessel development in different hosts could lead to increased insight into the mechanisms by which cells fashion and maintain extracellular matrix in order to match best the host stiffness while ensuring sufficient vascular integrity. PMID:23859752

  8. Valproic acid affects the engraftment of TPO-expanded cord blood cells in NOD/SCID mice.

    PubMed

    Vulcano, Francesca; Milazzo, Luisa; Ciccarelli, Carmela; Barca, Alessandra; Agostini, Francesca; Altieri, Ilaria; Macioce, Giampiero; Di Virgilio, Antonio; Screnci, Maria; De Felice, Lidia; Giampaolo, Adele; Hassan, Hamisa Jane

    2012-02-15

    Hematopoietic stem and progenitor cells (HSPC) can improve the long-term outcome of transplanted individuals and reduce the relapse rate. Valproic acid (VPA), an inhibitor of histone deacetylase, when combined with different cytokine cocktails, induces the expansion of CD34+ cell populations derived from cord blood (CB) and other sources. We evaluated the effect of VPA, in combination with thrombopoietin (TPO), on the viability and expansion of CB-HSPCs and on short- and long-term engraftability in the NOD/SCID mouse model. In vitro, VPA+TPO inhibited HSPC differentiation and preserved the CD34+ cell fraction; the self-renewal of the CD34+ TPO+VPA-treated cells was suggested by the increased replating efficiency. In vivo, short- and long-term engraftment was determined after 6 and 20 weeks. After 6 weeks, the median chimerism percentage was 13.0% in mice transplanted with TPO-treated cells and only 1.4% in those transplanted with TPO+VPA-treated cells. By contrast, after 20 weeks, the engraftment induced by the TPO+VPA-treated cells was three times more effective than that induced by TPO alone, and over ten times more effective compared to the short-term engraftment induced by the TPO+VPA-treated cells. The in vivo results are consistent with the higher secondary plating efficiency of the TPO+VPA-treated cells in vitro. PMID:22166516

  9. Cyclic ADP-ribose generation by CD38 improves human hemopoietic stem cell engraftment into NOD/SCID mice.

    PubMed

    Podestà, Marina; Pitto, Anna; Figari, Osvaldo; Bacigalupo, Andrea; Bruzzone, Santina; Guida, Lucrezia; Franco, Luisa; De Flora, Antonio; Zocchi, Elena

    2003-02-01

    Cyclic ADP-ribose (cADPR) is a potent and universal intracellular calcium mobilizer, recently shown to behave as a new hemopoietic cytokine stimulating the in vitro proliferation of both committed and uncommitted human hemopoietic progenitors (HP). Here, we investigated the effects of cADPR on engraftment of hemopoietic stem cells (HSC) into irradiated NOD/SCID mice. Two different protocols were used: i) a 24 h in vitro priming of cord blood-derived mononuclear cells (MNC) with micromolar cADPR, followed by their infusion into irradiated mice (both primary and secondary transplants); and ii) co-infusion of MNC with CD38-transfected, cADPR-generating, irradiated murine 3T3 fibroblasts. We demonstrated a dual effect of cADPR on human HP in vivo: i) enhanced proliferation of committed progenitors, responsible for improvement of short-term engraftment; ii) expansion of HSC, with increased long-term human engraftment into secondary recipients and a significantly higher expansion factor of CD34+ progenitors in mice co-infused with MNC and CD38+ 3T3 fibroblasts. These results hold promise for the possible therapeutic use of cADPR, and of cADPR-producing stroma, to achieve long-term expansion of human HSC, that is, those HP capable of self-renewal and responsible for repopulation of the bone marrow.

  10. Engraftment of low numbers of pediatric acute lymphoid and myeloid leukemias into NOD/SCID/IL2Rcγnull mice reflects individual leukemogenecity and highly correlates with clinical outcome.

    PubMed

    Woiterski, Jeanette; Ebinger, Martin; Witte, Kai E; Goecke, Barbara; Heininger, Vanessa; Philippek, Martin; Bonin, Michael; Schrauder, Andre; Röttgers, Silja; Herr, Wolfgang; Lang, Peter; Handgretinger, Rupert; Hartwig, Udo F; André, Maya C

    2013-10-01

    Although immortalized cell lines have been extensively used to optimize treatment strategies in cancer, the usefulness of such in vitro systems to recapitulate primary disease is limited. Therefore, the design of in vivo models ideally utilizing patient-derived material is of critical importance. In this regard, NOD.Cg-Prkdc(scid) IL2rg(tmWjl) /Sz (NSG) mice have been reported to provide superior engraftment rates. However, limited data exist on the validity of such a model to constitute a surrogate marker for clinical parameters. We studied primary and serial engraftment on more than 200 NSG mice with 54 primary pediatric B cell precursor acute lymphatic leukemia (B-ALL), myeloid leukemia (AML) and T cell leukemia (T-ALL) samples, characterized the leukemogenic profile and correlated engraftment kinetics with clinical outcome. Median time to engraftment was 7-10 weeks and 90% of the mice engrafted. Male recipients conferred significantly higher engraftment levels than female recipients (p ≤ 0.004). PCR-based minimal residual disease marker expression and fluorescence in situ hybridization confirmed the presence of patient-specific genetic aberrations in mice. Transcriptome cluster analysis of genes known to be important in the leukemogenesis of all three diseases revealed that well-known tumor-regulating genes were expressed to a comparable extent in mice and men. The extent of engraftment and overall survival of NSG mice highly correlated with the individual prognosis of B-ALL, AML and T-ALL patients. Thus, we propose an in vivo model that provides a valuable preclinical tool to explore the heterogeneity of leukemic disease and exploit patient-tailored leukemia-targeting strategies within multivariate analyses.

  11. Noninvasive Measurement of Microvascular and Interstitial Oxygen Profiles in a Human Tumor in SCID Mice

    NASA Astrophysics Data System (ADS)

    Torres Filho, Ivo P.; Leunig, Michael; Yuan, Fan; Intaglietta, Marcos; Jain, Rakesh K.

    1994-03-01

    Simultaneous measurements of intravascular and interstitial oxygen partial pressure (Po_2) in any tissue have not previously been reported, despite the importance of oxygen in health and in disease. This is due to the limitations of current techniques, both invasive and noninvasive. We have optically measured microscopic profiles of Po_2 with high spatial resolution in subcutaneous tissue and transplanted tumors in mice by combining an oxygen-dependent phosphorescence quenching method and a transparent tissue preparation. The strengths of our approach include the ability to follow Po_2 in the same location for several weeks and to relate these measurements to local blood flow and vascular architecture. Our results show that (i) Po_2 values in blood vessels in well-vascularized regions of a human colon adenocarcinoma xenograft are comparable to those in surrounding arterioles and venules, (ii) carbogen (95% O_2/5% CO_2) breathing increases microvascular Po_2 in tumors, and (iii) in unanesthetized and anesthetized mice Po_2 drops to hypoxic values at <200 μm from isolated vessels but drops by <5 mmHg (1 mmHg = 133 Pa) in highly vascularized tumor regions. Our method should permit noninvasive evaluations of oxygen-modifying agents and offer further mechanistic information about tumor pathophysiology in tissue preparations where the surface of the tissue can be observed.

  12. Articular Chondroprogenitor Cells Maintain Chondrogenic Potential but Fail to Form a Functional Matrix When Implanted Into Muscles of SCID Mice

    PubMed Central

    De Bari, Cosimo; Dell’Accio, Francesco; Archer, Charles W.

    2014-01-01

    Objective Articular cartilage is a complex tissue comprising phenotypically distinct zones. Research has identified the presence of a progenitor cell population in the surface zone of immature articular cartilage. The aim of the present study was to determine the in vivo plasticity of articular cartilage progenitor. Design Chondropogenitor cells were isolated from bovine metacarpalphalangeal joints by differential adhesion to fibronectin. Cells were labeled with PKH26 and injected into the thigh muscle of severe-combined immunodeficient (SCID) mice. After 2 weeks, the muscles were dissected and cryosectioned. Sections were stained with safranin O and labeled for sox9 and collagen type II. Polymerase chain reaction analysis was carried out to determine plasticity for a number of tissue-specific markers. Full-depth chondrocytes acted as a control. Results Fluorescent PKH26 labeled cells were detected after 2 weeks in all samples analyzed. A cartilage pellet was present after injection of freshly isolated chondrocytes. After injection with clonal and enriched populations of chondroprogenitors, no distinct pellet was detected, but diffuse cartilage nodules were found with regions of safranin O staining and Sox9. Low levels of collagen type II were also detected. Polymerase chain reaction analysis identified the presence of the endothelial cell marker PECAM-1 in one clonal cell line, demonstrating phenotypic plasticity into the phenotype of the surrounding host tissues. Conclusions The bovine articular cartilage progenitor cells were able to survive in vivo postimplantation, but failed to create a robust cartilage pellet, despite expressing sox9 and type II collagen. This suggests the cells require further signals for chondrogenic differentiation. PMID:26069702

  13. Metabolic studies of prostanozol with the uPA-SCID chimeric mouse model and human liver microsomes.

    PubMed

    Geldof, Lore; Lootens, Leen; Decroix, Lieselot; Botrè, Francesco; Meuleman, Philip; Leroux-Roels, Geert; Deventer, Koen; Van Eenoo, Peter

    2016-03-01

    Anabolic androgenic steroids are prohibited by the World Anti-Doping Agency because of their adverse health and performance enhancing effects. Effective control of their misuse by detection in urine requires knowledge about their metabolism. In case of designer steroids, ethical objections limit the use of human volunteers to perform excretion studies. Therefore the suitability of alternative models needs to be investigated. In this study pooled human liver microsomes (HLM) and an uPA(+/+)-SCID chimeric mouse model were used to examine the metabolism of the designer steroid prostanozol as a reference standard. Metabolites were detected by GC-MS (full scan) and LC-MS/MS (precursor ion scan). In total twenty-four prostanozol metabolites were detected with the in vitro and in vivo metabolism studies, which could be grouped into two broad classes, those with a 17-hydroxy- and those with a 17-keto-substituent. Major first phase metabolic sites were tentatively identified as C-3'; C-4 and C-16. Moreover, 3'- and 16β-hydroxy-17-ketoprostanozol could be unequivocally identified, since authentic reference material was available, in both models. Comparison with published data from humans showed a good correlation, except for phase II metabolism. As metabolites were in contrast to the human studies predominantly present in the free fraction. Two types of metabolites ((di)hydroxylated prostanozol metabolites) that have not been described before could be confirmed in a real positive doping control sample. Hence, the results provide further evidence for the applicability of chimeric mice and HLM to perform metabolism studies of designer steroids. PMID:26774429

  14. Transduction of Human CD34+ Repopulating Cells with a Self-Inactivating Lentiviral Vector for SCID-X1 Produced at Clinical Scale by a Stable Cell Line

    PubMed Central

    Lockey, Timothy; Mehta, Perdeep K.; Kim, Yoon-Sang; Eldridge, Paul W.; Gray, John T.; Sorrentino, Brian P.

    2012-01-01

    Abstract Self-inactivating (SIN)-lentiviral vectors have safety and efficacy features that are well suited for transduction of hematopoietic stem cells (HSCs), but generation of vector at clinical scale has been challenging. Approximately 280 liters of an X-Linked Severe Combined Immunodeficiency Disorder (SCID-X1) SIN-lentiviral vector in two productions from a stable cell line were concentrated to final titers of 4.5 and 7.2×108 tu/ml. These two clinical preparations and three additional development-scale preparations were evaluated in human CD34+ hematopoietic cells in vitro using colony forming cell (CFU-C) assay and in vivo using the NOD/Lt-scid/IL2Rγnull (NSG) mouse xenotransplant model. A 40-hour transduction protocol using a single vector exposure conferred a mean NSG repopulating cell transduction of 0.23 vector genomes/human genome with a mean myeloid vector copy number of 3.2 vector genomes/human genome. No adverse effects on engraftment were observed from vector treatment. Direct comparison between our SIN-lentiviral vector using a 40-hour protocol and an MFGγc γ-retroviral vector using a five-day protocol demonstrated equivalent NSG repopulating cell transduction efficiency. Clonality survey by linear amplification-mediated polymerase chain reaction (LAM-PCR) with Illumina sequencing revealed common clones in sorted myeloid and lymphoid populations from engrafted mice demonstrating multipotent cell transduction. These vector preparations will be used in two clinical trials for SCID-X1. PMID:23075105

  15. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity

    PubMed Central

    1991-01-01

    C.B-17 severe combined immune deficient (SCID) mice, which lack functional B and T lymphocytes, allow xenografts and, therefore, can be used to study the biology of human malignancies. Two different human B cell lymphoma cell lines, SU-DHL-4 and OCI-Ly8, which both harbor the t(14;18) chromosomal translocation, were injected into C.B-17 SCID mice. Mice injected intravenously or intraperitoneally developed tumors and died in a dose-dependent manner. The presence of tumor cells in various murine tissues could be demonstrated by a clonogenic tumor assay, staining of frozen sections with a monoclonal antibody (mAb) against a human B cell antigen (CD19), and with the polymerase chain reaction technique. A protocol using cytotoxic effector cells was developed and used to selectively deplete the tumor cells from bone marrow. These cells were developed by growing peripheral blood mononuclear cells in the presence of interferon gamma (IFN-gamma), anti- CD3 mAb, and interleukin 2 (IL-2). The timing of IFN-gamma treatment was critical and optimal if IFN-gamma was added before IL-2 treatment. The cells that were stimulated by IFN-gamma, followed by IL-2, could be expanded by treatment with a mAb directed against CD3. These cells could be further activated by IL-1, but not by tumor necrosis factor alpha. With this protocol, a tumor cell kill of 3 logs was obtained as measured by a clonogenic assay. Interestingly, despite their high cytotoxic activity against lymphoma cells, these cells had little toxicity against a subset of normal human hematopoietic precursor cells (granulocyte/macrophage colony-forming units). These cells were further tested by treating murine bone marrow contaminated with the human lymphoma cell line SU-DHL-4, and injecting these cells into SCID mice to assay for tumor growth in vivo. The animals injected with bone marrow contaminated with SU-DHL-4 cells had enhanced survival if the bone marrow was treated with the cytokine-induced killer cells before

  16. Arrested rearrangement of TCR V[beta] genes in thymocytes from children with x-linked severe combined immunodeficiency disease

    SciTech Connect

    Sleasman, J.W.; Harville, T.O.; White, G.B.; Barrett, D.J. ); George, J.F. ); Goodenow, M.M. Univ. of Alabama, Birmingham, AL )

    1994-07-01

    Human X-linked severe combined immunodeficiency disease (SCID) is an immunodeficiency disorder in which T cell development is arrested in the thymic cortex. B lymphocytes in children with X-linked SCID seem to differentiate normally. X-linked SCID is associated with a mutation in the gene that encodes the IL-2R [gamma]-chain. Because TCR-[beta] gene recombination is a pivotal initial event in T lymphocyte onteogeny within the thymus, the authors hypothesized that a failure to express normal IL-2R[gamma] could lead to impaired TCR-[beta] gene recombination in early thymic development. PCR was used to determine the status of TCR-[beta] gene-segment rearrangements in thymic DNA that had been obtained from children with X-linked SCID. The initial step in TCR-[beta] gene rearrangement, that of D[beta] to J[beta] recombination, was readily detected in all thymus samples from children with X-linked SCID; in contrast, V[beta] to DJ[beta] gene rearrangements were undetectable in the same samples. Both D[beta] to J[beta] and V[beta] to DJ[beta] TCR genes were rearranged in the thymic tissues obtained from immunologically normal children. The authors conclude that TCR[beta]-chain gene rearrangement is arrested in children with X-linked SCID. The results suggest a causative relationship between the failure of TCR [beta]-chain gene arrangements to proceed beyond DJ[beta] rearrangements and the production of a nonfunctional IL-2R [gamma]-chain. 45 refs., 3 figs.

  17. Islet-Specific CTL Cloned from a Type 1 Diabetes Patient Cause Beta-Cell Destruction after Engraftment into HLA-A2 Transgenic NOD/SCID/IL2RG Null Mice

    PubMed Central

    Unger, Wendy W. J.; Pearson, Todd; Abreu, Joana R. F.; Laban, Sandra; van der Slik, Arno R.; der Kracht, Sacha Mulder-van; Kester, Michel G. D.; Serreze, Dave V.; Shultz, Leonard D.; Griffioen, Marieke; Drijfhout, Jan Wouter

    2012-01-01

    Despite increasing evidence that autoreactive CD8 T-cells are involved in both the initiation of type 1 diabetes (T1D) and the destruction of beta-cells, direct evidence for their destructive role in-vivo is lacking. To address a destructive role for autoreactive CD8 T-cells in human disease, we assessed the pathogenicity of a CD8 T-cell clone derived from a T1D donor and specific for an HLA-A2-restricted epitope of islet-specific glucose-6-phosphatase catalytic-subunit related protein (IGRP). HLA-A2/IGRP tetramer staining revealed a higher frequency of IGRP-specific CD8 T-cells in the peripheral blood of recent onset human individuals than of healthy donors. IGRP265–273-specific CD8 T-cells that were cloned from the peripheral blood of a recent onset T1D individual were shown to secrete IFNγ and Granzyme B after antigen-specific activation and lyse HLA-A2-expressing murine islets in-vitro. Lytic capacity was also demonstrated in-vivo by specific killing of peptide-pulsed target cells. Using the HLA-A2 NOD-scid IL2rγnull mouse model, HLA-A2-restricted IGRP-specific CD8 T-cells induced a destructive insulitis. Together, this is the first evidence that human HLA-restricted autoreactive CD8 T-cells target HLA-expressing beta-cells in-vivo, demonstrating the translational value of humanized mice to study mechanisms of disease and therapeutic intervention strategies. PMID:23155466

  18. Homozygosity for a novel adenosine deaminase (ADA) nonsense mutation (Q3>X) in a child with severe combined immunodeficiency (SCID)

    SciTech Connect

    Santisteban, I.; Arrendondo-Vega, F.X.; Kelly, S. |

    1994-09-01

    A Somali girl was diagnosed with ADA-deficient SCID at 7 mo; she responded well to PEG-ADA replacement and is now 3.3 yr old. ADA mRNA was undetectable (Northern) in her cultured T cells, but was present in T cells of her parents and two sibs. All PCR-amplified exon 1 genomic clones from the patient had a C>T transition at bp 7 relative to the start of translation, replacing Gln at codon 3 (AGA) with a termination codon (TGA, Q3>X). Patient cDNA (prepared by RT-PCR with a 5{prime} primer that covered codons 1-7) had a previously described polymorphism, K80>R, but was otherwise normal, indicating that no other coding mutations were present. A predicted new genomic BfaI restriction site was used to establish her homozygosity for Q3>X and to analyze genotypes of family members. We also analyzed the segregation of a variable Alu polyA-associated TAAA repeat (AluVpA) situated 5{prime} of the ADA gene. Three different AluVpA alleles were found, one of which was only present in the father and was not associated with his Q3>X allele. Because the father`s RBCs had only {approximately}15% of normal ADA activity, we analyzed his ADA cDNA. We found a G>A transition at bp 425 that substitutes Gln for Arg142, a solvent-accessible residue, and eliminates a BsmAI site in exon 5. ADA activity of the R142>Q in vitro translation product was 20-25% of wild type ADA translation product, suggesting that R142>Q is a new {open_quote}partial{close_quote} ADA deficiency mutation. As expected, Q3>X mRNA did not yield a detectable in vitro translation product. We conclude that the patient`s father is a compound heterozygote carrying the ADA Q3>X/R142>Q genotype. {open_quote}Partial{close_quote} ADA deficiency unassociated with immunodeficiency is relatively common in individuals of African descent. The present findings and previous observations suggest that {open_quote}partial{close_quote} ADA deficiency may have had an evolutionary advantage.

  19. Severe Combined Immunodeficiency (SCID)

    MedlinePlus

    ... Patients Procedure for Accessing Lab Services Data Package Requirements AIDS Therapies Resource Guide In Vitro Efficacy Evaluations ... Assurances to Users Application and Approval Process User Requirements Malaria Vaccine Production Services Data Sharing and Release ...

  20. Reduced viral load and lack of CD4 depletion in SCID-hu mice infected with Rev-independent clones of human immunodeficiency virus type 1.

    PubMed Central

    Valentin, A; Aldrovandi, G; Zolotukhin, A S; Cole, S W; Zack, J A; Pavlakis, G N; Felber, B K

    1997-01-01

    The posttranscriptional control element CTE of the simian type D retrovirus has been shown to support replication of Rev-Rev-responsive-element (RRE)-deficient molecular clones of human immunodeficiency virus type 1 (HIV-1). Upon infection of peripheral blood mononuclear cells in vitro, these CTE-containing Rev-independent viruses that are nef+ or nef-minus showed lower replicative capacity and infectivity than the wild-type HIV-1. We studied the effects of Rev-RRE replacement by the CTE on HIV-1 expression with SCID-hu mice. The nef+ and nef-minus Rev-independent viruses established infection with kinetics slower than that of the nef-minus NL4-3. Most importantly, no depletion of CD4-bearing thymocytes was observed after 6 weeks for mice infected with these Rev-independent viruses. This is in contrast to the infection with both wild-type and nef-minus viruses, which led to varying depletion of thymocytes. These data suggest an attenuated phenotype for growth and cytotoxicity of the Rev-independent HIV-1 clones in SCID-hu mice, independent of the presence of Nef. The mutant viruses, which have the essential Rev-RRE regulatory system eliminated, display a distinct phenotype not previously observed with HIV mutant viruses having deletions of accessory genes. Therefore, replacement of the Rev-RRE regulatory axis may generate viruses with altered biological properties in vivo. PMID:9371653

  1. Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice

    PubMed Central

    Sarry, Jean-Emmanuel; Murphy, Kathleen; Perry, Robin; Sanchez, Patricia V.; Secreto, Anthony; Keefer, Cathy; Swider, Cezary R.; Strzelecki, Anne-Claire; Cavelier, Cindy; Récher, Christian; Mansat-De Mas, Véronique; Delabesse, Eric; Danet-Desnoyers, G.; Carroll, Martin

    2010-01-01

    Human leukemic stem cells, like other cancer stem cells, are hypothesized to be rare, capable of incomplete differentiation, and restricted to a phenotype associated with early hematopoietic progenitors or stem cells. However, recent work in other types of tumors has challenged the cancer stem cell model. Using a robust model of xenotransplantation based on NOD/SCID/IL2Rγc-deficient mice, we confirmed that human leukemic stem cells, functionally defined by us as SCID leukemia-initiating cells (SL-ICs), are rare in acute myelogenous leukemia (AML). In contrast to previous results, SL-ICs were found among cells expressing lineage markers (i.e., among Lin+ cells), CD38, or CD45RA, all markers associated with normal committed progenitors. Remarkably, each engrafting fraction consistently recapitulated the original phenotypic diversity of the primary AML specimen and contained self-renewing leukemic stem cells, as demonstrated by secondary transplants. While SL-ICs were enriched in the Lin–CD38– fraction compared with the other fractions analyzed, SL-ICs in this fraction represented only one-third of all SL-ICs present in the unfractionated specimen. These results indicate that human AML stem cells are rare and enriched but not restricted to the phenotype associated with normal primitive hematopoietic cells. These results suggest a plasticity of the cancer stem cell phenotype that we believe has not been previously described. PMID:21157036

  2. [Anti-mouse CD122 antibody promotes the hematopoietic repopulating capacity of cord blood CD34⁺ cells in NOD/SCID mice].

    PubMed

    Sheng, Men-Yao; Shi, Hui; Xing, Wen; Wang, Wen-Jun; Si, Xiao-Hui; Bai, Jie; Yuan, Wei-Ping; Zhou, Yuan; Yang, Feng-Chun

    2014-12-01

    The study was aimed to investigate the effect of anti-mouse CD122 antibody on the hematopoietic repopulating capacity of cord blood CD34⁺ cells in a humanized murine model-non obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. After sublethal irradiation with γ-ray, NOD/SCID mice were intraperitoneally injected with 200 µg mouse isotype control antibody or anti-mouse CD122 antibody. Human cord blood CD34⁺ cells or phosphate-buffered saline (PBS) were injected via the tail vein at 6-8 hours later. Cohort of the mice injected with anti-mice CD122 antibody or control antibody alone were sacrificed at different time point (at week 2, 3, and 4 weeks) after the injection, and the percentage of NK cells in the peripheral blood was analyzed by flow cytometry. To evaluate the effect of anti-mouse CD122 antibody on the repopulating capacity of cord blood CD34⁺ cells in the recipient mice, phenotype analysis was performed in the bone marrow at 6 and 8 weeks after the transplantation. The results showed that the proportion of NK cells in the peripheral blood were (4.6 ± 0.6)% and (5.7 ± 1.7)% at week 2 and 3 after anti-CD122 antibody injection respectively,which decreased by 60%, compared with the mice injected with isotype control antibody. After 6 and 8 weeks of cord blood CD34⁺ cell transplantation,the percentage of human CD45⁺ in the bone marrow of the recipient mice treated with anti-mice CD122 antibody was (63.0 ± 12.2)% and (53.2 ± 16.3)%,respectively,which were dramatically higher than that in the mice treated with isotype control antibody (7.7 ± 3.6)% and (6.1 ± 2.4)%. Moreover,at 8 weeks after transplantation,human CD34⁺ cells appeared significantly in the recipients treated with anti-CD122 antibody. It is concluded that the anti-mouse CD122 antibody enhances the hematopoietic repopulating capacity of cord blood CD34⁺ cells in the NOD/SCID mice through decreasing the proportion of NK cells.

  3. Absence of lactobacilli containing glycolipids with the α-galactose epitope and the enhanced fucosylation of a receptor glycolipid GA1 in the digestive tracts of immune-deficient scid mice.

    PubMed

    Iwamori, Masao; Tanaka, Kyoko; Adachi, Shigeki; Aoki, Daisuke; Nomura, Taisei

    2015-07-01

    The Lactobacillus species in the digestive tracts of immune-deficient scid mice was distinct from that in control mice, i.e. Lactobacillus murinus in scid and L. johnsonii in control mice, according to their 16S-rRNA, indicating that a symbiotic relationship between lactobacilli and a host is established under pressure from the immune system. The caecal and colonal contents rich in L. murinus of scid mice were loose with a strong sour smell, resulting in diarrhoea, and those with L. johnsonii in control mice included abundant solid materials. Lactobacillus glycolipids were revealed to be recognized by the immune system, and by TLC-immunostaining, LacTetH-DG (Galα1-6Galα1-6Galα1-2Glcα1-3'DG) of L. johnsonii was detected in the stomach, caecum and colon of control mice, but not in those of scid ones, in which fucosylation of a receptor GA1 for L. johnsonii was enhanced more than 4-fold compared with in the control mice. Thus, structural modification of receptor glycolipids was revealed to occur in the process of establishment of a symbiotic relationship between lactobacilli and a host. LacTetH-DG was also immunogenic to human, because of the presence of natural antibodies against it, and the antibody binding to it was comparable to that of blood group- and species-related glycosphingolipids.

  4. Use of standardized SCID-hu Thy/Liv mouse model for preclinical efficacy testing of anti-human immunodeficiency virus type 1 compounds.

    PubMed Central

    Rabin, L; Hincenbergs, M; Moreno, M B; Warren, S; Linquist, V; Datema, R; Charpiot, B; Seifert, J; Kaneshima, H; McCune, J M

    1996-01-01

    We have developed standardized procedures and practices for infection of SCID-hu Thy/Liv mice with human immunodeficiency virus type 1 for the prophylactic administration of antiviral compounds and for evaluation of the antiviral effect in vivo. Endpoint analyses included quantitation of viral load by intracellular p24 enzyme-linked immunosorbent assay, DNA PCR for the presence of proviral genomes, flow cytometry to measure the representation of CD4+ and CD8+ cells, and cocultivation for the isolation of virus. Efficacy tests in this model are demonstrated with the nucleoside analogs zidovudine and dideoxyinosine and with the nonnucleoside reverse transcriptase inhibitor nevirapine. This small-animal model should be particularly useful in the preclinical prioritization of lead compounds within a common chemical class, in the evaluation of alternative in vivo dosing regimens, and in the determination of appropriate combination therapy in vivo. PMID:8851606

  5. Use of standardized SCID-hu Thy/Liv mouse model for preclinical efficacy testing of anti-human immunodeficiency virus type 1 compounds.

    PubMed

    Rabin, L; Hincenbergs, M; Moreno, M B; Warren, S; Linquist, V; Datema, R; Charpiot, B; Seifert, J; Kaneshima, H; McCune, J M

    1996-03-01

    We have developed standardized procedures and practices for infection of SCID-hu Thy/Liv mice with human immunodeficiency virus type 1 for the prophylactic administration of antiviral compounds and for evaluation of the antiviral effect in vivo. Endpoint analyses included quantitation of viral load by intracellular p24 enzyme-linked immunosorbent assay, DNA PCR for the presence of proviral genomes, flow cytometry to measure the representation of CD4+ and CD8+ cells, and cocultivation for the isolation of virus. Efficacy tests in this model are demonstrated with the nucleoside analogs zidovudine and dideoxyinosine and with the nonnucleoside reverse transcriptase inhibitor nevirapine. This small-animal model should be particularly useful in the preclinical prioritization of lead compounds within a common chemical class, in the evaluation of alternative in vivo dosing regimens, and in the determination of appropriate combination therapy in vivo.

  6. In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells.

    PubMed

    Awad, A B; Fink, C S; Williams, H; Kim, U

    2001-12-01

    The dietary effect of phytosterols (PS) versus cholesterol on the growth and metastasis of the PC-3 human prostate cancer cells in SCID mice was studied. Also, their direct effect on the growth and migration of these cells in vitro was analysed. In the in vivo experiment, SCID mice were fed a diet containing 2% of either PS mixture or cholesterol plus 0.2% cholic acid and implanted with 2 x 10(6) tumour cells per mouse. Tumour growth was monitored for 8 weeks post inoculation. Animals fed the PS diet had tumours 40-43% smaller than those fed the cholesterol diet. Furthermore, the number of mice with lymph node and lung metastasis was almost one-half that of the cholesterol-fed group. In the in vitro studies, both beta-sitosterol and campesterol inhibited the growth of PC-3 cells by 70% and 14%, respectively, while cholesterol supplementation increased the growth by 18% when compared with controls. PS inhibited the invasion of PC-3 cells into Matrigel-coated membranes by 78% while cholesterol increased it by 43% as compared with the cells in the control media. Migration of tumour cells through 8 microm pore membranes was reduced by 60-93% when the PC-3 cells were in PS media, as compared with a 67% increase after cholesterol supplementation. PS supplementation reduced the binding of PC-3 cells to laminin by 15-38% and fibronectin by 23% while cholesterol increased binding to type IV collagen by 36%. It was concluded that PS indirectly (in vivo as a dietary supplement) and directly (in tissue culture media) inhibited the growth and metastasis of PC-3 cells. beta-Sitosterol was more effective than campesterol in offering this protection in most of the parameters studied.

  7. Methods of inducing inflammatory bowel disease in mice.

    PubMed

    Maxwell, Joseph R; Brown, William A; Smith, Carole L; Byrne, Fergus R; Viney, Joanne L

    2009-12-01

    Animal models of experimentally induced inflammatory bowel disease (IBD) are useful for understanding more about the mechanistic basis of disease, identifying new targets for therapeutic intervention, and testing novel therapeutic agents. This unit provides detailed protocols for four of the most commonly used mouse models of experimentally induced intestinal inflammation: chemical induction of colitis by dextran sodium sulfate (DSS), hapten-induced colitis via 2,4,6-trinitrobenzene sulfonic acid (TNBS), Helicobacter-induced colitis in mdr1a(-/-) mice, and the CD4(+) CD45RB(hi) SCID transfer colitis model.

  8. Targeting interleukin-13 with tralokinumab attenuates lung fibrosis and epithelial damage in a humanized SCID idiopathic pulmonary fibrosis model.

    PubMed

    Murray, Lynne A; Zhang, Huilan; Oak, Sameer R; Coelho, Ana Lucia; Herath, Athula; Flaherty, Kevin R; Lee, Joyce; Bell, Matt; Knight, Darryl A; Martinez, Fernando J; Sleeman, Matthew A; Herzog, Erica L; Hogaboam, Cory M

    2014-05-01

    The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung.

  9. Recent advances in transplantation for primary immune deficiency diseases: a comprehensive review.

    PubMed

    de la Morena, M Teresa; Nelson, Robert P

    2014-04-01

    Hematopoietic cell transplantation (HCT) is a curative therapeutic option for severe combined immunodeficiency (SCID), a group of diseases which otherwise carry life expectancies that are of limited duration and quality. Survival following HCT for SCID has improved from approximately 23 to 91 % over the last 40 years. Success with SCID prompted efforts to apply HCT to the therapeutic challenge of well over 20 molecularly defined primary immune deficiency diseases (PID). Such success is due to both early recognition of PIDs and advances in the field of transplantation. Such advances include high-resolution HLA DNA donor-recipient matching, expansion of donor sources, better tolerated conditioning, new antibiotics, and wider availability. International collaborative efforts have provided patients and caregivers information that permit better treatment decisions now, and direct clinicians and investigators to ensure progress in the future. Pioneers in screening for SCID have taken steps to correct the fundamental challenge to successful treatment, which is the rapid discovery and characterization of cases and offering the transplant option to an affected child early in life; blood spot testing for T and B cell receptor quantification is now available to a growing fraction of newborns. Organizations including the Primary Immune Deficiency Treatment Consortium in the USA, The European Society for Primary Immunodeficiency, the European Group for Blood and Marrow Transplantation, the Pediatric Blood and Marrow Transplant Consortium, the United States Immunodeficiency Network, the Immune Deficiency Foundation, and the Jeffrey Modell Foundation are contributing mightily to increase awareness and standardize optimal utilization to the benefit of patients. This review will update the allergist-immunologist concerning disease presentations, indications for transplantation, methodologies, conditioning regimens, and clinical outcomes for patients with PID for which timely HCT is

  10. Successful short-term ex vivo expansion of NOD/SCID repopulating ability and CAFC week 6 from umbilical cord blood.

    PubMed

    Kusadasi, N; van Soest, P L; Mayen, A E; Koevoet, J L; Ploemacher, R E

    2000-11-01

    In view of the limited potential for rapid hematological recovery after transplantation of umbilical cord blood cells (UCB) in adults, we have attempted to expand CD34+ selected hemopoietic stem cells (HSC) and progenitors in 2-week cultures of whole graft pools in the presence or absence of serum and stromal layers, and with various cytokine combinations including (1) FL + TPO; (2) FL + TPO plus SCF and/or IL6; or (3) SCF + IL6. Both in the input material and cultured grafts we determined the number of colony-forming cells (CFC), cobblestone area forming cells (CAFC), the NOD/SCID repopulating ability (SRA), and CD34+ CD38- subset by phenotyping. The highest fold-increase obtained for the number of nucleated cells (nc), CD34+, CD34+ CD38 cell numbers and CFC content was, respectively, 102 +/- 76, 24 +/- 19, 190 +/- 202 and 53 +/- 37 for stroma-free and 315 +/- 110, 25 +/- 3, 346 +/- 410 and 53 +/- 43 for stroma-supported cultures. CAFC week type 6 was maximally 11-fold expanded both under stroma-free and stroma-supported conditions. The FBMD-1 stromal cells supported a modest expansion of CD34+ CD38- cells (27 +/- 18-fold) and nc (6 +/- 4-fold), while a loss of CFC and CAFC subsets was observed. The stromal cells synergized with FL + TPO to give the highest expansion of hemopoietic progenitors. Stromal support could be fully replaced by complementing the FL + TPO stimulated cultures with SCF + IL6. FL + TPO were required and sufficient to give a 10- to 20-fold expansion of the ability of CD34+ UCB cells in 2-week cultures to engraft the BM of NOD/SCID mice. Stromal support, or complementation of the medium with SCF + IL6, did not significantly improve the in vivo engraftment potential. If the SRA and CAFC week 6 assays are accepted as tentative estimates of in vivo engrafting stem cells in humans, our findings may assist in the preparation of UCB grafts to meet the requirements for improved repopulation in the clinical setting. PMID:11069030

  11. Constitutive secretion of soluble interleukin-2 receptor by human T cell lymphoma xenografted into SCID mice. Correlation of tumor volume with concentration of tumor-derived soluble interleukin-2 receptor in body fluids of the host mice.

    PubMed Central

    Wasik, M. A.; Sioutos, N.; Tuttle, M.; Butmarc, J. R.; Kaplan, W. D.; Kadin, M. E.

    1994-01-01

    Increased serum concentration of soluble alpha-chain receptor for interleukin-2 (sIL-2R) has been noted in patients with a variety of inflammatory conditions and lymphoid malignancies including T cell leukemia and lymphoma. Elevated sIL-2R serum levels seen in lymphoid malignancies appear to correlate with the clinical stage of disease. However, because sIL-2R is produced by normal activated lymphocytes, it has been uncertain whether serum sIL-2R in such conditions is derived from tumor cells or normal immune cells responding to the tumor. To address this question, we used a model of human (CD30+) anaplastic, large T cell lymphoma transplanted into immunodeficient SCID mice. Reverse transcription polymerase chain reaction of tumor RNA showed that the tumor, designated mJB6, contains mRNA for alpha-chain of human IL-2R. Furthermore, 15 to 25% of tumor cells stained with anti-human IL-2R alpha-chain mAb. Solid phase ELISA analysis of serum samples from mice bearing mJB6 lymphoma showed high concentrations of human sIL-2R. None of the control mice without lymphoma or with human nonlymphoid tumors (prostatic carcinoma, ovarian carcinoma, and glioblastoma multiforme) showed detectable human sIL-2R. The sIL-2R serum titers of mJB6-bearing mice correlated strongly with tumor volume (P < 0.0001). Tumors as small as 0.4 to 0.8 mm3 could be detected by this method. The sensitivity of sIL-2R ELISA exceeded at least 150 times the sensitivity of conventional radioisotopic tumor detection. Total resection of mJB6 tumors resulted in complete clearance of sIL-2R from the murine serum within 48 hours with a half-life of 6 hours. Accordingly, partial resection led to a significant decrease in sIL-2R followed by gradual increase with tumor regrowth. sIL-2R was also detected in the urine of mJB6-transplanted mice. As in serum, urine concentrations of sIL-2R were proportional to tumor mass (P < 0.02). Based on these findings we postulate that malignant cells are a major source of serum

  12. Pathogens in children with severe combined immune deficiency disease or AIDS.

    PubMed Central

    Lauzon, D; Delage, G; Brochu, P; Michaud, J; Jasmin, G; Joncas, J H; Lapointe, N

    1986-01-01

    We evaluated the frequency and severity of illnesses caused by various microbial pathogens in 15 children with severe combined immune deficiency disease (SCID) and 8 with acquired immune deficiency syndrome (AIDS). There were 35 viral, 23 bacterial, 19 mycotic and 13 parasitic infections. Nineteen of the 23 patients died of infection; Pneumocystis carinii pneumonia, giant-cell pneumonia due to paramyxoviruses and various disseminated viral infections were responsible for most deaths in both groups. The emerging role of paramyxoviruses was illustrated by the fact that they were responsible for giant-cell pneumonia in seven patients. Viral enteric infections were frequent in both groups. The variety of infectious microorganisms and the severity of resulting illnesses in the patients with AIDS were similar to those in the patients with SCID. Images Fig. 1 PMID:3719484

  13. Histopathological characteristics of human non-tumor thyroid tissues in a long-term model of adenomatous goiter xenografts in the NOD/Shi-scid, IL-2Rγ(null) mouse.

    PubMed

    Fujii, Etsuko; Kato, Atsuhiko; Chen, Yu Jau; Matsubara, Koichi; Ohnishi, Yasuyuki; Suzuki, Masami

    2014-07-01

    There is a growing need for modeling the human thyroid to link data obtained from animals to humans because of its sensitivity to radiation exposure and endocrine disruption chemicals. In a scid mouse model produced by transplanting human thyroid tissues, leakiness and thymic lymphoma that occurs spontaneously in the scid mouse can complicate the interpretation of experimental results. Considering that the NOD.Cg-Prkdc(scid)Il2rg(tm1Sug)/Jic mouse (NOD/Shi-scid, IL-2Rγ(null) or NOG mouse) may be a better host because this strain has low incidence of leakiness and thymic lymphoma, we have evaluated the potential of a model that allows long-term observation of non-tumor human thyroid tissues in this mouse. We transplanted tissues of human adenomatous goiter into NOG mice and examined the tissues histopathologically. The morphology of human adenomatous goiter tissues was maintained from 24 to 44 weeks after transplantation in NOG mice with no noted differences between donor-matched tissues or the weeks after transplantation. The tissues expressed thyroglobulin protein and mRNA as well as thyroperoxidase. Endothelial cells originating from human were found in the transplanted tissues and were thought to be a characteristic of this model. The intactness of the tissues before transplantation was found to affect the rate of tissue engraftment. From the present results we have concluded that transplanted thyroid tissues in NOG mice maintain the histopathological characteristics of their origin for long terms. Therefore this model was thought feasible for toxicity evaluation.

  14. A cell surface marker gene transferred with a retroviral vector into CD34+ cord blood cells is expressed by their T-cell progeny in the SCID-hu thymus.

    PubMed

    Champseix, C; Maréchal, V; Khazaal, I; Schwartz, O; Fournier, S; Schlegel, N; Dranoff, G; Danos, O; Blot, P; Vilmer, E; Heard, J M; Péault, B; Lehn, P

    1996-07-01

    Gene transduction into immature hematopoietic cells collected at birth from the umbilical cord could be useful for the treatment of genetic or acquired disorders of the hematopoietic system diagnosed during pregnancy. The SCID-hu mouse is a convenient model to investigate T-cell lineage gene therapy, since it allows replication of human intrathymic T-cell development. CD34+ cells isolated from cord blood were cocultured with CRIP MFG-murine CD2 (mCD2) cells that produce recombinant retroviruses encoding the mCD2 antigen, a cell surface marker easily detectable by flow cytometry. After 3 and 4 days in coculture, a mean of 19% and 39% human hematopoietic cells, respectively, expressed the mCD2 antigen. CD34+ cells cocultured for 4 days were used to reconstitute human fetal thymus implanted in SCID mice. Five to 10 weeks later, the mCD2 antigen was detected on approximately 10% of human thymocytes repopulating the thymic grafts in four of nine SCID mouse chimeras. Vector genomes were detected in graft cell DNA by Southern blot. Analysis of vector integration indicated that positive cells were of polyclonal origin in three animals and predominantly monoclonal in the other one. Our data show that foreign genes can be transduced into CD34+ cord blood cells endowed with T-cell differentiation potential, and suggest strategies for T-cell lineage gene therapy in the neonate.

  15. Dynamics of gene-modified progenitor cells analyzed by tracking retroviral integration sites in a human SCID-X1 gene therapy trial.

    PubMed

    Wang, Gary P; Berry, Charles C; Malani, Nirav; Leboulch, Philippe; Fischer, Alain; Hacein-Bey-Abina, Salima; Cavazzana-Calvo, Marina; Bushman, Frederic D

    2010-06-01

    X-linked severe-combined immunodeficiency (SCID-X1) has been treated by therapeutic gene transfer using gammaretroviral vectors, but insertional activation of proto-oncogenes contributed to leukemia in some patients. Here we report a longitudinal study of gene-corrected progenitor cell populations from 8 patients using 454 pyrosequencing to map vector integration sites, and extensive resampling to allow quantification of clonal abundance. The number of transduced cells infused into patients initially predicted the subsequent diversity of circulating cells. A capture-recapture analysis was used to estimate the size of the gene-corrected cell pool, revealing that less than 1/100th of the infused cells had long-term repopulating activity. Integration sites were clustered even at early time points, often near genes involved in growth control, and several patients harbored expanded cell clones with vectors integrated near the cancer-implicated genes CCND2 and HMGA2, but remain healthy. Integration site tracking also documented that chemotherapy for adverse events resulted in successful control. The longitudinal analysis emphasizes that key features of transduced cell populations--including diversity, integration site clustering, and expansion of some clones--were established early after transplantation. The approaches to sequencing and bioinformatics analysis reported here should be widely useful in assessing the outcome of gene therapy trials.

  16. Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome

    PubMed Central

    Rucci, Francesca; Notarangelo, Luigi D.; Fazeli, Alex; Patrizi, Laura; Hickernell, Thomas; Paganini, Tiziana; Coakley, Kristen M.; Detre, Cynthia; Keszei, Marton; Walter, Jolan E.; Feldman, Lauren; Cheng, Hwei-Ling; Poliani, Pietro Luigi; Wang, Jing H.; Balter, Barbara B.; Recher, Mike; Andersson, Emma-Maria; Zha, Shan; Giliani, Silvia; Terhorst, Cox; Alt, Frederick W.; Yan, Catherine T.

    2010-01-01

    DNA ligase IV (LIG4) is an essential component of the nonhomologous end-joining (NHEJ) repair pathway and plays a key role in V(D)J recombination. Hypomorphic LIG4 mutations in humans are associated with increased cellular radiosensitivity, microcephaly, facial dysmorphisms, growth retardation, developmental delay, and a variable degree of immunodeficiency. We have generated a knock-in mouse model with a homozygous Lig4 R278H mutation that corresponds to the first LIG4 mutation reported in humans. The phenotype of homozygous mutant mice Lig4R278H/R278H (Lig4R/R) includes growth retardation, a decreased life span, a severe cellular sensitivity to ionizing radiation, and a very severe, but incomplete block in T and B cell development. Peripheral T lymphocytes show an activated and anergic phenotype, reduced viability, and a restricted repertoire, reminiscent of human leaky SCID. Genomic instability is associated with a high rate of thymic tumor development. Finally, Lig4R/R mice spontaneously produce low-affinity antibodies that include autoreactive specificities, but are unable to mount high-affinity antibody responses. These findings highlight the importance of LIG4 in lymphocyte development and function, and in genomic stability maintenance, and provide a model for the complex phenotype of LIG4 syndrome in humans. PMID:20133615

  17. Transplantation of human spleen into immunodeficient NOD/SCID IL2Rγ(null) mice generates humanized mice that improve functional B cell development.

    PubMed

    Chung, Yun Shin; Son, Jin Kyung; Choi, Bongkum; Park, Jae Berm; Chang, Jun; Kim, Sung Joo

    2015-12-01

    We previously generated humanized TB34N mice that received human fetal thymus (T), bone tissue (B) and fetal liver-derived (FL)-CD34(+) cells (34) in immunodeficient, NOD/SCID IL2Rγ(null) (N) mice. Although humanized TB34N mice had excellent hematopoiesis, here, we sought to further improve this model by additional transplantation of human spleen tissue (S) as a secondary hematopoietic tissue (TBS34N). The human spleen grafts were enlarged and differentiated into a similar morphology of adult humans, including follicular lymphoid structures with T- and B-cells. The TBS34N mice mimicked mature human immune system (HIS): mature T- and B-cells and follicular dendritic cells; activated germinal center B-cells expressing CD71, BR3(+) cells, memory B-cells and activation-induced cytidine deaminase(+) B-cells; CD138(+) plasma cells were enriched in the mouse spleen. HBsAg-specific hIgG antibodies were secreted into the sera of all TBS34N mice upon immunization with HBsAg. Taken together, the humanized TBS34N mice improved mature HIS and achieved adaptive antibody responses. PMID:26360254

  18. Transplantation of human spleen into immunodeficient NOD/SCID IL2Rγ(null) mice generates humanized mice that improve functional B cell development.

    PubMed

    Chung, Yun Shin; Son, Jin Kyung; Choi, Bongkum; Park, Jae Berm; Chang, Jun; Kim, Sung Joo

    2015-12-01

    We previously generated humanized TB34N mice that received human fetal thymus (T), bone tissue (B) and fetal liver-derived (FL)-CD34(+) cells (34) in immunodeficient, NOD/SCID IL2Rγ(null) (N) mice. Although humanized TB34N mice had excellent hematopoiesis, here, we sought to further improve this model by additional transplantation of human spleen tissue (S) as a secondary hematopoietic tissue (TBS34N). The human spleen grafts were enlarged and differentiated into a similar morphology of adult humans, including follicular lymphoid structures with T- and B-cells. The TBS34N mice mimicked mature human immune system (HIS): mature T- and B-cells and follicular dendritic cells; activated germinal center B-cells expressing CD71, BR3(+) cells, memory B-cells and activation-induced cytidine deaminase(+) B-cells; CD138(+) plasma cells were enriched in the mouse spleen. HBsAg-specific hIgG antibodies were secreted into the sera of all TBS34N mice upon immunization with HBsAg. Taken together, the humanized TBS34N mice improved mature HIS and achieved adaptive antibody responses.

  19. Cochlear repair by transplantation of human cord blood CD133+ cells to nod-scid mice made deaf with kanamycin and noise.

    PubMed

    Revoltella, Roberto P; Papini, Sandra; Rosellini, Alfredo; Michelini, Monica; Franceschini, Valeria; Ciorba, Andrea; Bertolaso, Lucia; Magosso, Sara; Hatzopoulos, Stavros; Lorito, Guiscardo; Giordano, Pietro; Simoni, Edi; Ognio, Emanuela; Cilli, Michele; Saccardi, Riccardo; Urbani, Serena; Jeffery, Rosemary; Poulsom, Richard; Martini, Alessandro

    2008-01-01

    We investigated the fate of human cord blood CD133+ hematopoietic stem cells (HSC) transplanted intravenously (IV) into irradiated nod-scid mice previously made deaf by ototoxic treatment with kanamycin and/ or intense noise, to verify whether HSC engraft the cochlea and contribute to inner ear restoration, in vivo. We tested the presence of HLA.DQalpha1 by PCR, used for traceability of engrafted cells, finding evidence that HSC migrated to various host tissues, including the organ of Corti (OC). By histology, antibody and lectin-staining analysis, we confirmed that HSC IV transplantation in mice previously damaged by ototoxic agents correlated with the repair process and stimulation ex novo of morphological recovery in the inner ear, while the cochlea of control oto-injured, nontransplanted mice remained seriously damaged. Dual color FISH analysis also provided evidence of positive engraftment in the inner ear and in various mouse tissues, also revealing small numbers of heterokaryons, probably derived from fusion of donor with endogenous cells, for up to 2 months following transplantation. These observations offer the first evidence that transplanted human HSC migrating to the inner ear of oto-injured mice may provide conditions for the resumption of deafened cochlea, emerging as a potential strategy for inner ear rehabilitation. PMID:18819255

  20. WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus–truncated CXCR4

    PubMed Central

    Kawai, Toshinao; Choi, Uimook; Cardwell, Lanise; DeRavin, Suk See; Naumann, Nora; Whiting-Theobald, Narda L.; Linton, Gilda F.; Moon, Jaehyun; Murphy, Philip M.; Malech, Harry L.

    2007-01-01

    WHIM(warts, hypogammaglobulinemia, recurrent bacterial infection, and myelokathexis) syndrome is a rare immunodeficiency caused in many cases by autosomal dominant C-terminal truncation mutations in the chemokine receptor CXCR4. A prominent and unexplained feature of WHIM is myelokathexis (hypercellularity with apoptosis of mature myeloid cells in bone marrow and neutropenia). We transduced healthy human CD34+ peripheral blood–mobilized stem cells (PBSCs) with retrovirus vector encoding wild-type (wt) CXCR4 or WHIM-type mutated CXCR4 and studied these cells ex vivo in culture and after engraftment in a nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenograft model. Neither wt CXCR4 nor mutated CXCR4 transgene expression itself enhanced apoptosis of neutrophils arising in transduced PBSC cultures even with stimulation by a CXCR4 agonist, stromal cell–derived factor-1 (SDF-1 [CXCL12]). Excess wt CXCR4 expression by transduced human PBSCs enhanced marrow engraftment, but did not affect bone marrow (BM) apoptosis or the release of transduced leukocytes into PB. However, mutated CXCR4 transgene expression further enhanced BM engraftment, but was associated with a significant increase in apoptosis of transduced cells in BM and reduced release of transduced leukocytes into PB. We conclude that increased apoptosis of mature myeloid cells in WHIM is secondary to a failure of marrow release and progression to normal myeloid cell senescence, and not a direct effect of activation of mutated CXCR4. PMID:16946301

  1. HAdV-2-suppressed growth of SV40 T antigen-transformed mouse mammary epithelial cell-induced tumours in SCID mice.

    PubMed

    Wu, Chengjun; Cao, Xiaofang; Yu, Di; Huijbers, Elisabeth J M; Essand, Magnus; Akusjärvi, Göran; Johansson, Staffan; Svensson, Catharina

    2016-02-01

    Human adenovirus (HAdV) vectors are promising tools for cancer therapy, but the shortage of efficient animal models for productive HAdV infections has restricted the evaluation of systemic effects to mainly immunodeficient mice. Previously, we reported a highly efficient replication of HAdV-2 in a non-tumorigenic mouse mammary epithelial cell line, NMuMG. Here we show that HAdV-2 gene expression and progeny formation in NMuMG cells transformed with the SV40 T antigen (NMuMG-T cells) were as efficient as in the parental NMuMG cells. Injection of HAdV-2 into tumours established by NMuMG-T in SCID mice caused reduced tumour growth and signs of intratumoural lesions. HAdV-2 replicated within the NMuMG-T-established tumours, but not in interspersed host-derived tissues within the tumours. The specific infection of NMuMG-T-derived tumours was verified by the lack of viral DNA in kidney, lung or spleen although low levels of viral DNA was occasionally found in liver.

  2. HAdV-2-suppressed growth of SV40 T antigen-transformed mouse mammary epithelial cell-induced tumours in SCID mice.

    PubMed

    Wu, Chengjun; Cao, Xiaofang; Yu, Di; Huijbers, Elisabeth J M; Essand, Magnus; Akusjärvi, Göran; Johansson, Staffan; Svensson, Catharina

    2016-02-01

    Human adenovirus (HAdV) vectors are promising tools for cancer therapy, but the shortage of efficient animal models for productive HAdV infections has restricted the evaluation of systemic effects to mainly immunodeficient mice. Previously, we reported a highly efficient replication of HAdV-2 in a non-tumorigenic mouse mammary epithelial cell line, NMuMG. Here we show that HAdV-2 gene expression and progeny formation in NMuMG cells transformed with the SV40 T antigen (NMuMG-T cells) were as efficient as in the parental NMuMG cells. Injection of HAdV-2 into tumours established by NMuMG-T in SCID mice caused reduced tumour growth and signs of intratumoural lesions. HAdV-2 replicated within the NMuMG-T-established tumours, but not in interspersed host-derived tissues within the tumours. The specific infection of NMuMG-T-derived tumours was verified by the lack of viral DNA in kidney, lung or spleen although low levels of viral DNA was occasionally found in liver. PMID:26707269

  3. Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

    PubMed Central

    Zhang, Xianyang; Cui, Tengjiao; He, Jinlin; Wang, Haibo; Cai, Renzhi; Popovics, Petra; Vidaurre, Irving; Sha, Wei; Schmid, Janine; Ludwig, Barbara; Block, Norman L.; Bornstein, Stefan R.; Schally, Andrew V.

    2015-01-01

    Agonists of growth hormone-releasing hormone (GHRH) have been previously reported to promote growth, function, and engraftment of islet cells following transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular insulin, insulin-like growth factor-1 (IGF1), and GHRH receptor, and also stimulated insulin secretion in response to glucose challenge. Exposure of INS-1 cells to GHRH agonists, MR-356 and MR-409, induced activation of ERK and AKT pathways. Agonist MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist, MR-409 significantly increased cell proliferation, islet size, and the expression of insulin. In vivo daily s.c. administration of 10 μg MR-409 for 3 wk dramatically reduced the severity of streptozotocin (STZ)-induced diabetes in nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in body weight, response to high glucose challenge, and induction of higher levels of serum insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist, MR-409, and received additional treatment with MR-409 posttransplantation. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus. PMID:26474831

  4. Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice.

    PubMed

    Zhang, Xianyang; Cui, Tengjiao; He, Jinlin; Wang, Haibo; Cai, Renzhi; Popovics, Petra; Vidaurre, Irving; Sha, Wei; Schmid, Janine; Ludwig, Barbara; Block, Norman L; Bornstein, Stefan R; Schally, Andrew V

    2015-11-01

    Agonists of growth hormone-releasing hormone (GHRH) have been previously reported to promote growth, function, and engraftment of islet cells following transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular insulin, insulin-like growth factor-1 (IGF1), and GHRH receptor, and also stimulated insulin secretion in response to glucose challenge. Exposure of INS-1 cells to GHRH agonists, MR-356 and MR-409, induced activation of ERK and AKT pathways. Agonist MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist, MR-409 significantly increased cell proliferation, islet size, and the expression of insulin. In vivo daily s.c. administration of 10 μg MR-409 for 3 wk dramatically reduced the severity of streptozotocin (STZ)-induced diabetes in nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in body weight, response to high glucose challenge, and induction of higher levels of serum insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist, MR-409, and received additional treatment with MR-409 posttransplantation. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus. PMID:26474831

  5. Kaposi's sarcoma-associated herpesvirus-positive primary effusion lymphoma tumor formation in NOD/SCID mice is inhibited by neomycin and neamine blocking angiogenin's nuclear translocation.

    PubMed

    Bottero, Virginie; Sadagopan, Sathish; Johnson, Karen E; Dutta, Sujoy; Veettil, Mohanan Valiya; Chandran, Bala

    2013-11-01

    Angiogenin (ANG) is a 14-kDa multifunctional proangiogenic secreted protein whose expression level correlates with the aggressiveness of several tumors. We observed increased ANG expression and secretion in endothelial cells during de novo infection with Kaposi's sarcoma-associated herpesvirus (KSHV), in cells expressing only latency-associated nuclear antigen 1 (LANA-1) protein, and in KSHV latently infected primary effusion lymphoma (PEL) BCBL-1 and BC-3 cells. Inhibition of phospholipase Cγ (PLCγ) mediated ANG's nuclear translocation by neomycin, an aminoglycoside antibiotic (not G418-neomicin), resulted in reduced KSHV latent gene expression, increased lytic gene expression, and increased cell death of KSHV(+) PEL and endothelial cells. ANG detection in significant levels in KS and PEL lesions highlights its importance in KSHV pathogenesis. To assess the in vivo antitumor activity of neomycin and neamine (a nontoxic derivative of neomycin), BCBL-1 cells were injected intraperitoneally into NOD/SCID mice. We observed significant extended survival of mice treated with neomycin or neamine. Markers of lymphoma establishment, such as increases in animal body weight, spleen size, tumor cell spleen infiltration, and ascites volume, were observed in nontreated animals and were significantly diminished by neomycin or neamine treatments. A significant decrease in LANA-1 expression, an increase in lytic gene expression, and an increase in cleaved caspase-3 were also observed in neomycin- or neamine-treated animal ascitic cells. These studies demonstrated that ANG played an essential role in KSHV latency maintenance and BCBL-1 cell survival in vivo, and targeting ANG function by neomycin/neamine to induce the apoptosis of cells latently infected with KSHV is an attractive therapeutic strategy against KSHV-associated malignancies.

  6. Humanizing NOD/SCID/IL-2Rγnull (NSG) mice using busulfan and retro-orbital injection of umbilical cord blood-derived CD34+ cells

    PubMed Central

    Kang, Young Kyung; Ko, Yunmi; Choi, Aery; Choi, Hyeong Jwa; Seo, Jin-Hee; Lee, Minyoung

    2016-01-01

    Background Humanized mouse models are still under development, and various protocols exist to improve human cell engraftment and function. Methods Fourteen NOD/SCID/IL-2Rγnull (NSG) mice (4‒5 wk old) were conditioned with busulfan and injected with human umbilical cord blood (hUCB)-derived CD34+ hematopoietic stem cells (HSC) via retro-orbital sinuses. The bone marrow (BM), spleen, and peripheral blood (PB) were analyzed 8 and 12 weeks after HSC transplantation. Results Most of the NSG mice tolerated the regimen well. The percentage of hCD45+ and CD19+ cells rose significantly in a time-dependent manner. The median percentage of hCD45+cells in the BM was 55.5% at week 8, and 67.2% at week 12. The median percentage of hCD45+ cells in the spleen at weeks 8 and 12 was 42% and 51%, respectively. The median percentage of hCD19+ cells in BM at weeks 8 and 12 was 21.5% and 39%, respectively (P=0.04). Similarly, the median percentage of hCD19+ cells in the spleen at weeks 8 and 12 was 10% and 24%, respectively (P=0.04). The percentage of hCD19+ B cells in PB was 23% at week 12. At week 8, hCD3+ T cells were barely detectable, while hCD7+ was detected in the BM and spleen. The percentage of hCD3+ T cells was 2‒3% at week 12 in the BM, spleen, and PB of humanized NSG mice. Conclusion We adopted a simplified protocol for establishing humanized NSG mice. We observed a higher engraftment rate of human CD45+ cells than earlier studies without any significant toxicity. And human CD45+ cell engraftment at week 8 was comparable to that of week 12. PMID:27104189

  7. Induction of WT1-specific human CD8+ T cells from human HSCs in HLA class I Tg NOD/SCID/IL2rgKO mice.

    PubMed

    Najima, Yuho; Tomizawa-Murasawa, Mariko; Saito, Yoriko; Watanabe, Takashi; Ono, Rintaro; Ochi, Toshiki; Suzuki, Nahoko; Fujiwara, Hiroshi; Ohara, Osamu; Shultz, Leonard D; Yasukawa, Masaki; Ishikawa, Fumihiko

    2016-02-11

    Induction of specific immune response against therapy-resistant tumor cells can potentially improve clinical outcomes in malignancies. To optimize immunotherapy in the clinic, we aimed to create an in vivo model enabling us to analyze human cytotoxic T-lymphocyte (CTL) responses against human malignancies. To this end, we developed NOD/SCID/IL2rgKO (NSG) mice expressing the HLA class I molecules HLA-A*0201 and A*2402. In the bone marrow (BM) and spleen of HLA class I transgenic (Tg) NSG mice transplanted with cord blood hematopoietic stem cells (HSCs), we found human memory CD8(+) T cells and antigen-presenting cells. To evaluate antigen-specific human CTL responses, we immunized HLA class I Tg NSG mice using polyinosinic:polycytidylic acid mixed Wilms tumor 1 (WT1) peptides, with or without WT1 peptide-loaded autologous dendritic cells. After immunization, the frequencies of HLA-restricted WT1-specific CTLs increased significantly in the spleen. Next, we transplanted the WT1-specific T-cell receptor (WT1-TCR) gene-transduced human HSCs into HLA class I Tg NSG newborn mice. WT1 tetramer-positive CD8(+) T cells differentiated from WT1-TCR-transduced HSCs in the recipients' BM, spleen, and thymus. Upon stimulation with WT1 peptide in vitro, these CTLs produced interferon-γ and showed lytic activity against leukemia cells in an antigen-specific, HLA-restricted manner. HLA class I Tg NSG xenografts may serve as a preclinical model to develop effective immunotherapy against human malignancies.

  8. Induction of WT1-specific human CD8+ T cells from human HSCs in HLA class I Tg NOD/SCID/IL2rgKO mice.

    PubMed

    Najima, Yuho; Tomizawa-Murasawa, Mariko; Saito, Yoriko; Watanabe, Takashi; Ono, Rintaro; Ochi, Toshiki; Suzuki, Nahoko; Fujiwara, Hiroshi; Ohara, Osamu; Shultz, Leonard D; Yasukawa, Masaki; Ishikawa, Fumihiko

    2016-02-11

    Induction of specific immune response against therapy-resistant tumor cells can potentially improve clinical outcomes in malignancies. To optimize immunotherapy in the clinic, we aimed to create an in vivo model enabling us to analyze human cytotoxic T-lymphocyte (CTL) responses against human malignancies. To this end, we developed NOD/SCID/IL2rgKO (NSG) mice expressing the HLA class I molecules HLA-A*0201 and A*2402. In the bone marrow (BM) and spleen of HLA class I transgenic (Tg) NSG mice transplanted with cord blood hematopoietic stem cells (HSCs), we found human memory CD8(+) T cells and antigen-presenting cells. To evaluate antigen-specific human CTL responses, we immunized HLA class I Tg NSG mice using polyinosinic:polycytidylic acid mixed Wilms tumor 1 (WT1) peptides, with or without WT1 peptide-loaded autologous dendritic cells. After immunization, the frequencies of HLA-restricted WT1-specific CTLs increased significantly in the spleen. Next, we transplanted the WT1-specific T-cell receptor (WT1-TCR) gene-transduced human HSCs into HLA class I Tg NSG newborn mice. WT1 tetramer-positive CD8(+) T cells differentiated from WT1-TCR-transduced HSCs in the recipients' BM, spleen, and thymus. Upon stimulation with WT1 peptide in vitro, these CTLs produced interferon-γ and showed lytic activity against leukemia cells in an antigen-specific, HLA-restricted manner. HLA class I Tg NSG xenografts may serve as a preclinical model to develop effective immunotherapy against human malignancies. PMID:26702062

  9. Human B-cell ontogeny in humanized NOD/SCID γcnull mice generates a diverse yet auto/poly- and HIV-1 reactive antibody repertoire

    PubMed Central

    Chang, Hong; Biswas, Subhabrata; Tallarico, Aimee St. Clair; Sarkis, Phuong Thi Nguyen; Geng, Shusheng; Panditrao, Madhura M.; Zhu, Quan; Marasco, Wayne A.

    2012-01-01

    Characterization of the human antibody (Ab) repertoire in mouse models of the human immune system is essential to establish their relevance in translational studies. Single human B-cells were sorted from bone marrow and periphery of humanized NOD/SCID γcnull mice at 8–10 months post-engraftment with human cord blood-derived CD34+ stem cells. Human immunoglobulin variable heavy (VH) and kappa (Vκ) genes were amplified, cognate VH-Vκ gene-pairs assembled as single-chain variable fragment-Fc antibodies (scFvFcs) and functional studies performed. Although overall distribution of VH genes approximated the normal human Ab repertoire, analysis of the VH-third complementarity determining regions (H-CDR3) in the mature B-cell subset demonstrated an increase in length and positive charges suggesting autoimmune characteristics. Additionally, >70% of Vκ sequences utilized Vκ4-1, a germline gene associated with autoimmunity. The mature B-cell subset-derived scFvFcs displayed the highest frequency of autoreactivity and polyspecificity, suggesting defects in checkpoint control mechanisms. Furthermore, these scFvFcs demonstrated binding to recombinant HIV envelope corroborating previous observations of poly/autoreactivity in anti-HIVgp140 antibodies. These data lend support to the hypothesis that anti-HIV BnAbs may be derived from auto/polyspecific Abs that escaped immune elimination and that the hNSG mouse could provide a new experimental platform for studying the origin of anti-HIV neutralizing Ab responses. PMID:22592523

  10. Virus and Autoantigen-Specific CD4+ T Cells Are Key Effectors in a SCID Mouse Model of EBV-Associated Post-Transplant Lymphoproliferative Disorders

    PubMed Central

    Linnerbauer, Stefanie; Behrends, Uta; Adhikary, Dinesh; Witter, Klaus; Bornkamm, Georg W.; Mautner, Josef

    2014-01-01

    Polyclonal Epstein-Barr virus (EBV)-infected B cell line (lymphoblastoid cell lines; LCL)-stimulated T-cell preparations have been successfully used to treat EBV-positive post-transplant lymphoproliferative disorders (PTLD) in transplant recipients, but function and specificity of the CD4+ component are still poorly defined. Here, we assessed the tumor-protective potential of different CD4+ T-cell specificities in a PTLD-SCID mouse model. Injection of different virus-specific CD4+ T-cell clones showed that single specificities were capable of prolonging mouse survival and that the degree of tumor protection directly correlated with recognition of target cells in vitro. Surprisingly, some CD4+ T-cell clones promoted tumor development, suggesting that besides antigen recognition, still elusive functional differences exist among virus-specific T cells. Of several EBV-specific CD4+ T-cell clones tested, those directed against virion antigens proved most tumor-protective. However, enriching these specificities in LCL-stimulated preparations conferred no additional survival benefit. Instead, CD4+ T cells specific for unknown, probably self-antigens were identified as principal antitumoral effectors in LCL-stimulated T-cell lines. These results indicate that virion and still unidentified cellular antigens are crucial targets of the CD4+ T-cell response in this preclinical PTLD-model and that enriching the corresponding T-cell specificities in therapeutic preparations may enhance their clinical efficacy. Moreover, the expression in several EBV-negative B-cell lymphoma cell lines implies that these putative autoantigen(s) might also qualify as targets for T-cell-based immunotherapy of virus-negative B cell malignancies. PMID:24853673

  11. Bovine antibody against Cryptosporidium parvum elicits a circumsporozoite precipitate-like reaction and has immunotherapeutic effect against persistent cryptosporidiosis in SCID mice.

    PubMed Central

    Riggs, M W; Cama, V A; Leary, H L; Sterling, C R

    1994-01-01

    Control of cryptosporidiosis is currently hampered by the absence of drugs or vaccines proven consistently effective against Cryptosporidium parvum. On the basis of observations that anti-C. parvum antibody has therapeutic effect against cryptosporidiosis, cows were immunized with C. parvum to produce hyperimmune colostral antibody. An antibody-rich fraction was prepared and differentiated from control (nonhyperimmune) antibody by enzyme-linked immunosorbent assay, immunofluorescence assay, immunoelectron microscopy, and in vitro neutralizing titer against DEAE-cellulose-isolated C. parvum sporozoites. Oocyst, purified sporozoite, and merozoite antigens recognized by hyperimmune antibody were defined by Western blot (immunoblot). Hyperimmune antibody recognized antigens common to oocysts, sporozoites, and merozoites, as well as stage-specific antigens. Upon incubation with hyperimmune antibody, sporozoites underwent distinct morphologic changes characterized by progressive formation and eventual release of membranous sporozoite surface antigen-antibody complexes, similar to the malaria circumsporozoite precipitate reaction. The infectivity of sporozoites having undergone this reaction was neutralized. The reaction was minimal or absent on sporozoites incubated with control antibody. To determine therapeutic effect in vivo, persistent C. parvum infection was established in adult severe combined immune-deficient (SCID) mice by oral inoculation with 10(7) oocysts. At 5 weeks postinfection, infected mice were treated for 10 days with hyperimmune or control antibody by inclusion in drinking water and daily gavage. Fecal oocyst shedding and infection scores in the gastrointestinal tract and gall bladder/common bile duct in hyperimmune antibody-treated mice were significantly lower than those in the control antibody-treated mice. Hyperimmune bovine antibody prepared against C. parvum may provide a first-generation therapy for control of cryptosporidiosis. Additionally

  12. Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy

    DOE PAGESBeta

    DebRoy, Swati; Hiraga, Nobuhiko; Imamura, Michio; Hayes, C. Nelson; Akamatsu, Sakura; Canini, Laetitia; Perelson, Alan S.; Pohl, Ralf T.; Persiani, Stefano; Uprichard, Susan L.; et al

    2016-06-08

    Legalon SIL (SIL) is a chemically hydrophilized version of silibinin, an extract of milk thistle (Silybum marianum) seeds that has exhibited hepatoprotective and antiviral effectiveness against hepatitis C virus (HCV) in patients leading to viral clearance in combination with ribavirin. In this paper, to elucidate the incompletely understood mode of action of SIL against HCV, mathematical modelling of HCV kinetics and human hepatocyte gene expression studies were performed in uPA-SCID-chimeric mice with humanized livers. Chronically HCV-infected mice (n = 15) were treated for 14 days with daily intravenous SIL at 469, 265 or 61.5 mg/kg. Serum HCV and human albuminmore » (hAlb) were measured frequently, and liver HCV RNA was analysed at days 3 and 14. Microarray analysis of human hepatocyte gene expression was performed at days 0, 3 and 14 of treatment. While hAlb remained constant, a biphasic viral decline in serum was observed consisting of a rapid 1st phase followed by a second slower phase (or plateau with the two lower SIL dosings). SIL effectiveness in blocking viral production was similar among dosing groups (median ε = 77%). However, the rate of HCV-infected hepatocyte decline, δ, was dose-dependent. Intracellular HCV RNA levels correlated (r = 0.66, P = 0.01) with serum HCV RNA. Pathway analysis revealed increased anti-inflammatory and antiproliferative gene expression in human hepatocytes in SIL-treated mice. Finally, the results suggest that SIL could lead to a continuous second-phase viral decline, that is potentially viral clearance, in the absence of adaptive immune response along with increased anti-inflammatory and antiproliferative gene expression in human hepatocytes.« less

  13. Stem cell transplantation for primary immunodeficiency diseases: The North American Experience

    PubMed Central

    Pai, Sung-Yun; Cowan, Morton J.

    2014-01-01

    Purpose of the Review This review describes recent studies on outcomes after allogeneic hematopoietic cell transplantation (HCT) for primary immunodeficiency (PID) in North America including severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Recent Findings Using uniform diagnostic criteria, the Primary Immune Deficiency Treatment Consortium (PIDTC) described the baseline characteristics of newly diagnosed infants with SCID in North America. Analysis of outcomes of HCT for SCID in North America from 2000–2009 showed that young infants, and older infants without active infection, had excellent survival irrespective of type of donor, or transplant approach with regards to conditioning. While pre-transplant conditioning with chemotherapy had a clear and strong negative impact on survival in infants with active infection at the time of transplant, among survivors, conditioning was associated with improved immune reconstitution. However, the potential late effects of conditioning in these infants remain to be characterized. Advances in transplant outcomes for WAS and CGD support the strategy of early transplantation before the onset of severe complications; additional multicenter studies are needed to fully define optimal approaches. Summary The formation of the PIDTC, a multi-institutional North American consortium, has contributed to our understanding of outcomes after transplant for PID. PMID:25259542

  14. Severe Papillomavirus Infection Progressing to Metastatic Squamous Cell Carcinoma in Bone Marrow-Transplanted X-Linked SCID Dogs

    PubMed Central

    Goldschmidt, Michael H.; Kennedy, Jeffrey S.; Kennedy, Douglas R.; Yuan, Hang; Holt, David E.; Casal, Margret L.; Traas, Anne M.; Mauldin, Elizabeth A.; Moore, Peter F.; Henthorn, Paula S.; Hartnett, Brian J.; Weinberg, Kenneth I.; Schlegel, Richard; Felsburg, Peter J.

    2006-01-01

    Canine X-linked severe combined immunodeficiency (XSCID) is due to mutations in the common gamma chain (γc) gene and is identical clinically and immunologically to human XSCID, making it a true homologue of the human disease. Bone marrow-transplanted (BMT) XSCID dogs not only engraft donor T cells and reconstitute normal T-cell function but, in contrast to the majority of transplanted human XSCID patients, also engraft donor B cells and reconstitute normal humoral immune function. Shortly after our initial report of successful BMT of XSCID dogs, it soon became evident that transplanted XSCID dogs developed late-onset severe chronic cutaneous infections containing a newly described canine papillomavirus. This is analogous to the late-onset cutaneous papillomavirus infection recently described for human XSCID patients following BMT. Of 24 transplanted XSCID dogs followed for at least 1 year post-BMT, 71% developed chronic canine papillomavirus infection. Six of the transplanted dogs that developed cutaneous papillomas were maintained for >3 1/2 years post-BMT for use as breeders. Four of these six dogs (67%) developed invasive squamous cell carcinoma (SCC), with three of the dogs (75%) eventually developing metastatic SCC, an extremely rare consequence of SCC in the dog. This finding raises the question of whether SCC will develop in transplanted human XSCID patients later in life. Canine XSCID therefore provides an ideal animal model with which to study the role of the γc-dependent signaling pathway in the response to papillomavirus infections and the progression of these viral infections to metastatic SCC. PMID:16775349

  15. CD8 T cells mediate direct biliary ductule damage in NOD autoimmune biliary disease

    PubMed Central

    Yang, Guo-Xiang; Wu, Yuehong; Tsukamoto, Hiroki; Leung, Patrick S.; Lian, Zhe-Xiong; Rainbow, Daniel B.; Hunter, Kara M.; Morris, Gerard A.; Lyons, Paul A.; Peterson, Laurence B.; Wicker, Linda S.; Gershwin, M.E.; Ridgway, William M.

    2016-01-01

    We previously described the NOD.c3c4 mouse, which is protected from type 1 diabetes (T1D) due to protective alleles at multiple insulin-dependent diabetes (Idd) genes, but develops autoimmune biliary disease (ABD) resembling primary biliary cirrhosis (PBC). Here we characterize the NOD.ABD strain, which is genetically-related to the NOD.c3c4 strain but develops both ABD and T1D. Histologically, NOD.ABD biliary disease is indistinguishable from that in NOD.c3c4 mice. The frequency of effector memory (CD44+CD62L-) and central memory (CD44+CD62L+) CD8 T cells is significantly increased in the intrahepatic lymphocyte fraction of NOD.ABD mice, and NOD.ABD CD8 T cells produce more IFN-γ and TNF-α, compared to controls. NOD.ABD splenocytes can transfer ABD and T1D to NOD.c3c4 scid mice, but only T1D to NOD scid mice, suggesting that the genetic origin of the target organ and/or its innate immune cells is critical to disease pathogenesis. The disease transfer model, importantly, shows that biliary duct damage (characteristic of PBC) and inflammation precede biliary epithelial cell proliferation. Unlike T1D where both CD4 and CD8 T cells are required for disease transfer, purified NOD.ABD CD8 T cells can transfer liver inflammation into NOD.c3c4 scid recipients, and disease transfer is ameliorated by co-transferring T regulatory cells. Unlike NOD.c3c4 mice, NOD.ABD mice do not develop antinuclear or anti-Smith autoantibodies; however, NOD.ABD mice do develop the anti-pyruvate dehydrogenase antibodies typical of human PBC. The NOD.ABD strain is a model of immune dysregulation affecting two organ systems, most likely by mechanisms that do not completely coincide. PMID:21169553

  16. Rescue of DNA-PK Signaling and T-Cell Differentiation by Targeted Genome Editing in a prkdc Deficient iPSC Disease Model

    PubMed Central

    Reimann, Christian; Mlambo, Tafadzwa; Alzubi, Jamal; Maeder, Morgan L.; Riedel, Heimo; Fisch, Paul; Cantz, Tobias; Rudolph, Cornelia; Mussolino, Claudio; Joung, J. Keith; Schambach, Axel; Cathomen, Toni

    2015-01-01

    In vitro disease modeling based on induced pluripotent stem cells (iPSCs) provides a powerful system to study cellular pathophysiology, especially in combination with targeted genome editing and protocols to differentiate iPSCs into affected cell types. In this study, we established zinc-finger nuclease-mediated genome editing in primary fibroblasts and iPSCs generated from a mouse model for radiosensitive severe combined immunodeficiency (RS-SCID), a rare disorder characterized by cellular sensitivity to radiation and the absence of lymphocytes due to impaired DNA-dependent protein kinase (DNA-PK) activity. Our results demonstrate that gene editing in RS-SCID fibroblasts rescued DNA-PK dependent signaling to overcome radiosensitivity. Furthermore, in vitro T-cell differentiation from iPSCs was employed to model the stage-specific T-cell maturation block induced by the disease causing mutation. Genetic correction of the RS-SCID iPSCs restored T-lymphocyte maturation, polyclonal V(D)J recombination of the T-cell receptor followed by successful beta-selection. In conclusion, we provide proof that iPSC-based in vitro T-cell differentiation is a valuable paradigm for SCID disease modeling, which can be utilized to investigate disorders of T-cell development and to validate gene therapy strategies for T-cell deficiencies. Moreover, this study emphasizes the significance of designer nucleases as a tool for generating isogenic disease models and their future role in producing autologous, genetically corrected transplants for various clinical applications. PMID:26000857

  17. Immunodeficient Mouse Models with Different Disease Profiles by In Vivo Infection with the Same Clinical Isolate of Enterovirus 71

    PubMed Central

    Liao, Chun-Che; Liou, An-Ting; Chang, Ya-Shu; Wu, Szu-Yao; Chang, Chih-Shin; Lee, Chien-Kuo; Kung, John T.; Tu, Pang-Hsien; Yu, Ya-Yen; Lin, Chi-Yung; Lin, Jen-Shiou

    2014-01-01

    ABSTRACT Like poliovirus infection, severe infection with enterovirus 71 (EV71) can cause neuropathology. Unlike poliovirus, EV71 is often associated with hand-foot-and-mouth disease (HFMD). Here we established three mouse models for experimental infection with the same clinical isolate of EV71. The NOD/SCID mouse model is unique for the development of skin rash, an HFMD-like symptom. While the NOD/SCID mice developed limb paralysis and death at near-100% efficiency, the gamma interferon receptor knockout (ifngr KO) and stat-1 knockout mice exhibited paralysis and death rates near 78% and 30%, respectively. Productive infection with EV71 depends on the viral dose, host age, and inoculation route. Levels of infectious EV71, and levels of VP1-specific RNA and protein in muscle, brain, and spinal cord, were compared side by side between the NOD/SCID and stat-1 knockout models before, during, and after disease onset. Spleen fibrosis and muscle degeneration are common in the NOD/SCID and stat-1 knockout models. The main differences between these two models include their disease manifestations and cytokine/chemokine profiles. The pathology of the NOD/SCID model includes (i) inflammation and expression of viral VP1 antigen in muscle, (ii) increased neutrophil levels and decreased eosinophil and lymphocyte levels, and (iii) hair loss and skin rash. The characteristic pathology of the stat-1 knockout model includes (i) a strong tropism of EV71 for the central nervous system, (ii) detection of VP1 protein in the Purkinje layer of cerebellar cortex, pons, brain stem, and spinal cord, (iii) amplification of microglial cells, and (iv) dystrophy of intestinal villi. Our comparative studies on these new models with oral or intraperitoneal (i.p.) infection underscored the contribution of host immunity, including the gamma interferon receptor, to EV71 pathogenesis. IMPORTANCE In the past decade, enterovirus 71 (EV71) has emerged as a major threat to public health in the Asia

  18. Carrier frequency of a nonsense mutation in the adenosine deaminase (ADA) gene implies a high incidence of ADA-deficient severe combined immunodeficiency (SCID) in Somalia and a single, common haplotype indicates common ancestry.

    PubMed

    Sanchez, Juan J; Monaghan, Gemma; Børsting, Claus; Norbury, Gail; Morling, Niels; Gaspar, H Bobby

    2007-05-01

    Inherited adenosine deaminase (ADA) deficiency is a rare metabolic disorder that causes immunodeficiency, varying from severe combined immunodeficiency (SCID) in the majority of cases to a less severe form in a small minority of patients. Five patients of Somali origin from four unrelated families, with severe ADA-SCID, were registered in the Greater London area. Patients and their parents were investigated for the nonsense mutation Q3X (ADA c7C>T), two missense mutations K80R (ADA c239A>G) and R142Q (ADA c425G>A), and a TAAA repeat located at the 3' end of an Alu element (AluVpA) positioned 1.1 kb upstream of the ADA transcription start site. All patients were homozygous for the haplotype ADA-7T/ADA-239G/ADA-425G/AluVpA7. Among 207 Somali immigrants to Denmark, the frequency of ADA c7C>T and the maximum likelihood estimate of the frequency of the haplotype ADA-7T/ADA-239G/ADA-425G/AluVpA7 were both 0.012 (carrier frequency 2.4%). Based on the analysis of AluVpA alleles, the ADA c7C/T mutation was estimated to be approximately 7,100 years old. Approximately 1 out of 5 - 10000 Somali children will be born with ADA deficiency due to an ADA c7C/T mutation, although within certain clans the frequency may be significantly higher. ADA-SCID may be a frequent immunodeficiency disorder in Somalia, but will be underdiagnosed due to the prevailing socioeconomic and nutritional deprivation.

  19. MDL 74,968, a new acyclonucleotide analog: activity against human immunodeficiency virus in vitro and in the hu-PBL-SCID.beige mouse model of infection.

    PubMed

    Bridges, C G; Taylor, D L; Ahmed, P S; Brennan, T M; Hornsperger, J M; Navé, J F; Casara, P; Tyms, A S

    1996-05-01

    The novel acyclonucleotide derivative of guanine, 9-[2-methylidene-3-(phosphonomethoxy)propyl] guanine (MDL 74,968), had antiviral activity comparable to those of 9-(2-phosphonomethoxyethyl) adenine (PMEA) and 2',3'-dideoxyinosine against laboratory strains of both human immunodeficiency virus (HIV) types 1 and 2 cultured in MT-4 cells and several clinical HIV isolates cultured in human peripheral blood mononuclear cells (PBMCs). MDL 74,968 was at least fourfold less toxic than PMEA to MT-4 cells or PBMCs, thereby producing a more favorable in vitro selectivity index for the former compound. Studies of acute toxicity in CD-1 mice showed that MDL 74,968 was not toxic at doses of 1,600 mg/kg of body weight via the intraperitoneal route or at doses of 500 mg/kg via the intravenous route. Furthermore, no adverse effects of MDL 74,968 were apparent when mice were treated at doses of 200 mg/kg twice daily for 5 days. Treatment by continuous subcutaneous infusion of MDL 74,968 or PMEA at the daily dose of 20 mg/kg in the hu-PBL-SCID.beige murine model of HIV infection significantly reduced the severity of infection compared with that in placebo-treated controls. Quantitation of virus recovery by endpoint titration of spleen cells in coculture with mitogen-activated PBMCs demonstrated that MDL 74,968 as well as PMEA significantly reduced the amount of virus (P < 0.02). Moreover, by using DNA extracted from spleens, the mean HIV:HLA PCR product ratio, which takes into account individual variation in immune system reconstitution, were 0.50 and 0.40 for MDL 74,968 and PMEA treatments, respectively, whereas animals receiving the placebo control had significantly higher levels of HIV proviral DNA (mean 0.78; P < 0.02). Taken together, these promising findings suggest that an orally bioavailable prodrug of MDL 74,968 should be developed for the treatment of HIV infection.

  20. Infusion of Trx-1-Overexpressing hucMSC Prolongs the Survival of Acutely Irradiated NOD/SCID Mice by Decreasing Excessive Inflammatory Injury

    PubMed Central

    Wang, Jun; Tang, YongYong; Liu, Hao; Zhang, Bin; Chen, Hu

    2013-01-01

    A protective reagent for ARI should have the ability to repair injured tissue caused by radiation and prevent continuous damage from secondary risk factors. Trx-1 was explored as a candidate therapy for ARI, as it scavenges reactive oxygen species, regulates cell growth and differentiation, participates in immune reactions, and inhibits apoptosis by acting inside and/or outside cells. Trx-1 can also decrease excessive inflammation in ARI by regulating the creation of inflamed media, by inhibiting the activation of complement, and by reducing the chemotaxis, adhesion, and migration of inflammatory cells. As effectively and stably expressing exogenous genes in the long term and regulating immune inflammation and tissue repair, MSC are a good choice for Trx-1 gene therapy. In this study, Trx-1-overexpressing hucMSC-Trx-1 were obtained by adenoviral vector-mediated infection. We first measured the redox capacity of hucMSC-Trx-1 with an antioxidant capacity (T-AOC) assay, a hydrogen peroxide (H2O2) content determination assay in vivo, a H2O2-induced oxidation hemolysis assay, and a lipid peroxidation assay in vitro. Then, we measured survival time, the protection of the hematopoietic system, and the regulation of inflammation in important organs in three treatment groups of NOD/SCID mice (treated with hucMSC-Trx-1, with hucMSC, and with saline) that were exposed to 4.5 Gy 60Co-γ-ray radiation. The hucMSC-Trx-1 group achieved superior antioxidation results, protecting bone marrow hematopoietic stem cells (Lin−CD117+: hucMSC-Trx-1 vs. hucMSC, P<0.05; hucMSC-Trx-1 vs. NS, P<0.01), promoting the formation of red blood cells and hemoglobin (hucMSC-Trx-1 vs. hucMSC or NS, P<0.05), reducing inflammation and damage in important organs (Bone marrow and lung: hucMSC-Trx-1 vs. NS, P<0.01; hucMSC-Trx-1 vs. hucMSC, P<0.05. Liver and intestine: hucMSC-Trx-1 vs. NS, P<0.05; hucMSC-Trx-1 vs. hucMSC, P<0.05), and prolonging survival (hucMSC-Trx-1 vs. hucMSC or NS, P<0.01). Therefore

  1. Rapid tumor formation of human T-cell leukemia virus type 1-infected cell lines in novel NOD-SCID/gammac(null) mice: suppression by an inhibitor against NF-kappaB.

    PubMed

    Dewan, M Zahidunnabi; Terashima, Kazuo; Taruishi, Midori; Hasegawa, Hideki; Ito, Mamoru; Tanaka, Yuetsu; Mori, Naoki; Sata, Tetsutaro; Koyanagi, Yoshio; Maeda, Michiyuki; Kubuki, Yoko; Okayama, Akihiko; Fujii, Masahiro; Yamamoto, Naoki

    2003-05-01

    We established a novel experimental model for human T-cell leukemia virus type 1 (HTLV-1)-induced tumor using NOD-SCID/gammac(null) (NOG) mice. This model is very useful for investigating the mechanism of tumorigenesis and malignant cell growth of adult T-cell leukemia (ATL)/lymphoma, which still remains unclear. Nine HTLV-1-infected cell lines were inoculated subcutaneously in the postauricular region of NOG mice. As early as 2 to 3 weeks after inoculation, seven cell lines produced a visible tumor while two transformed cell lines failed to do so. Five of seven lines produced a progressively growing large tumor with leukemic infiltration of the cells in various organs that eventually killed the animals. Leukemic cell lines formed soft tumors, whereas some transformed cell lines developed into hemorrhagic hard tumors in NOG mice. One of the leukemic cell lines, ED-40515(-), was unable to produce visible tumors in NOD-SCID mice with a common gamma-chain after 2 weeks. In vivo NF-kappaB DNA binding activity of the ED-40515(-) cell line was higher and the NF-kappaB components were changed compared to cells in vitro. Bay 11-7082, a specific and effective NF-kappaB inhibitor, prevented tumor growth at the sites of the primary region and leukemic infiltration in various organs of NOG mice. This in vivo model of ATL could provide a novel system for use in clarifying the mechanism of growth of HTLV-1-infected cells as well as for the development of new drugs against ATL.

  2. Long-Term Effects of Intravitreal Injection of GMP-Grade Bone-Marrow–Derived CD34+ Cells in NOD-SCID Mice with Acute Ischemia-Reperfusion Injury

    PubMed Central

    Caballero, Sergio; Bauer, Gerhard; Shibata, Bradley; Roth, Alan; Fitzgerald, Paul G.; Forward, Krisztina I.; Zhou, Ping; McGee, Jeannine; Telander, David G.; Grant, Maria B.; Nolta, Jan A.

    2012-01-01

    Purpose. To determine long-term safety of intravitreal administration of good manufacturing practice (GMP)–grade human bone-marrow–derived CD34+ cells in NOD-SCID (nonobese diabetic–severe combined immunodeficiency) mice with acute retinal ischemia-reperfusion injury, a model for retinal vasculopathy. Method. Acute ischemia-reperfusion injury was induced in the right eye of adult NOD-SCID mice (n = 23) by transient elevation of intraocular pressure. Seven days later, 12 injured eyes and 5 normal contralateral eyes were injected each intravitreally with 5 × 104 CD34+ cells isolated under GMP conditions from a healthy human donor bone marrow using an immunomagnetic cell isolation system. The remaining 11 injured eyes were not treated and served as controls. Mice were euthanized 1 day, 4 months, and 8 months later. Both eyes were enucleated and examined by immunohistochemical analysis and hematoxylin and eosin staining. Among mice followed for 8 months, electroretinography (ERG) was performed on both eyes before euthanization. All major organs were examined grossly and histologically after serial sectioning. Results. Immunohistochemical staining 4 months after injection showed detectable CD34+ cells in the retinal vasculature. ERG at 8 months after CD34+ cell injection showed signals that were similar in untreated eyes. Histology of the enucleated eyes injected with CD34+ cells showed no intraocular tumor or abnormal tissue growth after 8 months. Histologic analysis of all major organs showed no abnormal proliferation of human cells. Conclusions. Intravitreal administration of GMP-grade human bone-marrow–derived CD34+ cells appears to be well tolerated long-term in eyes with acute retinal ischemic injury. A clinical trial will start to further explore this therapy. PMID:22247454

  3. Sequential treatment of CD34+ cells from patients with primary myelofibrosis with chromatin-modifying agents eliminate JAK2V617F-positive NOD/SCID marrow repopulating cells.

    PubMed

    Wang, Xiaoli; Zhang, Wei; Tripodi, Joseph; Lu, Min; Xu, Mingjiang; Najfeld, Vesna; Li, Yan; Hoffman, Ronald

    2010-12-23

    Because primary myelofibrosis (PMF) originates at the level of the pluripotent hematopoietic stem cell (HSC), we examined the effects of various therapeutic agents on the in vitro and in vivo behavior of PMF CD34(+) cells. Treatment of PMF CD34(+) cells with chromatin-modifying agents (CMAs) but not hydroxyurea, Janus kinase 2 (JAK2) inhibitors, or low doses of interferon-α led to the generation of greater numbers of CD34(+) chemokine (C-X-C motif) receptor (CXCR)4(+) cells, which were capable of migrating in response to chemokine (C-X-C motif) ligand (CXCL)12 and resulted in a reduction in the proportion of hematopoietic progenitor cells (HPCs) that were JAK2V617F(+). Furthermore, sequential treatment of PMF CD34(+) cells but not normal CD34(+) cells with decitabine (5-aza-2'-deoxycytidine [5azaD]), followed by suberoylanilide hydroxamic acid (SAHA; 5azaD/SAHA), or trichostatin A (5azaD/TSA) resulted in a higher degree of apoptosis. Two to 6 months after the transplantation of CMAs treated JAK2V617F(+) PMF CD34(+) cells into nonobese diabetic/severe combined immunodeficient (SCID)/IL-2Rγ(null) mice, the percentage of JAK2V617F/JAK2(total) in human CD45(+) marrow cells was dramatically reduced. These findings suggest that both PMF HPCs, short-term and long-term SCID repopulating cells (SRCs), are JAK2V617F(+) and that JAK2V617F(+) HPCs and SRCs can be eliminated by sequential treatment with CMAs. Sequential treatment with CMAs, therefore, represents a possible effective means of treating PMF at the level of the malignant SRC.

  4. Consequences of Daily Administered Parathyroid Hormone on Myeloma Growth, Bone Disease, and Molecular Profiling of Whole Myelomatous Bone

    PubMed Central

    Pennisi, Angela; Ling, Wen; Li, Xin; Khan, Sharmin; Wang, Yuping; Barlogie, Bart; Shaughnessy, John D.; Yaccoby, Shmuel

    2010-01-01

    Background Induction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates. Methodology/Principal Findings We tested the effects of daily administered parathyroid hormone (PTH) on bone disease and myeloma growth, and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary myeloma cells engrafted in SCID-rab and SCID-hu mouse models. PTH resulted in increased bone mineral density of myelomatous bones and reduced tumor burden, which reflected the dependence of primary myeloma cells on the bone marrow microenvironment. Treatment with PTH also increased bone mineral density of uninvolved murine bones in myelomatous hosts and bone mineral density of implanted human bones in nonmyelomatous hosts. In myelomatous bone, PTH markedly increased the number of osteoblasts and bone-formation parameters, and the number of osteoclasts was unaffected or moderately reduced. Pretreatment with PTH before injecting myeloma cells increased bone mineral density of the implanted bone and delayed tumor progression. Human global gene expression profiling of myelomatous bones from SCID-hu mice treated with PTH or saline revealed activation of multiple distinct pathways involved in bone formation and coupling; involvement of Wnt signaling was prominent. Treatment with PTH also downregulated markers typically expressed by osteoclasts and myeloma cells, and altered expression of genes that control oxidative stress and inflammation. PTH receptors were not expressed by myeloma cells, and PTH had no effect on myeloma cell growth in vitro. Conclusions/Significance We conclude that PTH-induced bone formation in myelomatous bones is mediated by activation of multiple signaling pathways involved in osteoblastogenesis and attenuated bone resorption

  5. Arthritis severity and spirochete burden are determined by serotype in the Borrelia turicatae-mouse model of Lyme disease.

    PubMed Central

    Pennington, P M; Allred, C D; West, C S; Alvarez, R; Barbour, A G

    1997-01-01

    Immunodeficient mice infected with Borrelia turicatae, a relapsing fever agent, have a disorder that resembles disseminated Lyme disease. Two serotypes, A and B, differed in their arthritogenicity in both CB-17 SCID and C3H SCID mice. In CB-17 SCID mice infected with serotype A or B, arthritis was assessed by measurement of tibiotarsal diameter, functional ability on a beam walk test, and microscopic assessment of joint inflammation. Serotype B-infected mice had greater joint swelling, functional disability, and leukocytic infiltration in the joints than serotype A-infected mice. Joint swelling and disability peaked at 2 weeks of infection and then decreased, while leukocyte infiltration in the joints persisted. To investigate the basis for the differences in arthritogenicity of serotypes A and B, spirochete burdens in infected mice were measured by quantitative PCR of spirochete DNA in joints, direct immunofluorescence of spirochetes in joints, and counts of spirochetes in the blood. At 2 weeks of infection there were seven times more spirochetes in the joints of serotype B-infected mice than in those of serotype A-infected mice, measured by both quantitative PCR and direct enumeration. Although serotypes A and B had the same infectivity and growth rate in vivo, serotype B spirochetes were eightfold more abundant in the blood than serotype A spirochetes and produced greater fatality in newborn mice. These findings indicate that differences in disease severity in mice infected with serotype A or B are attributable to differences in the spirochete burden in the joints and blood. PMID:8975925

  6. Placental transfer of maternally-derived IgA precludes the use of guthrie card eluates as a screening tool for primary immunodeficiency diseases.

    PubMed

    Borte, Stephan; Janzi, Magdalena; Pan-Hammarström, Qiang; von Döbeln, Ulrika; Nordvall, Lennart; Winiarski, Jacek; Fasth, Anders; Hammarström, Lennart

    2012-01-01

    There is a need for neonatal screening tools to improve the long-term clinical outcome of patients with primary immunodeficiency diseases (PID). Recently, a PCR-based screening method for both TRECs and KRECs using Guthrie card samples has been developed. However, the applicability of these excision circle assays is limited to patients with severe T or B cell lymphopenia (SCID, XLA and A-T), whereas the most common forms of PID are not detected. Absence of serum IgA is seen in a major fraction of patients with immunological defects. As serum IgA in newborns is considered to be of fetal origin, eluates from routinely collected dried blood spot samples might thus be suitable for identification of children with PID. To assess the applicability of such screening assays, stored Guthrie card samples were obtained from 47 patients with various forms of primary immunodeficiency diseases (SCID, XLA, A-T, HIGM and IgAD), 20 individuals with normal serum IgA levels born to IgA-deficient mothers and 51 matched healthy newborns. Surprisingly, normal serum IgA levels were found in all SCID, XLA, A-T and HIGM patients and, additionally, in all those IgAD patients born to IgA-sufficient mothers. Conversely, no serum IgA was found in any of the 16 IgAD patients born by IgA-deficient mothers. Moreover, half of the IgA-sufficient individuals born by IgA-deficient mothers also lacked IgA at birth whereas no IgA-deficient individuals were found among the controls. IgA in neonatal dried blood samples thus appears to be of both maternal and fetal origin and precludes its use as a reliable marker for neonatal screening of primary immunodeficiency diseases. PMID:22916257

  7. Identification of Lymphomyeloid Primitive Progenitor Cells in Fresh Human Cord Blood and in the Marrow of Nonobese Diabetic–Severe Combined Immunodeficient (NOD-SCID) Mice Transplanted with Human CD34+ Cord Blood Cells

    PubMed Central

    Robin, Catherine; Pflumio, Françoise; Vainchenker, William; Coulombel, Laure

    1999-01-01

    Transplantation of genetically marked donor cells in mice have unambiguously identified individual clones with full differentiative potential in all lymphoid and myeloid pathways. Such evidence has been lacking in humans because of limitations inherent to clonal stem cell assays. In this work, we used single cell cultures to show that human cord blood (CB) contains totipotent CD34+ cells capable of T, B, natural killer, and granulocytic cell differentiation. Single CD34+ CD19−Thy1+ (or CD38−) cells from fresh CB were first induced to proliferate and their progeny separately studied in mouse fetal thymic organotypic cultures (FTOCs) and cocultures on murine stromal feeder layers. 10% of the clones individually analyzed produced CD19+, CD56+, and CD15+ cells in stromal cocultures and CD4+CD8+ T cells in FTOCs, identifying totipotent progenitor cells. Furthermore, we showed that totipotent clones with similar lymphomyeloid potential are detected in the bone marrow of nonobese diabetic severe combined immunodeficient (NOD-SCID) mice transplanted 4 mo earlier with human CB CD34+ cells. These results provide the first direct demonstration that human CB contains totipotent lymphomyeloid progenitors and transplantable CD34+ cells with the ability to reconstitute, in the marrow of recipient mice, the hierarchy of hematopoietic compartments, including a compartment of functional totipotent cells. These experimental approaches can now be exploited to analyze mechanisms controlling the decisions of such primitive human progenitors and to design conditions for their ampification that can be helpful for therapeutic purposes. PMID:10330439

  8. The novel chimeric anti-NCAM (neural cell adhesion molecule) antibody ch.MK1 displays antitumor activity in SCID mice but does not activate complement-dependent cytolysis (CDC).

    PubMed

    Klehr, Martin; Koehl, Ulrike; Mühlenhoff, Martina; Tawadros, Samir; Fischer, Thomas; Schomäcker, Klaus; Heuckmann, Johannes M; Bochennek, Konrad; Jensen, Markus

    2009-06-01

    A monoclonal chimeric antibody ch.MK1 was generated by immunizing F004 mice expressing human instead of murine IgG1/kappa immunoglobulin constant regions. The novel antibody specifically binds cell surface-expressed human neural cell adhesion molecule (NCAM) as shown by immunoprecipitation, flow cytometry and cytospins. Functional analysis revealed nearly complete absence of complement-dependent cytolysis in ch.MK1 and in all other anti-NCAM antibodies tested for reference (UJ13a, ERIC1, 123C3, ch.5A2, B159), indicating an unexpected and group-specific property of anti-NCAM antibodies. As a most plausible mechanism, posttranslational modification of NCAM by complement-inhibiting polysialic acid is discussed. The antibody ch.MK1 demonstrated significant in vivo activity against NCAM-positive neuroblastoma in SCID mice in presence of human peripheral blood mononuclear cell. In absence of human peripheral blood mononuclear cell no distinct antitumor activity of the antibody alone was observed. In ch.MK1 the cellular component of the immune system seems to be the dominant effector mechanism, whereas complement-dependent cytolysis seems not to be necessarily required for antitumor activity. These observations help us to understand immunotherapeutic mechanisms of native anti-NCAM antibodies and may additionally contribute to the understanding of results of currently ongoing clinical studies with conjugated anti-NCAM antibodies.

  9. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice.

    PubMed

    Peled, A; Kollet, O; Ponomaryov, T; Petit, I; Franitza, S; Grabovsky, V; Slav, M M; Nagler, A; Lider, O; Alon, R; Zipori, D; Lapidot, T

    2000-06-01

    Hematopoietic stem cell homing and engraftment require several adhesion interactions, which are not fully understood. Engraftment of nonobese/severe combined immunodeficiency (NOD/SCID) mice by human stem cells is dependent on the major integrins very late activation antigen-4 (VLA-4); VLA-5; and to a lesser degree, lymphocyte function associated antigen-1 (LFA-1). Treatment of human CD34(+) cells with antibodies to either VLA-4 or VLA-5 prevented engraftment, and treatment with anti-LFA-1 antibodies significantly reduced the levels of engraftment. Activation of CD34(+) cells, which bear the chemokine receptor CXCR4, with stromal derived factor 1 (SDF-1) led to firm adhesion and transendothelial migration, which was dependent on LFA-1/ICAM-1 (intracellular adhesion molecule-1) and VLA-4/VCAM-1 (vascular adhesion molecule-1). Furthermore, SDF-1-induced polarization and extravasation of CD34(+)/CXCR4(+) cells through the extracellular matrix underlining the endothelium was dependent on both VLA-4 and VLA-5. Our results demonstrate that repopulating human stem cells functionally express LFA-1, VLA-4, and VLA-5. Furthermore, this study implies a novel approach to further advance clinical transplantation. PMID:10828007

  10. Co-transplantation of human fetal thymus, bone and CD34(+) cells into young adult immunodeficient NOD/SCID IL2Rγ(null) mice optimizes humanized mice that mount adaptive antibody responses.

    PubMed

    Chung, Yun Shin; Son, Jin Kyung; Choi, Bongkum; Joo, Sung-Yeon; Lee, Yong-Soo; Park, Jae Berm; Moon, Hana; Kim, Tae Jin; Kim, Se Ho; Hong, Seokmann; Chang, Jun; Kang, Myung-Soo; Kim, Sung Joo

    2015-04-01

    Both the thymus (T) and bone (B) are necessary hematopoietic niches in adult humans. We previously showed that co-transplantation of human fetal T and B tissues into neonatal immunodeficient NOD/SCID IL2Rγ(null) (NSG, N) mice facilitated hematopoiesis. However, transplantation into neonatal mice resulted in high frequency of early death, making it unrealistic for repetitive experiments. In this study, young adult N mice were pre-engrafted with T and B, T alone, B alone or no tissues. The animals were irradiated and injected with autologous fetal liver (FL)-derived CD34(+) cells (34). The resultant mice were TB34N, T34N, B34N and 34N, respectively, and challenged with T cell dependent antigens (Ags). The humanized TB34N mice showed best performance of these mouse models in many aspects resembling the adult human Ag-experienced spleen. The TB34N mice exhibited better hematopoietic reconstitution; balanced development of T- and B-cell, and common progenitor cells; follicular lymphoid structures with a functional germinal center (GC) enriched with follicular dendritic cells (FDCs) and plasma cells (PCs); secretion of hIgG in the sera in response to Ags at comparable levels to those of human; derivations of hIgG mAb-secreting hybridoma clones. Collectively, the humanized TB34N mice could develop an adaptive immunity that was capable of producing Ag-specific hIgG at a significant level via class switching. This unprecedented TB34N platform in humanized mice would be useful in dissecting human immunity, for generating human Abs and clinical applications. PMID:25725428

  11. Co-transplantation of human fetal thymus, bone and CD34(+) cells into young adult immunodeficient NOD/SCID IL2Rγ(null) mice optimizes humanized mice that mount adaptive antibody responses.

    PubMed

    Chung, Yun Shin; Son, Jin Kyung; Choi, Bongkum; Joo, Sung-Yeon; Lee, Yong-Soo; Park, Jae Berm; Moon, Hana; Kim, Tae Jin; Kim, Se Ho; Hong, Seokmann; Chang, Jun; Kang, Myung-Soo; Kim, Sung Joo

    2015-04-01

    Both the thymus (T) and bone (B) are necessary hematopoietic niches in adult humans. We previously showed that co-transplantation of human fetal T and B tissues into neonatal immunodeficient NOD/SCID IL2Rγ(null) (NSG, N) mice facilitated hematopoiesis. However, transplantation into neonatal mice resulted in high frequency of early death, making it unrealistic for repetitive experiments. In this study, young adult N mice were pre-engrafted with T and B, T alone, B alone or no tissues. The animals were irradiated and injected with autologous fetal liver (FL)-derived CD34(+) cells (34). The resultant mice were TB34N, T34N, B34N and 34N, respectively, and challenged with T cell dependent antigens (Ags). The humanized TB34N mice showed best performance of these mouse models in many aspects resembling the adult human Ag-experienced spleen. The TB34N mice exhibited better hematopoietic reconstitution; balanced development of T- and B-cell, and common progenitor cells; follicular lymphoid structures with a functional germinal center (GC) enriched with follicular dendritic cells (FDCs) and plasma cells (PCs); secretion of hIgG in the sera in response to Ags at comparable levels to those of human; derivations of hIgG mAb-secreting hybridoma clones. Collectively, the humanized TB34N mice could develop an adaptive immunity that was capable of producing Ag-specific hIgG at a significant level via class switching. This unprecedented TB34N platform in humanized mice would be useful in dissecting human immunity, for generating human Abs and clinical applications.

  12. Somatic mosaicism due to monoallelic reversion of a mutation in T cells of an ADA-SCID patient and the effects of enzyme replacement therapy on the revertant phenotype

    PubMed Central

    Moncada-Vélez, Marcela; Vélez-Ortega, Alejandra C.; Orrego, Julio C.; Santisteban, Inés; Jagadeesh, Jayashree; Olivares, Margarita; Olaya, Natalia; Hershfield, Michael S.; Candotti, Fabio; Franco, Jose L.

    2011-01-01

    Patients with adenosine deaminase (ADA) deficiency exhibit spontaneous and partial clinical remission associated with somatic reversion of inherited mutations. We report a child with severe combined immunodeficiency (T-B-NK- SCID) due to ADA deficiency diagnosed at the age of 1 month, whose lymphocyte counts including CD4+ and CD8+ T and NK cells began to improve after several months with normalization of ADA activity in PBL, as a result of somatic mosaicism due to monoallelic reversion of the causative mutation in the ADA gene. Our patient was not eligible for hematopoietic stem cell transplantation (HSCT) or gene therapy (GT); therefore enzyme replacement therapy (ERT) with bovine PEG-ADA was initiated. The follow up of metabolic and immunologic responses to ERT included gradual improvement in ADA activity in erythrocytes and transient expansion of most lymphocyte subsets, followed by gradual stabilization of CD4+ and CD8+ T (with naïve phenotype) and NK cells, with sustained expansion of TCRγδ+ T cells. This was accompanied by disappearance of the revertant T cells as shown by DNA sequencing from PBL. Although the patient’s clinical condition improved marginally, he later developed a germinal cell tumor and eventually died at the age of 67 months from sepsis. This case adds to our current knowledge of spontaneous reversion of mutations in ADA deficiency and shows that the effects of the ERT may vary among these patients, suggesting that it could depend on the cell and type in which the somatic mosaicism is established upon reversion. PMID:21671975

  13. Quality Instruction Requires High Quality Materials: SCID.

    ERIC Educational Resources Information Center

    Norton, Robert E.

    The development of curriculum and instructional materials for competency-based education (CBE) is a costly and complex process involving many critical tasks. Failure to carry out any of these tasks can jeopardize the entire instructional development effort. The importance of the process demands that appropriate and effective procedures be used so…

  14. Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex

    PubMed Central

    King, M A; Covassin, L; Brehm, M A; Racki, W; Pearson, T; Leif, J; Laning, J; Fodor, W; Foreman, O; Burzenski, L; Chase, T H; Gott, B; Rossini, A A; Bortell, R; Shultz, L D; Greiner, D L

    2009-01-01

    Immunodeficient non-obese diabetic (NOD)-severe combined immune-deficient (scid) mice bearing a targeted mutation in the gene encoding the interleukin (IL)-2 receptor gamma chain gene (IL2rγnull) engraft readily with human peripheral blood mononuclear cells (PBMC). Here, we report a robust model of xenogeneic graft-versus-host-like disease (GVHD) based on intravenous injection of human PBMC into 2 Gy conditioned NOD-scid IL2rγnull mice. These mice develop xenogeneic GVHD consistently (100%) following injection of as few as 5 × 106 PBMC, regardless of the PBMC donor used. As in human disease, the development of xenogeneic GVHD is highly dependent on expression of host major histocompatibility complex class I and class II molecules and is associated with severely depressed haematopoiesis. Interrupting the tumour necrosis factor-α signalling cascade with etanercept, a therapeutic drug in clinical trials for the treatment of human GVHD, delays the onset and progression of disease. This model now provides the opportunity to investigate in vivo mechanisms of xenogeneic GVHD as well as to assess the efficacy of therapeutic agents rapidly. PMID:19659776

  15. Neurologic Diseases

    MedlinePlus

    ... muscular dystrophy Problems with the way the nervous system develops, such as spina bifida Degenerative diseases, where nerve cells are damaged or die, such as Parkinson's disease and Alzheimer's disease Diseases of the blood vessels that supply ...

  16. Altered cellular infiltration and cytokine levels during early Mycobacterium tuberculosis sigC mutant infection are associated with late-stage disease attenuation and milder immunopathology in mice

    PubMed Central

    Abdul-Majid, Khairul-Bariah; Ly, Lan H; Converse, Paul J; Geiman, Deborah E; McMurray, David N; Bishai, William R

    2008-01-01

    Background Mouse virulence assessments of certain Mycobacterium tuberculosis mutants have revealed an immunopathology defect in which high tissue CFU counts are observed but the tissue pathology and lethality are reduced. M. tuberculosis mutants which grow and persist in the mouse lungs, but have attenuated disease progression, have the immunopathology (imp) phenotype. The antigenic properties of these strains may alter the progression of disease due to a reduction in host immune cell recruitment to the lungs resulting in disease attenuation and prolonged host survival. Results In this study we focused on the mouse immune response to one such mutant; the M. tuberculosis ΔsigC mutant. Aerosol infection of DBA/2 and SCID mice with the M. tuberculosis ΔsigC mutant, complemented mutant and wild type strain showed proliferation of mutant bacilli in mouse lungs, but with decreased inflammation and mortality in DBA/2 mice. SCID mice shared the same phenotype as the DBA/2 mice in response to the ΔsigC mutant, however, they succumbed to the infection faster. Bronchoalveolar lavage (BAL) fluid analysis revealed elevated numbers of infiltrating neutrophils in the lungs of mice infected with wild type and complemented ΔsigC mutant strains but not in mice infected with the ΔsigC mutant. In addition, DBA/2 mice infected with the ΔsigC mutant had reduced levels of TNF-α, IL-1β, IL-6 and IFN-γ in the lungs. Similarly, there was a reduction in proinflammatory cytokines in the lungs of SCID mice. In contrast to the mouse model, the ΔsigC mutant had reduced initial growth in guinea pig lungs. A possible mechanism of attenuation in the ΔsigC mutant may be a reduction in neutrophilic-influx in the alveolar spaces of the lungs, and decreased proinflammatory cytokine secretion. In contrast to mouse data, the M. tuberculosis ΔsigC mutant proliferates slowly in guinea pig lungs, a setting characterized by caseating necrosis. Conclusion Our observations suggest that the

  17. Celiac Disease

    MedlinePlus

    ... small intestine. People with celiac disease cannot eat gluten, a protein found in wheat, barley, and rye. ... Disease Doctors treat celiac disease by prescribing a gluten-free diet. Symptoms significantly improve for most people ...

  18. Huntington's Disease

    MedlinePlus

    Huntington's disease (HD) is an inherited disease that causes certain nerve cells in the brain to waste ... express emotions. If one of your parents has Huntington's disease, you have a 50 percent chance of ...

  19. Wilson Disease

    MedlinePlus

    ... Share External Link Disclaimer Digestive Diseases Wilson Disease Alternate Versions Wilson Disease (444 KB) You can also ... things psychosis—when a person loses contact with reality Other Signs and Symptoms Other signs and symptoms ...

  20. Crohn's Disease

    MedlinePlus

    ... is one of a group of diseases called inflammatory bowel disease. Crohn's can affect any area from the mouth to the anus. It often affects the lower part of the small intestine called the ileum. The cause of Crohn's disease ...

  1. Pick disease

    MedlinePlus

    Semantic dementia; Dementia - semantic; Frontotemporal dementia; FTD; Arnold Pick disease; 3R tauopathy ... can help doctors tell Pick disease apart from Alzheimer disease. (Memory loss is often the main, and earliest, ...

  2. Bladder Diseases

    MedlinePlus

    ... frequent, urgent urination Bladder cancer Doctors diagnose bladder diseases using different tests. These include urine tests, x- ... National Institute of Diabetes and Digestive and Kidney Diseases

  3. β-l-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)] uracil (l-BHDU) prevents varicella-zoster virus replication in a SCID-Hu mouse model and does not interfere with 5-fluorouracil catabolism.

    PubMed

    De, Chandrav; Liu, Dongmei; Zheng, Bo; Singh, Uma S; Chavre, Satish; White, Catherine; Arnold, Robert D; Hagen, Fred K; Chu, Chung K; Moffat, Jennifer F

    2014-10-01

    The alphaherpesvirus varicella-zoster virus (VZV) causes chickenpox and shingles. Current treatments are acyclovir (ACV) and its derivatives, foscarnet and brivudine (BVdU). Additional antiviral compounds with increased potency and specificity are needed to treat VZV, especially to treat post-herpetic neuralgia. We evaluated β-l-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)] uracil (l-BHDU, 1) and 5'-O-valyl-l-BHDU (2) in three models of VZV replication: primary human foreskin fibroblasts (HFFs), skin organ culture (SOC) and in SCID-Hu mice with skin xenografts. The efficacy of l-BHDU in vivo and its drug-drug interactions were previously not known. In HFFs, 200μM l-BHDU was noncytotoxic over 3days, and l-BHDU treatment reduced VZV genome copy number and cell to cell spread. The EC50 in HFFs for l-BHDU and valyl-l-BHDU were 0.22 and 0.03μM, respectively. However, l-BHDU antagonized the activity of ACV, BVdU and foscarnet in cultured cells. Given its similar structure to BVdU, we asked if l-BHDU, like BVdU, inhibits 5-fluorouracil catabolism. BALB/c mice were treated with 5-FU alone or in combination with l-BHDU or BVdU. l-BHDU did not interfere with 5-FU catabolism. In SCID-Hu mice implanted with human skin xenografts, l-BHDU and valyl-l-BHDU were superior to ACV and valacyclovir. The maximum concentration (Cmax) levels of l-BHDU were determined in mouse and human tissues at 2h after dosing, and comparison of concentration ratios of tissue to plasma indicated saturation of uptake at the highest dose. For the first time, an l-nucleoside analog, l-BHDU, was found to be effective and well tolerated in mice.

  4. Heart Diseases

    MedlinePlus

    ... re like most people, you think that heart disease is a problem for others. But heart disease is the number one killer in the U.S. ... disability. There are many different forms of heart disease. The most common cause of heart disease is ...

  5. Diseases caused by mutations in ORAI1 and STIM1

    PubMed Central

    Lacruz, Rodrigo S.; Feske, Stefan

    2015-01-01

    Ca2+ release-activated Ca2+ (CRAC) channels mediate a specific form of Ca2+ influx called store-operated Ca2+ entry (SOCE) that contributes to the function of many cell types. CRAC channels are formed by ORAI1 proteins located in the plasma membrane, which form its ion-conducting pore. ORAI1 channels are activated by stromal interaction molecule (STIM) 1 and STIM2 located in the endoplasmic reticulum. Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes. CRAC channelopathy is caused by loss-of-function mutations in ORAI1 and STIM1 that abolish CRAC channel function and SOCE; it is characterized by severe combined immunodeficiency (SCID)-like disease, autoimmunity, muscular hypotonia, and ectodermal dysplasia, with defects in dental enamel. The latter defect emphasizes an important role of CRAC channels in tooth development. By contrast, autosomal dominant gain-of-function mutations in these genes result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca2+ levels that are associated with an overlapping spectrum of diseases, including non-syndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes, two syndromes defined, besides myopathy, by thrombocytopenia, thrombopathy, and bleeding diathesis. The fact that myopathy results from loss- and gain-of-function mutations in ORAI1 and STIM1 highlights the importance of CRAC channels for Ca2+ homeostasis in skeletal muscle function. The cellular dysfunction and clinical disease spectrum observed in mutant patients provide important information about the molecular regulation of ORAI1 and STIM1 proteins and the role of CRAC channels in human physiology. PMID:26469693

  6. Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia

    PubMed Central

    Sivagnanalingam, Umayal; Balys, Marlene; Eberhardt, Allison; Wang, Nancy; Myers, Jason R.; Ashton, John M.; Becker, Michael W.; Calvi, Laura M.; Mendler, Jason H.

    2015-01-01

    Cytogenetically normal acute myeloid leukemia (CN-AML) patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset could be explored. We utilized a well-characterized patient-derived, RUNX1-mutated CN-AML line (CG-SH). Tail vein injection of CG-SH into NOD scid gamma mice led to leukemic engraftment in the bone marrow, spleen, and peripheral blood within 6 weeks. Treatment of leukemic mice with anthracycline/cytarabine-based chemotherapy resulted in clearance of disease from the spleen and peripheral blood, but persistence of disease in the bone marrow as assessed by flow cytometry and secondary transplantation. Whole exome sequencing of CG-SH revealed mutations in ASXL1, CEBPA, GATA2, and SETBP1, not previously reported. We conclude that CG-SH xenografts are a robust, reproducible in vivo model of CN-AML in which to explore mechanisms of chemotherapy resistance and novel therapeutic approaches. PMID:26177509

  7. Kimura disease

    PubMed Central

    AlGhamdi, Fares E.; Al-Khatib, Talal A.; Marzouki, Hani Z.; AlGarni, Mohammed A

    2016-01-01

    Kimura disease is a chronic inflammatory disease that mainly manifests as a lump in the cervical region. Although the underlying pathophysiology is not clear yet, the diagnosis can be established based on specific histopathological characteristics. The first case of this disease was described in China, as well as the majority of subsequent cases that were also described in the Far East countries made Kimura disease traditionally a disease of adult patients of Asian descent. This report describes the occurrence of Kimura disease in pediatric non-Asian patient with a similar clinicopathologic presentation. PMID:26905356

  8. Celiac Disease

    MedlinePlus

    ... immune disease in which people can't eat gluten because it will damage their small intestine. If you have celiac disease and eat foods with gluten, your immune system responds by damaging the small ...

  9. Menkes Disease

    MedlinePlus

    ... therapy approaches to Menkes disease. 3 1. Kaler, SG. The neurology of STPAT copper transporter disease: emerging ... Reviews Neurology , 2001:7:15-19.. 2. Kaler SG, et al. Neonatal Diagnosis and Treatment of Menkes ...

  10. Sandhoff Disease

    MedlinePlus

    ... Sandhoff Disease? Sandhoff disease is a rare, inherited lipid storage disorder that progressively destroys nerve cells in ... results in the harmful accumulation of certain fats (lipids) in the brain and other organs of the ...

  11. Gaucher Disease

    MedlinePlus

    ... one of the inherited metabolic disorders known as lipid storage diseases. Lipids are fatty materials that include oils, fatty acids, ... research to find ways to treat and prevent lipid storage disorders such as Gaucher disease. For example, ...

  12. Huntington disease

    MedlinePlus

    Huntington chorea ... Huntington disease is caused by a genetic defect on chromosome 4. The defect causes a part of ... 10 to 28 times. But in persons with Huntington disease, it is repeated 36 to 120 times. ...

  13. Digestive diseases

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/007447.htm Digestive diseases To use the sharing features on this page, please enable JavaScript. Digestive diseases are disorders of the digestive tract, which ...

  14. Tickborne Diseases

    MedlinePlus

    ... for tickborne diseases ranges from studying the basic biology of the microbes that cause these diseases to ... Nucleotide Polymorphism Phylogenetics & Ontology Proteomics & Protein Analysis Systems Biology Data Portals Software Applications BCBB Mobyle Interface Designer ( ...

  15. Graves' Disease

    MedlinePlus

    ... our online catalog. ​ Additional Links Hashimoto's Disease Hyperthyroidism Hypothyroidism Pregnancy & Thyroid Disease Thyroid Tests Find a Specialist ... everyone who receives radioactive iodine treatment eventually develops hypothyroidism, which occurs when the thyroid does not make ...

  16. Fifth disease

    MedlinePlus

    Parvovirus B19; Erythema infectiosum; Slapped cheek rash ... Fifth disease is caused by human parvovirus B19. It often affects preschoolers or school-age children during the spring. The disease spreads through the fluids in the nose and ...

  17. Celiac Disease

    MedlinePlus

    ... having celiac disease? Yes, you can have gluten sensitivity without the immune system attack on the small ... gluten causes in celiac disease. Symptoms of gluten sensitivity are generally milder than those seen in celiac ...

  18. Kawasaki disease

    MedlinePlus

    ... pubmed/23283289 . Mason JC. Rheumatic diseases of the cardiovascular system. In: Mann DL, Zipes DP, Libby P, Bonow RO, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 10th ed. Philadelphia, PA: Elsevier Saunders; 2014: ...

  19. Bone Diseases

    MedlinePlus

    ... avoid smoking and drinking too much alcohol. Bone diseases can make bones easy to break. Different kinds ... break Osteogenesis imperfecta makes your bones brittle Paget's disease of bone makes them weak Bones can also ...

  20. Gaucher Disease

    MedlinePlus

    Gaucher disease is a rare, inherited disorder. It is a type of lipid metabolism disorder. If you have it, ... It usually starts in childhood or adolescence. Gaucher disease has no cure. Treatment options for types 1 ...

  1. Raynaud's Disease

    MedlinePlus

    Raynaud's disease is a rare disorder of the blood vessels, usually in the fingers and toes. It causes the ... secondary Raynaud's, which is caused by injuries, other diseases, or certain medicines. People in colder climates are ...

  2. Meniere's Disease

    MedlinePlus

    Meniere's disease is a disorder of the inner ear. It can cause severe dizziness, a roaring sound in your ... together over several days. Some people with Meniere's disease have "drop attacks" during which the dizziness is ...

  3. Legionnaires' Disease

    MedlinePlus

    Legionnaires' disease is a type of pneumonia caused by bacteria. You usually get it by breathing in mist from ... spread from person to person. Symptoms of Legionnaires' disease include high fever, chills, a cough, and sometimes ...

  4. Chagas Disease

    MedlinePlus

    Chagas disease is caused by a parasite. It is common in Latin America but not in the United States. ... nose, the bite wound or a cut. The disease can also spread through contaminated food, a blood ...

  5. Mitochondrial Diseases

    MedlinePlus

    ... disorder, something goes wrong with this process. Mitochondrial diseases are a group of metabolic disorders. Mitochondria are ... cells and cause damage. The symptoms of mitochondrial disease can vary. It depends on how many mitochondria ...

  6. Kidney Diseases

    MedlinePlus

    ... until you go to the bathroom. Most kidney diseases attack the nephrons. This damage may leave kidneys ... medicines. You have a higher risk of kidney disease if you have diabetes, high blood pressure, or ...

  7. Parasitic Diseases

    MedlinePlus

    ... a bug bite, or sexual contact. Some parasitic diseases are easily treated and some are not. Parasites ... be seen with the naked eye. Some parasitic diseases occur in the United States. Contaminated water supplies ...

  8. Liver Diseases

    MedlinePlus

    ... remove poisons. There are many kinds of liver diseases. Viruses cause some of them, like hepatitis A, ... the skin, can be one sign of liver disease. Cancer can affect the liver. You could also ...

  9. Endocrine Diseases

    MedlinePlus

    ... low, you may have a hormone disorder. Hormone diseases also occur if your body does not respond ... In the United States, the most common endocrine disease is diabetes. There are many others. They are ...

  10. Wilson Disease

    MedlinePlus

    Wilson disease is a rare inherited disorder that prevents your body from getting rid of extra copper. You need ... copper into bile, a digestive fluid. With Wilson disease, the copper builds up in your liver, and ...

  11. Addison Disease

    MedlinePlus

    ... blood pressure and water and salt balance. Addison disease happens if the adrenal glands don't make ... problem with your immune system usually causes Addison disease. The immune system mistakenly attacks your own tissues, ...

  12. Eye Diseases

    MedlinePlus

    ... the back of the eye Macular degeneration - a disease that destroys sharp, central vision Diabetic eye problems ... defense is to have regular checkups, because eye diseases do not always have symptoms. Early detection and ...

  13. Parkinson's Disease

    MedlinePlus

    Parkinson's disease (PD) is a type of movement disorder. It happens when nerve cells in the brain don't ... coordination As symptoms get worse, people with the disease may have trouble walking, talking, or doing simple ...

  14. Fifth Disease

    MedlinePlus

    Fifth disease is a viral infection caused by parvovirus B19. The virus only infects humans; it's not the same parvovirus that dogs and cats can get. Fifth disease mostly affects children. Symptoms can include a low ...

  15. Binswanger's Disease

    MedlinePlus

    ... and Information What is Binswanger's Disease? Binswanger's disease (BD), also called subcortical vascular dementia , is a type ... and brain tissue dies. A characteristic pattern of BD-damaged brain tissue can be seen with modern ...

  16. Kidney Disease

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Kidney Disease KidsHealth > For Teens > Kidney Disease Print A ... Syndrome Coping With Kidney Conditions What Do the Kidneys Do? You might never think much about some ...

  17. Addison disease

    MedlinePlus

    ... the adrenal glands (autoimmune disease) Infections such as tuberculosis , HIV, or fungal infections Hemorrhage into the adrenal glands Tumors Risk factors for the autoimmune type of Addison disease include ...

  18. Behcet's Disease

    MedlinePlus

    ... neurological disorders such as Behcet's disease. The National Human Genome Research Institute, another Institute of the National Institutes of Health, conducts research into the genomic basis of Behcet's disease. This research is aimed ...

  19. Lyme disease

    MedlinePlus

    ... The same disease occurs in many parts of Europe and Asia. In the United States, most Lyme ... Risk factors for Lyme disease include: Doing outside activities that increase tick exposure (for example, gardening, hunting, ...

  20. Lyme Disease

    MedlinePlus

    Lyme disease is a bacterial infection you get from the bite of an infected tick. The first symptom ... Muscle and joint aches A stiff neck Fatigue Lyme disease can be hard to diagnose because you may ...

  1. Colonic Diseases

    MedlinePlus

    ... where your body makes and stores stool. Many disorders affect the colon's ability to work properly. Some ... abdominal cramping and other symptoms Treatment for colonic diseases varies greatly depending on the disease and its ...

  2. Pneumococcal Disease

    MedlinePlus

    ... pneumococcal disease. Quick Facts About Pneumococcal Disease and Vaccination According to WHO, pneumococcal pneumonia and meningitis are ... of antibiotic treatment. (9, 10, 11) Conjugate pneumococcal vaccination is safe and effective for preventing severe childhood ...

  3. Gilbert disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000301.htm Gilbert disease To use the sharing features on this page, please enable JavaScript. Gilbert disease is a common disorder passed down through ...

  4. Liver disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000205.htm Liver disease To use the sharing features on this page, please enable JavaScript. The term "liver disease" applies to many conditions that stop the liver ...

  5. Parkinson Disease.

    PubMed

    Capriotti, Teri; Terzakis, Kristina

    2016-06-01

    Parkinson disease (PD) is a progressive neurodegenerative disease that affects one million people in the United States. This article reviews the etiology and pathophysiology of PD, risk factors, clinical manifestations, diagnostic criteria, and treatment of this common disease. Implications for home care clinicians are included.

  6. Crinkle Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Crinkle disease of hop was first described in Europe in 1930, and subsequent reports of the disease appear in literature published in the 1960s and 1970s. The disease appears to be of little importance in most regions of hop production. A fastidious rickettsia-like organism (RLO) is thought to cau...

  7. Rare Diseases

    MedlinePlus

    ... Are often very complex Are often caused by changes in genes It can be hard to find a specialist who knows how to treat your rare disease. Disease advocacy groups, rare disease organizations, and genetics clinics may help you to find ...

  8. Behcet's Disease

    MedlinePlus

    ... with Behçet’s disease keep their joints strong and flexible. What Is the Prognosis for a Person With Behçet’s Disease? Most people with Behçet’s disease can lead productive lives and control symptoms with proper medicine, rest, and exercise. Doctors ...

  9. Lyme Disease.

    ERIC Educational Resources Information Center

    Taylor, George C.

    1991-01-01

    This overview of the public health significance of Lyme disease includes the microbiological specifics of the infectious spirochete, the entomology and ecology of the ticks which are the primary disease carrier, the clinical aspects and treatment stages, the known epidemiological patterns, and strategies for disease control and for expanded public…

  10. Meniere's Disease.

    ERIC Educational Resources Information Center

    Schessel, David A.

    1997-01-01

    Meniere's disease is characterized by unpredictable spells of severe vertigo and fluctuations in hearing and tinnitus. This article discusses the incidence of Meniere's disease, the present status of our understanding of this disease, controversies in its diagnosis, and the multiple therapeutic modalities recruited in its treatment. (Contains…

  11. Prion Diseases

    PubMed Central

    Geschwind, Michael D.

    2016-01-01

    Purpose of Review This article presents an update on the clinical aspects of human prion disease, including the wide spectrum of their presentations. Recent Findings Prion diseases, a group of disorders caused by abnormally shaped proteins called prions, occur in sporadic (Jakob-Creutzfeldt disease), genetic (genetic Jakob-Creutzfeldt disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia), and acquired (kuru, variant Jakob-Creutzfeldt disease, and iatrogenic Jakob-Creutzfeldt disease) forms. This article presents updated information on the clinical features and diagnostic methods for human prion diseases. New antemortem potential diagnostic tests based on amplifying prions in order to detect them are showing very high specificity. Understanding of the diversity of possible presentations of human prion diseases continues to evolve, with some genetic forms progressing slowly over decades, beginning with dysautonomia and neuropathy and progressing to a frontal-executive dementia with pathology of combined prionopathy and tauopathy. Unfortunately, to date, all human prion disease clinical trials have failed to show survival benefit. A very rare polymorphism in the prion protein gene recently has been identified that appears to protect against prion disease; this finding, in addition to providing greater understanding of the prionlike mechanisms of neurodegenerative disorders, might lead to potential treatments. Summary Sporadic Jakob-Creutzfeldt disease is the most common form of human prion disease. Genetic prion diseases, resulting from mutations in the prion-related protein gene (PRNP), are classified based on the mutation, clinical phenotype, and neuropathologic features and can be difficult to diagnose because of their varied presentations. Perhaps most relevant to this Continuum issue on neuroinfectious diseases, acquired prion diseases are caused by accidental transmission to humans, but fortunately, they are the least common form and

  12. Glomerular disease.

    PubMed

    Vaden, Shelly L

    2011-08-01

    Glomerular diseases are a leading cause of chronic kidney disease in dogs but seem to be less common in cats. Glomerular diseases are diverse, and a renal biopsy is needed to determine the specific glomerular disease that is present in any animal. Familial glomerulopathies occur in many breeds of dogs. However, most dogs with glomerular disease have acquired glomerular injury that is either immune-complex mediated or due to systemic factors, both of which are believed to be the result of a disease process elsewhere in the body (i.e., neoplastic, infectious, and noninfectious inflammatory disorders). A thorough clinical evaluation is indicated in all dogs suspected of having glomerular disease and should include an extensive evaluation for potential predisposing disorders. Nonspecific management of dogs with glomerular disease can be divided into 3 major categories: (1) treatment of potential predisposing disorders, (2) management of proteinuria, and (3) management of uremia and other complications of glomerular disease and chronic kidney disease. Specific management of specific glomerular diseases has not been fully studied in dogs. However, it may be reasonable to consider immunosuppressive therapy in dogs that have developed a form of glomerulonephritis secondary to a steroid-responsive disease (e.g., systemic lupus erythematosus) or have immune-mediated lesions that have been documented in renal biopsy specimens. Appropriate patient monitoring during therapy is important for maximizing patient care. The prognosis for dogs and cats with glomerular disease is variable and probably dependent on a combination of factors. The purpose of this article is to discuss the general diagnosis and management of dogs with glomerular disease. PMID:21782143

  13. [Social diseases, civilization diseases or lifestyle diseases?].

    PubMed

    Betlejewski, Stansław

    2007-01-01

    In general, the development of civilization is viewed as a positive step for the well-being of the human species, leading to an increased duration and quality of life. The accelerated progress of civilization (mainly industrialization, urbanization and nutrition) has lead to new possibilities for adverse effects on human health. In former high civilization--like old Egypt, Greece, Roman, Chinese, Indian, Maya civilizations--the "modem civilization diseases" were unknown. Modem science through improved sanitation, vaccination and antibiotics as well as improved social and economical conditions, has eliminated the threat of death from most infectious diseases. In the years after World War II the social, economic and health conditions changed. Most deaths have resulted from heart disease, stroke, cancer and other diseases as a result of an inappropriate relationship of people with their environment and changed lifestyle. Lifestyle diseases are different from other diseases because they are potentially preventable and can be lowered with changes in diet, lifestyle and environment. PMID:18350729

  14. Gaucher disease.

    PubMed

    Nagral, Aabha

    2014-03-01

    Gaucher disease is the commonest lysosomal storage disease seen in India and worldwide. It should be considered in any child or adult with an unexplained splenohepatomegaly and cytopenia which are seen in the three types of Gaucher disease. Type 1 is the non-neuronopathic form and type 2 and 3 are the neuronopathic forms. Type 2 is a more severe neuronopathic form leading to mortality by 2 years of age. Definitive diagnosis is made by a blood test-the glucocerebrosidase assay. There is no role for histological examination of the bone marrow, liver or spleen for diagnosis of the disease. Molecular studies for mutations are useful for confirming diagnosis, screening family members and prognosticating the disease. A splenectomy should not be performed except for palliation or when there is no response to enzyme replacement treatment or no possibility of getting any definitive treatment. Splenectomy may worsen skeletal and lung manifestations in Gaucher disease. Enzyme replacement therapy (ERT) has completely revolutionized the prognosis and is now the standard of care for patients with this disease. Best results are seen in type 1 disease with good resolution of splenohepatomegaly, cytopenia and bone symptoms. Neurological symptoms in type 3 disease need supportive care. ERT is of no benefit in type 2 disease. Monitoring of patients on ERT involves evaluation of growth, blood counts, liver and spleen size and biomarkers such as chitotriosidase which reflect the disease burden. Therapy with ERT is very expensive and though patients in India have so far got the drug through a charitable access programme, there is a need for the government to facilitate access to treatment for this potentially curable disease. Bone marrow transplantation is an inferior option but may be considered when access to expensive ERT is not possible. PMID:25755533

  15. Parathyroid disease.

    PubMed

    Wen, Hong Yan; Schumacher, H Ralph; Zhang, Li Yun

    2010-11-01

    Patients with parathyroid disease can have important musculoskeletal problems.Hypoparathyroidism can cause subcutaneous calcifications, tetany, muscle cramps,and paresthesias, but also myopathies and an ankylosing spondylitis-like back disease. Hypoparathyroidism can occur in SLE caused by antiparathyroid antibodies.Patients with hyperparathyroidism can develop bone disease with cysts, erosions,and deformities. They can also develop pseudogout, gout, myopathies, and tendon ruptures.

  16. Infectious disease

    NASA Technical Reports Server (NTRS)

    Pierson, Duane L.

    1990-01-01

    This is a collection of viewgraphs on the Johnson Space Center's work on infectious disease. It addresses their major concern over outbreaks of infectious disease that could jeopardize the health, safety and/or performance of crew members engaged in long duration space missions. The Antarctic environment is seen as an analogous location on Earth and a good place to carry out such infectious disease studies and methods for proposed studies as suggested.

  17. Huntington's Disease

    PubMed Central

    Finkbeiner, Steven

    2011-01-01

    Huntington's disease (HD) is the most common inherited neurodegenerative disease and is characterized by uncontrolled excessive motor movements and cognitive and emotional deficits. The mutation responsible for HD leads to an abnormally long polyglutamine (polyQ) expansion in the huntingtin (Htt) protein, which confers one or more toxic functions to mutant Htt leading to neurodegeneration. The polyQ expansion makes Htt prone to aggregate and accumulate, and manipulations that mitigate protein misfolding or facilitate the clearance of misfolded proteins tend to slow disease progression in HD models. This article will focus on HD and the evidence that it is a conformational disease. PMID:21441583

  18. [Wilson's disease].

    PubMed

    Moilanen, Veikko; Mäkisalo, Heikki

    2010-01-01

    Wilson's disease is a disorder of the liver's copper metabolism. Accumulation of copper causes liver and central nervous system damage. Wilson's disease should always be suspected, when a liver disease is detected in a child or an adolescent. The disease may also manifest itself as severe neurological or neuropsychiatric disorders. The diagnosis is often delayed despite the fact that the accumulation of copper in the body can be shown by various means. Early started medication will stop the accumulation of copper into the body. If the treatment is delayed or ineffective, liver transplantation is required.

  19. [Cardiovascular disease in rheumatic diseases].

    PubMed

    Nasonov, E L; Popkova, T V; Novikova, D S

    2016-01-01

    The representatives of immunoinflammatory diseases are rheumatic ones, such as primarily rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus, and other systemic connective diseases, which are characterized by a high risk for untimely death. The high risk of untimely death in these diseases has been found to be associated with the severity of an immunoinflammatory process that gives rise to severe irreversible damage to vital organs and systems and with the development of a wide spectrum of comorbidities (infections, interstitial lung disease, malignant tumors, osteoporotic fractures, etc.). Among them, diseases of the cardiovascular system, which are most commonly caused by the early development and.accelerated progression of atherosclerotic coronary lesions, hold a central.position. The paper gives the data available in the recent literature on the impact.of antirheumatic therapy (disease-modifying antirheumatic drugs and biological agents) on' the cardiovascular system. PMID:27458622

  20. Alpers' Disease

    MedlinePlus

    ... caused by mutation in the gene for the mitochondrial DNA polymerase POLG. The disease occurs in about one in 100,000 persons. ... typically occur months before tissue samples show the mitochondrial DNA depletion, so ... with Alpers' disease develop symptoms in the first two years of ...

  1. Paget's disease.

    PubMed

    Bertoldi, I; Cantarini, L; Filippou, G; Frediani, B

    2014-01-01

    Paget's disease of bone is the most common metabolic bone disease after osteoporosis and affects 2-4% of adults over 55 years of age. Its etiology is only partly understood and includes both genetic and environmental factors. The disease may be asymptomatic and can be uncovered incidentally on x-ray or in biochemical tests performed for another condition. It can also manifest itself with bone pain, deformity, fracture or other complications. Paget's disease is diagnosed by x-rays and in general has very typical radiological features, but occasionally the clinical picture may be unusual and a differential diagnosis of sclerotic or lytic metastases needs to be considered. Plasma total alkaline phosphatase activity is the most clinically useful indicator of disease activity. It is elevated in most untreated patients, but may be within the normal range in patients with monostotic or limited disease. Bisphosphonate therapy is indicated for patients with symptoms and should also be considered in patients with disease sites that suggest a risk of complications, such as long bones, vertebrae or base of the skull. Orthopedic surgery in Paget's disease patients includes almost exclusively the correction of fractures and arthroplasty. PMID:25069498

  2. Kidney Disease

    MedlinePlus

    ... version of this page please turn Javascript on. Kidney Disease What is Kidney Disease? What the Kidneys Do Click for more information You have two ... damaged, wastes can build up in the body. Kidney Function and Aging Kidney function may be reduced ...

  3. Addison's Disease

    MedlinePlus

    ... is Addison’s disease? Addison’s disease affects your body’s adrenal glands. The adrenal glands are part of the endocrine system. The endocrine ... your moods, growth, metabolism, and tissue function. The adrenal glands are located just above your kidneys. They produce ...

  4. Endocrine Diseases

    MedlinePlus

    ... high or too low, you may have an endocrine disease or disorder. Endocrine diseases and disorders also occur if your body does not respond to hormones the way it is supposed to. Featured Topics Adrenal Insufficiency ... Topics Research Discoveries & News Children with Cushing ...

  5. Gaucher disease

    PubMed Central

    Rizk, Tamer M.; Ariganjoye, Rafiu O.; Alsaeed, Gihad I.

    2015-01-01

    We aim to describe an 8-year-old boy with an unusual clinical presentation of Gaucher disease (GD). Gaucher disease is a progressive lysosomal storage disorder due to deficiency of the specific enzyme glucocerebrosidase with varying clinical features, but often involving the monocytes-macrophages systems. This child ran a progressive course with a devastating outcome. Three distinct GD subtypes have been described with varying clinical features based on the presence or absence of neurologic involvement. Gaucher disease diagnosis is obtained via: enzyme activity assay, gene mutation study, bone marrow aspiration in addition to multiple other tests that have been successfully used in diagnosis of cases of GD. Treatment modalities include enzyme replacement treatment, substrate reduction therapy, bone marrow transplantation, blood transfusion, and surgery are available management modalities for GD. Gaucher disease is a chronic disease requiring a multidisciplinary team approach with regular follow up with multiple subspecialties. PMID:26166597

  6. Beryllium disease.

    PubMed Central

    Jones Williams, W.

    1988-01-01

    The increasing use of beryllium in a variety of industries continues to be a hazard. New cases are still being reported to the UK Beryllium Case Registry, now numbering 60 in the period 1945-1988. The majority of cases follow inhalation which results in acute beryllium disease (chemical pneumonitis) or more commonly chronic beryllium disease--a granulomatous pneumonitis. Granulomatous skin nodules also occur following local implantation. The clinical and radiological features are briefly described with the emphasis on pathology and immunology. Laser microprobe mass spectrometry analysis of tissue sections is a major advance in diagnosis. Detection of beryllium distinguishes the granulomas of chronic beryllium disease from other diseases, in particular sarcoidosis. The role of beryllium lymphocyte transformation tests is discussed. Chronic beryllium disease is steroid dependent and local excision of skin lesions appears to be curative. There is no evidence that beryllium is carcinogenic. Images Figure 1 PMID:3074283

  7. Alzheimer's disease.

    PubMed

    Scheltens, Philip; Blennow, Kaj; Breteler, Monique M B; de Strooper, Bart; Frisoni, Giovanni B; Salloway, Stephen; Van der Flier, Wiesje Maria

    2016-07-30

    Although the prevalence of dementia continues to increase worldwide, incidence in the western world might have decreased as a result of better vascular care and improved brain health. Alzheimer's disease, the most prevalent cause of dementia, is still defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality as proposed in the original amyloid hypothesis. Age-related, protective, and disease-promoting factors probably interact with the core mechanisms of the disease. Amyloid β42, and tau proteins are established core cerebrospinal biomarkers; novel candidate biomarkers include amyloid β oligomers and synaptic markers. MRI and fluorodeoxyglucose PET are established imaging techniques for diagnosis of Alzheimer's disease. Amyloid PET is gaining traction in the clinical arena, but validity and cost-effectiveness remain to be established. Tau PET might offer new insights and be of great help in differential diagnosis and selection of patients for trials. In the search for understanding the disease mechanism and keys to treatment, research is moving increasingly into the earliest phase of disease. Preclinical Alzheimer's disease is defined as biomarker evidence of Alzheimer's pathological changes in cognitively healthy individuals. Patients with subjective cognitive decline have been identified as a useful population in whom to look for preclinical Alzheimer's disease. Moderately positive results for interventions targeting several lifestyle factors in non-demented elderly patients and moderately positive interim results for lowering amyloid in pre-dementia Alzheimer's disease suggest that, ultimately, there will be a future in which specific anti-Alzheimer's therapy will be combined with lifestyle interventions targeting general brain health to jointly combat the disease. In this Seminar, we discuss the main developments in Alzheimer's research. PMID:26921134

  8. Alzheimer's disease.

    PubMed

    Scheltens, Philip; Blennow, Kaj; Breteler, Monique M B; de Strooper, Bart; Frisoni, Giovanni B; Salloway, Stephen; Van der Flier, Wiesje Maria

    2016-07-30

    Although the prevalence of dementia continues to increase worldwide, incidence in the western world might have decreased as a result of better vascular care and improved brain health. Alzheimer's disease, the most prevalent cause of dementia, is still defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality as proposed in the original amyloid hypothesis. Age-related, protective, and disease-promoting factors probably interact with the core mechanisms of the disease. Amyloid β42, and tau proteins are established core cerebrospinal biomarkers; novel candidate biomarkers include amyloid β oligomers and synaptic markers. MRI and fluorodeoxyglucose PET are established imaging techniques for diagnosis of Alzheimer's disease. Amyloid PET is gaining traction in the clinical arena, but validity and cost-effectiveness remain to be established. Tau PET might offer new insights and be of great help in differential diagnosis and selection of patients for trials. In the search for understanding the disease mechanism and keys to treatment, research is moving increasingly into the earliest phase of disease. Preclinical Alzheimer's disease is defined as biomarker evidence of Alzheimer's pathological changes in cognitively healthy individuals. Patients with subjective cognitive decline have been identified as a useful population in whom to look for preclinical Alzheimer's disease. Moderately positive results for interventions targeting several lifestyle factors in non-demented elderly patients and moderately positive interim results for lowering amyloid in pre-dementia Alzheimer's disease suggest that, ultimately, there will be a future in which specific anti-Alzheimer's therapy will be combined with lifestyle interventions targeting general brain health to jointly combat the disease. In this Seminar, we discuss the main developments in Alzheimer's research.

  9. Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus.

    PubMed Central

    Cahill, R J; Foltz, C J; Fox, J G; Dangler, C A; Powrie, F; Schauer, D B

    1997-01-01

    Inflammatory bowel disease (IBD) is thought to result from either an abnormal immunological response to enteric flora or a normal immunological response to a specific pathogen. No study to date has combined both factors. The present studies were carried out with an immunologically manipulated mouse model of IBD. Mice homozygous for the severe combined immunodeficiency (scid) mutation develop IBD with adoptive transfer of CD4+ T cells expressing high levels of CD45RB (CD45RB(high) CD4+ T cells). These mice do not develop IBD in germfree conditions, implicating undefined intestinal flora in the pathogenesis of lesions. In controlled duplicate studies, the influence of a single murine pathogen, Helicobacter hepaticus, in combination with the abnormal immunological response on the development of IBD was assessed. The combination of H. hepaticus infection and CD45RB(high) CD4+ T-cell reconstitution resulted in severe disease expression similar to that observed in human IBD. This study demonstrates that IBD develops in mice as a consequence of an abnormal immune response in the presence of a single murine pathogen, H. hepaticus. The interaction of host immunity and a single pathogen in this murine system provides a novel model of human IBD, an immunity-mediated condition triggered by bacterial infection. PMID:9234764

  10. Combinations of CD45 isoforms are crucial for immune function and disease.

    PubMed

    Dawes, Ritu; Petrova, Svetla; Liu, Zhe; Wraith, David; Beverley, Peter C L; Tchilian, Elma Z

    2006-03-15

    Expression of the CD45 Ag in hemopoietic cells is essential for normal development and function of lymphocytes, and both mice and humans lacking expression exhibit SCID. Human genetic variants of CD45, the exon 4 C77G and exon 6 A138G alleles, which alter the pattern of CD45 isoform expression, are associated with autoimmune and infectious diseases. We constructed transgenic mice expressing either an altered level or combination of CD45 isoforms. We show that the total level of CD45 expressed is crucial for normal TCR signaling, lymphocyte proliferation, and cytokine production. Most importantly, transgenic lines with a normal level, but altered combinations of CD45 isoforms, CD45(RABC/+) and CD45(RO/+) mice, which mimic variant CD45 expression in C77G and A138G humans, show more rapid onset and increased severity of experimental autoimmune encephalomyelitis. CD45(RO/+) cells produce more TNF-alpha and IFN-gamma. Thus, for the first time, we have shown experimentally that it is the combination of CD45 isoforms that affects immune function and disease. PMID:16517710

  11. Lyme disease.

    PubMed

    Nat, Laura Bogdana; Simiti, Adriana Liana; Poanta, Laura Irina

    2014-01-01

    Lyme disease (Borreliosis), also called the "disease of 1000 faces", is produced by a bacterium called Borrelia burgdorferi, transmitted by the Ixodes tick. The clinical picture is non-specific and polymorph, with multisystemic involvement. Diagnosis is most often one of exclusion, and certain diagnosis is based on the presence of Borellia antibodies. The treatment is done differently depending on the stage of the disease and the severity of injuries, being used antibiotics like Doxycycline, Amoxicillin, Erythromycin or Penicillin. Under treatment the disease quickly heals without sequel, in the early stages, but advanced stages are usually resistant to treatment and chronic injuries can occur. Symptoms get worse without treatment and become chronic. We present the case of a woman of 66-year-old with a complex history of disease, which began one year prior to admission, through multiple and nonspecific symptoms; she presented herself in numerous medical services (gastroenterology, rheumatology--where an immunosuppressive treatment was initiated, hematology) without determining a final diagnosis. She was admitted in our service with altered general state and worsening symptoms, predominantly fever, muscle pain, joint pain, the patient being immobilized in bed. After multiple investigations and the problem of differential diagnosis with multiple pathologies, we finally established the diagnosis of Lyme disease. The peculiarities of the case are represented by the severity of the clinical manifestations and fulminant disease evolution under the unjustified administration of immunosuppressive treatment, and atypical joint involvement regarding localization and evolution that raised the issue of differential diagnosis with osteosarcoma or bone tuberculosis. PMID:25726630

  12. Parkinson's disease.

    PubMed

    Playfer, J R

    1997-05-01

    Parkinson's disease is a common disabling disease of old age. The diagnosis of idiopathic Parkinson's disease is based on clinical signs and has poor sensitivity, with about 25% of patients confidently diagnosed as having the disease actually having other conditions such as multi-system atrophy and other parkinsonism-plus syndromes. Benign essential tremor and arteriosclerotic pseudo-parkinsonism can easily be confused with Parkinson's disease. The cause of Parkinson's disease remains unknown. Speculative research highlights the role of oxidative stress and free radical mediated damage to dopaminergic cells. Parkinson's disease is the one neurodegenerative disorder in which drugs have been demonstrated to be of value. There is now a wide variety of drugs and formulations available, including anticholinergics, amantidine, L-dopa, dopamine agonists including apomorphine, selegiline and soon to be available catechol-O-methyltransferase inhibitors. Disabling side-effects of treatment, fluctuations, dyskinesias and psychiatric problems require strategic use of the drugs available. There is an increasing potential for neurosurgical intervention. PMID:9196696

  13. [Castleman disease].

    PubMed

    Sánchez de Toledo Sancho, J; Fàbrega Sabaté, J; Marhuenda Irastorza, C; Lucaya Layret, X; Torán Fuentes, N; Gros Subias, L; Sábado Alvarez, C

    2005-07-01

    Castleman disease or angiofollicular hyperplasia is a rare disorder included in the group of lymphoproliferative disorders. This entity was originally described by Castleman in 1956. The etiology remains unknown but it is postulated to be a reactive lymphoid hyperplasia due to chronic antigenic stimulation caused by a viral infection. The disease presents in young adults and is more frequent in women; it is exceptionally rare in the pediatric age group. It is classified into two clinical groups (localized disease and disseminated disease) and there are two histologic variants (hyaline-vascular and plasma cell Castleman disease). Localized disease is usually asymptomatic, has a good prognosis, and is the most common presentation in pediatric patients, usually corresponding to highly vascularized mediastinal masses. Resection of the mass, which is curative, is associated with a high risk of blood loss. Recently, preoperative arteriography with embolization has been used satisfactorily in the preoperative management of these tumors. We present a case of localized Castleman disease in a 12-year-old girl satisfactorily treated with embolization before curative resection.

  14. Kummell disease

    PubMed Central

    Schucany, William G.; Opatowsky, Michael J.

    2013-01-01

    Kummell disease, or avascular necrosis of a vertebral body, presents as vertebral osteonecrosis typically affecting a thoracic vertebra with compression deformity, intravertebral vacuum cleft, and exaggerated kyphosis weeks to months after a minor traumatic injury. This rare disease is increasing in prevalence secondary to an aging population and the associated rise in osteoporosis. Treatment with vertebroplasty or surgical decompression and fusion is often required. We present a classic case of Kummell disease to illustrate the salient features of the condition, with associated imaging findings on computed tomography and magnetic resonance imaging. PMID:23814399

  15. Kummell disease.

    PubMed

    Nickell, Larry T; Schucany, William G; Opatowsky, Michael J

    2013-07-01

    Kummell disease, or avascular necrosis of a vertebral body, presents as vertebral osteonecrosis typically affecting a thoracic vertebra with compression deformity, intravertebral vacuum cleft, and exaggerated kyphosis weeks to months after a minor traumatic injury. This rare disease is increasing in prevalence secondary to an aging population and the associated rise in osteoporosis. Treatment with vertebroplasty or surgical decompression and fusion is often required. We present a classic case of Kummell disease to illustrate the salient features of the condition, with associated imaging findings on computed tomography and magnetic resonance imaging.

  16. Gaucher's disease.

    PubMed

    Bohra, Vijay; Nair, Velu

    2011-07-01

    Gaucher's disease (GD) is the most common amongst the various disorders classified under the lysosomal storage disorders. GD is a model for applications of molecular medicine to clinical delineation, diagnosis, and treatment. The multiorgan and varied presentation of the disease makes it a challenge to diagnose GD early. The advent of enzyme replacement therapy in the early 1990s changed the management, and survival, of patients with GD. In addition to this, development of substrate reduction, pharmacological chaperone, and gene therapies has broadened the horizon for this rare disease. However, in resource-poor countries like ours, optimal management is still a distant dream. PMID:21897894

  17. Gaucher disease

    MedlinePlus

    ... harmful substances to build up in the liver, spleen, bones, and bone marrow. These substances prevent cells ... common. It involves bone disease, anemia, an enlarged spleen and low platelets (thrombocytopenia). Type I affects both ...

  18. Fabry Disease

    MedlinePlus

    ... kidneys may become progressively impaired, leading to renal failure. Other signs include decreased sweating, fever, and gastrointestinal ... of complications from strokes, heart disease, or kidney failure. What research is being done? The mission of ...

  19. Planning Diseases.

    ERIC Educational Resources Information Center

    Gabel, Medard

    1984-01-01

    To solve societal problems, both local and global, a global approach is needed. Serious diseases that are crippling present-day problem solving and planning are discussed, and the characteristics of a healthy, effective planning approach are described. (RM)

  20. Stargardt Disease

    MedlinePlus

    ... ways to prevent it. A decrease in color perception also occurs in Stargardt disease. This is because photoreceptor cells involved in color perception are concentrated in the macula. Back to top ...

  1. Legionnaire disease

    MedlinePlus

    Legionella pneumonia; Pontiac fever; Legionellosis ... Edelstein PH, Roy CR. Legionnaires' disease and Pontiac fever. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious ...

  2. Sever's Disease

    MedlinePlus

    ... Are Reading Upsetting News Reports? What to Say Vaccines: Which Ones & When? Smart School Lunches Emmy-Nominated Video "Cerebral Palsy: Shannon's Story" 5 Things to Know About Zika & Pregnancy Sever's Disease KidsHealth > ...

  3. Prion Diseases

    MedlinePlus

    ... and sometimes polymerize in neurodegenerative disorders. Credit: NIAID Biology & Genetics Scientists are examining how abnormal prion protein ... the abnormal form. Read more about prion diseases biology and genetics Therapeutic Approaches Although there are no ...

  4. Canavan disease

    MedlinePlus

    ... want to have children and have a family history of Canavan disease. Counseling should be considered if both parents are of Ashkenazi Jewish descent. For this group, DNA testing can almost always tell if the parents ...

  5. Lung Diseases

    MedlinePlus

    ... on Carcinogens: Captafol A Human Health Perspective on Climate Change (Full Report) (4MB) Certain Glass Wool Fibers (Inhalable) ( ... Environmental Public Health (PEPH) (1MB) Programs and Initiatives: Climate Change and Human Health Respiratory Disease and the Environment ( ...

  6. Lung disease

    MedlinePlus

    ... the lungs to take in oxygen and release carbon dioxide. People with this type of lung disorder often ... the lungs to take up oxygen and release carbon dioxide. These diseases may also affect heart function. An ...

  7. Meningococcal Disease

    MedlinePlus

    ... at increased risk of meningococcal disease. This includes college students, military personnel, international travelers to areas where meningococcal ... You May Also Like An 18-Year-Old College Student’s Battle with Meningitis Meningococcal Serogroup B Cases and ...

  8. Whipple's disease

    MedlinePlus

    ... fatal. Treatment relieves symptoms and can cure the disease. ... Brain damage Heart valve damage (from endocarditis ) Nutritional deficiencies Symptoms return (which may be because of drug resistance) Weight loss

  9. Alzheimer's Disease

    MedlinePlus

    ... risk of urinary tract and other serious infections. Malnutrition or dehydration: People who have Alzheimer’s disease may ... swallow. It’s important to watch for signs of malnutrition. If you think that a loved one might ...

  10. Zoonotic Diseases

    MedlinePlus

    ... gov . One Health About One Health Zoonotic Diseases History of One Health One Health in Action The Story of the Rift Valley Fever Virus Vaccine Lead Poisoning Investigation in Northern Nigeria Domestic One Health Activities "Friends" Magazine Global One ...

  11. Pilonidal Disease

    MedlinePlus

    Skip to main content ASCRS Patients Educational Resources Diseases and Conditions Patient Education Library Patient Success Stories Treatments and Screening Resources Find a Surgeon Hereditary Colorectal Cancer Registries Helpful Links Physicians ...

  12. Batten Disease

    MedlinePlus

    ... gene codes has not been identified. In addition, research scientists are working with NCL animal models to improve understanding and treatment of these disorders. One research team, for example, is ... for scientists to study the genetics of these diseases. NIH ...

  13. Vascular Diseases

    MedlinePlus

    ... heart and blood vessels, such as diabetes or high cholesterol Smoking Obesity Losing weight, eating healthy foods, being active and not smoking can help vascular disease. Other treatments include medicines and surgery.

  14. Heart Disease

    MedlinePlus

    ... with heart disease? What do my cholesterol and triglyceride numbers mean? How can I lower my cholesterol? ... weight Know your numbers (blood pressure, cholesterol, and triglycerides) You can reduce your chances of getting heart ...

  15. Wilson Disease

    MedlinePlus

    ... Wilson disease. Growing knowledge of the copper transporting gene ATP7B, which in its mutated form causes WD, should lead to the design of better therapies for this disorder. NIH Patient Recruitment for Wilson ...

  16. Crohn disease

    PubMed Central

    Stappenbeck, Thaddeus S.; Rioux, John D.; Mizoguchi, Atsushi; Saitoh, Tatsuya; Huett, Alan; Darfeuille-Michaud, Arlette; Wileman, Tom; Mizushima, Noboru; Carding, Simon; Akira, Shizuo; Parkes, Miles; Xavier, Ramnik J.

    2011-01-01

    Crohn disease (CD) is a chronic and debilitating inflammatory condition of the gastrointestinal tract.1 Prevalence in western populations is 100–150/100,000 and somewhat higher in Ashkenazi Jews. Peak incidence is in early adult life, although any age can be affected and a majority of affected individuals progress to relapsing and chronic disease. Medical treatments rely significantly on empirical corticosteroid therapy and immunosuppression, and intestinal resectional surgery is frequently required. Thus, 80% of patients with CD come to surgery for refractory disease or complications. It is hoped that an improved understanding of pathogenic mechanisms, for example by studying the genetic basis of CD and other forms of inflammatory bowel diseases (IBD), will lead to improved therapies and possibly preventative strategies in individuals identified as being at risk. PMID:20729636

  17. Behcet's Disease

    MedlinePlus

    ... Old Silk Route,” which spans the region from Japan and China in the Far East to the ... the disease’s epidemiology is not well understood. In Japan, Behcet’s disease ranks as a leading cause of ...

  18. Alzheimer disease

    MedlinePlus

    Senile dementia - Alzheimer type (SDAT); SDAT; Dementia - Alzheimer ... The exact cause of Alzheimer disease (AD) is not known. Research shows that certain changes in the brain lead to AD. You are more likely ...

  19. Chagas disease

    MedlinePlus

    ... will help control the spread of the disease. Blood banks in Central and South America screen donors for ... discarded if the donor has the parasite. Most blood banks in the United States began screening for Chagas ...

  20. Parkinson's Disease

    MedlinePlus

    ... cells make and use a brain chemical called dopamine (say: DOH-puh-meen) to send messages to ... coordinate body movements. When someone has Parkinson's disease, dopamine levels are low. So, the body doesn't ...

  1. [Kawasaki disease].

    PubMed

    Gliwińska, E

    1995-01-01

    Kawasaki disease (KD), first described in Japan in 1967 by Dr. Tomisaku Kawasaki, is an acute multi system vasculitis of infancy and early childhood characterised by high fever, rash, conjunctivitis, inflammation of the mucous membranes, erythematous induration of the hands and feet and cervical lymphadenopathy. Synonyms for Kawasaki disease include "Kawasaki syndrome" and "mucocutaneous lymph node syndrome" (MCLS, MLNS, MCLNS). Kawasaki disease was initially presumed to occur only in Japan; but now this disease is known in the whole world. The first cases in the United States were reported in Hawaii in 1976. In poland 5 cases were recognized, and first time described in 1981. The etiology of Kawasaki disease remains unknown. Toxic, allergic and immunologic causes have been suspected, but most investigators favor an infectious cause or an immune response to an infectious agent. Among classes of microorganism suspected of causing Kawasaki disease were bacteria, leptospires, fungi, rickettsiae and a number of viruses. Recently, there has been considerable interest in the possibility, that Kawasaki disease is caused by RETROVIRUSES. Although the disease is generally benign and self-limited, about 20% of children develop coronary artery aneurysms. In 5% of cases, giant aneurysm/more then 8 mm/develop, predisposing the patient to acute coronary artery thrombosis, myocardial infarction and sudden death. This is the most serious complication of KD. Other manifestations of hearth involvement, include pericarditis, myocarditis, myocardial failure and mitral regurgitation. Besides this many other clinical findings are commonly noted in KD; such as: pneumonia, diarrhea, arthritis, aseptic meningitis, otitis media, obstructive jaundice, hydrops of gallbladder and others.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7545822

  2. [Kawasaki's disease].

    PubMed

    Cortes, J; Martínez, B; Montini, C; Barraza, P; Reyes, A

    1989-08-01

    We described a case of Kawasaki's disease in a chilean girl, one year and 5 months old of age, who presented the oral characteristics, cutaneous and systemic manifestation of the condition, that is not very common for the dentist but that it is necessary to know due to the heart complications and the mortality associated with the disease, and it is necessary that the dentist recognize early this condition.

  3. [Devic disease].

    PubMed

    Papeix, Caroline

    2006-11-01

    Devic disease, also known as neuromyelitis optica, is a severe rare condition characterized clinically by one or more episodes of optical neuritis and myelitis. Pathologically, it is characterized by extensive demyelination associated with axon loss and deposits of complement and immunoglobulins (IgM) within the lesions. Specific antibodies for this disease (IgG NMO) were recently identified. Immunosuppressive treatment is currently the best option for preventing relapse. PMID:17086129

  4. Fabry disease.

    PubMed

    Schiffmann, Raphael

    2015-01-01

    Fabry disease, an X-linked disorder of glycosphingolipids that is caused by mutations of the GLA gene that codes for α-galactosidase A, leads to dysfunction of many cell types and includes a systemic vasculopathy. As a result, patients have a markedly increased risk of developing ischemic stroke, small-fiber peripheral neuropathy, cardiac dysfunction and chronic kidney disease. Virtually all complications of Fabry disease are non-specific in nature and clinically indistinguishable from similar abnormalities that occur in the context of more common disorders in the general population. Recent studies suggested a much higher incidence of mutations of the GLA gene, suggesting that this disorder is under-diagnosed. However, some of the gene variants may be benign. Although the etiology of Fabry disease has been known for many years, the mechanism by which the accumulating α-D-galactosyl moieties cause this multi organ disorder has only recently been studied and is yet to be completely elucidated. Specific therapy for Fabry disease has been developed in the last few years but its role in the management of the disorder is still being investigated. Fortunately, standard 'non-specific' medical and surgical therapy is effective in slowing deterioration or compensating for organ failure in patients with Fabry disease. PMID:26564084

  5. Whipple's disease

    PubMed Central

    Ratnaike, R.

    2000-01-01

    Whipple's disease is a systemic bacterial infection and the common though not invariable manifestations are diarrhoea, weight loss, abdominal pain, and arthralgia. Arthritis or arthralgia may be the only presenting symptom, predating other manifestations by years. Virtually all organs in the body may be affected, with protean clinical manifestations. Various immunological abnormalities, some of which may be epiphenomena, are described. The causative organism is Tropheryma whippelii.
The disease is uncommon though lethal if not treated. Recent data suggest the disease occurs in an older age group than previously described. The characteristic histopathological features are found most often in the small intestine. These are variable villous atrophy and distension of the normal villous architecture by an infiltrate of foamy macrophages with a coarsely granular cytoplasm, which stain a brilliant magenta colour with PAS. These pathognomonic PAS positive macrophages may also be present in the peripheral and mesenteric lymph nodes and various other organs. The histological differential diagnoses include histoplasmosis and Mycobacterium avium-intercellulare complex.
The clinical diagnosis of Whipple's disease may be elusive, especially if gastrointestinal symptoms are not present. A unique sign of CNS involvement, if present, is oculofacial-skeletal myorhythmia or oculomasticatory myorhythmia, both diagnostic of Whipple's disease. A small bowel biopsy is often diagnostic, though in about 30% of patients no abnormality is present. In patients with only CNS involvement, a stereotactic brain biopsy can be done under local anaesthetic. A recent important diagnostic test is polymerase chain reaction of the 16S ribosomal RNA of Tropheryma whippelii.
Whipple's disease is potentially fatal but responds dramatically to antibiotic treatment. In this review the current recommended treatments are presented. The response to treatment should be monitored closely, as relapses are

  6. Aortic Valve Disease

    MedlinePlus

    ... Disease Tricuspid Valve Disease Cardiac Rhythm Disturbances Thoracic Aortic Aneurysm Pediatric and Congenital Heart Disease Heart abnormalities that ... Disease Tricuspid Valve Disease Cardiac Rhythm Disturbances Thoracic Aortic Aneurysm Aortic Valve Disease Overview The human heart has ...

  7. Behcet's disease.

    PubMed

    Suzuki Kurokawa, M; Suzuki, N

    2004-09-01

    Behcet's disease (BD) is a systemic disorder of recurrent acute inflammation, characterized by major symptoms of oral aphthous ulcers, uveitis, skin lesions and genital ulcers. Involvement of intestines, vessels, and central nervous system (CNS) sometimes leads to a poor prognosis. Patients with BD are known to distribute along the ancient Silk Road. The incidence is relatively higher from eastern Asia to the Mediterranean area as roughly 1-10 patients in 10,000 people, whereas only 1-2 patients in 1,000,000 people in UK and North America. Although etiology of the disease is still unknown, high prevalence of HLA-B51, increased expression of heat shock protein 60 and Th1 dominant immune responses in the patients are considered important in its pathogenesis. Non-infectious neutrophil activation and infection with Streptococcus sanguis and herpes simplex virus would also be associated. Because BD lacks any pathognomonic symptoms and laboratory findings, the diagnosis relies largely upon the criteria proposed by the International Study Group for Behcet's disease in 1990. In Japan, the diagnosis was also made according to the Japanese criteria revised in 1987. Recently, the Behcet's Disease Research Committee of Japan again revised the Japanese criteria in 2003 to avoid overdiagnosis. The new Japanese criteria are introduced in this review. Differential diagnosis excluding Sweet's disease, pemphigus, erythema nodosum and Crohn's disease is important, and positive laboratory data for pathergy test, prick test for dead Streptococci and HLA-B51 are emphasized to make appropriate diagnosis in these criteria. Pathological findings of the disease-affected site such as erythematous nodosum is also stressed. Treatment for the disease has been chosen according to the clinical symptoms. Non-steroidal anti-inflammatory drugs, immunosuppressants, corticosteroids and colchicine are basically introduced. Recently, effects of interferon-alpha/beta, anti-tumor necrosis factor antibody

  8. Cerebrovascular disease.

    PubMed

    Portegies, M L P; Koudstaal, P J; Ikram, M A

    2016-01-01

    With 16.9 million people who suffered a first-ever stroke in 2010 worldwide, stroke is a very common vascular disease. Epidemiologic studies have played an essential role in assessing this burden and in detecting the risk factors for stroke. Primary prevention of these risk factors, primarily hypertension, smoking, diabetes, and atrial fibrillation, has reduced the incidence in high-income countries. However, stroke remains a major cause of death and disability, and therefore research should be continued. Subarachnoid hemorrhages are less prevalent than strokes but have an even higher risk of death. Similar to stroke, epidemiologic studies identified smoking and hypertension as its most important risk factors, together with excessive alcohol intake. Although rare, arterial dissections, CADASIL, arteriovenous malformations, venous sinus thrombosis, moyamoya disease, and vasculitis can lead to serious symptoms. The burden and risk factors of those rare diseases are more challenging to assess. Whenever possible, they should be recognized in a timely manner for their increased risk of stroke, but most often they are diagnosed only at the time of stroke. Some cerebrovascular abnormalities do not result in immediate symptoms. This subclinical cerebrovascular disease includes silent infarcts, white-matter lesions, and microbleeds, and is incidentally found by neuroimaging. These lesions are not innocent, as several epidemiologic studies have associated subclinical cerebrovascular disease with an increased risk of stroke, cognitive decline, dementia, and death. PMID:27637962

  9. [Eales' disease].

    PubMed

    Errera, M-H; Pratas, A; Goldschmidt, P; Sedira, N; Sahel, J-A; Benesty, J

    2016-05-01

    The syndrome of recurrent vitreous hemorrhages in young men was described for the first time by Henry Eales in 1880. The association with a clinical manifestation of ocular inflammation was reported 5years later. Eales disease affects young adults who present with ischemic retinal vasculitis, with the peripheral retina most commonly affected. Most cases have been reported in South Asia. Although the etiology of this abnormality is unknown, it may be related to an immune sensitivity to Mycobacterium tuberculosis antigens. Its pathogenesis is related to extensive ischemia that affects the retina, secondary to an obliterative retinal vasculopathy with release of angiogenic factors of the VEGF type. Involvement of the retina is the hallmark of the disease, which manifests as follows: periphlebitis, retinal capillary ischemia most often affecting the periphery with secondary proliferative retinopathy and retinal and/or papillary neovascularization, recurrent vitreous hemorrhages and tractional retinal detachment. These complications are potentially blinding. The natural history of Eales disease varies, with temporary or permanent remission in some cases and continuous progression in others. Progression is often bilateral, which necessitates regular follow-up. The treatment of Eales disease depends on the stage of the disease and is not well defined. Observation only, pars plana vitrectomy surgery and/or intravitreal injections of anti-VEGF are recommended in cases of vitreous hemorrhage, associated with corticosteroids when retinal vasculitis is present. Laser pan-retinal photocoagulation is necessary when neovascularization is present. PMID:27185661

  10. Infection and Cardiovascular Disease

    ClinicalTrials.gov

    2016-02-17

    Cardiovascular Diseases; Coronary Disease; Cerebrovascular Accident; Heart Diseases; Myocardial Infarction; Infection; Chlamydia Infections; Cytomegalovirus Infections; Helicobacter Infections; Atherosclerosis

  11. Kawasaki Disease.

    PubMed

    Newburger, Jane W; Takahashi, Masato; Burns, Jane C

    2016-04-12

    Kawasaki disease is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and children. If not treated early with high-dose intravenous immunoglobulin, 1 in 5 children develop coronary artery aneurysms; this risk is reduced 5-fold if intravenous immunoglobulin is administered within 10 days of fever onset. Coronary artery aneurysms evolve dynamically over time, usually reaching a peak dimension by 6 weeks after illness onset. Almost all the morbidity and mortality occur in patients with giant aneurysms. Risk of myocardial infarction from coronary artery thrombosis is greatest in the first 2 years after illness onset. However, stenosis and occlusion progress over years. Indeed, Kawasaki disease is no longer a rare cause of acute coronary syndrome presenting in young adults. Both coronary artery bypass surgery and percutaneous intervention have been used to treat Kawasaki disease patients who develop myocardial ischemia as a consequence of coronary artery aneurysms and stenosis. PMID:27056781

  12. [Refsum disease].

    PubMed

    Hochner, I; Blickle, J F; Brogard, J M

    1996-01-01

    Refsum's disease, firstly described almost 50 years ago by the Norvegian neurologist Sigvald Refsum, is an autosomic recessive disease affecting mostly the Scandinavians and the populations originating from Northern Europe. The disease results from a specific enzyme deficiency of the first step of phytanic acid catabolism pathway. This deficiency leads to an accumulation of this C20 fatty acid in the serum and the tissues with a preference for adipose tissue, liver and kidneys. The clinical picture includes retinitis pigmentosa, peripheral neuropathy, ataxia and elevated cerebrospinal fluid protein concentration. Other less frequent manifestations include cranial nerves deficiency, myocardiopathy, renal tubular dysfunction and ichtyosis. The diagnosis relies on serum phytanic acid measurement. The treatment consists of a phytanic-acid free diet sometimes associated with plasmapheresis. This treatment is generally effective on neuropathy but not on cranial nerves dysfunction and retinitis pigmentosa.

  13. Dent's disease

    PubMed Central

    2010-01-01

    Dent's disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. These features are generally found in males only, and may be present in early childhood, whereas female carriers may show a milder phenotype. Prevalence is unknown; the disorder has been reported in around 250 families to date. Complications such as rickets or osteomalacia may occur. The disease is caused by mutations in either the CLCN5 (Dent disease 1) or OCRL1 (Dent disease 2) genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl-/H+ exchanger ClC-5, which belongs to the CLC family of Cl- channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP2) 5-phosphatase and mutations are also associated with Lowe Syndrome. The phenotype of Dent's disease is explained by the predominant expression of ClC-5 in the proximal tubule segments of the kidney. No genotype-phenotype correlation has been described thus far, and there is considerable intra-familial variability in disease severity. A few patients with Dent's disease do not harbour mutations in CLCN5 and OCRL1, pointing to the involvement of other genes. Diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia or renal insufficiency. Molecular genetic testing confirms the diagnosis. The differential diagnosis includes other causes of generalized dysfunction of the proximal tubules (renal Fanconi syndrome), hereditary, acquired, or caused by exogenous substances. Antenatal diagnosis and pre-implantation genetic testing is not advised. The care of patients with Dent's disease is supportive, focusing on the treatment of hypercalciuria and the prevention of

  14. Autoinflammatory Diseases

    MedlinePlus

    ... Behçet’s Disease Progress and Promise Key Words The Immune System When your body is attacked—perhaps by a virus or other germs—your immune system defends you. It “sees” and kills the germs ...

  15. Foodborne Diseases

    MedlinePlus

    ... Centers for Disease Control and Prevention Foodsafety.gov ​​ Javascript Error Your browser JavaScript is turned off causing certain features of the ... incorrectly. Please visit your browser settings and turn JavaScript on. Read more information on enabling JavaScript. Top ...

  16. Wilson Disease

    MedlinePlus

    ... or 414–961–0533 Email: info@wilsonsdisease.org Internet: www.wilsonsdisease.org National Organization for Rare Disorders ... or 203–744–0100 Fax: 203–798–2291 Internet: www.rarediseases.org Office of Rare Diseases Research ...

  17. SMUT DISEASES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A COMPREHENSIVE REVIEW OF MOST ASPECTS OF COMMON BUNT AND DWARF BUNT DISEASES OF WHEAT IS PRESENTED. INCLUDED ARE SECTIONS ON HISTORY, DISTRIBUTION AND ECONOMIC IMPORTANCE, TAXONOMY, MORPHOLOGY, SPORE GERMINATION, CULTURE, AND PHYSIOLOGY. EXTENSIVE SECTIONS DEAL WITH RESEARCH METHODOLOGY AND DISEA...

  18. Sunflower diseases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The sunflower disease chapter is part of the Sunflower Oilseeds Monograph, which will be a new publication in the AOCS Oilseeds Monograph series. The monograph contains an overview and history of sunflower crop development, how the oilseed is cultivated, how the oilseed is produced, how the seed is...

  19. Blount Disease

    MedlinePlus

    ... Fitness Diseases & Conditions Infections Q&A School & Jobs Drugs & Alcohol Staying Safe Recipes En Español Making a Change – Your Personal Plan Hot Topics Meningitis Choosing Your Mood Prescription Drug Abuse Healthy School Lunch Planner How Can I ...

  20. [Autoinflammatory diseases].

    PubMed

    Russo, Ricardo A G; Katsicas, María M

    2016-01-01

    The monogenic autoinflammatory diseases are rare, genetic disorders resulting in constitutive innate immune defects leading to excessive response to danger signals, spontaneous activation of inflammatory mediators or loss of inhibitory regulators. During the past 15 years, a growing number of monogenic inflammatory diseases have been described and their respective responsible genes identified. The proteins encoded by these genes are involved in the regulatory pathways of inflammation and are mostly expressed in cells of the innate immune system. Although a group of patients exhibit episodic systemic inflammation (periodic fevers), these disorders are mediated by continuous overproduction and release of pro-inflammatory mediators, notably IL-1β, and are best considered as autoinflammatory diseases rather than periodic fevers. The most common autoinflammatory diseases are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS) and the cryopyrin-associated periodic syndromes (CAPS). Clinical features often include fever, cutaneous rash, serosal involvement and acute phase reactants. Autoantibodies are usually absent but may accompany certain syndromes. Diagnosis remains clinical and is based on the different phenotypic features. Genetic diagnosis is of utmost importance, but must be performed judiciously and interpreted cautiously. Treatment with biologic agents that block proinflammatory cytokines, particularly IL-1, has proved to be dramatically effective in many patients. Still, in many cases of autoinflammation no genetic abnormalities are detected and treatment remains suboptimal, raising the question of novel pathogenic mutations in unexplored genes and pathways. PMID:27295706

  1. Lung Diseases

    MedlinePlus

    When you breathe, your lungs take in oxygen from the air and deliver it to the bloodstream. The cells in your body need oxygen to ... you breathe nearly 25,000 times. People with lung disease have difficulty breathing. Millions of people in ...

  2. Celiac disease.

    PubMed

    Rivera, E; Assiri, A; Guandalini, S

    2013-10-01

    Celiac disease, with a prevalence around 1% of the general population, is the most common genetically-induced food intolerance in the world. Triggered by the ingestion of gluten in genetically predisposed individuals, this enteropathy may appear at any age, and is characterized by a wide variety of clinical signs and symptoms. Among them, gastrointestinal presentations include chronic diarrhea, abdominal pain, weight loss or failure to thrive in children; but extra-intestinal manifestations are also common, and actually appear to be on the rise. They include a large variety of ailments, such as dermatitis Herpetiformis, anemia, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminases, and even female infertility. For the clinician interested in oral diseases, celiac disease can lead to delayed tooth eruption, dental enamel hypoplasia, recurrent oral aphthae. Diagnosing celiac disease requires therefore a high degree of suspicion followed by a very sensitive screening test: serum levels of the autoantibody anti-tissue transglutaminase. A positive subject will then be confirmed by an intestinal biopsy, and will then be put on a strict gluten-free diet, that in most cases will bring a marked improvement of symptoms. Newer forms of treatment which in the future will probably be available to the non-responsive patients are currently being actively pursued. PMID:23496382

  3. Celiac disease.

    PubMed

    Green, Peter H R; Lebwohl, Benjamin; Greywoode, Ruby

    2015-05-01

    This review will focus on the pathogenesis, clinical manifestations, diagnosis, and management of celiac disease (CD). Given an increasing awareness of gluten-related disorders, medical professionals of all varieties are encountering patients with a diagnosis of CD or who are thought to have food intolerance to gluten. The prevalence of CD among the general population is estimated to be 1% in Western nations, and there is growing evidence for underdiagnosis of the disease, especially in non-Western nations that were traditionally believed to be unaffected. The development of serologic markers specific to CD has revolutionized the ability both to diagnose and monitor patients with the disease. Additionally, understanding of the clinical presentations of CD has undergone a major shift over the past half century. Although it is well understood that CD develops in genetically predisposed subjects exposed to gluten, the extent of other environmental factors in the pathogenesis of the disease is an area of continued research. Currently, the main therapeutic intervention for CD is a gluten-free diet; however, novel nondietary agents are under active investigation. Future areas of research should also help us understand the relationship of CD to other gluten-related disorders.

  4. Huntington's Disease

    MedlinePlus

    ... rather than by the loss of individual cells, scientists are using cutting-edge methods such as optogenetics (where neurons are activated or silenced in the brains of living animals using light beams) to probe the cause ... defects in HD. Scientists are also using stem cells to study disease ...

  5. Lyme disease.

    PubMed

    Chomel, B

    2015-08-01

    Lyme disease is among the most frequently diagnosed zoonotic tick-borne diseases worldwide. The number of human cases has been on the increase since the first recognition of its aetiological agent. Lyme disease is caused by spirochete bacteria belonging to the genus Borrelia, with B. burgdorferi sensu stricto (s.s.) found in the Americas, and B. afzelii and B. garinii, in addition to B. burgdorferi s.s., in Europe and Asia. Environmental factors, such as human encroachment onto habitats favourable to ticks and their hosts, reduced deforestation, increased human outdoor activities, and climatic factors favouring a wider distribution of tick vectors, have enhanced the impact of the disease on both humans and animals. Clinical manifestations in humans include, in the early phases, erythema migrans, followed several weeks later by neuro-borreliosis (meningo-radiculitis, meningitis or meningo-encephalitis), Lyme arthritis and/or Borrelia lymphocytoma. In dogs, acute signs include fever, general malaise, lameness, lymph node enlargement and polyarthritis, as well as neuro-borreliosis in the chronic form. Diagnosis is mainly serological in both humans and animals, based on either a two-tier approach (an immunoenzymatic test followed by a Western blot confirmatory test) in humans or C(6) peptide, only in dogs. Early treatment with antibiotics, such as doxycycline or amoxicillin, for three weeks usually reduces the risk of chronic disease. Tick control, including the use of tick repellents for both humans and animals, particularly dogs, is highly reliable in preventing transmission. Vaccines are not available to prevent human infection, whereas several vaccines are available to reduce transmission and the clinical manifestations of infection in dogs.

  6. Lyme disease.

    PubMed

    Chomel, B

    2015-08-01

    Lyme disease is among the most frequently diagnosed zoonotic tick-borne diseases worldwide. The number of human cases has been on the increase since the first recognition of its aetiological agent. Lyme disease is caused by spirochete bacteria belonging to the genus Borrelia, with B. burgdorferi sensu stricto (s.s.) found in the Americas, and B. afzelii and B. garinii, in addition to B. burgdorferi s.s., in Europe and Asia. Environmental factors, such as human encroachment onto habitats favourable to ticks and their hosts, reduced deforestation, increased human outdoor activities, and climatic factors favouring a wider distribution of tick vectors, have enhanced the impact of the disease on both humans and animals. Clinical manifestations in humans include, in the early phases, erythema migrans, followed several weeks later by neuro-borreliosis (meningo-radiculitis, meningitis or meningo-encephalitis), Lyme arthritis and/or Borrelia lymphocytoma. In dogs, acute signs include fever, general malaise, lameness, lymph node enlargement and polyarthritis, as well as neuro-borreliosis in the chronic form. Diagnosis is mainly serological in both humans and animals, based on either a two-tier approach (an immunoenzymatic test followed by a Western blot confirmatory test) in humans or C(6) peptide, only in dogs. Early treatment with antibiotics, such as doxycycline or amoxicillin, for three weeks usually reduces the risk of chronic disease. Tick control, including the use of tick repellents for both humans and animals, particularly dogs, is highly reliable in preventing transmission. Vaccines are not available to prevent human infection, whereas several vaccines are available to reduce transmission and the clinical manifestations of infection in dogs. PMID:26601457

  7. Fabry disease

    PubMed Central

    2010-01-01

    Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs

  8. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells.

    PubMed

    Hoban, Megan D; Cost, Gregory J; Mendel, Matthew C; Romero, Zulema; Kaufman, Michael L; Joglekar, Alok V; Ho, Michelle; Lumaquin, Dianne; Gray, David; Lill, Georgia R; Cooper, Aaron R; Urbinati, Fabrizia; Senadheera, Shantha; Zhu, Allen; Liu, Pei-Qi; Paschon, David E; Zhang, Lei; Rebar, Edward J; Wilber, Andrew; Wang, Xiaoyan; Gregory, Philip D; Holmes, Michael C; Reik, Andreas; Hollis, Roger P; Kohn, Donald B

    2015-04-23

    Sickle cell disease (SCD) is characterized by a single point mutation in the seventh codon of the β-globin gene. Site-specific correction of the sickle mutation in hematopoietic stem cells would allow for permanent production of normal red blood cells. Using zinc-finger nucleases (ZFNs) designed to flank the sickle mutation, we demonstrate efficient targeted cleavage at the β-globin locus with minimal off-target modification. By co-delivering a homologous donor template (either an integrase-defective lentiviral vector or a DNA oligonucleotide), high levels of gene modification were achieved in CD34(+) hematopoietic stem and progenitor cells. Modified cells maintained their ability to engraft NOD/SCID/IL2rγ(null) mice and to produce cells from multiple lineages, although with a reduction in the modification levels relative to the in vitro samples. Importantly, ZFN-driven gene correction in CD34(+) cells from the bone marrow of patients with SCD resulted in the production of wild-type hemoglobin tetramers.

  9. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells

    PubMed Central

    Hoban, Megan D.; Cost, Gregory J.; Mendel, Matthew C.; Romero, Zulema; Kaufman, Michael L.; Joglekar, Alok V.; Ho, Michelle; Lumaquin, Dianne; Gray, David; Lill, Georgia R.; Cooper, Aaron R.; Urbinati, Fabrizia; Senadheera, Shantha; Zhu, Allen; Liu, Pei-Qi; Paschon, David E.; Zhang, Lei; Rebar, Edward J.; Wilber, Andrew; Wang, Xiaoyan; Gregory, Philip D.; Holmes, Michael C.; Reik, Andreas; Hollis, Roger P.

    2015-01-01

    Sickle cell disease (SCD) is characterized by a single point mutation in the seventh codon of the β-globin gene. Site-specific correction of the sickle mutation in hematopoietic stem cells would allow for permanent production of normal red blood cells. Using zinc-finger nucleases (ZFNs) designed to flank the sickle mutation, we demonstrate efficient targeted cleavage at the β-globin locus with minimal off-target modification. By codelivering a homologous donor template (either an integrase-defective lentiviral vector or a DNA oligonucleotide), high levels of gene modification were achieved in CD34+ hematopoietic stem and progenitor cells. Modified cells maintained their ability to engraft NOD/SCID/IL2rγnull mice and to produce cells from multiple lineages, although with a reduction in the modification levels relative to the in vitro samples. Importantly, ZFN-driven gene correction in CD34+ cells from the bone marrow of patients with SCD resulted in the production of wild-type hemoglobin tetramers. PMID:25733580

  10. Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease

    PubMed Central

    Petro, Christopher; González, Pablo A; Cheshenko, Natalia; Jandl, Thomas; Khajoueinejad, Nazanin; Bénard, Angèle; Sengupta, Mayami; Herold, Betsy C; Jacobs, William R

    2015-01-01

    Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies. To test the hypothesis that deletion of gD-2 unmasks protective antigens, we evaluated the efficacy and safety of an HSV-2 virus deleted in gD-2 and complemented allowing a single round of replication on cells expressing HSV-1 gD (ΔgD−/+gD−1). Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD−/+gD1 provided 100% protection against lethal intravaginal or skin challenges and prevented latency. ΔgD−/+gD1 elicited no disease in SCID mice, whereas 1000-fold lower doses of wild-type virus were lethal. HSV-specific antibodies were detected in serum (titer 1:800,000) following immunization and in vaginal washes after intravaginal challenge. The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity. Passive transfer of immune serum completely protected wild-type, but not Fcγ-receptor or neonatal Fc-receptor knock-out mice. These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine. DOI: http://dx.doi.org/10.7554/eLife.06054.001 PMID:25756612

  11. The Jeremiah Metzger Lecture: gene therapy for inherited disorders: from Christmas disease to Leber's amaurosis.

    PubMed

    High, Katherine A

    2009-01-01

    This paper will focus on recent developments in the field of gene therapy for inherited disorders. From a historical perspective, this Metzger lecture is a follow-on to one presented by Dr. William Kelley in 1987, entitled "Current Status of Human Gene Therapy" (Transactions Am Clin. Climatol. Assoc. 99:152-169) (1). In 1987, gene transfer studies in human subjects were yet to be undertaken; the first clinical studies, infusion of genetically modified autologous T cells into two young girls with ADA-SCID, would not take place until 1990 (2). Today's lecture will summarize progress since that time in one area, that of in vivo gene transfer for genetic disease. I will describe progress in two areas, gene therapy for the bleeding disorder hemophilia B, and for a subset of retinal degenerative disorders termed Leber's congenital amaurosis, due to mutations in the gene encoding retinal pigment epithelium-specific 65 kilodalton protein (RPE65). This lecture will demonstrate the interconnected nature of progress in these two areas, as careful delineation of the obstacles in hemophilia led to the realization that success could be achieved in Leber's.

  12. Huntington's Disease.

    PubMed

    Walker, Francis O

    2007-04-01

    Huntington's disease may present at any age, but most typically manifests between the ages of 35 and 45 years as a slowly progressive neurodegenerative movement disorder with cognitive and behavioral impairment. It is an autosomal-dominant disorder that has a substantial impact on family structure and dynamics in terms of providing care for affected family members and, for the offspring of an affected parent, dealing with at-risk status. Therapy that slows the progressive neuronal dysfunction or degeneration is unavailable, so pharmacotherapy is currently aimed primarily at managing behavioral and psychiatric symptoms, and, in selected cases, controlling severe chorea. Effective intervention by clinicians is possible, however, in terms of providing patients and families with accurate information about the disease, counseling them about availability of genetic testing at specialized centers, and in giving them sound advice regarding work, driving, relationships, finances, research participation, and support groups.

  13. Thyroid disease

    SciTech Connect

    Falk, S.

    1990-01-01

    Presenting a multidisciplinary approach to the diagnosis and treatment of thyroid disease, this volume provides a comprehensive picture of current thyroid medicine and surgery. The book integrates the perspectives of the many disciplines that deal with the clinical manifestations of thyroid disorders. Adding to the clinical usefulness of the book is the state-of-the-art coverage of many recent developments in thyroidology, including the use of highly sensitive two-site TSH immunoradionetric measurements to diagnose thyroid activity; thyroglobulin assays in thyroid cancer and other diseases; new diagnostic applications of MRI and CT; treatment with radionuclides and chemotherapy; new developments in thyroid immunology, pathology, and management of hyperthyroidism; suppressive treatment with thyroid hormone; and management of Graves' ophthalmopathy. The book also covers all aspects of thyroid surgery, including surgical treatment of hyperthyroidism; papillary, follicular, and other carcinomas; thyroidectomy; and prevention and management of complications.

  14. Gaucher disease.

    PubMed

    Mignot, Cyril; Gelot, Antoinette; De Villemeur, Thierry Billette

    2013-01-01

    Gaucher disease is an autosomal recessive condition due to glucocerebrosidase deficiency responsible for the lysosomal accumulation of glucosylceramide, a complex lipid derived from cell membranes, mainly in macrophages. It is due to mutations mostly in the GBA gene, although saposine C deficiency is due to mutations in the PSAP gene. It encompasses an extremely heterogeneous spectrum of clinical involvement from the fetus to adulthood. Splenomegaly, blood cytopenia, and bone involvement are the main manifestations of Gaucher disease, but nervous system degeneration is observed in about 5-10% of patients. The accumulation in neurons of glucosylceramide and its derivative, psychosine, are thought to underlie neuronal dysfunction and death, although Gaucher cells that mostly accumulate such substances are mainly macrophages. Enzyme replacement therapy dramatically improves the outcome of patients because of its extreme efficacy in the treatment of the systemic involvement. However, it has only limited effects on most neurological signs. PMID:23622393

  15. Morgellons disease?

    PubMed

    Accordino, Robert E; Engler, Danielle; Ginsburg, Iona H; Koo, John

    2008-01-01

    Morgellons disease, a pattern of dermatologic symptoms very similar, if not identical, to those of delusions of parasitosis, was first described many centuries ago, but has recently been given much attention on the internet and in the mass media. The present authors present a history of Morgellons disease, in addition to which they discuss the potential benefit of using this diagnostic term as a means of building trust and rapport with patients to maximize treatment benefit. The present authors also suggest "meeting the patient halfway" and creating a therapeutic alliance when providing dermatologic treatment by taking their cutaneous symptoms seriously enough to provide both topical ointments as well as antipsychotic medications, which can be therapeutic in these patients. PMID:18318880

  16. Morgellons disease?

    PubMed

    Accordino, Robert E; Engler, Danielle; Ginsburg, Iona H; Koo, John

    2008-01-01

    Morgellons disease, a pattern of dermatologic symptoms very similar, if not identical, to those of delusions of parasitosis, was first described many centuries ago, but has recently been given much attention on the internet and in the mass media. The present authors present a history of Morgellons disease, in addition to which they discuss the potential benefit of using this diagnostic term as a means of building trust and rapport with patients to maximize treatment benefit. The present authors also suggest "meeting the patient halfway" and creating a therapeutic alliance when providing dermatologic treatment by taking their cutaneous symptoms seriously enough to provide both topical ointments as well as antipsychotic medications, which can be therapeutic in these patients.

  17. Coronary heart disease

    MedlinePlus

    Heart disease, Coronary heart disease, Coronary artery disease; Arteriosclerotic heart disease; CHD; CAD ... down or stop. A risk factor for heart disease is something that increases your chance of getting ...

  18. [Wilsons disease].

    PubMed

    Mareček, Z; Brůha, R

    2013-07-01

    Wilsons disease is an autosomal recessive genetic disorder in which copper accumulates in tissues, especially in the liver and the brain. The genetic defect affects the P type ATPase gene (ATP7B). More than 500 mutations causing Wilsons disease have been described. The most common mutation in Central Europe concerns H1069Q. The symptoms of Wilsons disease include hepatic or neurological conditions. The hepatic condition is manifested as steatosis, acute or chronic hepatitis or cirrhosis. The neurological conditions are most often manifested after the age of 20 as motor disorders (tremor, speech and writing disorders), which may result in severe extrapyramidal syndrome with rigidity, dysarthria and muscle contractions. The dia-gnosis is based on clinical and laboratory assessments (neurological signs, liver lesions, low ceruloplasmin, increased free serum copper, high Cu volumes in urine, KayserFleischer ring). The dia-gnosis is confirmed by a high Cu level in liver tissue or genetic proof. Untreated Wilsons disease causes death of the patient. If treated properly the survival rate approximates to the survival rate of the common population. The treatment concerns either removal of copper from the body using chelating agents excreted into the urine (Penicillamine, Trientine) or limitation of copper absorption from the intestine and reducing the toxicity of copper (zinc, ammonium tetrathiomolybdate). In the Czech Republic, Penicillamine or zinc is used. A liver transplant is indicated in patients with fulminant hepatic failure or decompensated liver cirrhosis. In the family all siblings of the affected individual need to be screened in order to treat any asymptomatic subjects.

  19. [Wilsons disease].

    PubMed

    Mareček, Z; Brůha, R

    2013-07-01

    Wilsons disease is an autosomal recessive genetic disorder in which copper accumulates in tissues, especially in the liver and the brain. The genetic defect affects the P type ATPase gene (ATP7B). More than 500 mutations causing Wilsons disease have been described. The most common mutation in Central Europe concerns H1069Q. The symptoms of Wilsons disease include hepatic or neurological conditions. The hepatic condition is manifested as steatosis, acute or chronic hepatitis or cirrhosis. The neurological conditions are most often manifested after the age of 20 as motor disorders (tremor, speech and writing disorders), which may result in severe extrapyramidal syndrome with rigidity, dysarthria and muscle contractions. The dia-gnosis is based on clinical and laboratory assessments (neurological signs, liver lesions, low ceruloplasmin, increased free serum copper, high Cu volumes in urine, KayserFleischer ring). The dia-gnosis is confirmed by a high Cu level in liver tissue or genetic proof. Untreated Wilsons disease causes death of the patient. If treated properly the survival rate approximates to the survival rate of the common population. The treatment concerns either removal of copper from the body using chelating agents excreted into the urine (Penicillamine, Trientine) or limitation of copper absorption from the intestine and reducing the toxicity of copper (zinc, ammonium tetrathiomolybdate). In the Czech Republic, Penicillamine or zinc is used. A liver transplant is indicated in patients with fulminant hepatic failure or decompensated liver cirrhosis. In the family all siblings of the affected individual need to be screened in order to treat any asymptomatic subjects. PMID:23909262

  20. Beryllium disease

    SciTech Connect

    Not Available

    1991-12-20

    After two workers at the nuclear weapons plant at Oak Ridge National Laboratory in Tennessee were diagnosed earlier this year with chronic beryllium disease (CBD), a rare and sometimes fatal scarring of the lungs, the Department of Energy ordered up a 4-year probe. Now, part of that probe has begun - tests conducted by the Oak Ridge Associated Universities' Center for Epidemiological Research measuring beryllium sensitivity in 3,000 people who've been exposed to the metal's dust since Manhattan Project managers opened the Y-12 plant at Oak Ridge in 1943. Currently, 119 Y-12 employees process beryllium, which has a number of industrial uses, including rocket heat shields and nuclear weapon and electrical components. The disease often takes 20 to 25 years to develop, and the stricken employees haven't worked with beryllium for years. There is no cure for CBD, estimated to strike 2% of people exposed to the metal. Anti-inflammatory steroids alleviate such symptoms as a dry cough, weight loss, and fatigue. Like other lung-fibrosis diseases that are linked to lung cancer, some people suspect CBD might cause some lung cancer. While difficult to diagnose, about 900 cases of CBD have been reported since a Beryllium Case Registry was established in 1952. The Department of Energy (DOE) estimates that about 10,000 DOE employees and 800,000 people in private industry have worked with beryllium.

  1. Wilson's disease.

    PubMed

    Loudianos, G; Gitlin, J D

    2000-01-01

    Wilson's disease is an autosomal recessive disorder of copper metabolism resulting from the absence or dysfunction of a copper transporting P-type ATPase encoded on chromosome 13. This ATPase is expressed in hepatocytes where it is localized to the trans-Golgi network and transports copper into the secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Under physiologic circumstances, biliary excretion represents the sole mechanism for copper excretion, and thus affected individuals have progressive copper accumulation in the liver. When the capacity for hepatic storage is exceeded, cell death ensues with copper release into the plasma, hemolysis, and tissue deposition. Presentation in childhood may include chronic hepatitis, asymptomatic cirrhosis, or acute liver failure. In young adults, neuropsychiatric symptoms predominate and include dystonia, tremor, personality changes, and cognitive impairments secondary to copper accumulation in the central nervous system. The laboratory diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper content, and elevated hepatic copper concentration. Molecular genetic analysis is complex as more than 100 unique mutations have been identified and most individuals are compound heterozygotes. Copper chelation with penicillamine is an effective therapy in most patients and hepatic transplantation is curative in individuals presenting with irreversible liver failure. Elucidation of the molecular genetic basis of Wilson's disease has permitted new insights into the mechanisms of cellular copper homeostasis.

  2. Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma.

    PubMed

    Sonar, Sanchaita Sriwal; Hsu, Yen-Ming; Conrad, Melanie Lynn; Majeau, Gerard R; Kilic, Ayse; Garber, Ellen; Gao, Yan; Nwankwo, Chioma; Willer, Gundi; Dudda, Jan C; Kim, Hellen; Bailly, Véronique; Pagenstecher, Axel; Rennert, Paul D; Renz, Harald

    2010-08-01

    Studies in mice and humans have revealed that the T cell, immunoglobulin, mucin (TIM) genes are associated with several atopic diseases. TIM-1 is a type I membrane protein that is expressed on T cells upon stimulation and has been shown to modulate their activation. In addition to a recently described interaction with dendritic cells, TIM-1 has also been identified as a phosphatidylserine recognition molecule, and several protein ligands have been proposed. Our understanding of its activity is complicated by the possibility that TIM-1 possesses multiple and diverse binding partners. In order to delineate the function of TIM-1, we generated monoclonal antibodies directed to a cleft formed within the IgV domain of TIM-1. We have shown here that antibodies that bind to this defined cleft antagonize TIM-1 binding to specific ligands and cells. Notably, these antibodies exhibited therapeutic activity in a humanized SCID model of experimental asthma, ameliorating inflammation, and airway hyperresponsiveness. Further experiments demonstrated that the effects of the TIM-1-specific antibodies were mediated via suppression of Th2 cell proliferation and cytokine production. These results demonstrate that modulation of the TIM-1 pathway can critically influence activated T cells in a humanized disease model, suggesting that TIM-1 antagonists may provide potent therapeutic benefit in asthma and other immune-mediated disorders.

  3. Cardiovascular Disease

    PubMed Central

    Grace, Sherry L; Fry, Rick; Cheung, Angela; Stewart, Donna E

    2004-01-01

    Health Issue Cardiovascular disease (CVD) is the leading cause of death in Canadian women and men. In general, women present with a wider range of symptoms, are more likely to delay seeking medial care and are less likely to be investigated and treated with evidence-based medications, angioplasty or coronary artery bypass graft than men. Key Findings In 1998, 78,964 Canadians died from CVD, almost half (39,197) were women. Acute myocardial infarction, which increases significantly after menopause, was the leading cause of death among women. Cardiovascular disease accounted for 21% of all hospital admissions for Canadian women over age 50 in 1999. Admissions to hospital for ischemic heart disease were more frequent for men, but the mean length of hospital stay was longer for women. Mean blood pressure increases with age in both men and women. After age 65, however, high blood pressure is more common among Canadian women. More than one-third of postmenopausal Canadian women have hypertension. Diabetes increases the mortality and morbidity associated with CVD in women more than it does in men. Depression also contributes to the incidence and recovery from CVD, particularly for women who experience twice the rate of depression as men. Data Gaps and Recommendations CVD needs to be recognized as a woman's health issue given Canadian mortality projections (particularly heart failure). Health professionals should be trained to screen, track, and address CVD risk factors among women, including hypertension, elevated lipid levels, smoking, physical inactivity, depression, diabetes and low socio-economic status. PMID:15345078

  4. [Renal disease].

    PubMed

    Espinosa-Cuevas, María de Los Ángeles

    2016-09-01

    Chronic renal failure in its various stages, requires certain nutritional restrictions associated with the accumulation of minerals and waste products that cannot be easily eliminated by the kidneys. Some of these restrictions modify the intake of proteins, sodium, and phosphorus. Milk and dairy products are sources of these nutrients. This article aims to inform the reader about the benefits including milk and dairy products relying on a scientific and critical view according to the clinical conditions and the stage of renal disease in which the patient is. PMID:27603894

  5. [Renal disease].

    PubMed

    Espinosa-Cuevas, María de Los Ángeles

    2016-09-01

    Chronic renal failure in its various stages, requires certain nutritional restrictions associated with the accumulation of minerals and waste products that cannot be easily eliminated by the kidneys. Some of these restrictions modify the intake of proteins, sodium, and phosphorus. Milk and dairy products are sources of these nutrients. This article aims to inform the reader about the benefits including milk and dairy products relying on a scientific and critical view according to the clinical conditions and the stage of renal disease in which the patient is.

  6. [Bone diseases].

    PubMed

    Uebelhart, Brigitte; Rizzoli, René

    2016-01-13

    Calcium intake shows a small impact on bone mineral density and fracture risk. Denosumab is a more potent inhibitor of bone resorption than zoledronate. Abaloparatide, PTHrP analog, increases bone mineral density and decreases fracture incidence. Teriparatide could be delivered via a transdermic device. Romosozumab and odanacatib improve calculated bone strength. Sequential or combined treatments with denosumab and teriparatide could be of interest, but not denosumab followed by teriparatide. Fibrous dysplasia, Paget disease and hypophosphatasia are updated, as well as atypical femoral fracture and osteonecrosis of the jaw.

  7. Lyme disease.

    PubMed

    Goldings, E A; Jericho, J

    1986-08-01

    Although initially considered a localized epidemic form of arthritis. Lyme disease is now known to have protean manifestation (skin, joint, heart, nervous system) and worldwide distribution. It is caused by infection with the spirochaete Borrelia burgdorferi and is transmitted by a variety of hard ticks and, in some localities, fleas. Antigenic variation between isolates may determine the differences in clinical expression observed between cases in North America and Europe. The reservoir in the animal kingdom is primarily in deer and mice but house pets have also been implicated. The disease is easily treated with oral antibiotics (tetracycline or penicillin) at an early stage but requires parenteral penicillin and can become refractory to medication at late stages. Prompt diagnosis assures the best outcome. Whereas the classic rash, erythema chronicum migrans, is pathognomonic, diagnosis in its absence may rest on serological tests. Bacteriological isolation is seldom successful and is lengthy (Shrestha et al, 1985). Since cloning of the DNA for several of B. burgdorferi antigens has been accomplished, utilization of hybridization techniques may allow rapid detection of the presence of the organism and confirm difficult cases in the future.

  8. Celiac Disease

    PubMed Central

    Rubio-Tapia, Alberto; Murray, Joseph A

    2010-01-01

    Purpose of review To summarize recent advances in celiac disease (CD) published between August 2008 and July 2009. Recent findings CD affects ~1% of most populations but remains largely unrecognized. In the last year, work has shown that the prevalence of CD has increased dramatically, not simply due to increased detection. Also, undiagnosed CD may be associated with increased mortality. Significant progress has been made in understanding how gliadin peptides can cross the intestinal border and access the immune system. New genetic loci and candidate genes that may contribute to the risk of CD and its overlap with type 1 diabetes mellitus have been identified. New deamidated gliadin peptides antibodies have better diagnostic accuracy over native gliadin-based tests. The inclusion of duodenal bulb biopsy specimens may increase the rate of CD detection. The spectrum of CD likely includes a minority of patients with mild enteropathy. A practical 7-item instrument may facilitate standardized evaluation of gluten-free diet adherence. Finally, refractory CD, whilst rare, is associated with a poor prognosis. Summary Celiac disease is a global health problem that requires a multidisciplinary and increasingly cooperative multinational research effort. PMID:20040864

  9. [Refsum disease].

    PubMed

    Bernscherer, G; Berényi, E; Karabélyos, C; László, A; Dávid, Z; Hollódy, K; Tóth, E Z

    2000-01-01

    For the first time in literature the authors interpret the pathography of Refsum's disease, in the case of their patient, as pseudo-hypervitaminosis A. The biochemical basis of the clinical picture is a defect in the activity of phytanic-acid-alpha-hydrolase belonging to the peroxisomal system. As a consequence, phytanic acid accumulates in the serum and in the parenchymal tissues. Retinol, an alcohol with high molecular weight, is a natural ligand of nuclear RXR (retinoid-X-receptor), which plays an important role in the regulation of peroxisoma synthesis. In Refsum's disease the phytanic acid accumulated because of the enzyme defect competes with the biotransformation derivates (all-trans-retinoic acid, 9-cis-retinoic acid) of the all-trans-retinol (vitamin A) for the nuclear RX receptor binding sites, and as a very potent receptoractivator it causes the intestinal symptoms of hypervitaminosis A. The authors review the procedure of fatty-acid chromatography necessary for the establishment of the diagnosis and discuss--in addition to dietary restrictions--recent therapeutic possibilities, like plasmapheresis, cascade filtration, lipapheresis and oral batylalcohol treatment.

  10. Chagas' disease.

    PubMed Central

    Tanowitz, H B; Kirchhoff, L V; Simon, D; Morris, S A; Weiss, L M; Wittner, M

    1992-01-01

    Chagas' disease, caused by Trypanosoma cruzi, is an important cause of morbidity in many countries in Latin America. The important modes of transmission are by the bite of the reduviid bug and blood transfusion. The organism exists in three morphological forms: trypomastigotes, amastigotes, and epimastigotes. The mechanism of transformation and differentiation is currently being explored, and signal transduction pathways of the parasites may be involved in this process. Parasite adherence to and invasion of host cells is a complex process involving complement, phospholipase, penetrin, neuraminidase, and hemolysin. Two clinical forms of the disease are recognized, acute and chronic. During the acute stage pathological damage is related to the presence of the parasite, whereas in the chronic stage few parasites are found. In recent years the roles of tumor necrosis factor, gamma interferon, and the interleukins in the pathogenesis of this infection have been reported. The common manifestations of chronic cardiomyopathy are arrhythmias and thromboembolic events. Autoimmune, neurogenic, and microvascular factors may be important in the pathogenesis of the cardiomyopathy. The gastrointestinal tract is another important target, and "mega syndromes" are common manifestations. The diagnosis and treatment of this infection are active areas of investigation. New serological and molecular biological techniques have improved the diagnosis of chronic infection. Exacerbations of T. cruzi infection have been reported for patients receiving immuno-suppressive therapy and for those with AIDS. Images PMID:1423218

  11. Alzheimer's disease.

    PubMed

    De-Paula, Vanessa J; Radanovic, Marcia; Diniz, Breno S; Forlenza, Orestes V

    2012-01-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms, mostly affecting medial temporal lobe and associative neocortical structures. Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Aβ) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons. According to the amyloid hypothesis of AD, the overproduction of Aβ is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). Genetic, age-related and environmental factors contribute to a metabolic shift favoring the amyloidogenic processing of APP in detriment of the physiological, secretory pathway. Aβ peptides are generated by the successive cleavage of APP by beta-secretase (BACE-1) and gamma-secretase, which has been recently characterized as part of the presenilin complex. Among several beta-amyloid isoforms that bear subtle differences depending on the number of C-terminal amino acids, Aβ (1-42) plays a pivotal role in the pathogenesis of AD. The neurotoxic potential of the Aβ peptide results from its biochemical properties that favor aggregation into insoluble oligomers and protofibrils. These further originate fibrillary Aβ species that accumulate into senile and neuritic plaques. These processes, along with a reduction of Aβ clearance from the brain, leads to the extracellular accumulation of Aβ, and the subsequent activation of neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and cellular death. Intracerebral amyloidosis develops in AD patients in an age-dependent manner, but recent evidence indicate that it may be observed in some subjects as early as in the third or fourth decades of life, with increasing magnitude in late middle age

  12. [Pancreatic Diseases].

    PubMed

    Schöfl, Rainer

    2016-06-22

    The author presents his personal choice of practical relevant papers of pancreatic diseases from 2014 to 2015. Nutritional factors and hypertriglycidemia are discussed as causes of acute pancreatitis. Tools to avoid post-ERCP(endoscopic retrograde cholangiopancreatography) pancreatitis are described and the natural course of fluid collections and pseudocysts is demonstrated. The value of secretin-MRCP(magnetic resonance cholangiopancreatography) for diagnosis of chronic pancreatitis is illustrated. Data help to choose the minimally effective prednisolone dose in autoimmune pancreatitis. The increased prevalence of fractures in patients with chronic pancreatitis highlights the necessity of screening for bone density loss. The association of vitamin D intake with pancreatic cancer is described. The probability of cancer in IPNM is shown and innovative surgical concepts to reduce the loss of pancreatic function are presented. Finally neoadjuvant concepts for the treatment of pancreatic cancer are highlighted. PMID:27329710

  13. Disease Activity Measures in Paediatric Rheumatic Diseases

    PubMed Central

    Luca, Nadia J.; Feldman, Brian M.

    2013-01-01

    Disease activity refers to potentially reversible aspects of a disease. Measurement of disease activity in paediatric rheumatic diseases is a critical component of patient care and clinical research. Disease activity measures are developed systematically, often involving consensus methods. To be useful, a disease activity measure must be feasible, valid, and interpretable. There are several challenges in quantifying disease activity in paediatric rheumatology; namely, the conditions are multidimensional, the level of activity must be valuated in the context of treatment being received, there is no gold standard for disease activity, and it is often difficult to incorporate the patient's perspective of their disease activity. To date, core sets of response variables are defined for juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, and juvenile dermatomyositis, as well as definitions for improvement in response to therapy. Several specific absolute disease activity measures also exist for each condition. Further work is required to determine the optimal disease activity measures in paediatric rheumatology. PMID:24089617

  14. Vibroacoustic disease.

    PubMed

    Branco, N A A Castelo; Alves-Pereira, M

    2004-01-01

    Vibroacoustic disease (VAD) is a whole-body, systemic pathology, characterized by the abnormal proliferation of extra-cellular matrices, and caused by excessive exposure to low frequency noise (LFN). VAD has been observed in LFN-exposed professionals, such as, aircraft technicians, commercial and military pilots and cabin crewmembers, ship machinists, restaurant workers, and disk-jockeys. VAD has also been observed in several populations exposed to environmental LFN. This report summarizes what is known to date on VAD, LFN-induced pathology, and related issues. In 1987, the first autopsy of a deceased VAD patient was performed. The extent of LFN induced damage was overwhelming, and the information obtained is, still today, guiding many of the associated and ongoing research projects. In 1992, LFN-exposed animal models began to be studied in order to gain a deeper knowledge of how tissues respond to this acoustic stressor. In both human and animal models, LFN exposure causes thickening of cardiovascular structures. Indeed, pericardial thickening with no inflammatory process, and in the absence of diastolic dysfunction, is the hallmark of VAD. Depressions, increased irritability and aggressiveness, a tendency for isolation, and decreased cognitive skills are all part of the clinical picture of VAD. LFN is a demonstrated genotoxic agent, inducing an increased frequency of sister chromatid exchanges in both human and animal models. The occurrence of malignancies among LFN-exposed humans, and of metaplastic and displastic appearances in LFN-exposed animals, clearly corroborates the mutagenic outcome of LFN exposure. The inadequacy of currently established legislation regarding noise assessments is a powerful hindrance to scientific advancement. VAD can never be fully recognized as an occupational and environmental pathology unless the agent of disease--LFN--is acknowledged and properly evaluated. The worldwide suffering of LFN-exposed individuals is staggering and it is

  15. [Thyroid disease].

    PubMed

    Ashitaka, Y

    1990-08-01

    The incidence of pregnant women with thyroid dysfunction has been reported to be around 0.1-0.4%. Graves' disease accounts for more than half of these disorders. The main cause of thyroid disease in pregnancy and puerperium is autoimmune dysfunction. Whether there may be goitre or exophthalmus present, clinical signs as inappropriate weight gain, high systolic pressure, palpitation (greater than or equal to 110/min), emotional lability, fatigue, acceleration of suppression of the Achilles' tendon reflex should induce changes in the biochemical thyroid function tests. Parameters for the diagnosis and management for hyperthyroidism are serum levels of free T4 and TSH, while those of T3, reverse T3, and TSH are for hypothyroidism. Serum anti-microsomal antibodies and anti-thyroglobulin antibodies which have no effect on the fetus are also good markers for severity. The transplacental transfer of maternal TSH receptor antibodies consisting of stimulatory and inhibitory immunoglobulins and maternal thyroid-binding inhibiting immunoglobulins play roles in the development of transient neonatal hyper- or hypothyroidism. Fetal control is achieved by optimal maternal management. Untreated hyperthyroidism may be associated with fetal malformations. This risk may be reduced by antithyroid drug treatment of up to 150 mg/day of propylthiouracil which has less chance of placental passage and less secretion into the mother's milk than methyl-mercapto-imidazol. Maternal thyroid function should be kept in the upper limit of normal range, taking into consideration the fetal dysfunction induced by over-administration of the drug which passes through placenta. Children of hypothyroid women taking inadequate replacement therapy manifested lower IQ values compared to the progeny of euthyroid or hypothyroid women taking adequate therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Undifferentiated Connective Tissue Disease

    MedlinePlus

    ... Home Conditions Undifferentiated Connective Tissue Disease (UCTD) Undifferentiated Connective Tissue Disease (UCTD) Make an Appointment Find a Doctor ... L. Goldstein, MD, MMSc (February 01, 2016) Undifferentiated connective tissue disease (UCTD) is a systemic autoimmune disease. This ...

  17. American Lyme Disease Foundation

    MedlinePlus

    ... Infectious Diseases, 35: 451-464, 2002) What is Lyme Disease? Lyme disease (LD) is an infection caused by ... mission with your own tax-deductible contribution. American Lyme Disease Foundation, Inc. PO Box 466 Lyme, CT 06371 ...

  18. Motor Neuron Diseases

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Motor Neuron Diseases Information Page Condensed from Motor Neuron Diseases ... and Information Publicaciones en Español What are Motor Neuron Diseases? The motor neuron diseases (MNDs) are a ...

  19. Meniere's disease.

    PubMed

    Nakashima, Tsutomu; Pyykkö, Ilmari; Arroll, Megan A; Casselbrant, Margaretha L; Foster, Carol A; Manzoor, Nauman F; Megerian, Cliff A; Naganawa, Shinji; Young, Yi-Ho

    2016-01-01

    Meniere's disease (MD) is a disorder of the inner ear that causes vertigo attacks, fluctuating hearing loss, tinnitus and aural fullness. The aetiology of MD is multifactorial. A characteristic sign of MD is endolymphatic hydrops (EH), a disorder in which excessive endolymph accumulates in the inner ear and causes damage to the ganglion cells. In most patients, the clinical symptoms of MD present after considerable accumulation of endolymph has occurred. However, some patients develop symptoms in the early stages of EH. The reason for the variability in the symptomatology is unknown and the relationship between EH and the clinical symptoms of MD requires further study. The diagnosis of MD is based on clinical symptoms but can be complemented with functional inner ear tests, including audiometry, vestibular-evoked myogenic potential testing, caloric testing, electrocochleography or head impulse tests. MRI has been optimized to directly visualize EH in the cochlea, vestibule and semicircular canals, and its use is shifting from the research setting to the clinic. The management of MD is mainly aimed at the relief of acute attacks of vertigo and the prevention of recurrent attacks. Therapeutic options are based on empirical evidence and include the management of risk factors and a conservative approach as the first line of treatment. When medical treatment is unable to suppress vertigo attacks, intratympanic gentamicin therapy or endolymphatic sac decompression surgery is usually considered. This Primer covers the pathophysiology, symptomatology, diagnosis, management, quality of life and prevention of MD. PMID:27170253

  20. [Castleman disease].

    PubMed

    Belletti, Gerardo A; Savio, Verónica; Minoldo, Daniel; Caminos, Susana; Yorio, Marcelo A

    2004-01-01

    A 66 years female, who was since last year under astenia, arthralgias, pimply lesions in spread plates and tests showing eritrosedimentation over 100 mm, anemi, leucocitosis with neutrofilia, policlonal hypergammaglobulinemia, slight proteinuria and IgE on 900. This patient was sporadically treated with corticoids. When made the medical consult had lost 34lb., was under anorexy, as well as dyspepsia. Hemoglobyn 6.9 gr/dl, leucocytes 20000/mm3, neutrofils at 90%, proteinogram the same as former, with hypoalbuminemia. She was taking prednisona, 16 mg/day. When examined showed depress of conscience, astenia, and dermic lesions already quoted. 4 cm nonpainful right axillary adenopaty adhered to deep planes. Medulogram with increased iron, hyperegenerative. Ganglionar biopsia: linfoid hyperplasic process linked to inmune response. Toracoabdominal tomography with adenomegalia in torax and retroperitoneo. Skin biopsia: neutrofilic vasculitis. The patient suspends the 16 mg of prednisona and fever as well as generalized adenopatias come up. After laying aside other ethiologies, and understanding as Castleman Multicentric disease, it is started to supply prednisona 1 mg/kg of weight with a clinical and biochemical fast and outstanding response. After 7 months it was progressively suspended the esteroids and 60 days later, the process fall back; for that, corticoids are restarted, with a good evolution. The illness of Castleman although it is not very frequent, it should be considered as differential diagnosis in those clinical cases that are accompanied with important general commitment, linphadenopaties and respons to steroid therapy.

  1. Natural cytotoxicity in immunodeficiency diseases: preservation of natural killer activity and the in vivo appearance of radioresistant killing

    SciTech Connect

    Pierce, G.F.; Polmar, S.H.; Schacter, B.Z.; Brovall, C.; Hornick, D.L.; Sorensen, R.U.

    1986-01-01

    We studied spontaneous natural killer (NK) cell activity and radiation-resistant NK mediated cytotoxicity in four patients with clinically documented severe combined immune deficiency disease (SCID), and in one subject each with intestinal lymphangiectasia and cartilage-hair hypoplasia. We observed the preservation of spontaneous NK activity in all patients despite the presence of profound B- and T-lymphocytopenia and clinical immunodeficiency. NK activity was associated with relatively normal circulating numbers of OKM1+ lymphocytes, a population known to contain NK effectors. Spontaneous NK activity resistant to 3000 rad was increased in all patients, indicating the presence of activated natural killer cells in vivo. The concept of a chronically activated immune system in these patients was further supported by the presence of increased Ia positive T cells in all subjects tested, suggesting that radioresistant NK activity may be a useful parameter to measure when assessing in vivo immune activation. Our data, as well as that of others, supports the hypothesis that at least one population of NK cells is a distinct lineage arising at the differentiation level of myeloid and lymphoid stem cells in the bone marrow.

  2. Species-Specific Metastasis of Human Tumor Cells in the Severe Combined Immunodeficiency Mouse Engrafted with Human Tissue

    NASA Astrophysics Data System (ADS)

    Shtivelman, Emma; Namikawa, Reiko

    1995-05-01

    We have attempted to model human metastatic disease by implanting human target organs into the immunodeficient C.B-17 scid/scid (severe combined immunodeficiency; SCID) mouse, creating SCID-hu mice. Preferential metastasis to implants of human fetal lung and human fetal bone marrow occurred after i.v. injection of human small cell lung cancer (SCLC) cells into SCID-hu mice; the homologous mouse organs were spared. Clinically more aggressive variant SCLC cells metastasized more efficiently to human fetal lung implants than did cells from classic SCLC. Metastasis of variant SCLC to human fetal bone marrow was enhanced in SCID-hu mice exposed to γ-irradiation or to interleukin 1α. These data indicate that the SCID-hu mice may provide a model in which to study species- and tissue-specific steps of the human metastatic process.

  3. Inflammatory bowel disease and airway diseases

    PubMed Central

    Vutcovici, Maria; Brassard, Paul; Bitton, Alain

    2016-01-01

    Airway diseases are the most commonly described lung manifestations of inflammatory bowel disease (IBD). However, the similarities in disease pathogenesis and the sharing of important environmental risk factors and genetic susceptibility suggest that there is a complex interplay between IBD and airway diseases. Recent evidence of IBD occurrence among patients with airway diseases and the higher than estimated prevalence of subclinical airway injuries among IBD patients support the hypothesis of a two-way association. Future research efforts should be directed toward further exploration of this association, as airway diseases are highly prevalent conditions with a substantial public health impact. PMID:27678355

  4. Association between periodontal diseases and systemic diseases.

    PubMed

    Weidlich, Patrícia; Cimões, Renata; Pannuti, Claudio Mendes; Oppermann, Rui Vicente

    2008-01-01

    Current evidence suggests that periodontal disease may be associated with systemic diseases. This paper reviewed the published data about the relationship between periodontal disease and cardiovascular diseases, adverse pregnancy outcomes, diabetes and respiratory diseases, focusing on studies conducted in the Brazilian population. Only a few studies were found in the literature focusing on Brazilians (3 concerning cardiovascular disease, 7 about pregnancy outcomes, 9 about diabetes and one regarding pneumonia). Although the majority of them observed an association between periodontitis and systemic conditions, a causal relationship still needs to be demonstrated. Further studies, particularly interventional well-designed investigations, with larger sample sizes, need to be conducted in Brazilian populations. PMID:19838549

  5. Inflammatory bowel disease and airway diseases

    PubMed Central

    Vutcovici, Maria; Brassard, Paul; Bitton, Alain

    2016-01-01

    Airway diseases are the most commonly described lung manifestations of inflammatory bowel disease (IBD). However, the similarities in disease pathogenesis and the sharing of important environmental risk factors and genetic susceptibility suggest that there is a complex interplay between IBD and airway diseases. Recent evidence of IBD occurrence among patients with airway diseases and the higher than estimated prevalence of subclinical airway injuries among IBD patients support the hypothesis of a two-way association. Future research efforts should be directed toward further exploration of this association, as airway diseases are highly prevalent conditions with a substantial public health impact.

  6. Skin Diseases: Skin Health and Skin Diseases

    MedlinePlus

    Skip Navigation Bar Home Current Issue Past Issues Skin Diseases Skin Health and Skin Diseases Past Issues / Fall 2008 Table of Contents ... acne to wrinkles Did you know that your skin is the largest organ of your body? It ...

  7. Treatment of Celiac Disease

    MedlinePlus

    ... Mission Statement Press Releases 2015 CSA Youth Ambassador PEER Grants Awarded Bountiful Pantry DNI Group, LLC Earth ... for Celiac Disease International Symposium Celiac Disease 2013 Peer Review Research Application History of Gluten Induced Diseases ...

  8. Lipid Storage Diseases

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Lipid Storage Diseases Information Page Condensed from Lipid Storage ... en Español Additional resources from MedlinePlus What are Lipid Storage Diseases? Lipid storage diseases are a group ...

  9. Tay-Sachs Disease

    MedlinePlus

    ... metabolic disease caused by the harmful buildup of lipids (fatty materials such as oils and acids) in ... management, and therapy of rare diseases, including the lipid storage diseases. Additional research funded by the NINDS ...

  10. Tay-Sachs Disease

    MedlinePlus

    Tay-Sachs disease is a rare, inherited disease. It is a type of lipid metabolism disorder. It causes too ... cells, causing mental and physical problems. . Infants with Tay-Sachs disease appear to develop normally for the first few ...

  11. Sickle Cell Disease Quiz

    MedlinePlus

    ... False: People with sickle cell disease cannot get malaria. A True B False 4. True or False: ... False: People with sickle cell disease cannot get malaria. False People with sickle cell disease can get ...

  12. Digestive Diseases Materials

    MedlinePlus

    ... NIDDK Health Information NIDDK Home NIDDK Image Library Digestive Disease, Nutrition, and Weight-control Materials Healthy eating, ... Materials Statistics Tip Sheets Catalog Home | Diabetes Materials | Digestive Diseases Materials | Kidney and Urologic Diseases Materials Online ...

  13. Autoimmune liver disease panel

    MedlinePlus

    Liver disease test panel - autoimmune ... Autoimmune disorders are a possible cause of liver disease. The most common of these diseases are autoimmune hepatitis and primary biliary cirrhosis. This group of tests helps your health care provider ...

  14. Parkinson disease - discharge

    MedlinePlus

    Your doctor has told you that you have Parkinson disease . This disease affects the brain and leads to ... have you take different medicines to treat your Parkinson disease and many of the problems that may come ...

  15. Peripheral Vascular Disease

    MedlinePlus

    ... Information Center Back to previous page En español Aneurysms and Dissections Angina Arrhythmia Bundle Branch Block Cardiomyopathy ... blockage including peripheral artery disease or PAD Aortic aneurysms Buerger's Disease Raynaud's Phenomenon Disease of the veins ...

  16. Fibrocystic breast disease

    MedlinePlus

    Fibrocystic breast disease; Mammary dysplasia; Diffuse cystic mastopathy; Benign breast disease; Glandular breast changes ... FF, Fort GG, et al, eds. Fibrocystic breast disease. In: Ferri FF, ed. Ferri's Clinical Advisor 2015 . ...

  17. Chronic obstructive pulmonary disease

    MedlinePlus

    COPD; Chronic obstructive airways disease; Chronic obstructive lung disease; Chronic bronchitis; Emphysema; Bronchitis - chronic ... can do to relieve symptoms and keep the disease from getting worse. If you smoke, now is ...

  18. Ebola Virus Disease

    MedlinePlus

    ... 2014 Fact sheets Features Commentaries 2014 Multimedia Contacts Ebola virus disease Fact sheet Updated January 2016 Key ... for survivors of Ebola virus disease Symptoms of Ebola virus disease The incubation period, that is, the ...

  19. Lyme disease (image)

    MedlinePlus

    Lyme disease is an acute inflammatory disease characterized by skin changes, joint inflammation and symptoms similar to the ... that is caused by the bacterium Borrelia burgdorferi . Lyme disease is transmitted by the bite of a deer ...

  20. Kidney disease - resources

    MedlinePlus

    Resources - kidney disease ... The following organizations are good resources for information on kidney disease: National Kidney Disease Education Program -- www.nkdep.nih.gov National Kidney Foundation -- www.kidney.org National ...

  1. Heart disease - resources

    MedlinePlus

    Resources - heart disease ... The following organizations are good resources for information on heart disease: American Heart Association -- www.heart.org Centers for Disease Control and Prevention -- www.cdc.gov/heartdisease

  2. Acid Lipase Disease

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Acid Lipase Disease Information Page Synonym(s): Cholesterol Ester Storage ... Trials Related NINDS Publications and Information What is Acid Lipase Disease ? Acid lipase disease or deficiency occurs ...

  3. Diabetes and Kidney Disease

    MedlinePlus

    ... Disease, and Other Dental Problems Diabetic Eye Disease Diabetes and Kidney Disease What are my kidneys and ... urine until releasing it through urination. How can diabetes affect my kidneys? Too much glucose , also called ...

  4. Adult Still's disease

    MedlinePlus

    Still's disease - adult; AOSD ... than 1 out of 100,000 people develop adult-onset Still's disease each year. It affects women more often than men. The cause of adult Still's disease is unknown. No risk factors for ...

  5. Cholestatic liver disease masquerading as Wilson disease.

    PubMed

    Sood, Vikrant; Rawat, Dinesh; Khanna, Rajeev; Alam, Seema

    2015-03-01

    Wilson disease and cholestatic liver diseases may present as a diagnostic dilemma if standard guidelines incorporating markers of copper overload are followed. We hereby present a series of four cases of sclerosing cholangitis masquerading as Wilson disease. True Wilson disease cases had significantly lower ceruloplasmin (6 vs. 16 mg/dL) and higher 24-hour urinary copper (322.3 vs. 74.5 μg/day) as compared to mimickers. Initial low serum ceruloplasmin levels normalized in mimickers on follow up, and this may used as a diagnostic indicator. Standard Wilson disease diagnostic criteria thus need further modification especially in developing countries to help avoid mismanagement.

  6. Atheroembolic renal disease

    MedlinePlus

    Renal disease - atheroembolic; Cholesterol embolization syndrome; Atheroemboli - renal; Atherosclerotic disease - renal ... disorder of the arteries. It occurs when fat, cholesterol, and other substances build up in the walls ...

  7. Biomarker for Glycogen Storage Diseases

    ClinicalTrials.gov

    2016-08-25

    Fructose Metabolism, Inborn Errors; Glycogen Storage Disease; Glycogen Storage Disease Type I; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type IV; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VI; Glycogen Storage Disease Type VII; Glycogen Storage Disease Type VIII

  8. The integrated disease network.

    PubMed

    Sun, Kai; Buchan, Natalie; Larminie, Chris; Pržulj, Nataša

    2014-11-01

    The growing body of transcriptomic, proteomic, metabolomic and genomic data generated from disease states provides a great opportunity to improve our current understanding of the molecular mechanisms driving diseases and shared between diseases. The use of both clinical and molecular phenotypes will lead to better disease understanding and classification. In this study, we set out to gain novel insights into diseases and their relationships by utilising knowledge gained from system-level molecular data. We integrated different types of biological data including genome-wide association studies data, disease-chemical associations, biological pathways and Gene Ontology annotations into an Integrated Disease Network (IDN), a heterogeneous network where nodes are bio-entities and edges between nodes represent their associations. We also introduced a novel disease similarity measure to infer disease-disease associations from the IDN. Our predicted associations were systemically evaluated against the Medical Subject Heading classification and a statistical measure of disease co-occurrence in PubMed. The strong correlation between our predictions and co-occurrence associations indicated the ability of our approach to recover known disease associations. Furthermore, we presented a case study of Crohn's disease. We demonstrated that our approach not only identified well-established connections between Crohn's disease and other diseases, but also revealed new, interesting connections consistent with emerging literature. Our approach also enabled ready access to the knowledge supporting these new connections, making this a powerful approach for exploring connections between diseases.

  9. Interstitial Lung Diseases

    MedlinePlus

    Interstitial lung disease is the name for a large group of diseases that inflame or scar the lungs. The inflammation and scarring make it hard to ... air is responsible for some types of interstitial lung diseases. Specific types include Black lung disease among ...

  10. [Wilson's disease: clinical spectrum of liver disease].

    PubMed

    Ochoa Palominos, Alejandra; Ibáñez Samaniego, Luis; Catalina Rodríguez, María-Vega; Pajares Díaz, José; Clemente Ricote, Gerardo

    2013-02-01

    Wilson's disease is a hereditary autosomal recessive disorder of copper metabolism,characterized by copper accumulation in the liver and brain. This rare entity, which has a broad clinical spectrum, is often difficult to diagnose and should therefore always be suspected in patients with liver disease of unclear cause. We describe two types of manifestation of liver disease in two patients; the first developed fulminant hepatic failure requiring urgent liver transplantation and the second showed advanced chronic liver disease and received standard medical treatment. The objective of this clinical observation is to analyze the diagnosis of Wilson's disease in two patients with distinct onset, illustrating the broad clinical spectrum of the disease, and its treatment.

  11. Cardiovascular disease biomarkers across autoimmune diseases.

    PubMed

    Ahearn, Joseph; Shields, Kelly J; Liu, Chau-Ching; Manzi, Susan

    2015-11-01

    Cardiovascular disease is increasingly recognized as a major cause of premature mortality among those with autoimmune disorders. There is an urgent need to identify those patients with autoimmune disease who are at risk for CVD so as to optimize therapeutic intervention and ultimately prevention. Accurate identification, monitoring and stratification of such patients will depend upon a panel of biomarkers of cardiovascular disease. This review will discuss some of the most recent biomarkers of cardiovascular diseases in autoimmune disease, including lipid oxidation, imaging biomarkers to characterize coronary calcium, plaque, and intima media thickness, biomarkers of inflammation and activated complement, genetic markers, endothelial biomarkers, and antiphospholipid antibodies. Clinical implementation of these biomarkers will not only enhance patient care but also likely accelerate the pharmaceutical pipeline for targeted intervention to reduce or eliminate cardiovascular disease in the setting of autoimmunity.

  12. Human disease genes.

    PubMed

    Jimenez-Sanchez, G; Childs, B; Valle, D

    2001-02-15

    The complete human genome sequence will facilitate the identification of all genes that contribute to disease. We propose that the functional classification of disease genes and their products will reveal general principles of human disease. We have determined functional categories for nearly 1,000 documented disease genes, and found striking correlations between the function of the gene product and features of disease, such as age of onset and mode of inheritance. As knowledge of disease genes grows, including those contributing to complex traits, more sophisticated analyses will be possible; their results will yield a deeper understanding of disease and an enhanced integration of medicine with biology.

  13. [Periodontal disease in pediatric rheumatic diseases].

    PubMed

    Fabri, Gisele M C; Savioli, Cynthia; Siqueira, José T; Campos, Lucia M; Bonfá, Eloisa; Silva, Clovis A

    2014-01-01

    Gingivitis and periodontitis are immunoinflammatory periodontal diseases characterized by chronic localized infections usually associated with insidious inflammation This narrative review discusses periodontal diseases and mechanisms influencing the immune response and autoimmunity in pediatric rheumatic diseases (PRD), particularly juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (C-SLE) and juvenile dermatomyositis (JDM). Gingivitis was more frequently observed in these diseases compared to health controls, whereas periodontitis was a rare finding. In JIA patients, gingivitis and periodontitis were related to mechanical factors, chronic arthritis with functional disability, dysregulation of the immunoinflammatory response, diet and drugs, mainly corticosteroids and cyclosporine. In C-SLE, gingivitis was associated with longer disease period, high doses of corticosteroids, B-cell hyperactivation and immunoglobulin G elevation. There are scarce data on periodontal diseases in JDM population, and a unique gingival pattern, characterized by gingival erythema, capillary dilation and bush-loop formation, was observed in active patients. In conclusion, gingivitis was the most common periodontal disease in PRD. The observed association with disease activity reinforces the need for future studies to determine if resolution of this complication will influence disease course or severity.

  14. Prion diseases as transmissible zoonotic diseases.

    PubMed

    Lee, Jeongmin; Kim, Su Yeon; Hwang, Kyu Jam; Ju, Young Ran; Woo, Hee-Jong

    2013-02-01

    Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt-Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first reported in the United Kingdom in 1986. Variant CJD (vCJD) is a disease that was first detected in 1996, which affects humans and is linked to the BSE epidemic in cattle. vCJD is presumed to be caused by consumption of contaminated meat and other food products derived from affected cattle. The BSE epidemic peaked in 1992 and decreased thereafter; this decline is continuing sharply owing to intensive surveillance and screening programs in the Western world. However, there are still new outbreaks and/or progression of prion diseases, including atypical BSE, and iatrogenic CJD and vCJD via organ transplantation and blood transfusion. This paper summarizes studies on prions, particularly on prion molecular mechanisms, BSE, vCJD, and diagnostic procedures. Risk perception and communication policies of the European Union for the prevention of prion diseases are also addressed to provide recommendations for appropriate government policies in Korea. PMID:24159531

  15. Prion Diseases as Transmissible Zoonotic Diseases

    PubMed Central

    Lee, Jeongmin; Kim, Su Yeon; Hwang, Kyu Jam; Ju, Young Ran; Woo, Hee-Jong

    2013-01-01

    Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt–Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first reported in the United Kingdom in 1986. Variant CJD (vCJD) is a disease that was first detected in 1996, which affects humans and is linked to the BSE epidemic in cattle. vCJD is presumed to be caused by consumption of contaminated meat and other food products derived from affected cattle. The BSE epidemic peaked in 1992 and decreased thereafter; this decline is continuing sharply owing to intensive surveillance and screening programs in the Western world. However, there are still new outbreaks and/or progression of prion diseases, including atypical BSE, and iatrogenic CJD and vCJD via organ transplantation and blood transfusion. This paper summarizes studies on prions, particularly on prion molecular mechanisms, BSE, vCJD, and diagnostic procedures. Risk perception and communication policies of the European Union for the prevention of prion diseases are also addressed to provide recommendations for appropriate government policies in Korea. PMID:24159531

  16. New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland.

    PubMed

    Kayes, Timothy Daniel; Weisman, Gary A; Camden, Jean M; Woods, Lucas T; Bredehoeft, Cole; Downey, Edward F; Cole, James; Braley-Mullen, Helen

    2016-09-15

    Sixty to seventy percent of IFN-γ(-/-) NOD.H-2h4 mice given sodium iodide (NaI)-supplemented water develop a slow onset autoimmune thyroid disease, characterized by thyrocyte epithelial cell (TEC) hyperplasia and proliferation (H/P). TEC H/P develops much earlier in CD28(-/-) mice and nearly 100% (both sexes) have severe TEC H/P at 4 mo of age. Without NaI supplementation, 50% of 5- to 6-mo-old CD28(-/-)IFN-γ(-/-) mice develop severe TEC H/P, and 2-3 wk of NaI is sufficient for optimal development of severe TEC H/P. Mice with severe TEC H/P are hypothyroid, and normalization of serum thyroxine levels does not reduce TEC H/P. Activated CD4(+) T cells are sufficient to transfer TEC H/P to SCID recipients. Thyroids of mice with TEC H/P have infiltrating T cells and expanded numbers of proliferating thyrocytes that highly express CD40. CD40 facilitates, but is not required for, development of severe TEC H/P, as CD40(-/-)IFN-γ(-/-)CD28(-/-) mice develop severe TEC H/P. Accelerated development of TEC H/P in IFN-γ(-/-)CD28(-/-) mice is a result of reduced regulatory T cell (Treg) numbers, as CD28(-/-) mice have significantly fewer Tregs, and transfer of CD28(+) Tregs inhibits TEC H/P. Essentially all female IFN-γ(-/-)CD28(-/-) NOD.H-2h4 mice have substantial lymphocytic infiltration of salivary glands and reduced salivary flow by 6 mo of age, thereby providing an excellent new model of autoimmune exocrinopathy of the salivary gland. This is one of very few models where autoimmune thyroid disease and hypothyroidism develop in most mice by 4 mo of age. This model will be useful for studying the effects of hypothyroidism on multiple organ systems. PMID:27521344

  17. Regulation of Pulmonary Graft-versus-Host Disease by IL-26+CD26+CD4 T Lymphocytes

    PubMed Central

    Ohnuma, Kei; Hatano, Ryo; Aune, Thomas M.; Otsuka, Haruna; Iwata, Satoshi; Dang, Nam H.; Yamada, Taketo; Morimoto, Chikao

    2015-01-01

    Obliterative bronchiolitis is a potentially life-threatening noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In the current study, we identified a novel effect of IL-26 on transplant-related obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγnull mice transplanted with human umbilical cord blood (HuCB mice) gradually developed clinical signs of graft-versus-host disease (GVHD) such as loss of weight, ruffled fur, and alopecia. Histologically, lung of HuCB mice exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26+CD26+CD4 T cells. Concomitantly, skin manifested fat loss and sclerosis of the reticular dermis in the presence of apoptosis of the basilar keratinocytes, whereas the liver exhibited portal fibrosis and cholestasis. Moreover, although IL-26 is absent from rodents, we showed that IL-26 increased collagen synthesis in fibroblasts and promoted lung fibrosis in a murine GVHD model using IL-26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by HuCB CD4 T cells following CD26 costimulation, whereas Ig Fc domain fused with the N-terminal of caveolin-1 (Cav-Ig), the ligand for CD26, effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. These results therefore provide proof of principle that cGVHD of the lungs is caused in part by IL-26+CD26+CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy. PMID:25786689

  18. New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland.

    PubMed

    Kayes, Timothy Daniel; Weisman, Gary A; Camden, Jean M; Woods, Lucas T; Bredehoeft, Cole; Downey, Edward F; Cole, James; Braley-Mullen, Helen

    2016-09-15

    Sixty to seventy percent of IFN-γ(-/-) NOD.H-2h4 mice given sodium iodide (NaI)-supplemented water develop a slow onset autoimmune thyroid disease, characterized by thyrocyte epithelial cell (TEC) hyperplasia and proliferation (H/P). TEC H/P develops much earlier in CD28(-/-) mice and nearly 100% (both sexes) have severe TEC H/P at 4 mo of age. Without NaI supplementation, 50% of 5- to 6-mo-old CD28(-/-)IFN-γ(-/-) mice develop severe TEC H/P, and 2-3 wk of NaI is sufficient for optimal development of severe TEC H/P. Mice with severe TEC H/P are hypothyroid, and normalization of serum thyroxine levels does not reduce TEC H/P. Activated CD4(+) T cells are sufficient to transfer TEC H/P to SCID recipients. Thyroids of mice with TEC H/P have infiltrating T cells and expanded numbers of proliferating thyrocytes that highly express CD40. CD40 facilitates, but is not required for, development of severe TEC H/P, as CD40(-/-)IFN-γ(-/-)CD28(-/-) mice develop severe TEC H/P. Accelerated development of TEC H/P in IFN-γ(-/-)CD28(-/-) mice is a result of reduced regulatory T cell (Treg) numbers, as CD28(-/-) mice have significantly fewer Tregs, and transfer of CD28(+) Tregs inhibits TEC H/P. Essentially all female IFN-γ(-/-)CD28(-/-) NOD.H-2h4 mice have substantial lymphocytic infiltration of salivary glands and reduced salivary flow by 6 mo of age, thereby providing an excellent new model of autoimmune exocrinopathy of the salivary gland. This is one of very few models where autoimmune thyroid disease and hypothyroidism develop in most mice by 4 mo of age. This model will be useful for studying the effects of hypothyroidism on multiple organ systems.

  19. Obesity and cardiovascular disease.

    PubMed

    Jokinen, E

    2015-02-01

    Cardiovascular disease is the most common cause of mortality in rich countries and today it has the same meaning for health care as the epidemics of past centuries had for medicine in earlier times: 50% of the population in these countries die of cardiovascular disease. The amount of cardiovascular disease is also increasing in the developing countries together with economic growth. By 2015 one in three deaths will globally be due to cardiovascular diseases. Coronary heart disease is a chronic disease that starts in childhood, even if the symptoms first occur in the middle age. The risks for coronary heart disease are well-known: lipid disorders, especially high serum LDL-cholesterol concentration, high blood pressure, tobacco smoking, obesity, diabetes, male gender and physical inactivity. Obesity is both an independent risk factor for cardiovascular disease but is also closely connected with several other risk factors. This review focuses on the connection between overweight or obesity and cardiovascular disease. PMID:25387321

  20. Toponymous diseases of Australia.

    PubMed

    Appuhamy, Ranil D; Tent, Jan; Mackenzie, John S

    Names are more than just labels used to identify diseases. They can be windows into the discovery, characteristics and attributes of the disease. Toponymous diseases are diseases that are named after places. Hendra, Ross River, Bairnsdale, Murray Valley and Barmah Forest are all examples of Australian places that have had diseases named after them. They all have unique and interesting stories that provide a glimpse into their discovery, history and culture. Because of perceived negative connotations, the association of diseases with placenames has sometimes generated controversy. PMID:21143049

  1. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease.

    PubMed

    Eda, Homare; Santo, Loredana; Wein, Marc N; Hu, Dorothy Z; Cirstea, Diana D; Nemani, Neeharika; Tai, Yu-Tzu; Raines, Sarah E; Kuhstoss, Stuart Allen; Munshi, Nikhil C; Kronenberg, Henry M; Raje, Noopur S

    2016-06-01

    Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated β-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high-affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient bone marrow samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirm the role of sclerostin as a potential therapeutic target in MM bone disease

  2. Celiac disease - sprue

    MedlinePlus

    Sprue; Nontropical sprue; Gluten intolerance; Gluten-sensitive enteropathy; Gluten-free diet celiac disease ... When people with celiac disease eat foods with gluten, their immune system reacts by damaging the villi. ...

  3. Minimal change disease

    MedlinePlus

    ... seen under a very powerful microscope called an electron microscope. Minimal change disease is the most common ... biopsy and examination of the tissue with an electron microscope can show signs of minimal change disease.

  4. Chronic granulomatous disease

    MedlinePlus

    CGD; Fatal granulomatosis of childhood; Chronic granulomatous disease of childhood; Progressive septic granulomatosis ... In chronic granulomatous disease (CGD), immune system cells called phagocytes are unable to kill some types of bacteria and fungi. This ...

  5. McArdle disease

    MedlinePlus

    Glycogen storage disease type V (GSDV); Myophosphorylase deficiency; Muscle glycogen phosphorylase deficiency; PYGM deficiency ... the body cannot break down glycogen in the muscles. The disease is an autosomal recessive genetic disorder. ...

  6. Travelers' Health: Meningococcal Disease

    MedlinePlus

    ... Global TravEpiNet Mobile Apps RSS Feeds Chapter 3 Infectious Diseases Related to Travel Recommend on Facebook Tweet Share ... Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy ...

  7. Collagen vascular disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001223.htm Collagen vascular disease To use the sharing features on ... were previously said to have "connective tissue" or "collagen vascular" disease. We now have names for many ...

  8. Coronary Artery Disease

    MedlinePlus

    Coronary artery disease (CAD) is the most common type of heart disease. It is the leading cause of death ... both men and women. CAD happens when the arteries that supply blood to heart muscle become hardened ...

  9. Mitral Valve Disease

    MedlinePlus

    ... disease occurs when the mitral valve doesn’t work properly. Types of Mitral Valve Disease Types of ... until you are able to go back to work, depending on your job. Everyday activities such as ...

  10. Peri-Implant Diseases

    MedlinePlus

    ... and flossing and regular check-ups from a dental professional. Other risks factors for developing peri-implant disease include previous periodontal disease diagnosis, poor plaque control, smoking , and diabetes . It is essential to routinely ...

  11. Heart Disease Risk Factors

    MedlinePlus

    ... this? Submit What's this? Submit Button Related CDC Web Sites Division for Heart Disease and Stroke Prevention ... this? Submit What's this? Submit Button Related CDC Web Sites Division for Heart Disease and Stroke Prevention ...

  12. Men and Heart Disease

    MedlinePlus

    ... this? Submit What's this? Submit Button Related CDC Web Sites Heart Disease Stroke High Blood Pressure Salt ... this? Submit What's this? Submit Button Related CDC Web Sites Heart Disease Stroke High Blood Pressure Salt ...

  13. Polycystic kidney disease

    MedlinePlus

    Cysts - kidneys; Kidney - polycystic; Autosomal dominant polycystic kidney disease; ADPKD ... Polycystic kidney disease (PKD) is passed down through families (inherited). The 2 inherited forms of PKD are autosomal dominant ...

  14. Blood and Lymph Diseases

    MedlinePlus

    ... Medicine, National Institutes of Health. National Center for Biotechnology Information (US). Genes and Disease [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 1998-. Genes and Disease [Internet]. Show ...

  15. Hypothyroidism and Heart Disease

    MedlinePlus

    ... in Balance › Hypothyroidism and Heart Disease Fact Sheet Hypothyroidism and Heart Disease January 2014 Download PDFs English ... nervous system, body temperature, and weight. What is hypothyroidism and what are its symptoms? Hypothyroidism, also called ...

  16. Diseases and Conditions

    MedlinePlus

    ... Wars & Operations Exposure Categories A-Z Index Agent Orange Agent Orange Home Facts about Herbicides Veterans' Diseases Birth Defects ... Veterans Health Initiative Veterans Health Initiative Home Agent Orange Gulf War Infectious Diseases of Southwest Asia War ...

  17. Chagas Disease (American trypanosomiasis)

    MedlinePlus

    ... Features Commentaries 2014 Multimedia Contacts Chagas disease (American trypanosomiasis) Fact sheet Updated March 2016 Key facts About ... is essential. Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by ...

  18. Peripheral Arterial Disease

    MedlinePlus

    Peripheral arterial disease (PAD) happens when there is a narrowing of the blood vessels outside of your heart. The cause of ... smoking. Other risk factors include older age and diseases like diabetes, high blood cholesterol, high blood pressure, ...

  19. Degenerative Nerve Diseases

    MedlinePlus

    Degenerative nerve diseases affect many of your body's activities, such as balance, movement, talking, breathing, and heart function. Many of these diseases are genetic. Sometimes the cause is a medical ...

  20. Bone Marrow Diseases

    MedlinePlus

    ... that help with blood clotting. With bone marrow disease, there are problems with the stem cells or ... marrow makes too many white blood cells Other diseases, such as lymphoma, can spread into the bone ...

  1. Creutzfeldt-Jakob Disease

    MedlinePlus

    Creutzfeldt-Jakob disease (CJD) is a rare, degenerative brain disorder. Symptoms usually start around age 60. Memory problems, behavior changes, vision ... during a medical procedure Cattle can get a disease related to CJD called bovine spongiform encephalopathy (BSE) ...

  2. Pelvic Inflammatory Disease

    MedlinePlus

    Pelvic inflammatory disease (PID) is an infection and inflammation of the uterus, ovaries, and other female reproductive organs. It causes scarring ... United States. Gonorrhea and chlamydia, two sexually transmitted diseases, are the most common causes of PID. Other ...

  3. Sexually Transmitted Diseases

    MedlinePlus

    Sexually transmitted diseases (STDs) are infections that are passed from one person to another through sexual contact. The causes of STDs ... often help with the symptoms and keep the disease under control. Correct usage of latex condoms greatly ...

  4. Lewy Body Disease

    MedlinePlus

    Lewy body disease is one of the most common causes of dementia in the elderly. Dementia is the loss of mental ... to affect normal activities and relationships. Lewy body disease happens when abnormal structures, called Lewy bodies, build ...

  5. Cat Scratch Disease

    MedlinePlus

    Cat scratch disease (CSD) is an illness caused by the bacterium Bartonella henselae. Almost half of all cats carry the infection ... symptoms of CSD, call your doctor. Centers for Disease Control and Prevention

  6. Carotid Artery Disease

    MedlinePlus

    ... brain with blood. If you have carotid artery disease, the arteries become narrow, usually because of atherosclerosis. ... one of the causes of stroke. Carotid artery disease often does not cause symptoms, but there are ...

  7. Chronic Kidney Disease

    MedlinePlus

    ... control blood pressure, and make hormones. Chronic kidney disease (CKD) means that your kidneys are damaged and ... don't have any symptoms until their kidney disease is very advanced. Blood and urine tests are ...

  8. Rheumatoid lung disease

    MedlinePlus

    Lung disease - rheumatoid arthritis; Rheumatoid nodules; Rheumatoid lung ... Elsevier Saunders; 2016:chap 65. Lake F, Proudman S. Rheumatoid arthritis and lung disease: from mechanisms to a practical approach. Semin Respir ...

  9. Creutzfeldt-Jakob disease

    MedlinePlus

    ... be the same one that causes vCJD in humans. Varient CJD causes less than 1% of all ... Scrapie (found in sheep) Other very rare inherited human diseases, such as Gerstmann-Straussler-Scheinker disease and ...

  10. Chronic Kidney Diseases

    MedlinePlus

    ... Homework? Here's Help White House Lunch Recipes Chronic Kidney Diseases KidsHealth > For Kids > Chronic Kidney Diseases Print ... re talking about your kidneys. What Are the Kidneys? Your kidneys are tucked under your lower ribs ...

  11. Liver Disease and IBD

    MedlinePlus

    ... 34% of Crohn’s patients with disease of the terminal ileum (the last segment of the small intestine). ... increased risk for developing gallstones because the diseased terminal ileum cannot absorb bile salts, which are necessary ...

  12. Aspirin and heart disease

    MedlinePlus

    ... the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology ... NE, et al. Antithrombotic and thrombolytic therapy for ischemic ... of coronary heart disease. In: Mann DL, Zipes DP, Libby P, et ...

  13. Congenital heart disease

    MedlinePlus

    ... about genetic counseling and screening if you have a family history of cogenital heart disease. ... Fraser CD, Carberry KE. Congenital heart disease. In: Townsend CM ... Textbook of Cardiovascular Medicine . 10th ed. Philadelphia, PA: ...

  14. Cat scratch disease (image)

    MedlinePlus

    Cat scratch disease is an infectious illness associated with cat scratches, bites, or exposure to cat saliva, causing chronic swelling of the lymph nodes. Cat scratch disease is possibly the most common cause of chronic ...

  15. Treatments for Alzheimer's Disease

    MedlinePlus

    ... 3900 Find your chapter: search by state Home > Alzheimer's Disease > Treatments Overview What Is Dementia? What Is Alzheimer's? ... and move closer to a cure. Treatments for Alzheimer's disease Currently, there is no cure for Alzheimer's. But ...

  16. [Emerging noninfectious diseases].

    PubMed

    Consiglio, Ezequiel

    2008-11-01

    In recent years, emerging diseases were defined as being infectious, acquiring high incidence, often suddenly, or being a threat or an unexpected phenomenon. This study discusses the hallmarks of emerging diseases, describing the existence of noninfectious emerging diseases, and elaborating on the advantages of defining noninfectious diseases as emerging ones. From the discussion of various mental health disorders, nutritional deficiencies, external injuries and violence outcomes, work injuries and occupational health, and diseases due to environmental factors, the conclusion is drawn that a wide variety of noninfectious diseases can be defined as emergent. Noninfectious emerging diseases need to be identified in order to improve their control and management. A new definition of "emergent disease" is proposed, one that emphasizes the pathways of emergence and conceptual traits, rather than descriptive features.

  17. Head Lice: Disease

    MedlinePlus

    ... Treatment FAQs Malathion FAQs Epidemiology & Risk Factors Disease Biology Diagnosis Treatment Prevention & Control Resources for Health Professionals ... Frequently Asked Questions (FAQs) Epidemiology & Risk Factors Disease Biology Diagnosis Treatment Prevention & Control Resources for Health Professionals ...

  18. Autoimmune Inner Ear Disease

    MedlinePlus

    ... Find an ENT Doctor Near You Autoimmune Inner Ear Disease Autoimmune Inner Ear Disease Patient Health Information ... with a hearing loss. How Does the Healthy Ear Work? The ear has three main parts: the ...

  19. Celiac Disease: Diagnosis.

    PubMed

    Byrne, Greg; Feighery, Conleth F

    2015-01-01

    Historically the diagnosis of celiac disease has relied upon clinical, serological, and histological evidence. In recent years the use of sensitive serological methods has meant an increase in the diagnosis of celiac disease. The heterogeneous nature of the disorder presents a challenge in the study and diagnosis of the disease with patients varying from subclinical or latent disease to patients with overt symptoms. Furthermore the related gluten-sensitive disease dermatitis herpetiformis, while distinct in some respects, shares clinical and serological features with celiac disease. Here we summarize current best practice for the diagnosis of celiac disease and briefly discuss newer approaches. The advent of next-generation assays for diagnosis and newer clinical protocols may result in more sensitive screening and ultimately the possible replacement of the intestinal biopsy as the gold standard for celiac disease diagnosis.

  20. Parkinson disease - resources

    MedlinePlus

    Resources - Parkinson disease ... The following organizations are good resources for information on Parkinson disease : The Michael J. Fox Foundation -- www.michaeljfox.org National Institute of Neurological Disorders and Stroke -- www. ...