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Results for “Wiskott-Aldrich Syndrome”

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At least 19 recordsLinked to original sources
PubMed1978

Wiskott-Aldrich syndrome: detection of carrier state by metabolic stress of platelets.

A stress test has been designed which shows a consistent abnormality in platelets from carriers of the Wiskott-Aldrich-syndrome (W.A.S.) gene. 2-deoxy-D-glucose (D.D.G.), an inhibitor of glycolysis, completely inhibited second-wave adrenaline (epinephrine)-induced aggregation of platelets from 10 W.A.S. carriers, whereas it had no effect on the response of control platelets. Antimycin A (Ant A), an inhibitor of oxidative phosphorylation, had no effect on adrenaline-induced platelet aggregation of either carriers or controls. Incubation of control platelets with a combination of Ant A and D.D.G. inhibited aggregation in a way comparable to the effect of D.D.G. alone on carrier cells. Thus, W.A.S. carriers have a defect in platelet metabolism similar to that produced in normal platelets with Ant A. The D.D.G. stress test is a simple reproducible assay for detection of W.A.S. carriers.

Blood Coagulation Tests↗
PubMed1979

Transfer factor in immunodeficiency diseases.

Results of therapeutic trials of transfer factor in a number of laboratories suggest clinical benefit and enhancement of immunological reactivity in patients with primary or secondary immunodeficiency diseases. Long term follow-up of 32 patients with the Wiskott-Aldrich syndrome suggested that transfer factor caused conversion of immunologic reactivity, apparent clinical benefit, and prolonged survival in some, but not in all patients. In 18 patients with disseminated (Stage III) malignant melanoma treated with surgery and transfer factor, survival was better than would ordinarily be expected for disseminated disease (78% with mean follow-up of 2 years). A randomized trial has been initiated which will answer the question of the efficacy of transfer factor as surgical adjuvant therapy in malignant melanoma. Studies in human subjects suggested that transfer factor does not cause enhancement of reactivity in normal subjects, when evaluated in a controlled, double-blind fashion. Similar controlled studies in immunodeficient patients are necessary to ascertain whether transfer factor does cause enhancement of immune responses in these patients. Based on these observations, a guinea pig model was developed in which transfer factor caused abrogation of tolerance to ABA-Tyrosine.

Child↗
PubMed1975

Lymphocyte transformation in vitro in patients with immunodeficiency diseases: use in diagnosis, histocompatibility testing and monitoring treatment.

We have used lymphocyte stimulation in vitro to characterize the degree of cell-mediated immunodeficiency in different patients. The effect of treatment of patients with immunodeficiencies is illustrated by lymphocyte transformation in vitro before, during and after therapy (eg bone marrow transplantation of severe combined immunodeficiency and transfer factor treatment in Wiskott-Aldrich syndrome). The mixed lymphocyte culture test has been used for selection of bone marrow transplant donor for a patient with CID when an HL-A identical sib was not available. The results of the transplantation in this patient with graft from a donor who differed from the patient in respect of both HL-A haplotypes (but MLC identical with the patient) is reported. The MLC data on another family with 2 children with Nezelof disease are reported. The data indicate that one of the patients could be a chimera after intrauterine grafting of maternal immunocompetent cells.

Adolescent↗
PubMed1977

Transformation of rabbit kidney cells by BKV(MM) human papovavirus.

Primary rabbit kidney cells were transformed by BKV(MM), a papovavirus isolated from the urine of a child with the Wiskott-Aldrich syndrome. The transformed cells contained BK T-antigen, but no antigen that reacted with SV40 U-antiserum. The transformed cells failed to produce tumors in nude mice, and BKV (MM) was not rescued from transformed cells by cell fusion or chemical induction methods. The transformed cells supported the growth of rabbit kidney vacuolating virus (RKV), and could be used to quantitate RKV by plaque formation under an agar overlay.

Agar↗
PubMed1975

Physical map of the BK virus genome.

Two new human papovavirus isolates (JMV and MMV) from the urines of patients with Wiskott-Aldrich syndrome were morphologically and serologically identical to BK virus (BKV). The genomes of these two new isolates were found to be indistinguishable from prototype BKV DNA in a variety of nucleic acid hybridization experiments. Like BKV DNA, JMV and MMV DNAs share approximately 20% of their polynucleotide sequences with simian virus 40 DNA. The genome of JMV was indistinguishable from that of BKV by restriction endonuclease analysis; MMV DNA contained three instead of four R-Hind cleavage sites and one rather than no R-HpaII cleavage sites. Physical maps of the BKV and MMV genomes were constructed using restriction endonucleases, and these maps were oriented to the map of simian virus 40 DNA.

BK Virus↗
PubMed1978

The ultrastructure of defective human platelets.

Much of our current knowledge about the physiology of hemostasis has come from intensive study of platelets from patients with inherited and acquired bleeding disorders or an increased risk of thrombotic disease. Appreciation of the role of plasma proteins in platelet stickiness, of platelet surface membrane glyco-proteins in aggregation, of the substances stored in platelet organelles in cell-cell interaction, vascular injury and atherosclerosis, and of endoperoxides and thromboxanes in platelet intercellular communication have resulted largely from investigations on various types of defective platelets. While the techniques of physiology and biochemistry have generated critical details about abnormal platelets, electron microscopy and ultrastructural cytochemistry have provided an improved morphological framework in which to integrate the new discoveries. The present review has attempted to correlate physiological, biochemical and ultrastructural concepts as they relate to the current understanding of inherited platelet disorders.

Blood Platelet Disorders↗
PubMed1976

Hamster ependymomas produced by intracerebral inoculation of a human papovavirus (MMV).

Ependymomas were produced in 3 of 11 newborn hamsters inoculated intracerebrally with a human papovavirus (MMV) isolated from a malignant lymphoma of the brain of a child with Wiskott-Aldrich syndrome. One of the tumors was serially transplanted into weanling hamsters. Cells from the transplanted tumors and from cell cultures derived from these tumors contained an intranuclear "T" antigen that reacted with simian virus 40 T antibody.

Animals↗
PubMed2026

Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis.

BACKGROUND: Clonal hematopoiesis (CH) arising from mutations in hematopoietic genes has been identified as an important risk factor for atherosclerotic cardiovascular disease. Despite the established role of some CH mutations in promoting atherosclerosis progression, their role in clinically relevant LDL (low-density lipoprotein) lowering-induced plaque remodeling or regression has not been extensively studied. METHODS: To assess the effects of TET2 (tet methylcytosine dioxygenase 2) CH on plaque resolution, we prepared control or chimeric Tet2+/- CH mice with conditional deletion of Tet2 in hematopoietic stem cells during LDL lowering-induced plaque remodeling. After establishing atherosclerosis by Western diet feeding for 12 weeks in Ldlr-/- mice, Tet2 was deleted by tamoxifen injection, and hypercholesterolemia was either normalized to simulate clinical lipid management, or mice were continued on the Western diet. RESULTS: Unlike control mice, Tet2+/- CH mice failed to significantly reduce necrotic core area or increase fibrous cap thickness and showed impaired macrophage efferocytosis during LDL lowering. Single-cell RNA sequencing and gene set enrichment analysis of aortic cell populations revealed that Tet2 deficient monocyte/macrophage populations were defective in glycolysis, phagocytosis, and actin polymerization. Tet2-deficient bone marrow-derived macrophages and Tet2+/- induced pluripotent stem cell-derived human macrophages showed defective ability to sustain continuing rounds of efferocytosis. Bone marrow-derived macrophages displayed reduced apoptotic cell binding and internalization and impaired activity of Wiskott-Aldrich syndrome protein and SCAR (suppressor of cyclic AMP receptor) homolog complex mediated actin polymerization. We linked these defects to reduced anaerobic glycolysis and lactate levels and rescued them by lactate supplementation or by treatment with the HIF-1α (hypoxia-inducible factor 1α) activator molidustat. Molidustat treatment reversed the defects in necrotic core and fibrous cap formation during LDL lowering-induced plaque remodeling in Tet2+/- CH mice. Reduced plasma lactate levels were also shown in TET2 clonal hematopoiesis of indeterminate potential carriers in the UK Biobank. CONCLUSIONS: Our data identify impaired efferocytosis and glycolysis-lactate-actin polymerization pathways in advanced atherosclerosis as potential therapeutic targets to induce proresolving restructuring of the plaque immune cells and to promote beneficial atherosclerosis remodeling in subjects with TET2 CH.

LDL lowering↗
PubMed1975

Primary immunodeficiency diseases and malignancy.

The incidence of malignant tumors in the primary immunodeficiency diseases is dramatically increased. Four patients with primary immunodeficiencies who developed fatal malignancies are reported. Lymphoreticular tumors and leukemia predominate in most conditions, but epithelial neoplasms are the most common tumors in selective Iga deficiency, and they comprise over one-fourth of malignancies in common variable immunodeficiency. With the exception of common variable immunodeficiency and the Wiskott-Aldrich syndrome, hyperplasia of lymphoid tissue usually does not occur. Lymph node enlargement in any of the other immunodeficiencies is therefore most likely secondary to malignancy. Benign gastrointestinal nodular lymphoid hyperplasia occurs frequently in common variable immunodeficiency and in some instances may be impossible to differentiate roentgenologically from lymphoma.

Adenocarcinoma↗