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At least 307 records · Page 17Linked to original sources
PubMed1975

Defective heparan sulfate metabolism in the Sanfilippo syndrome and assay of this defect in the assessment of the mucopolysaccharidoses patient.

The Sanifilippo syndrome is an inherited dementia caused by defective degradation of heparan sulfate. In the course of its catabolism the heparan sulfate polymer must be desulfated. Heparan sulfate sulfatase activity was demonstrated in homogenates of normal tissues and cultured skin fibroblasts, and in normal urine. This activity was found to be grossly depressed or absent in necropsy specimens of liver and spleen from two Sanfilippo patients. The heparan sulfate sulfatase activity was not demonstrable in urine from eleven, or cultured fibroblasts from four Sanfilippo patients. Activities of alpha-N-acetyl-glucosaminidase, the site of the metabolic defect in the Sanfilippo B variant were either normal or slightly elevated in the Sanfilippo tissues and cultured fibroblasts whereas the mean level in the urine of our Sanfilippo patients was about one-third of that encountered in control urines.

Acetylglucosaminidase↗
PubMed2002

Avirulent Semliki Forest virus replication and pathology in the central nervous system is enhanced in IL-12-defective and reduced in IL-4-defective mice: a role for Th1 cells in the protective immunity.

Experimental infection of mice with avirulent Semliki Forest virus (SFV) has been used as a model of demyelinating disease in humans. A number of studies have shown that T cells may be important for mediating demyelination, but the role of T cells is still, unclear. Here, we show that neuronal necrosis, but not demyelination, was more severe in interleukin (IL)-12-defective mice compared with wild-type mice and this correlated with higher virus titers in the brain. In contrast, the severity of demyelination and neuronal depletion was reduced in IL-4-defective mice and this correlated with reduced brain virus titers and enhanced SFV-specific IFN-gamma production. The findings indicate that type 1 T cells play a role in the control of SFV replication but not directly in SFV-induced pathology in the CNS.

Alphavirus Infections↗
PubMed2003

Cholesterol biosynthesis is not defective in peroxisome biogenesis defective fibroblasts.

To evaluate the presumed peroxisomal involvement in cholesterol/isoprenoid biosynthesis, we determined the protein levels and activities of five different enzymes of the presqualene segment of the cholesterol/isoprenoid biosynthetic pathway in primary skin fibroblasts of selected patients with a peroxisomal biogenesis disorder (PBD). These five enzymes all have been reported to be partly or exclusively peroxisomal and include HMG-CoA reductase, mevalonate kinase, phosphomevalonate kinase, mevalonate pyrophosphate decarboxylase, and isopentenyl pyrophosphate isomerase. To exclude that genetic differences, resulting in different defects in peroxisomal biogenesis, have differential effects on the activity of the cholesterol biosynthetic enzymes and on de novo cholesterol biosynthesis, we chose fibroblasts of patients with defined defects in one of four different PEX genes leading to Zellweger syndrome (PEX1, PEX5, PEX16 or PEX19). We found that all enzymes measured are at least as active in the peroxisome-deficient cells cultured in cholesterol-depleted medium as in identically cultured control cells. This indicates that if these presumed peroxisomal proteins are mislocalized to the cytosol they do not loose their activity, nor get degraded unlike most other authentic peroxisomal proteins. We also measured de novo cholesterol synthesis from radio-labeled acetate in all cell lines and found similar or even elevated rates for the PBD cells when compared to controls. Our results imply that functional peroxisomes are not a prerequisite for the functioning of enzymes involved in cholesterol/isoprenoid biosynthesis and as such raise doubts about the true involvement of peroxisomes therein.

Carbon-Carbon Double Bond Isomerases↗
PubMed1981

A mouse temperature-sensitive mutant defective in H1 histone phosphorylation is defective in deoxyribonucleic acid synthesis and chromosome condensation.

By means of a temperature-sensitive mutant (ts85 strain), we have studied the effect of the decrease in H1 histone phosphorylation on DNA synthesis and chromosome condensation. When ts85 cells were incubated at 39 degrees C (nonpermissive temperature), the rate of H1 histone phosphorylation was decreased gradually and reached half that at 33 degrees C (permissive temperature) by 6-h incubation. Wild-type cells, growth-revertant ts85 cells (ts85R-MN3), and other ts mutants which were arrested mainly at the G2 phase at 39 degrees C had no defects in H1 histone phosphorylation. When ts85 cells were synchronized at the G1/S boundary at 33 degrees C and released from the blockade at 39 degrees C, approximately 70% of cells passed through the S phase and stopped at the G2 phase. The rest were distributed in G1/S to the S phase and mitotic cells were not detected at all. When ts85 cells, synchronized at the G1/S boundary, were further incubated for 8 h at 39 degrees C with a synchronizing agent, the rate of phosphorylation of H1 histone was decreased and the cells were not able to complete DNA synthesis after release from the blockade. Cytofluorometric analysis revealed that the cells had DNA contents of the S phase. Taken together with our earlier data [Matsumoto, Y., Yasuda, H., Mita, S., Marunouchi, T., & Yamada, M. (1980) Nature (London) 184, 181-183], both events, incomplete DNA replication and a defect in chromosome condensation, were thought to be ascribed to the decrease in H1 histone phosphorylation.

Animals↗
PubMed2005

Correction of a mineralization defect by overexpression of a wild-type cDNA for COL1A1 in marrow stromal cells (MSCs) from a patient with osteogenesis imperfecta: a strategy for rescuing mutations that produce dominant-negative protein defects.

Gene therapy for dominant-negative disorders presents a more difficult challenge than gene therapy for recessive disorders, since even partial replacement of a protein for a recessive disorder can reverse symptoms. Osteogenesis imperfecta (OI) has frequently served as a model disorder for dominant-negative defects of structural proteins. The disease is caused by mutations in type I collagen (COL1A1), the major structural component of bone, skin and other connective tissues. The severity of the phenotype is largely dependent on the ratio of normal to mutant type I procollagen synthesized by cells. Recently, attempts have been made to develop strategies for cell and gene therapies using the adult stem cells from bone marrow referred to as mesenchymal stem cells or marrow stromal cells (MSCs). In this study, we used MSCs from a patient with type III OI who was heterozygous for an IVS 41A+4C mutation in COL1A1. A hybrid genomic / cDNA construct of COL1A1 was transfected into the MSCs and the transfectants were expanded over a 200-fold. Transfected MSCs showed increased expression of the wild-type mRNA and protein. In vitro assays demonstrated that the transfected cells more efficiently differentiated into mineralizing cells. The results indicated that it is possible to overexpress COL1A1 cDNA in OI MSCs and thereby to correct partially the dominant-negative protein defect.

Bone Marrow Cells↗
PubMed2000

Modified Rastelli using an autograft: A new concept for correction of transposition of the great arteries with ventricular septal defect and left ventricular outflow tract obstruction (with an extension to other congenital heart defects).

We describe in this article a new approach in transposition of the great arteries (TGA), ventricular septal defect (VSD), and left ventricular outflow tract obstruction (LVOTO). It consists of an operation combining the intracardiac infundibular resection of the Lecompte procedure to allow a direct VSD-aorta connection and the right ventricle-pulmonary artery (RV-PA) connection with a segment of tubular aortic autograft, (with or without an additional monocusp patch). Thus, a viable conduit, capable of growth, is interposed between RV and PA. We have performed this procedure in 19 patients (age, 2 months to 11 years), 6 being under 1 year. All patients are doing well after a maximum follow-up of 72 months, exhibiting growth of the conduit and satisfactory RV pressures. This new approach allows primary correction even in the young and can be extended, we think, for other defects with pulmonary stenosis or atresia. It shares, however, with many other procedures, the valveless nature of the repair with the potential late need for valve replacement surgery. Copyright 2000 by W.B. Saunders Company

Journal Article↗
PubMed1981

[Fibrous metaphyseal defect (fibrous cortical defect, non-ossifying fibroma) (author's transl)].

Fibrous cortical defect and non-ossifying fibromas can be classified together as fibrous metaphyseal defects (FMD) since they have the same pathological substrate, with a tendency to the same localisation around the knee, and occurring at the same age. They have a tendency to spontaneous healing, are clinically silent and are usually discovered accidentally during radiological examination. A radiological survey of 5.674 metaphyseal regions in the upper and lower extremities of 2.065 unselected patients aged one to 20 years revealed an incidence of 1.8%; exclusive examination of the distal femur showed an incidence of 2.7%. 96% of all lesions were in the lower extremities and only 4% in the upper. The marked discrepancy in the incidence rate between American and German publications is discussed.

Adolescent↗
PubMed2002

Anterior lingual mandibular salivary gland defect (Stafne defect) presenting as a residual cyst.

Lingual mandibular salivary gland inclusion (Stafne defect) is a developmental anomaly represented by a bone concavity usually containing submandibular gland tissue. The posterior mandible region, particularly at the angle and below the mandibular canal, is the common location, and the anterior mandibular variants occur rather seldom. The latter is usually observed in the premolar and cuspid region, or more rarely in the symphysis, as a round or ovoid radiolucency sometimes appearing superimposed over the teeth's apices, resembling a true cystic lesion or an odontogenic tumor. We report an additional case of anterior lingual mandibular salivary gland defect occurring in a 42-year-old white man. It presented as an asymptomatic radiolucency located on the left side of the mandible, in the region of an absent second premolar and first molar, above the alveolar canal, mimicking a residual cyst. Histopathologic examination of the "cyst" content revealed the absence of a cyst lining and the presence of normal sublingual gland tissue.

Adult↗
PubMed1990

The genetic defect in Cockayne syndrome is associated with a defect in repair of UV-induced DNA damage in transcriptionally active DNA.

Cells from patients with Cockayne syndrome (CS) are hypersensitive to UV-irradiation but have an apparently normal ability to remove pyrimidine dimers from the genome overall. We have measured the repair of pyrimidine dimers in defined DNA sequences in three normal and two CS cell strains. When compared to a nontranscribed locus, transcriptionally active genes were preferentially repaired in all three normal cell strains. There was no significant variation in levels of repair between various normal individuals or between two constitutively expressed genes, indicating that preferential repair may be a consistent feature of constitutively expressed genes in human cells. Neither CS strain, from independent complementation groups, was able to repair transcriptionally active DNA with a similar rate and to the same extent as normal cells, indicating that the genetic defect in CS lies in the pathway for repair of transcriptionally active DNA. These results have implications for understanding the pleiotropic clinical effects associated with disorders having defects in the repair of DNA damage. In particular, neurodegeneration appears to be associated with the loss of preferential repair of active genes and is not simply correlated with reduced levels of overall repair.

Adenosine Deaminase↗
PubMed1993

Hematopoietic stem-cell defects underlying abnormal macrophage development and maturation in NOD/Lt mice: defective regulation of cytokine receptors and protein kinase C.

The immunopathogenesis of autoimmune insulin-dependent diabetes in NOD mice entails defects in the development of macrophages (M phi s) from hematopoietic precursors. The present study analyzes the cellular and molecular basis underlying our previous finding that the Mø growth factor colony-stimulating factor 1 (CSF-1) promotes a reduced level of promonocyte proliferation and M phi development from NOD bone marrow. CSF-1 stimulation of NOD marrow induced Møs to differentiate to the point that they secreted levels of tumor necrosis factor alpha equivalent to that of controls. However, CSF-1 failed to prime NOD M phi s to completely differentiate in response to gamma-interferon, as shown by their decreased lipopolysaccharide-stimulated interleukin 1 secretion. These defects, in turn, were associated with an inability of CSF-1 to up-regulate c-fms (CSF-1 receptor) and Ifgr (gamma-interferon receptor) expression. Even though the combination of CSF-1 and gamma-interferon up-regulated c-fms and Ifgr transcript levels in NOD M phi s to levels induced in control M phi s by CSF-1 alone, the protein kinase C activities coupled to these receptors remained 4-fold lower in NOD M phi s than in M phi s derived from the marrow of diabetes-resistant NON and SWR control mice. Despite expressing the diabetogenic H-2g7 haplotype, M phi s derived from cytokine-stimulated marrow of the NON.H-2g7 congenic stock were functionally more mature than similarly derived M phi s from NOD mice. Whereas diabetes resistance was abrogated in 67% of irradiated (NOD x NON)F1 females reconstituted with NOD marrow, no recipients became diabetic after reconstitution with a 1:1 mixture of marrow from NOD and the congenic stock. Thus, failure to develop functionally mature monocytes may be of pathogenic significance in NOD mice.

Animals↗
PubMed1997

A fibroblast cell line defective in alkyl-dihydroxyacetone phosphate synthase: a novel defect in plasmalogen biosynthesis.

Using fluorescence-activated cytotoxicity selection, followed by colony autoradiographic screening of the surviving population, we have isolated a unique plasmalogen-deficient Chinese hamster ovary (CHO) cell line. The mutant, NZel-1, showed a dramatic (90%) reduction in the rate of biosynthesis and levels of plasmalogens, as determined using short- and long-term labeling with 32Pi. Enzymatic assays and lipid supplementation studies showed that NZel-1 was defective in a single step in the biosynthetic pathway for plasmalogens. This step, catalyzed by the peroxisomal enzyme, alkyl-dihydroxyacetone phosphate (DHAP) synthase, is responsible for the introduction of the ether bond found in plasmalogens. The activity of alkyl-DHAP synthase was reduced in whole-cell homogenates from NZel-1 to 18% of wild-type values. Unlike previously described plasmalogen-deficient mutants, NZel-1 contained peroxisomes, as confirmed by immunofluorescence microscopy and catalase release by digitonin. Peroxisomal functions, including the breakdown of very long-chain (>20 carbons) fatty acids, phytanic acid oxidation, and the acylation of DHAP, were normal. Cell fusion studies revealed that the mutation is recessive and belongs to a new complementation group. To our knowledge this is the first report describing the isolation and characterization of a mutant CHO cell line defective in plasmalogen biosynthesis which contains intact, functional peroxisomes. These cells will allow us to examine the role of ether lipids in cellular functions without complications associated with peroxisome deficiency.

Alkyl and Aryl Transferases↗
PubMed1999

Human cells compromised for p53 function exhibit defective global and transcription-coupled nucleotide excision repair, whereas cells compromised for pRb function are defective only in global repair.

After exposure to DNA-damaging agents, the p53 tumor suppressor protects against neoplastic transformation by inducing growth arrest and apoptosis. A series of investigations has also demonstrated that, in UV-exposed cells, p53 regulates the removal of DNA photoproducts from the genome overall (global nucleotide excision repair), but does not participate in an overlapping pathway that removes damage specifically from the transcribed strand of active genes (transcription-coupled nucleotide excision repair). Here, the highly sensitive ligation-mediated PCR was employed to quantify, at nucleotide resolution, the repair of UVB-induced cyclobutane pyrimidine dimers (CPDs) in genetically p53-deficient Li-Fraumeni skin fibroblasts, as well as in human lung fibroblasts expressing the human papillomavirus (HPV) E6 oncoprotein that functionally inactivates p53. Lung fibroblasts expressing the HPV E7 gene product, which similarly inactivates the retinoblastoma tumor-suppressor protein (pRb), were also investigated. pRb acts downstream of p53 to mediate G(1) arrest, but has no demonstrated role in DNA repair. Relative to normal cells, HPV E6-expressing lung fibroblasts and Li-Fraumeni skin fibroblasts each manifested defective CPD repair along both the transcribed and nontranscribed strands of the p53 and/or c-jun loci. HPV E7-expressing lung fibroblasts also exhibited reduced CPD removal, but only along the nontranscribed strand. Our results provide striking evidence that transcription-coupled repair, in addition to global repair, are p53-dependent in UV-exposed human fibroblasts. Moreover, the observed DNA-repair defect in HPV E7-expressing cells reveals a function for this oncoprotein in HPV-mediated carcinogenesis, and may suggest a role for pRb in global nucleotide excision repair.

DNA Repair↗
PubMed2004

Loss of the Max-interacting protein Mnt in mice results in decreased viability, defective embryonic growth and craniofacial defects: relevance to Miller-Dieker syndrome.

The Mnt gene encodes a Mad-family bHLH transcription factor located on human 17p13.3. Mnt is one of 20 genes deleted in a heterozygous fashion in Miller-Dieker syndrome (MDS), a contiguous gene syndrome that consists of severe neuronal migration defects and craniofacial dysmorphic features. Mnt can inhibit Myc-dependent cell transformation and is hypothesized to counterbalance the effects of c-Myc on growth and proliferation in vivo by competing with Myc for binding to Max and by repressing target genes activated by Myc : Max heterodimers. Unlike the related Mad family members, Mnt is expressed ubiquitously and Mnt/Max heterodimers are found in proliferating cells that contain Myc/Max heterodimers, suggesting a unique role for Mnt during proliferation. To examine the role of Mnt in vivo, we produced mice with null (Mnt(KO)) and loxP-flanked conditional knock-out (Mnt(CKO)) alleles of Mnt. Virtually all Mnt(KO/KO) mutants in a mixed (129S6 x NIH Black Swiss) or inbred (129S6) genetic background died perinatally. Mnt-deficient embryos exhibited small size throughout development and showed reduced levels of c-Myc and N-Myc. In addition, 37% of the mixed background mutants displayed cleft palate as well as retardation of skull development, a phenotype not observed in the inbred mutants. These results demonstrate an important role for Mnt in embryonic development and survival, and suggest that Mnt may play a role in the craniofacial defects displayed by MDS patients.

Animals↗
PubMed1987

Defective production of antibody to herpes simplex virus in neonates: defective production of T helper lymphokine and induction of suppression.

Defective production of antibodies to herpes simplex virus (HSV) and low resistance to HSV infection in neonatal mice could be reconstituted by using macrophages from syngeneic adult mice plus concanavalin A-stimulated supernatants prepared from adult mouse spleen cells or adult human peripheral blood lymphocytes. In each supernatant, interleukin-2 (IL-2) produced by T helper cells (positive for Lyt 1.2 or OKT4) was necessary to provide reconstitution. Supernatants from neonatal mice failed to mediate reconstitution because of an age-dependent absence of production of IL-2. Although supernatants from neonatal human cell cultures contained IL-2, they failed to reconstitute production of antibody to HSV and resistance to HSV infection because of a suppressor of IL-2 activity. Early antibody production and antibody-dependent cellular effector function are important defenses against HSV infection and are critically defective in the neonate.

Animals↗
PubMed1991

Congenital laminar defect of the upper lumbar spine associated with pars defect. A report of eleven cases.

Lumbar spondylolysis generally is considered to be a fatigue fracture of the pars interarticularis, and no unequivocal case of congenital spondylolysis has been reported. The authors describe 11 cases of unilateral spondylolysis (possibly congenital laminar defect associated with pars defect) of the upper lumbar spine. They have roentgenographic characteristics distinct from conventional spondylolysis of the lumbar spine, including hypoplasia of the spinal accessory process, rotation of the spinous process contralaterally to the spondylolysis, and prominent ipsilateral lamina. The anomaly found in these 11 patients probably is congenital, and its clinical significance is not known.

Adolescent↗
PubMed2004

Role of mobile interstitial oxygen atoms in defect processes in oxides: interconversion between oxygen-associated defects in SiO(2) glass.

The role of mobile interstitial oxygen atoms (O(0)) in defect processes in oxides is demonstrated by interconversion between the oxygen dangling bond and the peroxy radical (POR) in SiO2 glass. Superstoichiometric O(0) was created by F2 laser photolysis of the interstitial O2. On annealing above 300 degrees C, O(0) migrated and converted the oxygen dangling bond to POR. Exposure to 5.0 eV light converted POR back to a pair of the oxygen dangling bond and O(0) (quantum yield: approximately 0.1). These findings suggest that various defect processes typically occurring in SiO2 glass at approximately 300-500 degrees C are related to migration of O(0), which exists in the glass network in the peroxy linkage form.

Journal Article↗
PubMedDate not supplied

Defective clearance of adenovirus in IRF-1 mice associated with defects in NK and T cells but not macrophages.

A replication-defective adenovirus-LacZ recombinant virus (AdLacZ) was injected intravenously into IRF-1(-/-) mice and wild-type mice to characterize the contribution of IRF-1 to the immune-mediated clearance of Ad vector. Compared with wild-type mice, IRF-1(-/-) mice expressed higher levels of the LacZ gene product in the liver. After infusion of the AdLacZ, the expression of IRF-1 mRNA was upregulated in the liver of wild-type mice, but not in IRF-1(-/-) mice. Both spleen and liver mononuclear cells from IRF-1(-/-) mice initially exhibited a markedly lower number of NK, NK-T and CD8 T cells. At day 7 after the administration of AdLacZ, there was a significantly increased population of NK, NK-T and CD8 T cells in both spleen and liver, and also CD11b(+) cells in liver of IRF-1(-/-) mice, compared with the increased in wild-type mice. As IRF-1 is an important signal for production of IFN-gamma by CD8 T and NK cells as well as production of IL-12 by CD11b(+) cells, we determined whether there were lower levels of these cytokines in IRF-1(-/-) mice after Ad challenge. Surprisingly, there were lower levels of IL-12, but higher levels of IFN-gamma and IL-18 in IRF-1(-/-) compared with wild-type mice at day 7 after administration with AdLacZ. These results indicate that delayed clearance of Ad is associated with partial correction of defects of the NK, NK-T and CD8 T cells and increased production of IFN-gamma and IL-18 in IRF-1(-/-) mice.

Adenoviridae↗
PubMed1993

Confirmation of Rb gene defects in B-CLL clones and evidence for variable predominance of the Rb defective cells within the CLL clone.

In 70 B-CLL patients, deletion or translocation, at or near the retinoblastoma (Rb) site, was detected in 20 by cytogenetic analysis. Purified B cell clones from 13 of these B-CLL patients were isolated and studied for Rb gene status, Rb mRNA and the Rb protein product. Southern blot analysis of the Rb site detected internal deletions (N = 1) or a single allele loss (N = 2) in five patients. Northern blots detected reduced Rb mRNA in four patients. Immunoblot of whole cell lysate revealed reduced levels of unphosphorylated Rb protein in six CLL patients. No CLL B cell clone contained phosphorylated Rb species. These molecular studies have confirmed the cytogenetic alteration of 13q12-14 sites in B-CLL cells. In addition, cytogenetic and molecular biologic analysis suggest heterogeneity in the B cell clone for Rb gene abnormality. B-CLL patients with abnormalities in both cytogenetic and Rb DNA/RNA analysis will have a dominance of B cells with an Rb abnormality (N = 5). In patients whose Rb defective CLL cells constitute only a minor subpopulation of the total B cell clone, only cytogenetic defects would likely be detected (N = 7).

Blotting, Northern↗