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Biomedical subjects

J Lund

Publications and source records attributed to J Lund.

213 records · Page 12Linked to original sources
PubMed1967

Metabolism of vitamin D3-3H in vitamin D-resistant rickets and familial hypophosphatemia.

The fate of an intravenous dose of tritiated vitamin D(3) was studied in seven normal subjects, four children with vitamin D-resistant rickets, and four adults with a familial history of vitamin D-resistant rickets and persistent hypophosphatemia. An abnormal metabolism of vitamin D in vitamin D-resistant rickets was defined and characterized by a decrease in the plasma fractional turnover rate, a marked increase in plasma water-soluble metabolites, and a relative decrease in the conversion of vitamin D to a polar, biologically active metabolite. Alterations in vitamin D metabolism in the adults with persistent hypophosphatemia were similar but less severe than those of affected children with vitamin D-resistant rickets. It is tentatively concluded that the abnormalities in vitamin D metabolism documented in patients with vitamin D-resistant rickets and familial hypophosphatemia may account for the observed osseous and biochemical changes.

Adolescent↗
PubMed1966

Biologically active metabolite of vitamin D3 from bone, liver, and blood serum.

Radioactive metabolites present in bone, blood, liver, and feces of rats given (3)H vitamin D(3) have been isolated. Of these the aqueous soluble metabolite(s) from tissue and all those isolated from feces did not cure rickets in rats, while all the others were at least partially active in this regard. One of the metabolites proved to be as active as the parent vitamin in curing rickets and was found in large amounts in liver, blood, and bone. As much as 50-80% of the radioactivity in bone was found in this metabolite after a 500 IU oral dose of (3)H vitamin D(3). With 10 IU doses of 1,2-(3)H vitamin D(3), most of the radioactivity of the organs examined was found in this metabolite fraction. This metabolite appears to be more polar than vitamin D and is not an esterified form of the vitamin nor a complex of the vitamin with tissue lipids. Its possible role as the metabolically active form of the vitamin is discussed.

Animals↗
PubMedDate not supplied

In vitro characterization of possible mechanisms underlying the selective in vivo accumulation of the PCB metabolite 4,4'-bis(methylsulphonyl)-2,2',5,5'-tetrachlorobiphenyl in the lung.

In vivo, the polychlorinated biphenyl (PCB) metabolite 4,4'-bis(methylsulphonyl)-2,2',5,5'- tetrachlorobiphenyl--(MeSO2)2TCB--selectively accumulates in the Clara cells of the bronchiolar epithelium and in the secretory contents of the bronchiolar lumen. In vitro characterization of the interaction of tritiated (MeSO2)2TCB with the lung suggests that this selective accumulation is due to the presence of a secreted ([3H]MeSO2)2TCB-binding protein in the respiratory tract of rats, mice and man. The protein appears to be an almost globular, low-molecular-weight acidic protein which binds ([3H]MeSO2)2TCB and certain other methylsulphonyl PCBs with high affinity. Because of the pathway outlined for accumulation, it is suggested that methylsulphonyl PCBs should be included in studies designed to elucidate the mechanism(s) of PCB-induced lung toxicity.

Animals↗
PubMedDate not supplied

No influence of the antidepressant paroxetine on carbamazepine, valproate and phenytoin.

A single-blind, placebo-controlled, cross-over trial investigating possible interactions between paroxetine, a serotonin re-uptake inhibitor, and carbamazepine (CBZ), valproate (VPA) and phenytoin (PHT) was carried out in 20 outpatients with epilepsy. Patients on long-term treatment with CBZ, VPA, or PHT were given a 7-day placebo treatment, followed by paroxetine co-treatment for 16 days. Side effects were infrequent and mild. Paroxetine caused no changes in the plasma concentrations and all values were within the recommended ranges. No changes in protein binding were found. Plasma concentrations of paroxetine at steady state (8-147 ng/ml) were in the normal range for a 30-mg daily dosing regimen. None of the patients experienced epileptic seizures during the study.

Adult↗
PubMedDate not supplied

The influence of glycosylation on the thermal stability and effector function expression of human IgG1-Fc: properties of a series of truncated glycoforms.

Antibodies are multifunctional molecules that following the formation of antibody antigen complexes, may activate mechanisms to effect the clearance and destruction of the antigen (pathogen). The IgG molecule is comprised of three globular protein moieties (2Fab+Fc) linked through a flexible hinge region. While the Fabs bind antigens, the Fc triggers effector mechanisms through interactions with specific ligands, e.g. cellular receptors (FcgammaR), and the C1 component of complement. Glycosylation of IgG-Fc has been shown to be essential for efficient activation of FcgammaR and C1. We report the generation of a series of truncated glycoforms of IgG-Fc, and the analysis of the contribution of the residual oligosaccharide to IgG-Fc function and thermal stability. Differential scanning microcalorimetry has been used to compare the stabilities of the homogeneous glycoforms of IgG1-Fc. The results show that all truncated oligosaccharides confer a degree of functional activity, and thermodynamic stability to the IgG1-Fc, in comparison with deglycosylated IgG1-Fc. The same truncated glycoforms of an intact IgG1 anti-MHC Class II antibody are shown to exhibit differential functional activity for FcgammaRI and C1 ligands, relative to deglycosylated IgG1. The minimal glycoform investigated had a trisaccharide attached to each heavy chain and can be expected to influence protein structure primarily in the proximity of the N-terminal region of the C(H)2 domain, implicated as a binding site for multiple effector ligands. These data provide a thermodynamic rationale for the modulation of antibody effector functions by different glycoforms.

Calorimetry, Differential Scanning↗
PubMedDate not supplied

Immunohistochemical staining of metastatic ductal carcinomas of the breast by monoclonal antibodies used in imaging and therapy: A comparative study.

Five monoclonal antibodies (MoAbs)(L6, 170H.82, 155, BrE-3 and BR96), most of which have been previously shown to target breast cancer and not normal tissues by immunoscintigraphic imaging, were evaluated for their frequency and pattern and immunohistochemical staining in 67 to 116 metastatic lesions from patients with ductal carcinoma of the breast. Immunoperoxidase staining in 75% or more of the cells occurred in 56/116 (48%) for L6, 44/89 (49%) for Br, -96, 58/102 (57%) for 155, 62/99 (84%) for 170H.82, and 65.67 (97%) for BrE-3. With the first three MoAbs, an additional 6-10% of the tumors showed staining in 50-75% of tumor cells. These results illustrate that most patients with metastatic ductal carcinoma have cancer tissue in which a high percent of cells will react to several of these selected MoAbs that target different epitopes. The high expression of the MoAb targets throughout the tumor tissue makes these antibodies potential candidates to carry immunologically directed radioimmunotherapy and is an aid in selecting patients for treatment.

Animals↗
PubMedDate not supplied

Transcriptional regulation of the bovine CYP17 gene: two nuclear orphan receptors determine activity of cAMP-responsive sequence 2.

The CYP17 gene contains in its promoter region at least two cis-acting elements (cAMP-responsive sequence 1 and 2, CRS1 and CRS2) that are necessary for adrenocorticotropin (ACTH) induced transcription. The CRS2 element contains a 6 bp repeat similar to binding sites for members of the nuclear hormone receptor superfamily of transcription factors. We present data that establish the repeated part of CRS2 (repCRS2) as a target of two nuclear orphan receptors; steroidogenic factor 1 (SF-1) and chicken ovalbumin upstream promoter transcription factor (COUP-TF). The repCRS2 element was found to form COUP-TF-related complexes with nuclear extracts from all cell lines tested, whereas SF-1-related complexes were only formed with extracts from steroidogenic Y1 cells. Transfection studies of steroidogenic cells demonstrated that SF-1 acts as an activator of repCRS2-dependent transcription of reporter genes.

Animals↗
PubMedDate not supplied

Biochemical and functional analysis of nuclear receptors as targets in cAMP-dependent control of bovine CYP17.

Several lines of evidence have suggested that the nuclear receptor Steroidogenic Factor-1 (SF-1 or Ad4BP) may be directly involved in the cAMP-dependent regulation of steroid hydroxylase genes in adrenocortical cells. In the bovine CYP17 gene, which encodes the cytochrome P450 17alpha-hydroxylase, an SF-1 site is present within cAMP-responsive sequence 2 (CRS2) and mutations which interfere with SF-1 binding correlate with decreases in cAMP-stimulated transcription of a linked reporter gene. In order to determine whether the cAMP response relies on structures within SF-1 itself, mutations and deletions were introduced. We demonstrate that even a single point mutation (E454A) in the transactivating AF-2 domain drastically reduces the ability of SF-1 to mediate cAMP-dependent transcription. Furthermore, the mutation results in a protein which acts in a dominant negative fashion with respect to cAMP-dependent regulation of the bovine CYP17 gene. Finally, we demonstrate that the coactivators CBP and SRC-1 are limiting with respect to cAMP-induced CRS2-dependent transcription in Y1 adrenocortical tumor cells, suggesting that part of the action of cAMP may be to influence the interaction of SF-1 with other cofactors via the AF-2 domain.

Adrenal Cortex Neoplasms↗
PubMedDate not supplied

Lectin receptors in the human cornea.

Five different biotin labeled lectins, Concanavalin-A (Con A), wheat germ agglutinin (WGA), Ricinus communis agglutinin I (RCA1), Ulex europaeus agglutinin (UEA1), and soybean agglutinin (SBA) were used to study lectin receptors on formalin-fixed paraffin embedded human corneas. Con A stained the cytoplasm, cell, and nuclear membranes of the epithelial cells and stained the stroma diffusely. WGA stained the superficial epithelial cells, the epithelial cell membranes, and the keratocytes of the stroma. SBA did not react with any of the corneal layers. RCA1 heavily stained the keratocytes but did not stain the epithelium. UEA1 lightly stained the epithelial cell cytoplasm and interstitial stroma. All staining reactions could be abolished by omission of the lectin or by the use of the appropriate inhibitory sugar. The lectin binding patterns reported here provide a means for further investigation of carbohydrate structures in the human cornea in both normal and disease states.

Cornea↗
PubMedDate not supplied

Target cells for the polychlorinated biphenyl metabolite 4,4'-bis(methylsulfonyl)-2,2',5,5'-tetrachlorobiphenyl in lung and kidney.

Light microscope autoradiography was used to determine the cellular localization of the polychlorinated biphenyl metabolite 4,4'-bis([14C] methylsulfonyl)-2,2',5-5'-tetrachlorobiphenyl ([3H]TCB) in the lung and kidney of mice and rats. Microautoradiograms prepared from thaw-mounted freeze sections showed that the radioactivity in the lung was localized in the bronchiolar lumen and epithelium. In methacrylate sections (74-82% of radioactivity extracted), a highly selective labeling was registered in the apical cytoplasm of the Clara cells. A pronounced labeling was present also in certain goblet-like cells containing periodic acid-Schiff-positive granules. Gel permeation chromatography and density gradient centrifugation showed that 80-95% of the radioactivity in lung lavage fluid was bound to a specific protein previously characterized in rat and mouse lung cytosol. The protein appeared to be enriched in the lavage fluid, as compared to lung cytosol. These data suggest that [3H]TCB binds to a protein residing in the Clara and goblet-like cells and that the labeled TCB-protein complex is subsequently secreted into the airway lumen. As shown by microautoradiography, the radioactivity in the kidney was confined to a restricted portion of the nephron, predominantly to the apical region of the proximal tubular cells.

Animals↗
PubMedDate not supplied

Cellular and subcellular localization of a binding protein for polychlorinated biphenyls in rat lung.

Enriched cell populations from rat lung were isolated by use of elutriation. An in vitro ligand binding assay as well as a Western immunoblot assay were used to determine the levels of a binding protein for certain polychlorinated biphenyls (PCBs) in cytosolic preparations from these cell populations. The cell population enriched in Clara cells (30% Clara cells) contained by far the largest amount of the PCB-binding protein, 759 +/- 81 pmol/mg of cytosolic protein as judged by an in vitro ligand binding assay. Western immunoblot analysis of cytosolic preparations from the enriched cell preparations, using antibodies to the PCB-binding protein, showed levels of immunoreactive material in these fractions that corresponded to the level of the PCB-binding protein as determined by the in vitro ligand binding assay. By use of the peroxidase-antiperoxidase method of immunoperoxidase staining, antibodies to the PCB-binding protein were found to stain the Clara cells in sections of paraffin-embedded rat lungs. Intense immunoperoxidase staining of the material lining the airway epithelium was also observed. The protein was predominantly localized to the secretory granules in the apical cytoplasm of the Clara cells as determined using antibodies to the protein, protein A-gold, and electron microscopy. Previous studies have shown a selective in vivo accumulation of methylsulfonyl-PCBs in Clara cells of rodent lung and the present investigation, demonstrating the presence in the Clara cells of a secretory Mr 13,000 protein that binds methylsulfonyl-PCBs with high affinity, gives further support to the contention that the protein is an important factor in determining the in vivo disposition of these compounds.

Animals↗