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Biomedical subjects

J Lund

Publications and source records attributed to J Lund.

At least 109 records · Page 6Linked to original sources
PubMed1992

Distinct biochemical mechanisms for cAMP-dependent transcription of CYP17 and CYP21.

Optimal steroidogenic capacity in the adrenal cortex is regulated by ACTH via cAMP and involves transcription of the genes encoding the adrenocortical steroid hydroxylases. The microsomal steroid hydroxylases, P45017 alpha and P450C21, are encoded by CYP17 and CYP21, respectively. These genes are thought to have arisen from a common progenitor gene and are coordinately regulated by ACTH. The cAMP responsive sequences (CRS) located in the 5'-flanking regions of these genes are distinct from one another and from known consensus sequences imparting cAMP responsiveness in other genes. The CYP21 CRS binds a putative adrenal-specific nuclear protein. In contrast, the CYP17 CRSI binds a ubiquitous protein that is apparently active only in steroidogenic cells. Thus the ACTH-dependent transcription of these two genes, which have a common evolutionary origin and are coordinately expressed in the adrenal cortex, involves distinct biochemical mechanisms.

Adrenal Glands↗
PubMed1992

Electronic performance monitoring: A review of research issues.

The research literature on electronic performance monitoring (EPM) has attributed different outcomes to monitoring, including improved worker performance, reduced job satisfaction and increased job stress. A variety of research methods (case study, cross-sectional and laboratory designs) has been utilized to study these effects of EPM. In this paper, these methods are reviewed, and the results of several studies are summarized. The existing literature often does not clearly specify what is meant by monitoring. Future research on outcomes associated with monitoring should describe carefully the type of monitoring technology and system used - who does the monitoring, when it is done, and what aspect of performance is monitored. It is further suggested that future EPM research should describe in greater detail the work environment, the job tasks, and the organizational climate of monitored and non-monitored workers to determine whether these groups are comparable with respect to these factors, and that observed outcomes are not misattributed to EPM.

Journal Article↗
PubMed1992

Rat lung polycholorinated biphenyl-binding protein: effect of glucocorticoids on the expression of the Clara cell-specific protein during fetal development.

Certain metabolites of polychlorinated biphenyls (PCBs) are retained in the Clara cells and in the airway lumen of rodent lung due to their interaction with a secretory 13-kDa protein. The expression of this Clara cell-specific, PCB-binding protein (PCB-BP) during the fetal development of the rat lung was studied by means of ligand binding and a monospecific antiserum. The PCB-BP and specific 4,4'-bis([3H]methylsulfony)-2,2',5,5'-tetrachlorobiphenyl binding was first detected on gestational Day 19 and subsequently the levels of PCB-BP and specific ligand binding increased as a function of gestational age. The start site of transcription for the rat PCB-BP gene was determined by primer extension analysis and the information thus obtained was used to develop a quantitative assay for the corresponding mRNA based on solution hybridization and S1 nuclease mapping. The appearance of PCB-BP mRNA during fetal lung development preceded the detection of immunoreactive protein and ligand binding by 1 day. By Day 21, the level of PCB-BP mRNA was 15 ng/100 micrograms total lung RNA which is approximately 30-40% of adult levels. In utero exposure to the synthetic glucocorticoid betamethasone was shown to increase specific 4,4'-bis([3H]methylsulfonyl)2,2',5,5'- tetrachlorobiphenyl binding, PCB-BP protein, and PCB-BP mRNA if administered from gestational Day 18 and onward. By Days 21-22, glucocorticoid treatment resulted in a two- to threefold increase in the levels of specific ligand binding, immunoreactivity, and mRNA, i.e., to approximately adult levels.

Animals↗
PubMed1992

Multiple binding sites on the CH2 domain of IgG for mouse Fc gamma R11.

Important mammalian defensive functions such as phagocytosis are triggered in leukocytes by the interaction of the Fc region of IgG with cell surface receptors (Fc gamma R). The CH2 domain of IgG has been implicated previously as the site of interaction with human and mouse Fc gamma R. This domain was mapped for interaction with mouse Fc gamma R11 expressed by the macrophage-like cell line P388D1, using two panels of a total of 32 site-directed mutants of mouse IgG2b and chimeric human IgG3 monoclonal antibodies. Two potential binding sites have been identified: one in or within the vicinity of the lower hinge site on IgG for human Fc gamma R1, and one within the binding site on IgG for Clq. The three mutant IgGs (Gly 237----Ala, Asn 297----Ala, and Glu 318----Ala) which do not interact in complexed form also fail to bind as monomers. A 1H NMR study of the three non-binding monomeric mutants suggests that the mutations are largely site-specific, indicating that IgG interacts with mouse Fc gamma R11 at two regions within the CH2 domain. This interaction dictates phagocytosis mediated by Fc gamma R11 of the P388D1 cell line.

Animals↗
PubMed1992

Mapping and comparison of the interaction sites on the Fc region of IgG responsible for triggering antibody dependent cellular cytotoxicity (ADCC) through different types of human Fc gamma receptor.

In the present study 3-iodo-4-hydroxy-5-nitrophenacetyl (NIP)-specific antibodies were compared for induction of antibody dependent lysis of NIP-derivatised red blood cells effected by pre-stimulated U937 or HL-60 cells and by K cells. The chimaeric antibodies have heavy chains corresponding to human IgG subclasses 1-4, and include site-directed mutants of IgG3 as well as the aglycosylated form of IgG3; a mouse IgG2b antibody and a site-directed mutant IgG2b were also examined. rIFN stimulated U937 or HL-60 cells express increased levels of Fc gamma R1 compared to unstimulated cells; PMA stimulated HL-60 and U937 cells express an increased level of Fc gamma R11 compared to unstimulated cells; K cells express Fc gamma R111. Using these effector cell populations and the target cells mentioned above, we have compared anti-NIP antibodies with different heavy chain constant domains for their ability to induce ADCC through human Fc gamma R1, Fc gamma R11 and Fc gamma R111. The results suggest that all three human Fc gamma receptors appear to recognise a binding site on IgG within the lower hinge (residues 234-237) and trigger ADCC via this site, but that each receptor sees this common site in a different way. The possibility that other amino acid residues also participate in the binding/triggering site(s) cannot be excluded.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1992

A novel 3',5'-cyclic adenosine monophosphate-responsive sequence in the bovine CYP17 gene is a target of negative regulation by protein kinase C.

The bovine 17 alpha-hydroxylase cytochrome P450 gene (CYP17) contains at least two cAMP-responsive sequences (CRS) within its 5'-flanking region. In this study it is demonstrated that one of the sequences, CRS1, is also a target for protein kinase C (PKC)-mediated regulation. Forskolin-induced, CRS1-dependent transcription of a heterologous minimal promoter/structural gene which had been transfected into the mouse adrenocortical tumor cell line Y1 was suppressed by activation of PKC by phorbol esters such as 12-O-tetradecanoyl phorbol-14-acetate and phorbol 12,13-didecanoate-beta (PDD beta). Use of the active and inactive forms of PDD (PDD alpha and PDD beta) as well as down-regulation of PKC by prolonged treatment of the cells with 12-O-tetradecanoyl phorbol-14-acetate demonstrated that the effect of phorbol esters on transcription conferred by CRS1 was mediated through the PKC pathway and not a consequence of general toxicity to the cells. Analysis of the different steps in the signal transduction pathway between the adenylate cyclase and the CRS1 element suggests that phrobol esters do not exert their effect by altering the forskolin-induced cAMP production, activation of PKA, or the binding of nuclear proteins to CRS1. These results establish the CRS1 element as a target not only for PKA, but also for the PKC-mediated signal transduction pathway. They further suggest that PKC interferes with the transcriptional activation competence of factors bound to CRS1 and the minimal promoter.

Animals↗
PubMed1992

Correlation of eye color on self-paced and reactive motor performance.

Researchers continue to examine the distinctiveness of motor performance by dark- versus light-eyed individuals. Dark-eyed individuals generally perform better at reactive type tasks (boxing, hitting a ball, defensive positions in football, rotary pursuit), while light-eyed individuals perform better at self-paced tasks (bowling, golf, pitching baseballs). Subjects performed two tasks, rotary pursuit and ball tossing (with light and dark background). Eye color (light or dark) and accuracy of performance were recorded for each subject. No significant difference was found between eye color and performance on the pursuit rotor (reactive activity). A significant difference was found between men's and women's performance in throwing a ball (self-paced activity) at a light-colored background.

Adult↗
PubMed1991

Human Fc gamma RI and Fc gamma RII interact with distinct but overlapping sites on human IgG.

Cellular receptors for IgG (Fc gamma R) mediate important protective functions. By using site-specific mutants of a chimeric antibody (mouse V H domain and L chain; human IgG3 C H domains), we have demonstrated that human Fc gamma RI interacts with a site in the lower hinge of human IgG (residues 234 to 237) and that this interaction dictates Fc gamma RI-mediated superoxide generation. Mutations at position 235 resulted in the most profound reductions in Fc gamma RI recognition. We have also mapped an interaction site for Fc gamma RII to the same region; however, mutations at position 234 and 237 resulted in the greatest reductions in Fc gamma RII recognition. The two receptors appear to recognize overlapping but nonidentical sites on the lower hinge of IgG. Deviations from the optimal motif 234-Leu-Leu-Gly-Gly-237 may then explain the human IgG subclass specificity profile for human Fc gamma RI and Fc gamma RII.

Antigens, Differentiation↗
PubMed1991

Activation of transcription in cell-free extracts by a novel cAMP-responsive sequence from the bovine CYP17 gene.

An in vitro transcription system has been developed to study the transcriptional control of steroid hydroxylase gene expression in steroidogenic tissues using upstream sequences of these genes in rabbit beta-globin promoter/reporter constructs. Analysis of deletion mutants of the upstream region of the bovine CYP17 (p45017 alpha) gene in whole cell extracts prepared from mouse Y1 adrenocortical cells revealed that sequences activating transcription in vitro are identical to those previously identified in vivo, namely the novel cAMP-responsive sequences crsI (-243 to -225 base pairs) and crsII (-80 to -40 base pairs). These sequences do not contain the known cAMP response elements, CRE or AP-2. In similar extracts from nonsteroidogenic mouse SVT2 cells, crsI was unable to activate transcription. Partially purified protein factor(s) binding to crsI were prepared from Y1 extracts by crsI-specific DNA affinity chromatography. This fraction activated transcription in vitro in SVT2 extracts only when crsI was present in the template. This in vitro transcription system will permit further investigation of crsI and its cognate factors and of the transcriptional regulation of the other steroid hydroxylase genes.

Animals↗
PubMed1991

Pharmacokinetics of paroxetine in patients with cirrhosis.

In a 14-day multiple-dose study the pharmacokinetics of paroxetine was investigated in 12 patients with alcoholic cirrhosis and in 6 subjects without liver disease. The dose of 20-30 mg paroxetine daily was adjusted to the reduction in liver function, as assessed by the galactose elimination capacity. Accordingly, all but two of the cirrhotic patients received 20 mg, while all six control subjects received 30 mg. Dose-corrected, trough drug concentration at steady state (CSSmin) and dose-corrected AUC24h were significantly higher in the patients with liver diseases than in the control subjects [3.4 vs 1.5 ng.ml-1 per mg paroxetine and 89 vs 43 h (ng).ml-1 per mg paroxetine]. The elimination t1/2 was prolonged [83 vs 36 h], but the difference was not statistically significant, and the cirrhotic patients were still able to clear almost all the paroxetine by metabolism. All but two patients with cirrhosis experienced nausea during the first two or three days after the first dose, while none of the controls had this symptom. The study showed slower elimination of paroxetine and consequently higher plasma levels in patients with cirrhosis, suggesting that in the latter the dose of paroxetine should be in the lower end of the therapeutic range.

Adult↗
PubMed1991

Kinetics of ATP release and Pi binding during the ATPase cycle of lethocerus flight muscle fibres, using phosphate-water oxygen exchange.

Rate constants have been obtained using oxygen isotope exchange techniques for steps controlling ATP release and Pi binding in the ATPase cycle of insect flight muscle fibres from the giant waterbug Lethecerus. The new exchange data for Pi binding and ATP release are compatible with a model developed previously in which only the rate constants controlling Pi and ATP release change during fibre activation. Phosphate-water oxygen exchange occurs into ATP remaining after partial hydrolysis by chemically skinned fibres in (18O) water. For fully activated fibres, the results are compatible with a single set of rate constants controlling this exchange and give a rate constant for ATP release of 1 s-1 (21 degrees C, pH 7.0 I = 120 mM). Oxygen exchange also occurs between (18O4)Pi in the medium and water during ATP hydrolysis. There is a strong correlation between the measured rate constant of exchange and the value of keat for the ATPase activity at different levels of activation. For fibres fully activated by oscillation or strain, the rate constant for Pi binding to an actomyosin. ADP state is greater than 960 M-1 s-1.

Adenosine Diphosphate↗
PubMed1991

Trends in long-stay hospitalization in Denmark: a descriptive register study, 1972-1987.

By means of 4 cross-sections at 5-year intervals from 1972 to 1987, information on long-stay inpatients and daypatients was extracted from the computerized, cumulative psychiatric case register in Denmark. Long-stay refers to continuous hospitalization of more than 1 year. The prevalence of long-stay patients declined from 101 per 100,000 general population in 1972 to 38 per 100 000 in 1987. As the prevalence of all diagnoses declined, regardless of age and sex, it is suggested that the major cause of the observed trends is altered political and administrative strategies, influenced by and influencing altered capabilities and methods of treatment. The trends are described in detail and their implications discussed.

Adolescent↗
PubMed1991

Purification and level of expression in bronchoalveolar lavage of a human polychlorinated biphenyl (PCB)-binding protein: evidence for a structural and functional kinship to the multihormonally regulated protein uteroglobin.

A human lung polychlorinated biphenyl (PCB)-binding protein was purified by sequential chromatography of lavage fluid incubated with the tritium-labeled, high-affinity ligand, 4,4'-bis(methylsulfonyl)-2,2',5,5'-tetrachlorobiphenyl. From sodium dodecyl sulfate polyacrylamide gel electrophoresis gradient gels, it was evident that a single band with an approximate molecular weight of 13 kD was present in the eluate from the final chromatographic step. Antibodies raised against the human lung PCB-binding protein detected a single band of corresponding size in lavage fluid in immunoblotting experiments. Furthermore, the antibodies detected significantly higher levels of the lung PCB-binding protein in lavage fluid from nonsmokers as compared to smokers. The purified protein was sequenced, and an alignment of the obtained aminoterminal amino acid residues of the human lung PCB-binding protein to uteroglobin and to a rat lung PCB-binding protein revealed an overall positional identity of approximately 45%. The amino acids suggested to participate in ligand binding of uteroglobin were extensively conserved in the PCB-binding proteins. Thus, we conclude that we have purified and raised antibodies against a human lung PCB-binding protein and that it has a structural as well as a functional kinship to the steroid-binding and multihormonally regulated rabbit protein uteroglobin.

Amino Acid Sequence↗