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Biomedical subjects

J Lund

Publications and source records attributed to J Lund.

At least 19 recordsLinked to original sources
PubMed2001

A two-receptor pathway for catabolism of Clara cell secretory protein in the kidney.

Clara cell secretory protein (CCSP) is a transport protein for lipophilic substances in bronchio-alveolar fluid, plasma, and uterine secretion. It acts as a carrier for steroid hormones and polychlorinated biphenyl metabolites. Previously, the existence of receptors for uptake of CCSP.ligand complexes into the renal proximal tubules had been suggested. Using surface plasmon resonance analysis, we demonstrate that CCSP binds to cubilin, a peripheral membrane protein on the surface of proximal tubular cells. Binding to cubilin results in uptake and lysosomal degradation of CCSP in cultured cells. Surprisingly, internalization of CCSP is blocked not only by cubilin antagonists but also by antibodies directed against megalin, an endocytic receptor that does not bind CCSP but associates with cubilin. Consistent with a role of both receptors in renal uptake of CCSP in vivo, patients deficient for cubilin or mice lacking megalin exhibit a defect in tubular uptake of the protein and excrete CCSP into the urine. These findings identify a cellular pathway consisting of a CCSP-binding protein (cubilin) and an endocytic coreceptor (megalin) responsible for tissue-specific uptake of CCSP and associated ligands.

Animals↗
PubMed2001

Butyrate increases production of human chimeric IgG in CHO-K1 cells whilst maintaining function and glycoform profile.

The influence of sodium butyrate on the production and glycosylation of recombinant mouse/human chimeric antibody by transfected CHO-K1 cells was investigated. We selected cells expressing 'wild-type' antibody with a human IgG3 heavy chain and a mutant of this molecule in which Phe 243 is replaced by Ala. These proteins have previously been shown to exhibit very different glycoform profiles with the mutant IgG being comprised of glycoforms having a high galactose and sialic acid content. Cell culture with 0-5 mM butyrate was shown to effect a 2-4-fold increase in antibody production whilst the induction of apoptosis was observed in a dose-dependent manner. The optimal butyrate concentration was observed to be 2 mM. The glycoform profile of each antibody produced in the presence of butyrate was analyzed by HPAEC-PAD and shown to be unchanged, relative to that produced in the absence of butyrate. Biological activity was evaluated by the ability of the antibodies to trigger superoxide generation, through Fc gamma RI, and shown to be independent of production in the presence or absence of butyrate. A similar increase in production was observed for a high antibody-producing cell line when expanded in a hollow fibre bioreactor under low-serum conditions (1%). These results demonstrated that butyrate is of value for increasing the productivity of CHO-K1 for recombinant IgG and does not compromise either glycosylation or biological activity.

Animals↗
PubMed2001

Permanent impairments, disabilities and disability pensions related to accidents in Norway.

The purpose of this study was to estimate the burden of accidents in terms of new disability pensioners related to accidental injuries in Norway and to use this information to supplement the picture of the epidemiology of accidents in Norway. The basis of the study was 7,241 new disability pensioners due to accidents in the Disability Register of the National Insurance Administration in Norway for 1992-1997. Included in the analyses are some data from health surveys in USA and Norway. The rate of disability pensioners (16-66 years old) due to accidents increased 4% annually during 1992-1997, and in the age group 16-44 years 8% annually. The increase is found in all types of accidents, except for home and the group other accidents, where the rate is constant. 45% had been injured in traffic accidents, 33% in occupational accidents, 16% in leisure accidents, 4% in home accidents and 2% in other accidents. The rates of disability pensionings due to occupational accidents are three to four times higher among 'blue collar' workers than among 'white collar' workers. While disability pensioning rate in the age group 16-66 years due to accidents has increased 4% annually, the accident mortality for the age group 15-64 years has decreased 3% annually. The relationship between disability pensioning and mortality in the age group 15-64 years is found to be approximately 2:1 for all accidents. For occupational accidents the relationship is 5:1, for traffic accidents 2.5:1, for leisure and other accidents 1:1 and for home accidents 1:2.7. The complete epidemiologic picture due to accidents in Norway per 100,000 of population seems to be: medically treated, 10,000; hospitalised, 1,200; permanently impaired, 800 (of whom probably 50% are treated as out-patients); disabled (restricted activity), 400; fatalities, 40; and disability pensioned in the age group 16-66 years, 50. Medically treated and hospitalised patients due to accidents seem to show a slightly decreasing rate, fatalities a higher decreasing rate. This supplement to the epidemiological picture of rates and trends of impairments, disability and disability pensionings (the more serious consequences of accidents), points to the need to focus on the current trends for accident prevention.

Accident Prevention↗
PubMed2000

[Symptomatic helium treatment of upper and lower airway obstruction].

Since 1934 several clinical trials have been performed to investigate the effect of helium in the symptomatic treatment of upper and lower airway obstructions, especially in children. Controlled studies have only been produced during the last decade. Heliox, a mixture of helium and oxygen, has a significantly lower density than N2/O2-mixtures. This produces better flow and hence a decrease in respiratory work, improvement of distal gas exchange and theoretically less tendency to air-trapping and hyperinflation. When holding more than 40% O2 the clinical effect decreases. There are case reports of rapid subjective release, less stridor, lower respiratory rate and a normalization of hypercapnia and acidosis. Controlled studies confirm this and demonstrate a decrease in the need for intubation and mechanical ventilation. Time is bought until conventional therapy with steroids, epinephrine and beta 2-agonist inhalation works. Helium has its place in treatment of airway obstructions, but more clinical trials are needed to define the indication for symptomatic heliox treatment.

Administration, Inhalation↗
PubMed2000

Comparative sequence analysis of 634 kb of the mouse chromosome 16 region of conserved synteny with the human velocardiofacial syndrome region on chromosome 22q11.2.

Mouse genomic DNA sequence extending 634 kb on proximal mouse chromosome 16 was compared to the corresponding human sequence from chromosome 22q11.2. Haploinsufficiency for this region results in velocardiofacial syndrome (VCFS) in humans. The mouse region is rearranged into three conserved blocks relative to human, but gene content and position are highly conserved within these blocks. Examination of the boundaries of one of these blocks suggested that the evolutionary chromosomal rearrangement occurred in the mouse lineage, resulting in inactivation of the mouse orthologue of ZNF74. Sequence analysis identified 21 genes and 15 ESTs. These include 2 novel genes, Srec2 and Cals2, and previously undescribed splice variants of several other genes. Exon discovery was carried out using GRAIL2, MZEF, or comparative analysis across 491 kb of conserved mouse and human sequence. Sequence comparison was highly effective, identifying every gene and nearly every exon without the high frequency of false-positive predictions seen when algorithmic methods were used alone. In combination, these procedures identified every gene with no false-positive predictions. Comparative sequence analysis also revealed regions of extensive conservation among noncoding sequences, accounting for 6% of the sequence. A library of such sequences has been established to form a resource for generalized studies of regulatory and structural elements.

Abnormalities, Multiple↗
PubMed2000

Determining fatigue allowances for grocery order selectors.

This paper compares and contrasts four fatigue allowance worksheets commonly used to establish fatigue (relaxation) allowances for production standards; the factors, weights, degree of documentation and other operational characteristics of these worksheets are also examined. We briefly review the fatigue literature including objective physical measures of fatigue. Results of an experiment in which 11 industrial engineers independently applied the four worksheets to a standardized job analysis and video tape of a grocery order selector are reported. We conclude that inter-rater reliability and cross-validation are very low for the four worksheets and suggest validation studies using objective physiological measures of fatigue would be appropriate.

Fatigue↗
PubMed2000

Changes in rapidly extracted auditory evoked potentials during tracheal intubation.

BACKGROUND: One of the problems encountered in assessment of the hypnotic level during anesthesia is the extraction of a consistent and reliable measure online and close to real time. Hemodynamic parameters such as heart rate and blood pressure are not, at least with the traditional single parameter versus time presentation, adequate for ensuring an optimal level of anesthesia, especially when using neuromuscular blocking agents (NMBA). In the literature, it has been demonstrated that auditory evoked potentials (AEP) are able to provide two aspects relevant to determining level of anesthesia: firstly, they have identifiable anatomical significance and, secondly, their characteristics reflect the way the brain perceives a stimulus. METHODS: The aim of this study was to evaluate the AEP index based on a system identification model, the autoregressive model with exogenous input (ARX-model), and to compare it to the classical method, the moving time average (MTA). The ARX enables the extraction within 15-25 sweeps, depending on the signal-to-noise ratio (SNR), whereas MTA typically needs 250-500 sweeps. The hypothesis of the present study was that since the ARX-model extracts the AEP faster than the MTA-model, the former should be able to detect changes during the brief, intense stimulus of endotracheal intubation. Twelve female patients scheduled for gynecological surgery were included in the study. Anesthesia was initiated with thiopentone and maintained with isoflurane and alfentanil. The AEP was mapped into an index (AEP-index) normalized to 100 when the individual was awake and decreasing to an average of 25 during thiopentone induced anaesthesia. The results were compared to those obtained by MTA-extracted AEP. RESULTS: During tracheal intubation 9 patients showed an increase in the ARX-extracted AEP-index larger than 15, and 6 of these patients showed an increase larger than 25 (mean increase=33, SD=18). The MTA-extracted AEP-index showed only one patient with an increase larger than 15. The ARX-extracted AEP changed significantly faster than the MTA-extracted AEP. CONCLUSION: The ARX-extracted AEP-index increases during tracheal intubation. There is a significant difference between the ARX-extracted AEP and the traditional MTA-extracted AEP, in terms of response time. In order to trace short-lasting changes in the hypnotic level by AEP, the AEP should be extracted by a method with a fast response such as the ARX-model.

Adult↗
PubMed2000

Expression and characterization of truncated forms of humanized L243 IgG1. Architectural features can influence synthesis of its oligosaccharide chains and affect superoxide production triggered through human Fcgamma receptor I.

The properties of IgG and its subcomponents are being exploited to generate new therapeutics with selected biological activities. In this study, a series of truncated, humanized IgG1 antibodies was expressed in Chinese hamster ovary cells, to evaluate the contribution of structural components to glycosylation and function. The series includes L243 IgG1 (alpha-MHC Class II) lacking a CH3 domain pair (DeltaCH3-IgG1), single-chain Fv fusion proteins with Fc or a hinge-CH2 domain, Fc with/out a hinge, and a single CH2 domain. Glycosylation of IgG Fc is important for recognition by effector ligands such as Fcgamma receptors. HPLC analysis of released and pyridylaminated oligosaccharides indicates that intact IgG1 and scFvFc antibodies are galactosylated and sialylated to levels similar to those observed previously for normal human IgG1. The truncated forms express increased levels of digalactosylated (30-83%) or sialylated (9-21%) oligosaccharide chains with the highest levels observed for the single CH2 domain. These data show which architectural components influence IgG glycosylation processing and that the (CH3)2 pair is particularly influential. When MHC Class II bearing (JY) cells were sensitized with L243 DeltaCH3-IgG1, scFvFc, or scFvhCH2 they elicited superoxide production, from U937 cells, at levels of 35-45% relative to that obtained for intact L243 IgG1 (100%). Mild reduction and alkylation of the hinge disulphide bonds of scFvhCH2 greatly decreased its capacity to trigger superoxide production. Thus, the L243 scFvhCH2 homo-dimer constitutes the minimal truncated form that binds the MHC Class II antigen and triggers superoxide production through FcgammaRI.

Amino Acid Sequence↗
PubMed2000

Pulmonary phenotype of CCSP/UG deficient mice: a consequence of CCSP deficiency or altered Clara cell function?

Clara cell secretory protein (CCSP) is the most abundant secreted protein within airways of the lung. Moreover, CCSP levels are modulated in human lung disease, supporting a potentially important role for CCSP and/or Clara cells in lung homeostasis. However, in vivo roles for CCSP remain elusive. A popular hypothesis is that CCSP is a regulator of the inflammatory response. The purpose of this review is to provide an overview of the phenotype of CCSP null mice and relate this phenotype to proposed functions for the protein. Phenotypic analysis of mice homozygous for the CCSP-1 null allele of the CCSP gene (CCSP-/-1) revealed susceptibility to inhaled oxidant gases. Sensitivity of CCSP-/-1 mice to inhaled ozone is unrelated to alterations in antioxidant defenses, but is associated with increased cellular injury. Additional studies investigating inflammatory control in CCSP deficient mice found no differences between wild-type and CCSP-/-1 mice in their inflammatory response to low-dose inhaled endotoxin exposure, arguing against a role for CCSP in regulation of pulmonary inflammation. The findings among CCSP-/-1 mice of ultrastructural alterations to Clara cell secretory apparatus, with associated changes in airway lining fluid protein composition, demonstrate that the CCSP-/-1 genotype results in more complex changes to airways than CCSP deficiency per se. It can be concluded that CCSP does not regulate endotoxin-induced pulmonary inflammation. Moreover, CCSP-/-1 mice represent a valuable tool for probing functional roles for Clara cells in regulation of airway lining fluid composition and lung pollutant susceptibility.

Air Pollutants↗
PubMed2000

Clara cell secretory protein. Levels in BAL fluid after smoking cessation.

STUDY OBJECTIVES: The bronchiolar Clara cell is a major target for tobacco smoke exposure. To improve our understanding of the putative regenerative/repair mechanism(s) in the bronchiolar epithelium, we measured the levels of the Clara cell secretory protein (CCSP) in BAL fluid in healthy volunteers following smoking cessation. DESIGN: BAL was performed before smoking cessation, and at 1, 3, 6, 9, and 15 months following smoking cessation, in eight healthy volunteers with a previous mean cigarette consumption of 19 pack-years. The levels of CCSP in BAL fluid were assessed in immunoblotting experiments using an antibody against human CCSP. RESULTS: Significantly (p < 0.05) higher levels of CCSP in BAL fluid were observed at 3, 6, and 9 months after smoking cessation, while the levels of CCSP in BAL fluid at 15 months after smoking cessation were the same as those before smoking cessation. CONCLUSIONS: Despite the long history of smoking among patients in the present study group, signs of early regeneration in the bronchiolar epithelium were noted, in that the levels of CCSP in BAL fluid were elevated at the indicated time points following smoking cessation. Furthermore, we propose that the insult to the bronchiolar epithelium made by cigarette smoking caused the levels of CCSP in the BAL fluid at 15 months after smoking cessation to return to the levels noted before smoking cessation. The present study suggests a role for CCSP as a marker for nonciliated bronchiolar cell function.

Adult↗
PubMed1999

Role of Sp1 in cAMP-dependent transcriptional regulation of the bovine CYP11A gene.

The pituitary peptide hormone ACTH regulates transcription of the cholesterol side chain cleavage cytochrome P450 (CYP11A) gene via cAMP and activation of cAMP-dependent protein kinase. A G-rich sequence element conferring cAMP-dependent regulation has been found to reside within region -118 to -100 of the bovine CYP11A promoter. Previous studies have suggested that it binds a protein antigenically related to the transcription factor Sp1. We now report that the -118/-100 element binds both Sp1 and Sp3, members of the Sp family of transcription factors. We have made use of Drosophila SL2 cells, which lack endogenous Sp factors, to dissect the possible functional roles of Sp1, Sp3, and Sp4. All factors stimulated the activity of cotransfected reporter constructs in which the promoter of the bovine CYP11A gene regulates luciferase expression. Sp3 did not repress Sp1-dependent activation, as has previously been shown for other G-rich promoters. Mutation of the -118/-100 element of CYP11A abolished Sp1-mediated activation of a CYP11A reporter gene in SL2 cells as well as cAMP responsiveness in human H295R cells. Furthermore, cotransfection of SL2 cells with the catalytic subunit of cAMP-dependent protein kinase together with Sp1 and a CYP11A reporter construct enhanced Sp1-dependent activation of the reporter 4.2-fold, demonstrating that Sp1 confers cAMP responsiveness in these cells. Thus, we show that introduction of Sp1 alone in an Sp-negative cell such as SL2 is sufficient to achieve the cAMP-dependent regulation observed using the -118/-100 element of CYP11A in adrenocortical cells.

Adrenal Cortex↗
PubMed1999

Purine metabolites suppress proliferation of human NK cells through a lineage-specific purine receptor.

NK cell proliferation is suppressed in some patients with cancer by unknown mechanisms. Because purine metabolites released into the extracellular space during cell lysis may affect cell function, we hypothesized that these metabolites could serve as feedback regulators of NK cell proliferation. Sorted NK (CD56+/CD3-) cells were incubated with IL-2 (1000 U/ml) in a 4-day thymidine uptake assay with or without 10-10,000 microM of nucleotides. Adenine nucleotides inhibited NK cell proliferation, with ATP = ADP > 5'-adenylylimidodiphosphate > AMP = adenosine; ADP-ribose and nicotinamide adenine dinucleotide, but not nicotinamide or UTP, caused a dose-dependent suppression of thymidine uptake. A total of 100 microM ATP, a concentration that induced a maximal (80%) inhibition of thymidine uptake, did not inhibit cytotoxic activity against K562 targets. Because NK cells retained the ability to lyse K562 targets 4 days after exposure to 500 microM ATP or 1000 microM adenosine, inhibition of thymidine uptake was not due to cell death. Incubation of NK cells with dibutyryl cAMP and forskolin also suppressed thymidine uptake. Cholera toxin and pertussis toxin suppressed NK cell proliferation. Pertussis toxin did not block the adenine nucleotide effects. Further, ATP, but not adenosine or other nucleotides, markedly increased intracellular cAMP in a dose-dependent manner. The ATP-induced increase in cAMP was specific to cytolytic cells, because CD19+ B cells and CD4+ T cells did not increase their intracellular cAMP. These studies demonstrate that NK proliferation is regulated through purine receptors by adenine nucleotides, which may play a role in decreased NK cell activity. The response to adenine nucleotides is lineage-specific.

Adenosine Diphosphate↗
PubMed1999

Glycosylation of human IgG-Fc: influences on structure revealed by differential scanning micro-calorimetry.

Glycosylation of the Fc region of IgG (IgG-Fc) is essential for the full expression of Fc effector functions. The profound differences in functional activity observed between glycosylated and aglycosylated IgG have not previously been paralleled by the demonstration of large-scale structural changes. In the present study differential scanning microcalorimetry (DSMC) was used to investigate IgG-Fc glycoprotein stability and to determine the thermodynamic parameters for thermal unfolding, which will include a contribution from the intra-molecular oligosaccharide-protein interactions. The thermogram obtained for glycosylated IgG1-Fc yielded two clearly defined transitions whilst the glycosylated IgG4-Fc exhibited a single transition. The methodology was also able to reveal measurable differences in the stability of IgG4-Fc glycoforms differing by the presence or absence of terminal galactose residues; deglycosylated IgG4-Fc exhibited two transitions with evidence for destabilisation of the C(H)2 domain.

Calorimetry, Differential Scanning↗
PubMed1999

[Back problems during military service--significance for later back problems. A 12-year follow-up study].

One thousand and fifty-eight conscripts participating in an investigation of back problems among conscripts in 1979-80 were re-examined 12 years later with an identical questionnaire concerning back problems. The questionnaire was answered by seven hundred and eighty-four persons (74%). The lifetime prevalence for low-back trouble was 73%, the one-year prevalence 53% and the point prevalence 26%. At the time of follow-up the incidence of low-back trouble depended on ever having had back pains and on having an X-ray made because of back problems. The probability for sick leave from work caused by lowback trouble was increased when back troubles had been reported at the time of the initial investigation. A significant amount of the conscripts that had been rejected due to back problems (60%) had been unfit for work because of low-back trouble in the follow-up period, and 95% of them had had low-back trouble in the year before follow-up, compared to 51% of the other conscripts. Previous back trouble increases the risk of getting back trouble once again. The risk of sick leave from work caused by low-back trouble increases with the incidence of back trouble up to the investigation in 1979-80. Rejection from service due to back problems increases the risk of later low-back trouble and sick leave from work caused by low-back troubles.

Adult↗
PubMed1999

Sequence-ready physical map of the mouse chromosome 16 region with conserved synteny to the human velocardiofacial syndrome region on 22q11.2.

Proximal mouse Chromosome (Chr) 16 shows conserved synteny with human Chrs 16, 8, 22, and 3. The mouse Chr 16/human Chr 22 conserved synteny region includes the DiGeorge/Velocardiofacial syndrome region of human Chr 22q11.2. A physical map of the entire mouse Chr 16/human Chr 22 region of conserved synteny has been constructed to provide a substrate for gene discovery, genomic sequencing, and animal model development. A YAC contig was constructed that extends ca. 5.4 Mb from a region of conserved synteny with human Chr 8 at Prkdc through the region conserved with human Chr 3 at DVL3. Sixty-one markers including 37 genes are mapped with average marker spacing of 90 kb. Physical distance was determined across the 2.6-Mb region from D16Mit74 to Hira with YAC fragmentation. The central region from D16Jhu28 to Igl-C1 was converted into BAC and PAC clones, further refining the physical map and providing sequence-ready template. The gene content and borders of three blocks of conserved linkage between human Chr 22q11.2 mouse Chr 16 are refined.

Animals↗