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Biomedical subjects

S Karlsson

Publications and source records attributed to S Karlsson.

At least 109 records · Page 6Linked to original sources
PubMed1997

Initiating activity of the anti-estrogen tamoxifen, but not toremifene in rat liver.

A striking difference between two structurally related anti-estrogen medicines is that tamoxifen is strongly hepatocarcinogenic in the rat, whereas toremifene lacks such activity. To study the basis for this difference, the initiating potential of tamoxifen and toremifene were studied by measurement of rapid induction of hepatocellular altered foci (HAF) that express placental-type glutathione S-transferase in the livers of female Sprague-Dawley (S-D) rats and female Fischer 344 (F344) rats. Both agents were administered by gavage at equimolar doses up to a dose that produced marked weight gain suppression. In rats given the high dose of 40 mg/kg per day tamoxifen continuously for 36 weeks, 75% of S-D rats developed liver neoplasms, in contrast to only 10% of F344 rats. In the S-D strain, tamoxifen produced a tendency to increased HAF at 2 weeks at the dose of 40 mg/kg per day and by 12 weeks, a dose-related increase was evident. In contrast, toremifene induced no HAF even at the equimolar high dose of 42.4 mg/kg per day for 12 weeks. The induction of HAF by tamoxifen was less in the F344 rats. Neither agent elicited increases in hepatocellular proliferation in S-D or F344 rats. When phenobarbital was administered for 24 weeks as a promoting agent after the anti-estrogens, S-D rats given tamoxifen at 20 mg/kg per day for 12 weeks, developed liver neoplasms, but not F344 rats or rats of either strain given even a higher dose (42.4 mg/kg) of toremifene. Thus, tamoxifen has initiating activity in these rat strains whereas toremifene does not.

Animals↗
PubMed1997

Aromatic DNA adducts in foundry workers in relation to exposure, life style and CYP1A1 and glutathione transferase M1 genotype.

Levels of aromatic DNA adducts in foundry workers and controls were followed at four annual samplings. During this time exposure to polycyclic aromatic hydrocarbons (PAH) decreased and the level of DNA adducts decreased accordingly. In the total group exposure was related to the level of adducts. Adduct levels correlated with urinary 1-hydroxypyrene (LOGU1OH), air benzo[a]pyrene, weekly working hours and daily cigarette consumption. In a multivariate model 1-hydroxypyrene had a consistent effect. Neither glutathione transferase M1 (GSTM1) nor cytochrome P450 1A1 (CYP1A1) genotypes had clear effects. Yet the individuals lacking GSTM1 had a stronger effect of LOGU1OH and some effect by other sources of PAH, such as charcoal broiled food, although all these variables were not significant in the multivariate model. The rare individuals with a CYP1A1 polymorphism MspI containing an amino acid change at isoleucine had an increased level of adducts. The results showed that the postlabelling method used was able to detect an increase in aromatic DNA adducts in leukocytes when exposure to benzo[a]pyrene in air was approximately 5 ng/m3. At such low levels smoking and charcoal broiled food may be important contributors to adducts.

Adult↗
PubMed1997

Descriptive physiological data on a sleep bruxism population.

We studied 24 bruxers (23-67 years old). They often complained of orofacial and bodily pain and presented autonomic symptoms (sweating 23%, palpitations at night 62%, decreased libido 50%); 19% had increased blood pressure requiring treatment, and 65% reported frequent headaches in the morning. Deep sleep and rapid eye movement (REM) were delayed. An average of 167 orofacial episodes developed during the night. The mean number of masseter bursts strictly defined as bruxism was 79, the mean delay for the first occurrence after sleep onset 18 minutes. The majority of bruxism occurred in stage 2 sleep and REM sleep. The mean number of shifts of sleep stages was 70, one-third occurring within the first minute following a bruxing episode, and 15% of bruxing episodes developed after a shift in sleep stage. Electroencephalogram showed alpha-delta pattern in 15% of the subjects. Short-lasting alpha activity was often encountered during the 10 seconds preceding the development of a bruxing episode. Tachycardia developed at its onset, persisting for 10 seconds. We suggest that, as a minor alarm response to endogenous/exogenous stimuli, arousal develops and is often followed by motor activation, such as a burst of bruxing, with, as in any situation when motor activity suddenly increases, a secondary increase of heart activity.

Adolescent↗
PubMed1997

The use of physical restraints in elder care in relation to fall risk.

Physical restraints are a frequently used but disputed method to prevent falls. The aim of the present study was to investigate how the use of restraints in institutional elder care relates to previous falls and to the estimated fall risk of the individual patient. A total of 1142 patients, mean age 82 years, were included in the study. A questionnaire, the Multi-Dimensional Dementia Assessment Scale (MDDAS), was used to measure motor function, vision, hearing, ADL performance, behavioral symptoms, psychiatric symptoms, cognitive impairment and use of medication. Questions concerning the use of physical restraints and known previous falls were added to the instrument. Based on data from the questionnaire (MDDAS), a score on the Downton Fall Risk Index was calculated for each patient. All in all, 248 (22%) of the patients had been subject to restraints and for 155 of them (14%) such measures had been taken to prevent falls. Only weak connections were found between the restraining of patients to prevent falls and the prevalence of known previous falls during hospital stay (phi = 0.05), and estimated fall risk (phi = 0.07). The results indicate that the use of physical restraints is poorly connected with the estimated fall risk. Therefore, this study may point to a possible overuse of these measures.

Accidental Falls↗
PubMed1997

Presynaptic sympathetic mechanism in the insulinostatic effect of epinephrine in mouse pancreatic islets.

The catecholamines inhibit insulin release. It is not established whether presynaptic mechanisms contribute to this effect. We therefore examined the relative contribution of presynaptic and postsynaptic mechanisms to the insulinostatic effects of epinephrine and norepinephrine. Mice were injected with 6-hydroxydopamine (6-OHDA; 0.19 mmol/kg) or its vehicle. Islets were isolated after 48 h. Islets from vehicle-injected control animals contained numerous tyrosine hydroxylase (TH)-immunoreactive nerve terminals (marker for sympathetic nerves). In contrast, TH-immunoreactive nerves were not detected in islets from 6-OHDA-treated animals, indicating sympathetic denervation. Basal (5.6 mmol/l glucose) or glucose-stimulated (16.7 mmol/l) insulin secretion did not differ between incubated islets from vehicle-injected control animals and islets from 6-OHDA-treated animals. The insulinostatic effect of epinephrine, but not that of norepinephrine, was markedly impaired in islets from 6-OHDA-treated animals: the lowest effective insulinostatic concentration of epinephrine was 0.01 nmol/l in islets from vehicle-injected animals and 1 nmol/l in islets from 6-OHDA-treated animals. We conclude that in isolated mouse islets the insulinostatic effect of epinephrine, but not that of norepinephrine, partially depends on sympathetic nerve terminals, suggesting an important role for presynaptic mechanisms in epinephrine-induced inhibition of insulin secretion.

Animals↗
PubMed1997

Pancreatic exocrine secretion during the first days after weaning in pigs.

Feed replacement at weaning plays an important role in the induction of pancreatic maturation. To understand the changes in the exocrine pancreas at weaning and the relation to postweaning problems, we studied the function of the exocrine pancreas and changes of intestinal hemolytic Escherichia coli in four pigs. The pigs were chronically fitted with pancreatic duct catheters and T-shaped cannula inserted into the duodenum for reintroduction of pancreatic juice. One day before weaning (at 30 d of age), pancreatic juice was collected for 1 h before and 1 h after a morning and an evening suckling. The pigs were not creep fed, but from weaning the pigs received a standard weaning diet ad libitum. On d 1, 2, 3, and 5 after weaning, pancreatic juice was collected continuously for the 24-h period. The total pancreatic secretion was measured at hourly intervals, 1.5-mL samples were taken for analysis, and the remaining juice was returned to the animal. On these days, samples from the duodenum, ileum, and rectum were also taken for analyses of hemolytic E. coli. From the day before to 5 d after weaning, a gradual increase in pancreatic secretion was observed concerning volume (P < .001) and protein (P < .01) and trypsin (P < .02) levels. An increase (P < .01) in hemolytic E. coli in the duodenal contents was also documented during this period. We assume that the gradual increase in the measured variables of pancreatic secretion is related to the increasing consumption of solid feed. However, the appearance of E. coli and disappearance of milk components from the gastrointestinal tract could be other factors stimulating the exocrine pancreas.

Aging↗
PubMed1997

Selection of retrovirally transduced cells to enhance the efficiency of gene therapy.

Retrovirally mediated gene transfer is the approach of choice for many laboratories interested in gene therapy. One problem, however, is that the efficiency of therapeutic gene transfer to some important target cells is low. A strategy employed by a number of investigators to overcome this shortcoming is to construct recombinant viruses that employ selection modalities. These strategies can be classified broadly into either metabolic or cell-surface selection strategies. This article examines each selection approach and notes their important strengths and weaknesses. Further, the various gene products used in each approach to effect sorting of transduced cells is detailed.

Animals↗
PubMed1997

Gene therapy of haematopoietic cells.

Gene therapy of haematopoietic stem cells (HSCs) has been under investigation for 15 years. HSCs can be easily transduced with retroviral vectors (Moloney murine leukaemia virus = MMLV) in the mouse and expression of transferred genes can be achieved in long-term reconstituted mice. While human haematopoietic progenitor cells can be transduced with high efficiency using amphotropic MMLV retroviral vectors, and expression of the transferred gene is easily obtained in their progeny cells, it has proven problematic to transfer genes efficiently into the HSCs of humans in clinical trials. Efforts are now under way, in many laboratories, to increase the gene transfer efficiency of retroviral vectors, or alternatively, to develop new vectors that can transduce quiescent human HSCs with higher efficiency than is currently possible. This brief review will address the two main research areas that are being explored. Firstly, investigations in human haematopoiesis to gain understanding into the molecular and cellular mechanisms that control HSC behaviour in vitro and in vivo. Secondly, development of new vectors that can transfer genes to quiescent human HSCs.

Adenoviridae↗
PubMed1996

Transduction of nondividing cells using pseudotyped defective high-titer HIV type 1 particles.

The use of Moloney murine leukemia virus (Mo-MLV)-based vectors to deliver therapeutic genes into target cells is limited by their inability to transduce nondividing cells. To test the capacity of HIV-based vectors to deliver genes into nondividing cells, we have generated replication-defective HIV type 1 (HIV-1) reporter vectors carrying neomycin phosphotransferase or mouse heat stable antigen, replacing the HIV-1 sequences encoding gp160. These vectors also harbor inactive vpr, vpu, and nef coding regions. Pseudotyped HIV-1 particles carrying either the ecotropic or the amphotropic Mo-MLV envelope proteins or the vesicular stomatitis virus G protein were released after single or double transfections of either human 293T or monkey COS-7 cells with titers of up to 10(7) colony-forming units per milliliter. A simple ultrafiltration procedure resulted in an additional 10- to 20-fold concentration of the pseudotyped particles. These vectors along with Mo-MLV-based vectors were used to transduce primary human skin fibroblasts and human peripheral blood CD34+ cells. The HIV-1 vector system was significantly more efficient than its Mo-MLV-based counterpart in transducing human skin fibroblasts arrested at the G0/G1 stage of the cell cycle by density-dependent inhibition of growth. Human CD34+ cells were transduced efficiently using HIV-1 pseudotype particles without prior stimulation with cytokines.

Animals↗
PubMed1996

Involvement of phospholipase A2 and arachidonic acid in cholecystokinin-8-induced insulin secretion in rat islets.

Cholecystokinin (CCK) has been shown to stimulate insulin secretion through an effect which involves mediation by phospholipase C (PLC) and protein kinase C (PKC). However, data exist suggesting involvement also of other transduction pathways. We investigated possible involvement of phospholipase A2 (PLA2) and arachidonic acid (AA) in mechanisms of insulin secretion, induced by the C-terminal octapeptide of CCK (CCK-8) in isolated rat islets. At 5.6 mM glucose, the specific PLA2 inhibitor p-amylcinnamoylantranilic acid (ACA; 50 microM) diminished CCK-8 (100 nM)-stimulated insulin secretion (by 57 +/- 16%; P = 0.001). Furthermore, at 5.6 mM glucose, CCK-8 significantly increased the efflux of [3H]arachidonic acid from prelabelled islets (by 130 +/- 25%; P < 0.001). These results imply that CCK-8 activates PLA2 to form AA in islets. To study whether the insulinotropic effect of CCK-8 is due to AA per se or to its metabolites, the oxidative pathways of the AA metabolism were inhibited. However, the cyclooxygenase inhibitors, indomethacin (30 microM) and salicylate (1.25 mM) as well as the lipoxygenase inhibitors baicalein (1-100 microM) and esculetin (0.5-50 microM), did not affect CCK-8-induced insulin secretion. We conclude that CCK-8-induced insulin secretion is partially mediated by a pathway involving PLA2, and that the formed AA, rather than its metabolites, is of importance.

Animals↗
PubMed1996

Adrenomedullin: localization in the gastrointestinal tract and effects on insulin secretion.

Adrenomedullin is a novel hypotensive adrenal polypeptide originally isolated from a human pheochromocytoma and is structurally related to calcitonin gene-related peptide and islet amyloid polypeptide. Using immunocytochemistry, the occurrence of adrenomedullin in the adrenal gland and gastro-entero-pancreatic region in the rat was examined and its effect on insulin secretion from isolated rat islets was determined. Adrenomedullin-like immunoreactivity occurred in noradrenaline- and adrenaline-producing cells in the adrenal gland. Gastrointestinal endocrine cells, with increased density distally, displayed adrenomedullin-like immunoreactivity; these cells constituted a subpopulation of the enterochromaffin (serotonin-containing) cells. Co-localization of adrenomedullin with somatostatin, glicentin, gastrin/cholecystokinin, peptide YY or islet amyloid polypeptide was not encountered. Adrenomedullin-immunoreactive cells were not observed in the pancreatic islets. At 1, 10 and 100 nmol/l, adrenomedullin stimulated insulin release from isolated rat islets in the presence of 3.3 mmol/l glucose (P < 0.05) and at 100 nmol/l, the peptide potentiated insulin secretion also in the presence of 8.3 mmol/l glucose (P < 0.05). These findings suggest that, besides being an adrenal hypotensive peptide, adrenomedullin may be a gut hormone with a potential insulinotropic function.

Adrenal Glands↗
PubMed1996

A bicistronic therapeutic retroviral vector enables sorting of transduced CD34+ cells and corrects the enzyme deficiency in cells from Gaucher patients.

Corrective gene transfer for therapeutic intervention in metabolic and hematopoietic disorders has been hampered by the relatively inefficient transduction of human hematopoietic stem cells. To overcome this, a bicistronic recombinant retrovirus has been generated that delivers both a therapeutic glucocerebrosidase (GC) cDNA for the treatment of Gaucher disease, and a small murine cell surface antigen (heat-stable antigen [HSA]) as a selectable marker. An amphotropic retroviral-producing cell clone was created, and filtered supernatant was used to transduce NIH 3T3 cells. Sorting of transduced cells by flow cytometry enabled separation into populations based on cell surface fluorescence intensity derived from the expressed HSA. Significant increases in GC enzyme activity were seen for the transduced and especially the transduced and sorted cells. Similarly, increases in GC specific activity were seen in transduced and sorted skin fibroblasts from a patient with Gaucher disease. To streamline future transfer and sorting protocols for hematopoietic cells, transformed B-cell lines from Gaucher patients were created. Type I B cells were transduced and sorted, and large increases in GC specific activity occurred with concomitant increases in integrated retroviral copy numbers. In addition, toward the goal of using this selectable approach for corrective gene transfer to bone marrow stem cells, CD34+ cells were isolated from normal BM donors, transduced, and sorted based on cell surface expression of HSA. Proviral DNA was detected in approximately 40% of clonogenic progenitor colonies derived from unsorted, transduced CD34+ cells, demonstrating the high titer of the vector. However, after sorting, 100% of the colonies had the corrective GC cDNA, demonstrating the efficiency of this selective system for human hematopoietic progenitors. It is expected that strategies based on this approach will allow sorting of transduced cells of many types before implantation of transduced cells to animals or patients. This vector system may also be used to simplify manipulations and studies on retroviral-mediated gene delivery in vitro and for in vivo models.

3T3 Cells↗
PubMed1996

Autoimmune manifestations in the transforming growth factor-beta 1 knockout mouse.

Targeted disruption of the transforming growth factor-beta 1 (TGF-beta 1) gene in mice results in the development of a massive multifocal inflammatory disease in many tissues. Because no detectable pathogen was identified, we examined whether autoimmune mechanisms played a role in initiating or maintaining the inflammatory disease. The serum of TGF-beta 1 knockout mice contained elevated titers of antibodies to nuclear antigens (ssDNA, dsDNA, Sm, and RNP) as well as reactivity against the 16/6 idiotype (16/6 Id). In addition, Ig deposits were detected in renal glomeruli of TGF- beta 1 knockout mice. Transplantation of TGF-beta 1 knockout hematopoietic cells into normal irradiated recipients resulted in a similar profile of autoantibody production as well as in the induction of inflammatory lesions. Our results describe autoimmune activity that ensues when the TGF-beta 1 cytokine is absent.

Animals↗
PubMed1996

Gastrin-releasing peptide mobilizes calcium from intracellular stores in HIT-T15 cells.

The mechanism by which gastrin-releasing peptide (GRP) increases cytoplasmic calcium [Ca2+]ic was studied in insulin-producing HIT-T15-cells. At zero glucose, GRP (100 nM) rapidly increased [Ca2+]ic in the presence and absence of extracellular Ca2+. The effect was potentiated by glucose, impaired by the inhibitor of microsomal Ca(2+)-ATPase, thapsigargin, and abolished by the inhibitor of phospholipase C U73122. In contrast, the inhibitor of Ca2+ induced Ca2+ release, ryanodine, was without effect. Furthermore, the GRP-induced increase in [Ca2+]ic was potentiated by forskolin and impaired by activation of protein kinase C (PKC) by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Based on these results, we conclude: 1) that GRP mobilizes Ca2+ from a thapsigargin-sensitive intracellular Ca2+ pool through activation of phospholipase C, and 2) that the GRP-induced mobilization of Ca2+ is potentiated by cyclic AMP.

Animals↗
PubMed1996

Mouse and rat cystatin C: Escherichia coli production, characterization and tissue distribution.

Recombinant mouse (Mus musculus) and rat (Rattus norvegicus) cystatin C were produced by expression in Escherichia coli, isolated and functionally characterized. The mouse and rat inhibitors were both fully active in titrations of papain. Determination of equilibrium constants for dissociation (Ki) for their complexes with the target proteinase, cathepsin B, produced values not largely different from that for human cystatin C (Ki 0.07-0.13 nM). Rabbit antisera against mouse and rat cystatin C were produced and used for improved affinity purification of the recombinant inhibitors. Affinity purified immunoglobulins isolated from the antiserum against mouse cystatin C were used for construction of a sensitive enzyme-linked immunosorbent assay. The assay was used to demonstrate a high degree of immunological cross-reactivity between mouse and rat cystatin C and could be used for cystatin C quantification in mouse and rat tissue homogenates. All tissues analyzed contained cystatin C, with a relative content very similar to that of human tissues. For all species, brain tissue contained the highest cystatin C amounts and liver the lowest, whereas kidney, spleen and muscle tissues were intermediate in content. In the mouse, a notable high cystatin C content in parotid gland tissue was observed. The high degree of similarity in distribution pattern and functional properties for mouse, rat and human cystatin C indicates that a murine model should be relevant for studies of the human disease, hereditary cystatin C amyloid angiopathy.

Amino Acid Sequence↗