Biomedical subjects
Publications and source records attributed to K Larsson.
This chapter will give personal accounts of the neural basis of male rat sexual behavior from two somewhat different perspectives, one tilted towards neuroanatomy (K.L.), and one tilted towards monoaminergic pharmacology (S.A.). Both perspectives were strongly influenced by the Zeitgeist, the former imperceptibly merging into the latter as relations between the neural substrate for monoaminergic neurotransmission was elucidated.
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BACKGROUND: Workers in the poultry industry have increased frequencies of respiratory health problems. The aim of the present study was to investigate acute health effects from exposure in poultry houses and to compare the health effects observed in a cage rearing system and the alternative "cage-less" rearing system for laying hens. METHODS: Thirty-four subjects were exposed for 3 hr in confined poultry houses. The subjects were randomized into three groups: one was exposed in a building with a cage rearing system and the two other groups were exposed in buildings with a cage-less system, with either young hens and fresh bedding material or with older hens and old bedding material. RESULTS: Inhalable dust levels were approximately 4 mg/m3 in the buildings with the cage-less system and 2 mg/m3 in the building with cage rearing system; the endotoxin concentration was approximately 100 ng/m3 in both systems. Bronchial responsiveness to methacholine increased approximately fivefold in all groups following exposure. The concentration of the proinflammatory cytokine interleukin-6 (IL-6) increased in nasal lavage fluid and in peripheral blood as a result of the exposure. The number of leukocytes in peripheral blood increased only in the groups exposed among loose laying hens. CONCLUSION: In the present study, we have demonstrated among previously non-exposed subjects, that 3-hr exposure in confined buildings for egg production induces an acute inflammatory reaction in the upper airways and increased bronchial responsiveness. There is a tendency towards stronger reactions in the groups exposed in the buildings with loose housing for laying hens.
BACKGROUND AND OBJECTIVE: Inhalation of dust from swine confinement buildings results in an acute inflammatory reaction in the respiratory tract. The dust has a high microbial content, dominated by Gram positive bacteria. The aim of the present study was to evaluate the significance of bacteria in the induction of IL-6 and IL-8 release from respiratory epithelial cells and alveolar macrophages. The results would give an indication to what extent the bacteria contribute to the toxic inflammation following exposure to swine dust. METHODS: Epithelial cells from a human lung carcinoma cell line (A549) and human alveolar macrophages obtained from healthy subjects by bronchoalveolar lavage, were stimulated with swine dust, LPS, one Gram negative and four Gram positive bacteria strains. The dose-response release of IL-6 and IL-8 were studied. In addition, a bacteria-free supernatant was prepared from each strain and used for stimulation. RESULTS: With a few exceptions, a dose-dependent IL-6 and IL-8 release was demonstrated from both cell types after stimulation with bacteria. In epithelial cells, Escherichia coli was the most potent bacteria at the highest concentration of 400 bacteria/cell regarding secretion of both IL-6 and IL-8 (P < 0.001), followed by Staphylococcus hominis and Staphylococcus lentus. In alveolar macrophages, S. lentus was the most potent strain (P < 0.001) in inducing cytokine release (P < 0.001), followed by S. hominis and E. coli concerning IL-6 secretion or Micrococcus luteus and E. coli with respect to IL-8 secretion (P < 0.001). Differences in potency between the various bacteria could be demonstrated, both within the two cell types as well as between the epithelial cells and macrophages. Bacteria-free supernatants were also able to induce cytokine release in both cell types. In macrophages the supernatants were even more potent stimuli than whole bacteria. CONCLUSIONS: The results indicate that bacteria or bacterial products could be an important contributing factor to the inflammatory reaction following exposure to swine dust.
Glucocorticoids are potent anti-inflammatory agents capable of influencing cytokine release in a number of cell types. The aim of the present study was to investigate whether glucocorticoids, frequently used in the treatment of asthma, interfere with cytokine secretion by lung epithelial cells and alveolar macrophages in vitro. Inhalation of swine dust induces airway inflammation with influx of inflammatory cells and release of proinflammatory cytokines in the lungs. Therefore, human lung epithelial cells (A549) and human alveolar macrophages were stimulated with swine dust or lipopolysaccharide (LPS), and the inhibitory effect of budesonide and fluticasone propionate on cytokine release was studied in a dose-response (10(-13)-10(-8) M) manner. The time course for the steroid effect was also investigated. Both steroids caused a dose-dependent, almost total, inhibition of swine dust-induced IL-6 and IL-8 release from epithelial cells and LPS-induced IL-6 and TNF-alpha from alveolar macrophages. The steroids only partially inhibited IL-8 release from alveolar macrophages. Budesonide was approximately 10 times less potent than fluticasone propionate. Preincubation with the steroids did not inhibit cytokine release more than simultaneous incubation with stimulus and steroid. In conclusion, budesonide and fluticasone propionate, in concentrations that probably occur in the airway lining fluid during inhalational therapy, inhibited cytokine release from human lung epithelial cells (IL-6, IL-8) and alveolar macrophages (TNF-alpha, IL-6, IL-8). In vitro, the onset of this effect was rapid.
Exposure to swine dust causes airway inflammation with increased levels of proinflammatory cytokines, and inflammatory cells in nasal and bronchoalveolar lavage fluid (BALF) in healthy subjects. Earlier studies have suggested that lipopolysaccharides (LPS) might be an important proinflammatory factor in swine dust. Since respiratory epithelial cells and alveolar macrophages are target cells for the inhaled dust, we therefore compared the release of proinflammatory cytokines from normal human bronchial epithelial cells (NHBE), an epithelial cell line (A549) and from human alveolar macrophages obtained from BALF from healthy subjects in vitro after incubation with dust collected in swine houses or LPS. Swine dust or LPS was added to the wells with A549 cells or macrophages and incubated for 8 h at concentrations of 12.5, 25, 50 and 100 microg/ml. NHBE cells were incubated with swine dust at a concentration of 25, 50 or 100 microg/ml or with LPS at a concentration of 50 or 100 microg/ml and incubated for 24 h. The supernatants were collected, centrifuged, and IL-6, IL-1beta and tumour necrosis factor-alpha (TNF-alpha) production was measured using an ELISA method and expressed per 106 cells. Swine dust and LPS caused a dose-dependent increase of IL-6 production in NHBE cells, swine dust being more potent than LPS. In A549 cells, only swine dust, but not LPS caused an increase of IL-6 production. Neither swine dust nor LPS induced IL-1beta or TNF-alpha release from A549 cells. Both swine dust and LPS caused a dose-dependent increase of IL-1beta, IL-6 and TNF-alpha in alveolar macrophages. Swine dust which contained 2.2 (0.2) ng endotoxin/100 microg swine dust (0.02 per thousand) was almost as potent as LPS in inducing cytokine release from alveolar macrophages in vitro. We conclude that both epithelial cells and alveolar macrophages have the capability to contribute to the release of proinflammatory cytokines following exposure to swine dust. Some agent(s) other than LPS in the dust contribute to the marked airway inflammatory reaction.
The in vitro potency of house dust to induce cytokine response in A549 lung epithelial cells was studied. Dusts collected from carpet, bed, shelf and floor of a villa and an apartment by vacuuming were found to trigger the production of interleukin-8 (IL-8) and interleukin-6 (IL-6) in a dose-dependent manner, and the interleukin production was several-fold higher than of swine dust (used as a positive control). The IL-8 and IL-6 production of pure Escherichia coli lipopolysaccharide was significantly lower than of the dusts and a peptidoglycan-polysaccharide complex did not show any stimulatory effect at all. The lipopolysaccharide and peptidoglycan contents of the samples were determined by gas chromatography-tandem mass spectrometry analysis of, respectively, 3-hydroxy fatty acids and muramic acid; in addition, ergosterol was monitored for fungal biomass. The inflammatory properties of house dust upon inhalation may be reflected in its high potency to induce cytokine response in lung epithelial cells.
OBJECTIVES: The inhalation of dust from swine confinement buildings causes inflammatory responses in the airways with a rise of interleukin-6 (IL-6). The purpose of this study was to confirm the increase in serum IL-6 after inhalation of swine dust and investigate a possible increase in plasma fibrinogen. METHODS: Eight healthy nonsmoking volunteers inhaled dust for 4 hours inside a swine confinement building. Inhalable dust and endotoxin were sampled. The concentrations of IL-6 and fibrinogen were determined in serum and plasma. RESULTS: The study showed a clear increase in the concentrations of IL-6 and fibrinogen after exposure. CONCLUSIONS: As fibrinogen is an important risk factor for ischemic heart disease, the increased concentration of fibrinogen among persons exposed to swine dust may increase the risk for this disease.
By complementation of a salt-sensitive mutant of Saccharomyces cerevisiae, we cloned the SOP1 gene, encoding a 114.5-kDa protein of 1033 amino acids. Cells deleted for SOP1 exhibited sensitivity to sodium stress, but showed no sensitivity to general osmotic stress. Following exposure of sop1Delta cells to NaCl stress, the intracellular Na+ level and the Na+/K+ ratio rose to values significantly higher than in wild type cells. Deletion of SOP2, encoding a protein sharing 54% amino acid identity with Sop1p, produced only slight Na+ sensitivity. Cells carrying a sop1Deltasop2Delta double deletion became, however, hypersensitive to Na+ and exhibited increased sensitivity also to Li+ and K+, suggesting involvement of both SOP1 and SOP2 in cation homeostasis. The predicted amino acid sequences of Sop1p and Sop2p show significant homologies with the cytoskeletal-associated protein encoded by the Drosophila lethal(2)giant larvae tumor suppressor gene. Immunolocalization of Sop1p revealed a cytoplasmic distribution and cell fractionation studies showed that a significant fraction of Sop1p was recovered in a sedimentable fraction of the cytosolic material. Expression of a Drosophila l(2)gl cDNA in the sop1Deltasop2Delta strain partially restored the Na+ tolerance of the cells, indicating a functional relationship between the Sop proteins and the tumor suppressor protein, and a novel function in cell homeostasis for this family of proteins extending from yeast to human.
STUDY DESIGN: The effects of nucleus pulposus and various treatments to block tumor necrosis factor alpha activity were evaluated in an experimental set-up using immunohistochemistry and nerve conduction velocity recordings. OBJECTIVES: To assess the presence of tumor necrosis factor alpha in pig nucleus pulposus cells, and to see if block of tumor necrosis factor alpha also blocks the nucleus-pulposus-induced reduction of nerve root conduction velocity. SUMMARY AND BACKGROUND DATA: A meta-analysis of observed effects induced by nucleus pulposus revealed that these effects might relate to one specific cytokine-tumor necrosis factor alpha. METHODS: Series-1: Cultured nucleus pulposus cells were stained immunohistologically with a monoclonal antibody for tumor necrosis factor alpha. Series-2: Nucleus pulposus was harvested from lumbar discs and applied to the sacrococcygeal cauda equina in 13 pigs autologously. Four pigs received 100 mg of doxycycline intravenously; five pigs had a blocking monoclonal antibody to tumor necrosis factor alpha applied locally in the nucleus pulposus, and four pigs remained nontreated, forming a control group. Three days after the application, the nerve root conduction velocity was determined over the application zone by local electrical stimulation. RESULTS: Series-1: Tumor necrosis factor alpha was found to be present in the nucleus pulposus cells. Series-2: The selective antibody to tumor necrosis factor alpha limited the reduction of nerve conduction velocity, although in comparison with the control group this was not statistically significant. However, treatment with doxycycline significantly blocked the nucleus-pulposus-induced reduction of conduction velocity. CONCLUSION: For the first time, a specific substance, tumor necrosis factor alpha, has been linked to the nucleus-pulposus-induced effects of nerve roots after local application. Although the effects of this substance may be synergistic with those of other similar substances, the data of the current study may be of significant importance for the continued understanding of nucleus pulposus' biologic activity, and of possible potential use for future strategies in managing sciatica.
BACKGROUND: Several preventive strategies against cytomegalovirus (CMV) disease have been developed during the last decade. These have frequently been used in combination, and it has been difficult to identify each strategy's contribution. METHODS: Risk factors for CMV disease, death in CMV disease and transplant-related mortality were analyzed in 584 patients, who underwent a total of 594 allogeneic bone marrow transplants. RESULTS: The overall probability of CMV disease was 8.9%. No seronegative patient who had a seronegative marrow donor developed CMV disease. The corresponding probabilities for seronegative patients with seropositive donors, seropositive patients with seronegative donors, and seropositive patients with seropositive donors were 5.4%, 13.7%, and 11.7%, respectively. In multivariate Cox models, the use of preemptive antiviral therapy and being CMV-seronegative reduced the risk for CMV disease, CMV-associated death, and transplant-related mortality (TRM). Patients who received unrelated or mismatched family donor transplants had increased risks for CMV disease, CMV-associated death, and TRM. Older age was a significant risk factor for CMV disease and TRM. A total of 258 patients who were monitored by polymerase chain reaction for CMV DNA were analyzed separately to assess whether addition of another CMV preventive strategy could give benefit. Patients who received mismatched or unrelated donor transplants had increased risk for CMV disease, death in CMV disease, and TRM. High-dose acyclovir prophylaxis or addition of intravenous immune globulin had no influence. CONCLUSIONS: Preemptive therapy based on polymerase chain reaction for CMV DNA was associated with reduced risks for CMV disease, CMV-associated death, and TRM, whereas other prophylactic modalities did not give additional benefit.
STUDY DESIGN: Nerve conduction velocity in pig nerve roots was assessed after application of various preparations of nucleus pulposus and control. OBJECTIVE: To study whether cultured nucleus pulposus cells could reduce nerve conduction velocity after epidural application. SUMMARY OF BACKGROUND DATA: It is known that nucleus pulposus applied epidurally may reduce the nerve conduction velocity of the adjacent nerve roots and that this reduction seems to be related to the cells of the nucleus pulposus. METHODS: Nucleus pulposus cells and fibroblasts were cultured for 3 weeks, and various preparations were applied to the cauda equina in 29 pigs. The cells were always from the same animals from which they had been harvested. After 1 week, nerve conduction velocity was determined by local electrical stimulation. RESULTS: Application of live fibroblasts and conditioned culture medium from the nucleus pulposus cell culture dishes did not induce significant reduction of conduction velocity, compared with application of dead fibroblasts, which served as control. However, application of live and dead nucleus pulposus cells induced significant reductions. CONCLUSIONS: Application of nucleus pulposus cells reproduced the previously seen reduction in nerve conduction velocity induced by nonmodified nucleus pulposus. Because membranes of the nucleus pulposus cells had similar effects, it can be assumed that the effects are related to membrane-bound substances or structures.
The administration of the 5-hydroxytryptamine (5-HT) precursor 5-hydroxytryptophan (5-HTP) (25 mg/kg i.p.), in combination with an inhibitor of peripheral 5-HTP decarboxylase, produced a dose-dependent increase in the ejaculation latency of male rats, and this effect was enhanced by additional treatment with the 5-HT1 receptor antagonist (-)-pindolol (2 mg/kg s.c.). The 5-HT2A/C receptor agonist (+/-) 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125-0.5 mg/kg s.c.) did not by itself affect male ejaculatory behavior, but additional treatment with (-)-pindolol (2 mg/kg s.c.) produced a dose-dependent decrease in number of ejaculating animals. The increased ejaculation latency produced by 5-HTP was fully antagonized by treatment with the 5-HT1B receptor antagonist isamoltane (4 mg/kg s.c.), but not by ritanserin (2 mg/kg s.c.) treatment. The selective 5-HT1A receptor antagonist WAY-100635 (0.15 mg/kg s.c.) enhanced the inhibitory actions of 5-HTP on the male rat ejaculatory behavior, and this dose of WAY-100635 fully antagonized 8-OH-DPAT-induced facilitation (0.25 mg/kg s.c.) of the ejaculatory behavior. WAY-100635 (0.04-0.60 mg/kg s.c.) did not, by itself, significantly affect male rat sexual behavior. Taken together, the results suggest an inhibitory role for postsynaptic 5-HT1B receptors in the effects produced by 5-HTP on male rat ejaculatory behavior. Furthermore, 5-HTP-induced inhibition of male rat ejaculatory behavior is partially controlled by stimulation of inhibitory 5-HT1A autoreceptors, since the effects of 5-HTP were accentuated by treatment with (-)-pindolol, as well as by the more selective 5-HT1A receptor antagonist WAY-100635.
Patients who receive transplants of autologous peripheral stem cells have a shorter duration of neutropenia than patients who receive autologous bone marrow transplants. There is conflicting evidence regarding the risk of infections. A retrospective analysis on 123 patients who received transplants of either autologous bone marrow or peripheral blood stem cells for multiple myeloma or breast cancer was performed to study whether this shorter duration of neutropenia can influence the risk of and the severity of infection. Patients who underwent peripheral blood stem cell transplantation (PBSCT) had faster engraftment than the group treated with autologous bone marrow transplantation (ABMT). Furthermore, the requirement for transfusions of red blood cells and platelets was a reduced. The number of days needed in hospital was significantly lower in PBSCT patients. No reduction in the frequency of infectious complications was found in PBSCT as compared with ABMT patients, but the numbers of days with fever and with antibiotic treatment were significantly lower in the PBSCT patients. Breast cancer patients had significantly faster engraftment but no fewer infectious complications than myeloma patients, regardless of the type of transplantation. Significantly lower numbers of clinically verified infections were found in the group of patients receiving colony-stimulating factors (CSF) after transplantation even though there was no difference in the duration of neutropenia. The need for antibiotic treatment was also significantly less in the group treated with CSF.
In an attempt to evaluate whether experimental disc herniation can result in changes in walking pattern, presumably indicating pain, four groups of rats - sham (n = 5), disc puncture (NP, n = 5), displacement of nerve root and ganglion (DIS, n = 5), and the combination of disc puncture and displacement (NP + DIS, n = 6) - were assessed when walking in a Plexiglas corridor at day 2-14 after surgery. All surgical procedures were performed at the L4-5 level on the left side. Step length analysis showed that rats in the NP and DIS series had no difference between the legs initially, but a tendency towards slightly shorter left steps at day 8-12, whereas the animals in the NP + DIS series had slightly shorter right steps day 2-10. However, no statistically significant differences compared with the sham series could be detected for any of the groups. Nerve dysfunction on the operated side was only observed on one occasion in two rats and on 2 days in one rat, all from the NP + DIS series. Apparent limping was seen in three of the animals in the NP + DIS series and in one in the DIS series. Limping and nerve dysfunction only co-incided on one occasion out of a total of 13 observations of limping, suggesting that the limping was induced by pain and not neurologic deficit. In conclusion, the combination of epidural nucleus pulposus and displacement induced a limping whereas nucleus pulposus or displacment alone did not. Assessment of limping thus seemed to provide adequate information of presence of pain, but step length measurement did not provide any useful data. Although walking analysis may be a valuable assessment of sciatic pain, better modalities must be developed to analyze experimentally induced nerve root pain.
A male rat put in an open-field arena in which it is free to spend time in the vicinity of--but not in contact with--an estrous female, or in the vicinity of a male, usually spends more time with the female than with the male or elsewhere. Tentatively, the percentage of time spent in the vicinity of the female in this paradigm may be regarded as a measure of sexual motivation. In humans, treatment with selective serotonin reuptake inhibitors (SSRIs) may cause reduced libido. To investigate to what extent serotonin reuptake inhibition influences sexual motivation also in rats, we have tested the effect of subchronic treatment with fluoxetine on the behavior in the sexual motivation test described above; in addition, the effect of fluoxetine on male copulatory behavior was studied. Fluoxetine significantly reduced sexual motivation at subchronic but not at acute administration; moreover, fluoxetine-treated rats displayed an increased ejaculation latency. It is concluded that humans and rats respond similarly to the SSRI fluoxetine with respect to various aspects of sexual behavior.
Treatment with serotonin reuptake inhibitors (SRIs) has been shown to cause reduced libido and anorgasmia in women. A large body of evidence suggests that serotonin may influence sexual behavior in estradiol + progesterone primed, gonadectomized female rats; however, the influence of selective SRIs on the estrous behavior of intact female rats has not been described previously. In the present study, the effect of 1 to 3 weeks of fluoxetine administration (10 mg/kg daily) on vaginal and behavioral estrus in intact female rats was studied; in addition, the effect of fluoxetine (same dose, 1-8 weeks) on copulatory behavior and on sexual motivation in hormone-primed gonadectomized rats was investigated. Subchronic administration of fluoxetine did not influence cyclicity as judged by the examination of vaginal smears but significantly reduced the percentage of rats displaying receptive behavior in the estrous phase. In addition, fluoxetine significantly reduced receptive behavior, including lordosis, in ovariectomized female rats primed with estradiol (6.25 micrograms/rat; -48 hr) plus progesterone (1.0 mg/rat, -4 hr); in contrast, sexual motivation--as reflected by the amount of time these rats elected to spend in the vicinity of a male rather than in the vicinity of a female or elsewhere--was little affected by the treatment.
Alveolar macrophages are the most common cells in bronchoalveolar lavage fluid. The macrophages participate in the inflammatory response and defence of the airways by secretion of mediators and by phagocytizing foreign particles such as bacteria and viruses. beta-Agonists and glucocorticosteroids are the most frequently used drugs in asthma. Alveolar macrophages have beta 2-adrenoceptors on their surface but the functional role of these receptors is unknown. Glucocorticosteroids interact with mediator release from macrophages. However, nothing is known about the effects of those drugs on the phagocytic capacity of alveolar macrophages. Therefore, the present study has investigated phagocytosis of alveolar macrophages from nine healthy volunteers after incubation with a beta 2-agonist, terbutaline (10(-8), 10(-6) and 10(-4) M) and a glucocorticosteroid, budesonide (10(-9), 10(-7) and 10(-5) M). Alveolar macrophages were incubated with FITC-labelled Escherichia coli, and the drugs and phagocytosis was assessed by flow cytometry. Phagocytosis was measured as the proportion of phagocytizing cells and mean fluorescence intensity (MFI). MFI was highly correlated with phagocytized E. coli per cell assessed by fluorescence microscopy (r = 0.996). The proportion of phagocytizing macrophages (control) was [median (25th-75th) percentiles] 46% (40-63) and 29% (18-60), and MFI were 174 (154-205) and 122 (90-271) in the terbutaline and budesonide experiments, respectively. Terbutaline did not affect the phagocytosis significantly, while budesonide decreased the phagocytic capacity (percent phagocytizing cells and MFI) in a dose-dependent manner (P < 0.01). At the highest budesonide concentration (10(-5) M), phagocytosis was approximately half of the control situation. In conclusion, this in vitro study indicate that a glucocorticosteroid decreases phagocytosis in alveolar macrophages in a concentration that may be relevant in the airway lining fluid. Further investigations regarding the effect on other micro-organisms and in vivo effects are necessary to further elucidate these findings.