Biomedical subjects

M Petersson

Publications and source records attributed to M Petersson.

At least 19 recordsLinked to original sources

PubMed2000

Systemic oxytocin treatment modulates alpha 2-adrenoceptors in telencephalic and diencephalic regions of the rat.

Systemic subchronic oxytocin treatment significantly and substantially increased the B(max) values of the alpha 2 agonist [(3)H]UK14.304 binding sites in the hypothalamus, the amygdala and the paraventricular thalamic nucleus of the rat as shown by quantitative receptor autoradiography. These results suggest that long-term modulation of autonomic and neuroendocrine functions and emotional behaviours elicited by brain oxytocin may involve enhancement of central alpha 2-adrenoceptor function.

Adrenergic alpha-Agonists↗

PubMed2000

Alternative methods providing enhanced sensitivity and selectivity in capillary electroseparation experiments.

The study of alternative and novel techniques for altering selectivity and enhancing sensitivity as well as injection and detection protocols are important in the ongoing development of capillary electroseparation protocols. Some recent research from our laboratory in these fields is presented and discussed in this review. To improve sensitivity an off-line sample enrichment technique utilising solvent evaporation in a levitated drop or an on-line solid-phase extraction protocol was used. The selectivity was tuned by the use of protein gels or molecularly imprinted polymer mediated capillary electrochromatography. Furthermore, a picolitre droplet injection method is described as well as a detection protocol based on laser-induced fluorescence imaging.

Electrophoresis, Capillary↗

PubMed2000

T cell tolerance based on avidity thresholds rather than complete deletion allows maintenance of maximal repertoire diversity.

Given the flexible nature of TCR specificity, deletion or permanent disabling of all T cells with the capacity to recognize self peptides would severely limit the diversity of the repertoire and the capacity to recognize foreign Ags. To address this, we have investigated the patterns of CD8+ CTL reactivity to a naturally H-2Kb-presented self peptide derived from the elongation factor 1alpha (EF1alpha). EF1alpha occurs as two differentially expressed isoforms differing at one position of the relevant peptide. Low avidity CTLs could be raised against both variants of the EF1alpha peptide. These CTLs required 100-fold more peptide-H-2Kb complexes on the target cell compared with CTLs against a viral peptide, and did not recognize the naturally expressed levels of EF1alpha peptides. Thus, low avidity T cells specific for these self peptides escape tolerance by deletion, despite expression of both EF1alpha isoforms in dendritic cells known to mediate negative selection in the thymus. The low avidity in CTL recognition of these peptides correlated with low TCR affinity. However, self peptide-specific CTLs expressed elevated levels of CD8. Furthermore, CTLs generated against altered self peptide variants displayed intermediate avidity, indicating cross-reactivity in induction of tolerance. We interpret these data, together with results previously published by others, in an avidity pit model based on avidity thresholds for maintenance of both maximal diversity and optimal self tolerance in the CD8+ T cell repertoire.

Animals↗

PubMed2000

Antagonistic oxytocin/alpha2-adrenoreceptor interactions in the nucleus tractus solitarii: relevance for central cardiovascular control.

The modulation of the central cardiovascular effects of alpha2-adrenoceptor activation by oxytocin in the nucleus tractus solitarii has been evaluated by cardiovascular analysis and by quantitative receptor autoradiography. Microinjections in the nucleus tractus solitarii of a threshold dose of oxytocin effectively and significantly counteracted the vasodepressor and bradycardic actions of an ED50 dose of the alpha2-adrenoceptor agonist clonidine. The coinjection of a threshold dose of oxytocin with a threshold dose of clonidine did not produce any changes in the mean arterial pressure but a tachycardic response was observed. Receptor autoradiographical experiments showed that oxytocin (3 nM) significantly increased the Kd and Bmax values of [3H]p-aminoclonidine binding sites in the nucleus tractus solitarii compatible with a possible antagonistic interaction with the alpha2-adrenoceptors, and this effect was blocked by the presence of the specific oxytocin receptor antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin. These findings suggest the existence of an antagonistic oxytocin/alpha2-adrenoceptor interaction in nucleus tractus solitarii that may be of relevance for the demonstrated modulation of alpha2-adrenoceptor induced cardiovascular responses by oxytocin.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2000

Oxytocin/alpha(2)-Adrenoceptor interactions in feeding responses.

The modulation of alpha(2)-adrenoceptor-induced food intake by oxytocin has been evaluated in studies on food intake and by quantitative receptor autoradiography in the hypothalamus and the amygdala of the rat. The effects of lateral intracerebroventricular administration of clonidine and oxytocin were evaluated on food intake in satiated animals. Food consumption was measured at 30, 90, 240 min and 22 h (1,320 min) after injection. The coinjection of oxytocin and clonidine was found to counteract the increase in food intake produced by clonidine (p < 0.001) in satiated rats. Receptor autoradiographic experiments showed that oxytocin significantly increased the K(d) values of [(3)H]p-aminoclonidine alpha(2)-agonist-binding sites in the hypothalamus. Effective oxytocin concentrations ranged between 0.3 and 1 nM (p < 0.05) with a maximal action of 250% at 1 nM. The B(max) value was significantly increased (p < 0.05) for all concentrations of oxytocin. In the amygdala, oxytocin also increased both the K(d) of [(3)H]p-aminoclonidine-binding sites by about 190% at 1 nM and the B(max) values at 1 and 3 nM (p < 0.05). Oxytocin (1 nM) also significantly and substantially (p < 0.01) increased the K(d) and B(max) values of the [(3)H]UK 14.304 alpha(2)-agonist-binding sites in the hypothalamus and amygdala in agreement with the results obtained with the other agonist of the alpha(2)-adrenoceptor [(3)H]p-aminoclonidine. This effect was partially blocked by the presence of the specific oxytocin receptor antagonist, CAP. These findings suggest the existence of an antagonistic oxytocin/alpha(2)-receptor interaction in the hypothalamus and amygdala that may be of relevance for the demonstrated modulation of alpha(2)-adrenoceptor-induced feeding responses by oxytocin.

Adrenergic alpha-Agonists↗

PubMed1999

Oxytocin enhances the effects of clonidine on blood pressure and locomotor activity in rats.

Oxytocin treatment decreases blood pressure and changes the pattern of spontaneous motor activity. The aim of this study was to explore if alpha 2-adrenoreceptors that are involved in the regulation of blood pressure and spontaneous motor activity are influenced by oxytocin treatment. For this purpose, male rats were pretreated with oxytocin (1 mg/kg subcutaneously (s.c.)) or saline once a day during 5 days. Clonidine (alpha 2-adrenoreceptor agonist) decreased blood pressure (2.5 microg/kg intracerebroventricularly (i.c.v.) and 100 microg/kg s.c.) and changed spontaneous motor activity (100 microg/kg s.c.), observed in an open field arena, significantly more in oxytocin pretreated rats compared to saline pretreated controls (P < 0.05). In contrast, idazoxan (alpha 2-adrenoreceptor antagonist) (50 microg/kg i.c.v.) caused a significantly smaller elevation of blood pressure in the oxytocin pretreated rats (P < 0.05). In addition, the effect on blood pressure of an alpha 1-adrenoreceptor agonist, phenylephrine, was evaluated. It increased blood pressure equally in the oxytocin- and saline pretreated rats. The present study shows that subchronic oxytocin treatment increases the effects of clonidine on blood pressure and spontaneous motor activity in rats. These findings imply that alpha 2-adrenoreceptors are involved in the effects of oxytocin treatment on blood pressure and spontaneous motor activity.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1999

Identification of new HER2/neu-derived peptide epitopes that can elicit specific CTL against autologous and allogeneic carcinomas and melanomas.

Twenty-two new HLA-A2.1-binding peptides derived from the protooncogene HER2/neu were identified and analyzed for their capacity to elicit peptide and tumor-specific CTL responses. We used peptide-pulsed autologous DC from the ascites of patients with ovarian carcinomas to induce CTL. Of the 22 tested new HER2/neu-derived epitopes that could bind HLA-A2 with high (IC50 < 50 nM) or intermediate (50 nM < IC50 < 500 nM) affinity, we report the recognition by CTL of at least four novel epitopes, including HER2(9435), HER2(9665), HER2(9689), and HER2(10952), and confirm that of the known HER2 (9369) epitope. These epitopes were able to elicit CTL that specifically killed peptide-sensitized target cells and, most importantly, a HER2/neu-transfected cell line and the autologous tumor cells. We also confirm that HER2/neu is overexpressed in several melanoma lines, and as a new finding, report that some of these lines are sensitive to CTL induced by the HER2 (9369), HER2(9435), and HER2(9689) epitopes. Finally, CTL clones specific for HER2 (9369), HER2(9435), and HER2(9689) epitopes were isolated from tumor-specific CTL lines, further demonstrating the immunodominance of these epitopes. These findings broaden the potential application of HER2/neu-based immunotherapy.

Carcinoma↗

PubMed1999

Primary chemically induced tumors induce profound immunosuppression concomitant with apoptosis and alterations in signal transduction in T cells and NK cells.

Whereas transplantable tumors can be readily cured with immunotherapeutic approaches, similar therapies in cancer patients have been less effective. This difference may be explained by an immunosuppression resulting from the presence of a slowly growing primary tumor in the patient, whereas the immune system in a mouse with a rapidly proliferating transplantable tumor would be less affected. As a more appropriate model to the immune dysfunction in patients, slowly progressing primary tumors were induced by the carcinogen methylcholanthrene (MC) in mice. Their ability to induce immunosuppression in T cells and natural killer (NK) cells was compared to that of rapidly growing transplanted MC-induced tumors. The results demonstrate that mice bearing primary MC tumors had significantly diminished T-cell and NK-cell functions, impaired capacity to produce Th1 cytokines, and markedly reduced levels of the signal-transducing zeta chain in T cells and NK cells, similar to that described in cancer patients. Moreover, a substantial number of CD8+ T cells in mice with large primary MC tumors were undergoing apoptosis, correlating with alterations in CD4/CD8 ratios. In contrast, T cells and NK cells from mice bearing rapidly growing transplanted tumors were only marginally affected. These findings could explain the apparent discrepancy between the consistent findings of a diminished immune response and alterations in signal transduction in cancer patients as compared to the less reproducible observations in murine transplantable tumors. In addition, they could explain the differences in the high efficacy of immunotherapy in mice with transplantable tumors and the low therapeutic results in cancer patients.

Animals↗

PubMed1999

Oxytocin causes a sustained decrease in plasma levels of corticosterone in rats.

The aim of this study was to investigate how oxytocin (OXT) influences plasma levels of ACTH and corticosterone in rats. A single injection of OXT (1 mg/kg s.c.) caused a transient increase in ACTH and corticosterone. In contrast, 1 mg/kg OXT (but not 10-100 microg/kg) decreased corticosterone, but not ACTH levels, 6 h after the injection. OXT (1 mg/kg s.c.) administered once a day for 5 days, decreased cortiocosterone for 10 days after the last injection. An acute challenge with ACTH increased corticosterone to the same level in rats pretreated with OXT and controls. Dexamethasone decreased corticosterone to equal levels in both groups. Thus, OXT seems to be able to stimulate as well as to inhibit the activity within the HPA-axis within a short- and a long-term perspective, respectively.

Adrenocorticotropic Hormone↗

PubMed1999

Treatment of dysphagia improves nutritional conditions in stroke patients.

Dysphagia is a common symptom in stroke patients, and malnutrition is prevalent among these patients. Thus far, nutritional effects of dysphagic treatment have not been evaluated. The aim of the present report was to study the effects of swallowing techniques on nutritional and anthropometric variables. A survey with follow-up was performed at the Departments of Geriatric Medicine and Neurology, Malmö University Hospital, Sweden. Thirty-eight stroke patients, 53-89 years of age, with subjective complaints of dysphagia and oral/pharyngeal dysfunction according to videofluoroscopic barium swallowing examination (VSBE), were given swallowing treatment. The treatment included oral motor exercise, different swallowing techniques, positioning, and diet modification. Plasma protein levels, body composition, VSBE, and a viso-analogical scale for subjective complaints were repeated before and after treatment. At baseline, 94% of cases had signs of penetration and 50-72% had plasma protein levels below recommended levels. Treatment reduced the degree of oral dysfunction, (dissociation) and pharyngeal dysfunction (penetration and constrictor paresis). Sixty percent of cases showed an improved overall VSBE score, and improved levels of albumin and total iron-binding capacity were restricted to this group. In cases with unchanged or decreased VSBE score, body weight was reduced and a negative correlation to total iron-binding capacity was noted (r = -0.60, p < 0.05). Changes of subjective complaints did not correlate with swallowing function or nutritional improvements. Swallowing treatment improves swallowing function, and improved swallowing function is associated with improvements in nutritional parameters. Subjective complaints is not sufficient to evaluate the clinical course, and nutritional parameters should be monitored in patients with oral or pharyngeal dysfunction.

Aged↗

PubMed1999

Tumor-induced immune dysfunction.

Immune system-based approaches for the treatment of malignant disease over the past decades have often focused on cytolytic effector cells such as cytotoxic T lymphocytes (CTL), and natural killer (NK) cells. It has also been demonstrated that tumor-bearing mice can be cured using a wide variety of approaches, some of which involve cytokine-mediated enhancement of CTL and NK cell activity. However, the apparent success in mice stands in contrast to the current situation in the clinic, wherein only a minority of patients have thus far benefited from CTL- or NK cell-based antitumor approaches. The underlying causes of tumor-associated immune suppression of CTL and NK cell activity are discussed, and features of interest shared with HIV infection, leprosy, and rheumatoid arthritis are also be mentioned. Remarkable and very recent observations have shed more light upon the causes of dysfunctional alterations in CTL and NK cells often associated with these diseases, that in turn have suggested new immunotherapeutic approaches for cancer and infectious disease.

Animals↗

PubMed1999

Short-term increase and long-term decrease of blood pressure in response to oxytocin-potentiating effect of female steroid hormones.

To investigate how the effects of oxytocin on blood pressure are influenced by female sex hormones, oxytocin (1 mg/kg, s.c.) was given to intact cycling and ovariectomized (OVX) female rats. Oxytocin caused a transient increase in blood pressure, most pronounced during proestrus (p < 0.01) and estrus (p < 0.01). This increase was partially antagonized by an oxytocin antagonist. When oxytocin was given for 5 days, blood pressure decreased (intact rats: 123+/-1.5 vs. 130+/-1.3 mm Hg; p < 0.001, OVX rats: 120+/-3.0 vs. 129+/-1.1 mm Hg; p < 0.001). This decrease, not abolished by the oxytocin antagonist, persisted for 3 weeks in intact rats and for 8 days in OVX rats. If oxytocin treatment of OVX rats continued, a nadir of 12 mm Hg (118+/-1.7 mm Hg; p < 0.001) was reached after 8 days. Thereafter heart rate decreased significantly (p < 0.05). One daily oxytocin injection for 12 days to OVX rats decreased blood pressure for 3 weeks, as in intact rats. These results show that acute and chronic oxytocin treatment cause opposite effects on blood pressure, and that these effects are modified by female sex hormones.

Analysis of Variance↗

PubMed1999

Long-term changes in gastrin, cholecystokinin and insulin in response to oxytocin treatment.

The present study was designed to investigate how repeated injections of oxytocin influence plasma levels of vagally controlled hormones such as gastrin, cholecystokinin (CCK), insulin and somatostatin, as well as of endogenous oxytocin and glucose. Since oxytocin may enhance the activity of centrally located alpha2-adrenoreceptors, a second aim of this study was to explore whether these receptors are involved in the effects. For this purpose, oxytocin (1.0 mg/kg) or NaCl was given subcutaneously (s.c.) once a day during 5 days to male rats. Rats were decapitated 1, 3 and 10 days after the last injection, blood was collected and hormone levels were radioimmunoassayed. The oxytocin treatment caused an elevation of plasma levels of oxytocin 1 day (p < 0.05) but not 3 and 10 days after treatment. Gastrin levels were decreased on day 1, 3 and 10 (ANOVA; p < 0.01). In addition, both insulin and CCK levels were decreased in response to the oxytocin treatment when measured 3 and 10 days after the last injection (ANOVA; insulin p < 0.01, CCK p < 0.05). When the alpha2-adrenoreceptor agonist clonidine (2.5 microgram/kg intracerebroventricularly) was administered 3 days after the 5-day treatment period with oxytocin or saline, plasma levels of insulin and CCK increased significantly (p < 0.05) in the oxytocin-treated rats, when compared to saline-treated controls receiving clonidine only. No change in glucose or somatostatin levels was found in response to the oxytocin treatment. In conclusion, these results show that oxytocin induces long-lasting changes in plasma levels of gastrin, CCK and insulin, without affecting somatostatin or glucose levels. These effects may be mediated by changes in vagal nerve activity.

Adrenergic alpha-Agonists↗

PubMed1998

Oxytocin increases locus coeruleus alpha 2-adrenoreceptor responsiveness in rats.

Oxytocin induces several antistress-like effects in rats. As the central noradrenergic nucleus locus coeruleus (LC) participates in arousal reactions and cardiovascular control, we used extracellular single-cell recording techniques to investigate a potential influence of oxytocin on LC neuronal activity. Oxytocin (1 mg/kg s.c.) given once a day for 5 days to male rats, increased the responsiveness of noradrenergic LC neurons to intravenous (i.v.) administration of clonidine, when compared to controls treated with saline for 5 days (P < 0.01). The spontaneous firing rate was not affected by oxytocin treatment. This study indicates that oxytocin treatment increases the responsiveness of LC alpha 2-adrenoreceptors.

Adrenergic alpha-Agonists↗

PubMed1998

Constitutive IL-10 production accounts for the high NK sensitivity, low MHC class I expression, and poor transporter associated with antigen processing (TAP)-1/2 function in the prototype NK target YAC-1.

Tumor cells that are treated with rIL-10 or transfected with the IL-10 gene show phenotypic changes. These include low but peptide-inducible expression of MHC class I, low sensitivity to specific CTL-mediated lysis, and increased NK sensitivity. In vitro-established mouse tumor lines were screened for IL-10 expression and production, and a large proportion of plasmocytomas or T cell lymphomas were found to produce IL-10. Since one of these lines was the prototype NK target cell YAC-1, we investigated whether the high IL-10 production of this cell line was related to its high NK sensitivity and its defects in MHC class I expression. The decrease in H-2 expression following the in vitro culture of in vivo-passaged YAC-1 cells was accompanied by a gradual increase in IL-10 production, whereas the reverse was found when passing in vitro-grown YAC-1 in vivo as an ascites tumor in syngenic mice. In addition, differences in YAC-1 MHC class I expression correlated with alterations in the functional activity of TAP-1/2 proteins. YAC-1 cells that were transduced with a retroviral IL-10 antisense construct (Y-IL-10 AS) only produced about half of the IL-10 that was produced by YAC-1 transduced with the control construct (Y-IL-10 Mock). Relative to Y-IL-10 Mock cells, the expression of H-2 on Y-IL-10 AS cells was markedly increased, and NK sensitivity was decreased. These data argue for a mechanism wherein IL-10 production is causally related to the low H-2 expression, decreased TAP function, and high NK sensitivity of YAC-1 cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Sample enrichment in a single levitated droplet for capillary electrophoresis.

This paper describes sample enrichment in a single levitated droplet for capillary electrophoresis (CE) analysis. The droplet was trapped in an acoustical field. The minute sample volumes needed for the enrichment procedure were precisely handled using a piezoelectric flow-through liquid microdispenser. Droplets with a volume of 65 pl were ejected from the device at a repetition rate ranging from one single droplet up to several hundreds per second. By counting the number of droplets ejected and accumulated in the levitated drop the sample volume was controlled. Through solvent evaporation the analytes were enriched in the diminishing droplet. The droplet was then injected into a CE capillary and the analytes, dansyl-Gly and dansyl-Val dissolved in ethanol, were separated in a 100 mM borate buffer (pH 9.0) utilising UV-absorption detection at 200 nm near the capillary outlet. Enrichment of 36000 sample droplets (2.3 microl) through solvent evaporation in the levitated drop resulted in a concentration limit of detection (CLOD) of 15 nM for the dansylated amino acids as compared to a CLOD of 2.5 microM which was achieved using standard hydrodynamic injection without preconcentration.

Electrophoresis, Capillary↗

PubMed1998

Immunization with a lymphocytic choriomeningitis virus peptide mixed with heat shock protein 70 results in protective antiviral immunity and specific cytotoxic T lymphocytes.

Heat shock proteins (hsp's) isolated from murine cancer cells can elicit protective immunity and specific cytotoxic T lymphocytes (CTLs) by channeling tumor-derived peptides bound to hsp's to the major histocompatibility class I antigen presentation pathway. Here we have investigated if hsp70 can be used in a novel peptide vaccine for the induction of protective antiviral immunity and memory CTLs. A CTL epitope from the well-defined lymphocytic choriomeningitis virus (LCMV) system was mixed with recombinant hsp70 in vitro under conditions that optimize peptide binding to hsp70. Mice were immunized with the hsp70-peptide mixture and challenged with LCMV. Virus titers were reduced 10-100-fold in these mice compared to control mice. Immunization with the hsp70-peptide mixture resulted in the development of CTL memory cells that could be reactivated during LCMV infection, and that in a 51Cr-release assay could lyse cells pulsed with the same peptide, but not cells pulsed with another LCMV peptide. These results show that hsp70 can be used with CTL epitopes to induce efficient protective antiviral immunity and the generation of peptide-specific CTLs. The results also demonstrate the usefulness of hsp70 as an alternative to adjuvants and DNA vectors for the delivery of CTL epitopes to antigen-presenting cells.

Adjuvants, Immunologic↗

PubMed1998

Oxytocin increases the survival of musculocutaneous flaps.

The aim of the present study was to evaluate the effect of oxytocin on survival of musculocutaneous flaps in male Sprague-Dawley rats. For this purpose oxytocin (0.1 or 1.0 mg/kg), an oxytocin antagonist (1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin) (1.0 mg/kg) alone or in combination with oxytocin (1.0 mg/kg) or saline was given subcutaneously (s.c.), 24 hours and 1 hour before and 24 hours after flap surgery. In addition, oxytocin (1 microg/kg) or saline was given intracerebroventricularly (i.c.v.) according to the same schedule. Six days after surgery the amount of viable tissue was measured. Oxytocin 1.0 (but not 0.1) mg/kg s.c. and 1.0 microg/kg i.c.v. increased survival of the flaps (s.c.: 13.8+/-14.6% versus 6.10+/-5.45%; p<0.05 and i.c.v.: 25.5+/-14.0% versus 10.3+/-5.79%; p<0.01). This effect was abolished by the oxytocin antagonist. Furthermore, the oxytocin-treated rats had significantly higher plasma levels of insulin-like growth factor-1 (IGF-1) (p<0.05). These data indicate that oxytocin increases the survival of musculocutaneous flaps. The effect seems to be exerted within the central nervous system since a 1000 fold lower dose of oxytocin given i.c.v. increased flap survival to the same extent as the s.c. given dose. IGF-1 might be one of the mediators of this effect.

Animals↗