Biomedical subjects

J Sauer

Publications and source records attributed to J Sauer.

At least 55 records · Page 3Linked to original sources

PubMed1996

Interleukin-2 (IL-2) and IL-6 regulate c-fos protooncogene expression in human pituitary adenoma explants.

We have previously shown that interleukin-2 (IL-2) and IL-6, which are expressed in the anterior pituitary, affect anterior pituitary cell proliferation in normal rats and cell lines. Here we examined their effects on the c-fos expression by human anterior pituitary adenomas. Adenoma cells in culture do not express c-fos mRNA. In adenoma explants, however, c-fos expression was detected and was regulated by IL-2 or IL-6. In different tumors (ACTH-, PRL-, GH-secreting and non functioning adenomas), these interleukins had inhibitory or stimulatory effects but the kind of response does not seem to be associated to tumor type or size. Using blocking antibodies, we observed that intrinsic IL-2 and IL-6 regulate c-fos expression in the same way. Our data suggest that IL-2 and IL-6 are not only involved in the regulation of pituitary adenoma function but may also, given the role of c-fos in cell proliferation, be implicated in the development of human pituitary adenomas.

Adenoma↗

PubMed1996

Molecular and functional evidence for in vitro cytokine enhancement of human and murine target cell sensitivity to glucocorticoids. TNF-alpha priming increases glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis.

Cytokine-induced glucocorticoid secretion and glucocorticoid inhibition of cytokine synthesis and pleiotropic actions act as important safeguards in preventing cytokine overreaction. We found that TNF-alpha increased glucocorticoid-induced transcriptional activity of the glucocorticoid receptor (GR) via the glucocorticoid response elements (GRE) in L-929 mouse fibroblasts transfected with a glucocorticoid-inducible reporter plasmid. In addition, TNF-alpha also enhanced GR number. The TNF-alpha effect on transcriptional activity was absent in other cell lines that express TNF-alpha receptors but not GRs, and became manifest when a GR expression vector was cotransfected, indicating that TNF-alpha, independent of any effect it may have on GR number, has a stimulatory effect on the glucocorticoid-induced transcriptional activity of the GR. Moreover, TNF-alpha increased GR binding to GRE. As a functional biological correlate of this mechanism, priming of L-929 cells with a low (noncytotoxic) dose of TNF-alpha significantly increased the sensitivity to glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis. TNF-alpha and IL-1 beta had the same stimulatory action on glucocorticoid-induced transcriptional activity of the GR via the GRE, in different types of cytokine/glucocorticoid target cells (glioma, pituitary, epithelioid). The phenomenon may therefore reflect a general molecular mechanism whereby cytokines modulate the transcriptional activity of the GR, thus potentiating the counterregulation by glucocorticoids at the level of their target cells.

Animals↗

PubMed1996

Omission of the pelvic irradiation in stage I testicular seminoma: a study of postorchiectomy paraaortic radiotherapy.

PURPOSE: To review the survival, cure rate, and pattern of relapse or progression of patients with histologically confirmed Stage I testicular seminoma who underwent orchiectomy and radiation therapy to paraaortic lymphatics only. The pelvic ipsilateral lymph nodes were not irradiated. METHODS AND MATERIALS: Between 1978 and 1992, 150 patients with Stages I or II testicular seminoma received treatment at the Department of Radiation Oncology of the University of Wuerzburg. The distribution by stage was Stage I, 117 patients of which 93 were pT1 N0 M0 and 24 were pT2 N0 M0. Four patients were staged as Stage II (pT3 N0 M0), and in 29 patients the T Stage was not specified. Eighty-six patients from the 117 Stage I (pT1-pT2, N0 M0 according to the TNM classification) seminoma received postorchiectomy irradiation, and are analyzed for outcome in this article. The distribution of the Stage I patients by pT Stage was 71 pT1 and 15 pT2 patients. All these 86 patients had their paraaortic nodes (the biological target volume extending from top of L1 to the bottom of L5) irradiated with four field technique. Tumor dose was specified at normalization point along the central axis. The median tumor dose was 30 Gy given in 1.8-2.0 Gy fractions. Elective irradiation to the ipsilateral hemipelvis (iliac nodes) was totally abandoned. RESULTS: The 10-year disease-free survival and overall survival were 95.3 and 100%. No recurrence in the irradiated field was noted. Four patients (4.7%) experienced relapse of disease outside the treated volume. The most common site of solitary failure was the ipsilateral hemipelvis (one iliacal and one inguinal). One patient developed metastatic disease to the lung. One patient developed a mediastinal recurrence with superior vena cava syndrome and was successfully salvaged by mediastinal irradiation and chemotherapy. CONCLUSIONS: Recommendation for the future management of Stage I seminoma include: reduced biological target volume to the paraaortal lymph nodes (from lumbar vertebra L1 to L5). Complete elimination of irradiation to the pelvic nodes is warranted. Radiation dose should not exceed 30 Gy.

Adult↗

PubMed1996

Effects of granulocyte colony-stimulating factor on plasma cytokine and cytokine receptor levels and on the in vivo host response to endotoxin in healthy men.

We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on cytokine and cytokine receptor plasma levels and on the in vivo host response to Salmonella abortus equi endotoxin in healthy males. Twenty volunteers received 0.8 ng/kg endotoxin and saline intravenously 1 week apart in randomized order. Twelve hours before both experiments, 10 of these subjects were pretreated with 300 micrograms G-CSF subcutaneously. G-CSF itself increased granulocyte and monocyte counts and the plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R) p55, and p75 and interleukin-1 receptor antagonist (IL-1ra). G-CSF did not influence plasma IL-1 beta and IL-6 levels. In the G-CSF-pretreated subjects endotoxin-induced surges in rectal temperature and in the plasma levels of TNF-alpha plasma levels were about 50% increased, and surges in the plasma levels of both sTNF-Rs and IL-1ra were about twice as high as in the control group. Endotoxin-induced increases in IL-6, cortisol, and heart rate were not modified by G-CSF pretreatment. Endotoxin administration induced a transient 50% reduction in leukocyte counts in the G-CSF-pretreated subjects that was not seen in the control group. We conclude that a single stand dose of G-CSF increases the plasma levels of cytokines and cytokine receptors and considerably modifies the host response of healthy humans to a low dose of endotoxin.

Bacterial Toxins↗

PubMed1996

Syntheses and selective inhibitory activities of terphenyl-bisamidines for serine proteases.

Biphenyl nitriles 5a-c, terphenyl dinitriles 11a-d, and naphthalene-bis(benzonitrile) 11c were prepared by palladium-catalyzed cross coupling reactions and subsequently converted to biphenyl amidines 8a-c and bis(benzamidines) 4a-e. Among the biphenyl amidines 8 only the meta-derivative 8b inhibits factor Xa and trypsin (Ki = 10 microM). The terphenyl bisamidine 4c does not inhibit factor Xa, trypsin, thrombin, and plasmin, while 4a and 4d are almost equipotent inhibitors of these enzymes (Ki 1-6 microM), and 4b and 4e are selective for trypsin (Ki = 0.2 and 0.3 microM; but Ki > 1 microM for factor Xa, thrombin, and plasmin). X-ray analysis of crystals of 4b complexed with bovine trypsin revealed a unique binding mode: one benzamidino group binds in the S1 site to the side chain carboxylate of Arg189. The central phenyl group is twisted away from the S2/S3 sites and the second amidino group contacts the Asn143 side chain.

Amidines↗

PubMed1996

Skill maintenance in extended spaceflight: a human factors analysis of space and analogue work environments.

This paper discusses the implications of increasing mission lengths of manned spaceflight for the design of future space systems from a human factors point of view. It is argued that the increase in mission duration has brought about a number of new problems, which have not been sufficiently addressed in space research. Therefore, a review of analogue work environments is carried out to make up for the paucity of space research found in the area of human performance in long-duration spaceflight. This resulted in an evaluation of seven analogue environments concerning their similarity to space with industrial process control and nuclear submarines coming out as the closest match on the technical dimension. Finally, some recommendations are given from the lessons learned in spaceflight, simulation studies and appropriate analogue environments.

Aerospace Medicine↗

PubMed1996

Cognitive fatigue and complex decision making under prolonged isolation and confinement.

Cognitive fatigue and subjective state were assessed in four healthy subject (three males and one female), confined for a period of 60 days in a hyperbaric chamber stimulating a space station environment. They were required to carry out daily a working memory/decision-making test, simulating the management of the levels of contaminants present in a spacecraft atmosphere. Information about a set of contaminants is presented on a 'reference screen.' This has to be memorized, then used to make decisions about the need for corrective action across a sequence of four 'status screens.' Subjects may check back to the reference information at any time. A low error rate was emphasized in the instructions and training. In addition to error rate, performance was also measured in terms of the time taken to make decisions and checks of reference screens (decision time and check time). Subjective measures were also made of workload and environmental resources (personal control and support), levels of anxiety and fatigue before the task, and cognitive effort expended during the task. The search for decrements during the second half of the isolation period was complicated by evidence of a continued learning process during the first half, probably because of insufficient practice before isolation. Learning curves (negative exponential functions) were fitted to the data points for the first half of the isolation period, and residuals between predicted and observed data for the second four weeks were analyzed. All subjects showed increases in decision time and check time during the last weeks of isolation, with one subject also showing an increase in errors. Workload levels were reported as moderate, but varied across the four subjects, The same was true for resources. Anxiety was low and relatively stable over the entire 60-day period, but fatigue levels were elevated during the second half. This was particularly true for the two subjects who maintained the required low error rate. Effort was also quite stable, through it tended to follow changes in work demands and fatigue. Individual subjects are seen to adapt to the stress of prolonged isolation in different ways. Two subjects maintained low error rates under increasing subjective demands by additional cognitive effort and slowing of performance. The other two subjects exhibit more widespread decrement, including high error rates, without increase in subjective demands. The analysis of individual patterns of adaptation is recommended as a way of understanding and predicting the impact of isolation and confinement during spaceflights.

Adaptation, Psychological↗

PubMed1996

Inhibition of lipopolysaccharide-induced monocyte interleukin-1 receptor antagonist synthesis by cortisol: involvement of the mineralocorticoid receptor.

Glucocorticoids, as a part of their physiological role in the control of inflammatory and immune processes, suppress the expression of interleukin-1 (IL-1) and other cytokines. Human monocyte IL-1 receptor antagonist (IL-1ra) messenger ribonucleic acid (mRNA) expression and protein secretion are inhibited by dexamethasone. We have now further studied the regulation of IL-1ra by the major physiological human glucocorticoid, cortisol. We found that cortisol incubation induced a decrease in IL-1ra mRNA expression and a significant inhibition of IL-1ra protein secretion in cell cultures of human peripheral monocytes stimulated with the bacterial endotoxin lipopolysaccharide (LPS). Oral administration of 276 mumol cortisol to normal subjects also decreased LPS-induced IL-1ra synthesis in cultured monocytes. By coincubating the monocytes with either the mineralocorticoid antagonist spironolactone or the glucocorticoid receptor antagonist RU 38486, the in vitro cortisol-induced inhibition of LPS-stimulated IL-1ra secretion was partially reversed. The mineralocorticoid aldosterone exerted a significant decrease in LPS-induced monocyte IL-1ra secretion in vitro, which was blocked by coincubation with spironolactone. In addition, the expression of mineralocorticoid receptor mRNA in human monocytes was observed by PCR of reversed transcribed RNA. Our results further indicate that corticosteroids physiologically control the IL-1/IL-1ra system during inflammatory or immune processes. Moreover, we provide evidence that, in addition to a glucocorticoid receptor-mediated effect, the mineralocorticoid receptor is involved in the inhibition of monocyte IL-1ra secretion by cortisol.

Adult↗

PubMed1995

The glucocorticoid sensitivity of lymphocytes changes according to the activity of the hypothalamic-pituitary-adrenocortical system.

Cortisol inhibition of phytohemagglutinin (PHA)-induced lymphocyte activation was studied in vitro in peripheral blood mononuclear cells (PBMC) of patients with pathologies of the hypothalamic-pituitary-adrenocortical (HPA) system (n = 18) as well as in students under and out of academic stress. In patients with HPA pathologies, cortisol-induced inhibition of lymphocyte interleukin-2 (IL-2) secretion in vitro positively correlated (p < .005) with IL-2 synthesis, such that lymphocytes secreting less IL-2 were less cortisol sensitive. Similarly, in stressed students there was a positive correlation (p < .02) between lymphocyte DNA synthesis and cortisol inhibition in vitro. Academic stress also resulted in a decrease (p < .01) of lymphocyte cortisol sensitivity. The same tendency was observed in patients with Cushing's syndrome when compared with hypocortisolemic patients. Normal controls whose lymphocytes were glucocorticoid resistant showed higher lymphocyte activation than glucocorticoid sensitive subjects. This pattern of glucocorticoid sensitivity was reversed in individuals with abnormal glucocorticoid secretion due to HPA pathology or stress.

Adult↗

PubMed1995

Expression and localization of endothelin-1 and endothelin receptors in human meningiomas. Evidence for a role in tumoral growth.

In addition to its well-known homoeostatic actions in the cardiovascular system, ET-1 has been shown to constitute a potent growth regulatory peptide in various tissues. We have studied the expression of ET-1 and its receptors (ET-Ar and ET-Br) in human meningiomas (n = 35) as well as their involvement in cellular growth. By PCR of reverse-transcribed RNA we detected ET-1 mRNA in 91% (32 of 35), ET-Ar mRNA in 82% (29 of 35), and ET-Br mRNA in 42% (15 of 35) of human meningiomas examined. The localization of ET-1 mRNA, ET-Ar mRNA, and ET-1 peptide in tumoral cells was observed by in situ hybridization and immunohistochemistry, whereas ET-Br mRNA was expressed at low level only in cells belonging to blood vessels. In addition, we found that ET-1 stimulated [3H] thymidine incorporation in primary cell cultures of 20 meningiomas and that this effect could be blocked by BQ-123, a specific antagonist for ET-Ar. In contrast, RES-701-3, an antagonist of ET-Br, did not block the proliferative effect of ET-1. In conclusion, our data provide evidence that ET-1 constitutes an important growth factor for meningiomas acting via ET-Ar. We can hypothesize that ET-1, acting in concert with other growth factors and cytokines, is involved in the meningioma tumorigenesis.

Adult↗

PubMed1995

Corticotropin-releasing hormone differentially modulates the interleukin-1 system according to the level of monocyte activation by endotoxin.

The interleukin-1 (IL-1) system is constituted by IL-1 alpha and IL-1 beta and IL-1 receptor antagonist (IL-1ra) that bind the same IL-1 receptors. Hypothalamic-pituitary-adrenal axis hormones are major mediators of the neuroendocrine control over immune function. Corticotropin-releasing hormone (CRH) is produced in peripheral inflammatory sites; its direct effects on inflammatory cytokine synthesis, however, remain unclear. We have studied the effects of CRH (0.1-100 nM) on IL-1 beta and IL-1ra expression by human peripheral monocytes in culture activated with different doses of lipopolysaccharide (LPS). In the absence of LPS, CRH up-regulated IL-1ra and IL-1 beta messenger RNA expression as well as protein synthesis. No significant changes were observed with low doses of LPS (1 ng/ml). In contrast, in combination with high doses of LPS (1 microgram/ml), CRH caused inhibition of IL-1ra and IL-1 beta transcription and secretion. The CRH effects were blocked by its antagonist alpha-helical CRH and mediated by intracellular cAMP. These data indicate that CRH modulates the IL-1 system; depending on the state of activation of the monocyte, CRH exerts an inhibitory control on the activated cell and a stimulatory action on the resting monocyte.

Cells, Cultured↗

PubMed1995

Involvement of interleukin-1 and interleukin-1 receptor antagonist in rat pituitary cell growth regulation.

Interleukin-1 (IL-1), one of the mediators of the interaction between the immune and the neuroendocrine system, is well known to modulate anterior pituitary hormone secretion. As IL-1 influences growth of various cell types, we investigated whether IL-1 is also a growth factor of pituitary cells. We demonstrate that IL-1 dose and time dependently inhibits the growth of normal rat pituitary cells under serum-free conditions. The inhibitory potencies of IL-1 alpha (ED50, 8 pg/ml) and IL-1 beta (ED50, 6 pg/ml) were nearly identical. In the presence of low amounts of serum, both IL-1 alpha (ED50, 130 pg/ml) and IL-1 beta (ED50, 90 pg/ml) were less effective in inhibiting growth. The IL-1-induced growth inhibition was IL-1 receptor mediated, because both IL-1 alpha- and IL-1 beta-mediated growth suppression could be completely reversed by the IL-1 receptor antagonist, the physiological counterpart of IL-1. In the mammosomatotroph GH3 rat pituitary tumor cell line, IL-1 failed to influence growth, indicating that either IL-1 receptors are missing or the IL-1 signaling pathway is uncoupled from the growth regulation. In contrast to growth, in our rat pituitary monolayer cell culture system, IL-1 did not affect ACTH, GH, or PRL secretion as described previously. This discrepancy suggests the involvement of different mechanisms in the IL-1-induced mediation of growth and hormone secretion.

Adrenocorticotropic Hormone↗

PubMed1994

Maternal psychiatric disorders in pediatric inflammatory bowel disease and cystic fibrosis.

The mothers of 72 children and adolescents with inflammatory bowel disease (IBD) and 44 mothers of children and adolescents with cystic fibrosis (CF) were given A-SADS interviews. Fifty-one percent of IBD mothers and 41% of cystic fibrosis mothers had a lifetime history of depression. More IBD than CF mothers had a history of suicide gestures or attempts, and were more likely to have a history of obsessive compulsive disorder. However, CF mothers were more likely to have experienced panic attacks.

Adolescent↗

PubMed1994

Correlates of depression in new onset pediatric inflammatory bowel disease.

Of thirty six children with new-onset inflammatory bowel disease given a Kiddie-SADS interview, five children were depressed and ten had some depressive symptoms. Depressed children had less severe illness, and were more likely to have a maternal history of depression, more life events, and families characterized by less cohesion and more conflict.

Adolescent↗

PubMed1994

Inhibition of interleukin-2-mediated lymphocyte activation in patients with Cushing's syndrome: a comparison with hypocortisolemic patients.

We investigated the lymphocyte interleukin-2 (IL-2) system, which is critically involved in lymphocyte activation, in patients with disorders or the hypothalamic-pituitary-adrenal (HPA) axis. Patients with Cushing's syndrome (n = 9) showed a significant (p < 0.05) inhibition of phytohemagglutinin (PHA)-stimulated IL-2 secretion by peripheral lymphocytes and a decrease of sensitivity to cortisol inhibition in vitro compared to normal subjects (n = 9). Circulating soluble interleukin-2 receptor (sIL-2R) levels were significantly decreased (p < 0.05), whereas no significant difference was observed in PHA-induced sIL-2R release in vitro. In patients with hypocortisolism (n = 12), in vitro IL-2 synthesis was increased compared to normal subjects and to patients with Cushing's syndrome (p < 0.01). In vitro sIL-2R release was significantly higher (p < 0.01) compared to patients with Cushing's syndrome. In contrast to patients with secondary adrenal insufficiency (n = 7), patients with an adrenal origin of hypocortisolism (Addison's disease, bilateral adrenalectomy; n = 5) showed significantly elevated circulating sIL-2R levels compared to normal subjects and patients with Cushing's syndrome (p < 0.005). There was no significant difference between the study groups in mitogen-induced DNA synthesis. This is the first description of alterations of cytokine secretion in patients with HPA axis disorders. The contrary effects of long-term hypercortisolism and insufficient or absent adrenal glucocorticoid secretion on IL-2-mediated lymphocyte activation could account for the immune states previously observed in these patients.

Adult↗

PubMed1994

Glucocorticoids suppress interleukin-1 receptor antagonist synthesis following induction by endotoxin.

Glucocorticoids, as part of their physiological role in the control of inflammatory and immune processes, suppress the expression of IL-1 and other cytokines. We have found a dose-dependent inhibition by dexamethasone (10 nM to 10 microM) of mRNA levels of the recently cloned IL-1 receptor antagonist (IL-1ra) in endotoxin-stimulated human monocytes. At the same concentrations, both dexamethasone and cortisol inhibited the secretion of IL-1ra. These inhibitory effects were reversed by blocking glucocorticoid receptors with the specific antagonist RU 38486, but not by adding exogenous IL-1, even up to 100 ng/ml, to the monocytes. A similar inhibition of IL-1ra mRNA and protein secretion was found in monocytes obtained after dexamethasone administration in vivo. In addition, we observed parallel increases in glucocorticoid and IL-1ra levels following endotoxin administration to normal volunteers. Our results show that glucocorticoids shut down not only IL-1 but also IL-1ra expression, ruling out induction of IL-1ra as part of the glucocorticoid antiinflammatory mechanism. The control of the delicate immunoregulatory balance of the IL-1/IL-1ra system during endotoxemia underscores the physiological importance of glucocorticoids in the final control of immune responses.

Adult↗

PubMed1994

Expression of interleukin-1 receptor antagonist in human pituitary adenomas in vitro.

The production of cytokines and their receptors in the pituitary gland as well as receptor-mediated cytokine effects on pituitary function have been demonstrated. We have investigated whether the naturally occurring interleukin-1 receptor antagonist (IL-1ra), which has been shown to block IL-1 biological actions during inflammatory processes, could be expressed in human pituitary adenomas (n = 16) cultured in vitro. By polymerase chain reaction of reverse-transcribed RNA we detected IL-1ra messenger RNA in cultures of all types of pituitary adenomas under basal conditions as well as after stimulation of the cells with endotoxin or phorbol myristate acetate. The amplified complementary DNA fragment was identical to the fragment observed when RNA from purified human monocytes was subjected to reverse transcription polymerase chain reaction. In addition, we provide evidence that the IL-1ra messenger RNA detected in human pituitary adenomas corresponds to the intracellular IL-1ra variant. By using specific primers for the monocyte/macrophage marker CD14 as a control, we could exclude a contamination by monocytes or macrophages in the cell cultures of pituitary adenomas as a source of IL-1ra expression. Immunofluorescence studies showed the presence of cellular IL-1ra protein in the pituitary adenoma cultures and the colocalization with hormone-producing cells in GH- and ACTH-secreting adenomas. Production of IL-1ra within the anterior pituitary may act as a protective mechanism, modulating the sensitivity of pituitary cells to circulating or intrinsically produced IL-1 during inflammatory or tumoral processes.

Adenoma↗

PubMed1993

Interleukin involvement in anterior pituitary cell growth regulation: effects of IL-2 and IL-6.

The pituitary gland plays a central role in the interactions between the immune and neuroendocrine systems. The expression of receptors for interleukin-1 (IL-1), IL-2, and IL-6 and the intrinsic production of these ILs by pituitary cells have been described. Previous studies have focused on the way cytokines influence hormone secretion. We have determined whether, in addition to these effects, ILs could affect pituitary cell proliferation. In GH3 cells, both IL-2 (1-100 U/ml) and IL-6 (10-500 U/ml) significantly stimulated [3H]thymidine incorporation and cell count. In contrast, inhibitory effects of both IL-2 and IL-6 at the same concentrations were observed on normal rat anterior pituitary cell growth. This finding was clearly evident when cells were cultured in Minimum Essential Medium-D-valine medium, a condition that results in cultures virtually free of fibroblasts. Autoradiographic studies confirmed that [3H]thymidine was only incorporated in the nucleus of nonfibroblastic pituitary cells. No direct correlation between the effects of IL-2 and IL-6 on cell growth and hormone secretion was apparent. By immunofluorescence, we observed IL-2 receptor expression on GH3 cells and, for the normal rat cultures, a high percentage of PRL-secreting and a lower percentage of GH-producing cells expressing IL-2 receptors, providing new evidence for a direct site of action of IL-2 on pituitary cells. Considering that uncontrolled division of cells may result from either excessive growth stimulation or deficient growth inhibition, the regulation of pituitary cell growth by IL-2 and IL-6 together with their intrinsic pituitary production could be of potential importance in pituitary adenoma pathogenesis.

Animals↗