Biomedical subjects

S Herrmann

Publications and source records attributed to S Herrmann.

At least 55 records · Page 3Linked to original sources

PubMed1992

Norepinephrine sensitivity of the endocrine pancreas in aging F344 rats.

The effect of norepinephrine (NE) infusion on glucose-stimulated insulin secretion was evaluated in whole perfused pancreases isolated from 6-, 12-, and 26-month-old male Fischer 344 (F344) rats. Glucose-stimulated insulin secretion was significantly inhibited by NE in all age groups. There was no significant effect of aging on the sensitivity or magnitude of inhibition at any of the concentrations of NE. In contrast, vascular pressure attained during NE infusion was significantly less in the 26-month-old rats compared to 6- and 12-month-old animals. These results suggest that the adrenoceptor neuroeffector mechanism of the smooth muscle declines at a faster age-related rate than does the beta-cell's adrenoceptor mechanism.

Aging↗

PubMed1992

Ketamine as a probe for medetomidine stereoisomer inhibition of human liver microsomal drug metabolism.

Medetomidine (MED) is a novel, selective, alpha 2 adrenergic agonist with potent sedative, hypnotic, and analgesic properties, currently undergoing evaluation as an anesthetic adjuvant. The pharmacologic effects of MED are stereospecific, due entirely to the D-isomer (DMED), whereas the L-isomer (LMED) is essentially inactive. DMED, a 4(5)substituted imidazole, has been shown to inhibit adrenal steroidogenesis and human liver microsomal alfentanil metabolism, reactions mediated by cytochrome P-450. The mechanism of MED inhibition of cytochrome P-450 is unknown. The purpose of this investigation was to determine the mechanism of DMED inhibition of human cytochrome P-450-mediated microsomal metabolism, using ketamine as a probe. Ketamine undergoes extensive hepatic biotransformation and has been used previously to characterize the effects of imidazole anesthetics on human P-450-catalyzed drug metabolism. Ketamine N-demethylation by microsomes from three human livers was measured by gas chromatography-mass spectrometry with selected-ion monitoring. DMED was a potent, competitive inhibitor of S(+) ketamine N-demethylation, with a Ki of 0.11-0.18 microM for the high affinity ketamine demethylase. The IC50 for DMED inhibition of therapeutic concentrations of racemic ketamine (10 microM) was 0.15 +/- 0.02 microM. Preincubation of DMED with microsomes and an NADPH generating system prior to ketamine addition had no additional effect on the inhibition of ketamine demethylase activity, thereby implicating the parent compound rather than a DMED metabolite as the inhibitory species. LMED, although pharmacologically inactive, had a greater inhibitory effect than DMED on racemic ketamine and ketamine enantiomer demethylation at therapeutic concentrations. Spectral studies showed that DMED interacted with microsomal cytochrome P-450 to elicit a Type II binding spectrum.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1992

Age and gender effects on insulin secretion and glucose sensitivity of the endocrine pancreas.

Glucose-stimulated insulin secretion was evaluated in whole perfused pancreases and islets of Langerhans (90 to 110 microns diam) isolated from female and male Fischer 344 (F344) rats aged 6, 12, and 26 mo. Total glucose-stimulated (11.1 mmol/l) insulin release of whole perfused pancreases from male rats did not differ among age groups. In contrast, insulin secretion of 26-mo-old female rats was significantly greater than 6- and 12-mo-old female rats. Insulin secretion by islets of Langerhans incubated in glucose concentrations of 11.1, 16.7, and 22.2 mmol/l was greater in male rats compared with age-matched female animals at all three ages, and was greater in 6-vs. 26-mo-old male rats. Insulin secretion of female rats revealed some significant differences among the age groups, although no clear pattern was evident. Sensitivity of the islets to glucose was estimated from the rate of glucose oxidation. At incubation medium glucose concentrations of 11.1 mmol/l or higher, no effect of gender was observed, although the glucose oxidation rate of islets from male 26-mo-old rats was greater than that of islets from gender-matched 6-mo-old rats. These data indicate that in both the whole perfused pancreas and isolated islets of Langerhans, glucose-stimulated insulin secretion is not significantly altered with age or gender in the F344 rat. However, it appears that maintenance of insulin secretory capacity by aging male rats is achieved by enhancement of beta-cell sensitivity to glucose.

Aging↗

PubMed1990

IL-7 supports the generation of cytotoxic T lymphocytes from thymocytes. Multiple lymphokines required for proliferation and cytotoxicity.

Current data suggest that the combination of IL-2 plus IL-6 or IL-4 supports the generation of a CTL response. In this report, we investigated whether IL-7 alone or in combination with other lymphokines supports the generation of active CTL from murine thymocytes. Added alone, IL-7 produced a modest CTL response, and this response was augmented (more than an additive response) by the addition of either IL-2, IL-6, or IL-4. After culture with IL-7, the removal of CD8+ cells correlated with a marked decrease in killing, whereas removal of the CD4+ population resulted in an enhanced CTL response. IL-7 generated a proliferative response to which the addition of other lymphokines resulted in an additive increase at best. To determine if the CTL response was found with IL-7 was dependent on the presence of endogenous lymphokines, we added blocking mAb and found that anti-IL-2 or anti-IL-6 blocked the level of CTL generated in the presence of IL-7. In contrast, anti-IL-4 was unable to inhibit CTL generation. The effect of the mAb on proliferation was somewhat paradoxical. The addition of anti-IL-2, anti-IL-6, or anti-IL-4 to cultures containing IL-7 all caused a significant decrease in proliferation that was overcome by the addition of the corresponding human lymphokines for IL-2 and IL-6. If thymocytes were fractionated and then cultured in the presence of IL-7, the double negative population gave the greatest proliferative response, the single positive thymocytes gave a response that was approximately 40% less, and the double positive thymocytes did not proliferate. These data indicate that IL-7 supports the induction of a cytotoxic response, however, this appears to require the presence of both IL-2 and IL-6.

Animals↗

PubMed1990

[Contrast medium assisted nuclear magnetic resonance tomography. Signal intensity of gliomatous tumors].

In 124 patients with different types of gliomas signal intensity was studied with and without contrast material using T1-weighted sequences. The diagnostic possibilities equal those of computed tomography scans. Except grade II and III astrocytomas, the extent of the observed disorders of the blood-brain-barrier corresponds to the malignancy of the tumour. A distinction between glioblastomas, anaplastic astrocytomas and mixed gliomas is not possible. The differences on examination with and without contrast medium in grade I and II astrocytomas and grade I oligodendro-gliomas can be important for differential diagnosis. In addition the T1-weighted sequences require less time for investigation than other sequences which demonstrate disorders of the blood-brain-barrier without contrast material.

Astrocytoma↗

PubMed1989

Oxygen tension at the subcutaneous implantation site of glucose sensors.

To elucidate potential influences of the average tissue pO2 on the function of implanted glucose sensors, non-miniaturized polarographic oxygen electrodes and glucose oxidase/H2O2 glucose electrodes were implanted in the subcutaneous tissue of spontaneously breathing normal and diabetic dogs. There was no appreciable run-in phenomenon of oxygen sensors but normally a pronounced initial decrease in current after implantation of glucose sensors. The subcutaneous pO2 amounted to an average of 7 kPa in air-breathing animals with no difference between normal and insulin-dependent diabetic dogs. It showed oscillations of approximately +/- 2 kPa but the mean was stable over the maximum duration of experiments of 16 h. Induced alterations of tissue pO2 between less than 2 and greater than 20 kPa (as verified by measurements of arterial pO2) were not followed by alterations in the current of nearby implanted glucose sensors. It is concluded that the frequently observed instabilities and losses in sensitivity of the system "implanted glucose sensor in situ + tissue glucose compartment" are not caused by alterations in tissue pO2.

Animals↗

PubMed1988

Interaction of CD2 with its ligand, LFA-3, in human T cell proliferation.

Recently, it has been demonstrated that lymphocyte function-associated Ag (LFA-3) is a natural ligand for CD2 and that this receptor-ligand interaction functions in cell-cell adhesion. In this report, we demonstrate that LFA-3 plays a role in T cell activation. L cells were transfected with human genomic DNA and sorted for expression of LFA-3. We demonstrate that LFA-3+ L cells, together with anti-CD3 mAb or with suboptimal doses of PHA, stimulate proliferation of human peripheral blood T cells. Furthermore, thymocyte proliferation was induced by LFA-3+ L cells and suboptimal doses of PHA. Proliferation was inhibited by mAb directed against either CD2 or LFA-3. Stimulation of thymocytes by the combination of PHA and LFA-3+ L cells resulted in the increased expression of the IL-2R, as well as of the surface Ag 4F2, transferrin receptor, and HLA-DR. These data support the conclusion that LFA-3 plays a role in CD2-dependent T cell activation. LFA-3 is widely distributed and is expressed on all APC and target cells. Thus, the ability of the CD2/LFA-3 interaction to costimulate with an anti-CD3 mAb suggests that the CD2/LFA-3 interaction may be involved not only in an Ag-independent alternate pathway of T cell activation but also in Ag-specific T cell activation.

Animals↗

PubMed1987

Characterization of antigen association with accessory cells: specific removal of processed antigens from the cell surface by phospholipases.

To characterize the basis for the cell surface association of processed antigen with the antigen-presenting cell (APC) we analyzed its sensitivity to enzymatic digestion. Antigen-exposed APC that are treated with phospholipase and then immediately fixed lose their ability to stimulate antigen-plus-Ia-specific T-T hybridomas. This effect is seen with highly purified phospholipase A2 and phospholipase C. In addition it is observed with three distinct antigens--ovalbumin, bovine insulin, and poly(LGlu56LLys35LPhe9) [(GluLysPhe)n]. The effect of phospholipases is highly specific. Identically treated APC are equivalent to controls in their ability to stimulate alloreactive hybridomas specific for precisely the same Ia molecule that is corecognized by antigen-plus-Ia-specific hybrids. Furthermore, the antigen-presenting function of enzyme-treated, fixed APC can be reconstituted by the addition of exogenous in vitro processed or "processing independent" antigens. In parallel studies 125I-labeled avidin was shown to specifically bind to APC that were previously exposed and allowed to process biotin-insulin. Biotin-insulin-exposed APC that are pretreated with phospholipase bind significantly less 125I-labeled avidin than do untreated, exposed APC. Identical enzyme treatment does not reduce the binding of avidin to a biotinylated antibody already bound to class II major histocompatibility complex molecules of APC. At least some of the biotin-insulin surface sites are immunologically relevant, because the presentation of processed biotin-insulin by fixed APC is blocked by avidin. This effect is specific. Avidin binding to biotin-insulin-exposed APC does not inhibit allospecific stimulation nor the presentation of unconjugated insulin. These studies demonstrate that phospholipase effectively removes processed cell surface antigen.

Animals↗

PubMed1985

Defining cytolytic T lymphocyte recognition of chemically modified self. I. Response to trinitrophenyl-H-2Kk.

We used purified class I antigen incorporated into liposomes to examine the response of secondary cytolytic T lymphocytes (CTL) to chemically modified self. By generating the secondary response in the presence of T cell helper factor, the level of CTL response was limited by CTL recognition of added antigen rather than by helper cell generation of lymphokines. We found a strong secondary response against chemically modified self when spleen cells from trinitrophenyl (TNP)-primed C3H/HeJ mice were stimulated with a) TNP-modified liposomes containing H-2Kk, b) liposomes containing H-2Kk purified from TNP-modified RDM-4 (H-2k) cells, or c) liposomes containing the limited trypsin proteolysis product of H-2Kk that had been directly modified with TNP. In contrast, we were not able to generate a significant CTL response with unmodified H-2Kk incorporated into vesicles along with TNP-modified membrane components lacking H-2Kk. These results suggest that TNP-modified H-2Kk is a major antigenic site recognized by CTL from C3H/HeJ mice after priming against TNP-modified self.

Animals↗

PubMed1981

Cellular interactions in the generation of cytolytic T lymphocyte responses. Analysis of the helper T cell pathway.

Murine splenic lymphocytes exhibit a requirement for helper T cells for the induction of a cytolytic T lymphocyte response to suboptimal doses of allogeneic cells, membranes from allogeneic cells, or purified H-2 antigen in liposomes. The conditions where a requirement for help is apparent are the same conditions where a dependence on splenic adherent cells (SAC) has been demonstrated (Weinberger, O. et al., PROC. Natl. Acad, Sci, USA 1980. 77: 6091). Help can be provided in the form of primed, radioresistant, Ly-1+ spleen or lymph node cells or helper factor (interleukin 2, IL-2). A factor generated from phytohemagglutinin-stimulated human lymphocytes, when added to culture in the presence of antigen, bypassed the requirement for Ia+ SAC and helper cells. IL-2 reconstituted the response to H-2K(k) in liposomes in cultures depleted of SAC, strongly suggesting that the helper cell must see antigen re-expressed by an antigen-presenting cell, whereas the prekiller does not. IL-2 could be generated by culturing Ly-1+ murine spleen cells with H-2K(k) pulsed on SAC.

Animals↗

PubMed1981

Antigen-presenting cell function in induction of helper T cells for cytotoxic T-lymphocyte responses: evidence for antigen processing.

We demonstrate that splenic adherent cells (SACs) play an active role in the presentation of H-2Kk antigen for an alloreactive cytotoxic T-lymphocyte (CTL) response. If antigen is incubated with SACs for 12 hr, they will provide maximal stimulation and present the antigen in the context of their Ia molecules. UV irradiation of these SACs, prior to the 12-hr incubation with H-2Kk antigen, abrogates this stimulatory capacity. Macrophage-bound antigen is not sufficient for stimulation of a response; a second signal is required as well, that, in our system, is provided by phorbol myristic acetate. The SACs are involved in the activation of helper T cells; however, they are not required for presentation of antigen to the precytotoxic T-lymphocyte, which requires two signals for activation, one provided by antigen and the other by a T-cell-derived helper factor.

Animals↗

PubMed1980