Comment on "determination of interlayer diffusion parameters for Ag/Ag(111)".
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Letter↗
Biomedical subjects
S Heinrichs
Publications and source records attributed to S Heinrichs.
Inhibition of anti-IgM-induced translocation of protein kinase C beta I inhibits ERK2 activation and increases apoptosis.
Expression of the COOH-terminal residues 179-330 of the LSP1 protein in the LSP1(+) B-cell line W10 increases anti-IgM- or ionomycin-induced apoptosis, suggesting that expression of this LSP1 truncate (B-LSP1) interferes with a Ca(2+)-dependent step in anti-IgM signaling. Here we show that inhibition of Ca(2+)-dependent conventional protein kinase C (cPKC) isoforms with Gö6976 increases anti-IgM-induced apoptosis of W10 cells and that expression of B-LSP1 inhibits translocation of PKCbetaI but not of PKCbetaII or PKCalpha to the plasma membrane. The increased anti-IgM-induced apoptosis is partially reversed by overexpression of PKCbetaI. This shows that the B-LSP1-mediated inhibition of PKCbetaI leads to increased anti-IgM-induced apoptosis. Expression of constitutively active PKCbetaI protein in W10 cells activates the mitogen-activated protein kinase ERK2, whereas expression of B-LSP1 inhibits anti-IgM-induced activation of ERK2, suggesting that anti-IgM-activated PKCbetaI is involved in the activation of ERK2 and that inhibition of ERK2 activation contributes to the increased anti-IgM-induced apoptosis. Pull-down assays show that LSP1 interacts with PKCbetaI but not with PKCbetaII or PKCalpha in W10 cell lysates, while in vitro LSP1 and B-LSP1 bind directly to PKCbetaI. Thus, B-LSP1 is a unique reagent that binds PKCbetaI and inhibits anti-IgM-induced PKCbetaI translocation, leading to inhibition of ERK2 activation and increased apoptosis.
Antibodies, Anti-Idiotypic↗
Influence of promoter DNA topology on sequence-specific DNA binding and transactivation by tumor suppressor p53.
Transcriptional activation by the tumor suppressor p53 is regulated at multiple levels, including posttranslational modifications of the p53 protein, interaction of p53 with various regulatory proteins, or at the level of sequence-specific DNA binding to the response elements in p53's target genes. We here propose as an additional regulatory mechanism that the DNA topology of p53-responsive promoters may determine the interaction of p53 with its target genes. We demonstrate that sequence-specific DNA binding (SSDB) and transcriptional activation by p53 of the mdm2 promoter is inhibited when this promoter is present in supercoiled DNA, where it forms a non-B-DNA structure which spans the p53-responsive elements. Relaxation of the supercoiled DNA in vitro resulted in conversion of the non-B-DNA to a B-DNA conformation within the mdm2 promoter, and correlated with an enhanced SSDB of p53 and an elevated expression of a reporter gene. In contrast, sequence specific DNA binding and transcriptional activation of the p21 promoter were not inhibited by DNA supercoiling. We propose that conformational alterations within p53-responsive sites, which either promote or prohibit sequence specific DNA binding of p53, are an important feature in orchestrating the activation of different p53 responsive promoters.
Binding Sites↗
Variability of the metabolic effect of soluble insulin and the rapid-acting insulin analog insulin aspart.
OBJECTIVE: To study the intra- and interindividual variability of the metabolic activity of soluble insulin and of the rapid-acting insulin analog insulin aspart after subcutaneous injection. RESEARCH DESIGN AND METHODS: A total of nine healthy male volunteers received subcutaneous injections of soluble insulin (0.2 U/kg) in the abdominal region on each of the four study days. Another 10 volunteers received an injection of insulin aspart four times. Glucose infusion rates necessary to neutralize the blood glucose-lowering effect of the administered insulin were registered during euglycemic glucose clamps (blood glucose 5.0 mmol/l; basal intravenous insulin infusion 0.15 mU x kg(-1) x min(-1) over the subsequent 600 min. We investigated the variation in metabolic activity by calculating coefficients of variation (CVs). RESULTS: In comparison to soluble insulin, subcutaneous injections of insulin aspart led to a more rapid onset of action and a shorter duration of action. Subcutaneous injection of the insulin preparations resulted in intraindividual CVs of the summary measures between 10 and 30% (soluble insulin vs. insulin aspart: maximal metabolic activity 15+/-7 vs. 16+/-10%, time to maximal metabolic activity 14+/-10 vs. 11+/-6%; NS between the preparations [means +/- SD]). The decline to half-maximal activity after maximal activity showed a lower intraindividual CV with insulin aspart (19+/-9 vs. 11+/-5%; P = 0.018). The interindividual CVs were higher than the intraindividual CVs (26 vs. 28, 23 vs. 19, and 26 vs. 17%). Generally, the pharmacodynamic variability was higher than the pharmacokinetic variability. For the pharmacokinetic measures, the intra- and interindividual variability in t(max) was lower for insulin aspart than for soluble insulin. CONCLUSIONS: The metabolic effect of soluble insulin shows an intraindividual variability of 10-20% in healthy volunteers, even under strictly controlled experimental conditions. The overall variability of action of insulin aspart was comparable to that of soluble insulin.
Adult↗
Time-action profiles of novel premixed preparations of insulin lispro and NPL insulin.
OBJECTIVE: To study the pharmacodynamic properties of three premixed formulations of the rapid-acting insulin analog insulin lispro and its protamine-retarded preparation, neutral protamine lispro (NPL) insulin. RESEARCH DESIGN AND METHODS: In this open, single-center, euglycemic glucose clamp study, 30 healthy volunteers (12 women, 18 men) aged 27 +/- 2 years (mean +/- SD), whose BMI was 23.0 +/- 2.3 kg/m2, received subcutaneous injections of 0.3 U/kg body wt of insulin mixture (high-mixture 75/25, mid-mixture 50/50, or low-mixture 25/75 insulin lispro/NPL insulin), insulin lispro, or NPL insulin on one of the five study days in randomized order. Glucose infusion rates were determined over a period of 24 h after administration. RESULTS: Maximal metabolic activity decreased after subcutaneous injection of the mixtures with lower insulin lispro content; however, the time point of maximal and of early half-maximal metabolic activity was comparable among the three mixtures. Higher proportions of insulin lispro resulted in higher values for area under the curve within the first 360 min after injection and a more rapid decline to late half-maximal activity. Serum insulin concentrations showed a similar pattern. CONCLUSIONS: This study shows that the pharmacodynamic and pharmacokinetic properties of insulin lispro are preserved in stable mixtures with NPL insulin.
Adult↗
Demonstration of silver-stained nucleolar organizer region associated proteins (AgNORs) after wet autoclave pretreatment in breast carcinoma: correlation to tumor stage and long-term survival.
Argyrophilic nucleolar organizer region associated proteins (AgNORs) are known to reflect cellular and nucleolar activity. Due to a novel staining procedure, which substantially improves visualisation of AgNORs on formalin-fixed and paraffin-embedded material, AgNORs can be reliably demonstrated as true substructures of the nucleoli. The aim of the present study was to apply a standardized morphometric AgNOR quantification on a large series of breast carcinomas with regard to its prognostic relevance. AgNOR quantity was evaluated on archival tumor tissues of 115 adenocarcinomas of the breast treated with the wet autoclave method prior to standardized silver-staining and morphometric analysis. AgNOR parameters were correlated to prognostic features (steroid hormonal receptor status, tumor type, tumor size, histological grading, pTNM, and UICC stage) carrying out both univariate and multivariate survival analyses. AgNOR number and area were proven to be statistically significantly related (Pearson correlation coefficient: 0.67, Bonferroni adjusted P = 0.0001). Almost all AgNOR parameters, in particular CV (coefficient of variation) of corrected area (delta-area) and CV of number, were statistically significantly correlated to estrogen and progesterone receptor status as well as histological grading of tumors. Increased AgNOR parameters were statistically significantly associated with early tumor relapse and cancer related death. Univariate and multivariate analysis by means of Cox regression revealed independent prognostic significance for CV of delta-area and number of AgNORs. Various AgNOR parameters (CV of number, CV of delta-area, CV of area, mean delta-area, and mean area of AgNORs per nucleus) determined on wet autoclave pre-treated formalin-fixed and paraffin-embedded breast cancer tissues are statistically highly significantly associated with the prognostic outcome, independently predicting tumor-free and overall survival.
Adenocarcinoma↗
Neurobiology of corticotropin releasing factor (CRF) receptors and CRF-binding protein: implications for the treatment of CNS disorders.
The actions of CRF in the brain and in the periphery are mediated through multiple binding sites. There are three receptors, CRF1, CRF2 alpha and CRF2 beta, which encode 411, 415 and 431 amino acid proteins and transduce signals via the stimulation of intracellular cAMP production. The recent identification of high-affinity non-peptide CRF receptor antagonists should allow for rapid progress in drug development of CRF receptor antagonists. In addition to the receptors, the actions of CRF in brain and in the periphery can also be modulated by a binding protein of 322 amino acids. Ligands of CRF-BP, such as CRF (6-33) can elevate brain levels of 'free' CRF and improve learning and memory without stress-like side effects of CRF receptor agonists. Urocortin, a mammalian CRF-related peptide with close sequence homology to fish urotensin, interacts with CRF1, CRF2 receptors and with CRF-BP. These data indicate that CRF receptor antagonists may be useful for the treatment of the disease states where CRF is elevated such as anxiety and depression, anorexia nervosa and stroke and that ligand inhibitors of CRF-BP may be used to elevate brain levels of 'free' urocortin and other CRF-related peptides.
Animals↗
The role of corticotropin-releasing factor in the anxiogenic effects of ethanol withdrawal.
In summary, endogenous CRF has been demonstrated to play an important role in the endocrine but also autonomic and behavioral responses to a stressor and to mediate some of the signs and symptoms observed in human affective and anxiety disorders. These findings led to the hypothesis that the anxiety that characterizes drug withdrawal, such as ethanol withdrawal in humans, may be related in part to the action of CRF-producing neurons in the CNS. Indeed, rats made dependent on an ethanol liquid diet showed significant signs of enhanced stress responsiveness that was blocked by intracerebral administration of a CRF antagonist. At this time little is known about the specific site of action for endogenous CRF. However, recent studies using local administration of CRF antagonist and in vivo CRF microdialysis suggest that the central nucleus of the amygdala may be an important site for the increases in CRF activity associated with the anxiogenic effects of ethanol withdrawal. Although preliminary, these results propound that ethanol dependence may involve a prolonged dysregulation of the CRF system in the basal forebrain that may contribute to the increased motivational effect of ethanol withdrawal.
Alcoholism↗
Alcohol, the reward system and dependence.
Evidence is presented to show that multiple neurotransmitter systems of the brain reward systems including GABA, glutamate, dopamine, serotonin and opioid peptides are involved in alcohol reinforcement. Dependence is associated with changes in many of these same systems, but also with changes in other neurotransmitters, such as brain corticotropin releasing factor. A midbrain forebrain circuitry that involves parts of the nucleus accumbens and amygdala is hypothesized to be the focus for the neuropharmacology of alcohol reinforcement.
Alcoholism↗
[Diagnostic and prognostic value of plasma ANP determination after myocardial infarction].
In the present study the prognostic value of ANP measurement was investigated in 52 patients undergoing coronary angiography. 22 normotensive and 30 hypertensive subjects were included. A significant inverse correlation between left ventricular ejection fraction (EF) and plasma ANP was found in normotensives, but not in hypertensives. In patients with chronic myocardial infarction, there was no difference in ANP levels compared to patients without infarction in either group, provided that EF was normal. However, hypertensives showed a 35% increase in ANP compared to normotensives. This was true for subjects with and without myocardial infarction. These results show that in normotensives ANP levels have a prognostic value on a statistical rather than an individual basis. This does not apply to hypertensives, whose ANP level is increased by factors other than impaired ejection fraction.
Angiocardiography↗
[Elevated levels of atrial natriuretic peptide and plasma catecholamines in arterial hypertension--indications for an interaction].
In this study plasma levels of atrial natriuretic peptide and of the catecholamines epinephrine and norepinephrine were investigated in hypertensive patients (HT) (n = 30). 22 normotensive patients (NT) served as controls. Hypertensives showed an elevated ANP-level in comparison with controls (46.8 +/- 3.3 vs. 36.8 +/- 3.3 pg/ml, M +/- SEM, p less than 0.01). When patients with myocardial infarction or with reduced ejection fraction were excluded, the same relation was demonstrated (49.3 +/- 3.2 vs. 33.6 +/- 2.0 pg/ml, p less than 0.01). Plasma norepinephrine was 230.8 +/- 52.3 pg/ml in HT compared with 138.0 +/- 19.6 pg/ml in NT (p less than 0.05). Epinephrine was 70.8 +/- 10.5 vs. 54.8 +/- 9.7 pg/ml in HT and NT. To exclude an increased left ventricular enddiastolic - and hence left atrial - pressure as the cause for the elevation of ANP and norepinephrine, HT and NT were matched for the same levels of enddiastolic pressure (LVEDP) (n = 18). For each level of LVEDP ANP was higher in HT than in NT (p less than 0.01). The same held true for norepinephrine (p less than 0.05) and to a lesser extent for epinephrine (p = 0.09). Our results demonstrate that patients with essential hypertension exhibit markedly elevated levels for ANP and catecholamines which is not due to myocardial failure. We propose that the increased secretion of the vasodilatory hormone ANP serves as counterregulation against the vasoconstrictor norepinephrine. The endocrine function of the heart may play a pivotal role in the modulation of sympathetic activity.
Aged↗
Identification of neurons in the transmission electron microscope after retrograde labelling with the dye Lucifer Yellow.
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Animals↗
Neurosecretory cells in the circadian-clock system of the scorpion, Androctonus australis.
The somata of the efferent neurosecretory fibers that control the circadian sensitivity rhythm in the median eyes of the scorpion, Androctonus australis, were detected in the brain by retrograde labeling with Lucifer Yellow CH. A total of 20-40 neurons are arranged in two groups displaying a bilaterally symmetrical, marginal position near the circumesophageal connectives. Half the cells in each group send fibers into the ipsilateral optic nerve; the fibers from the other half enter the contralateral optic nerve.
Animals↗
Differential retrograde labelling with horseradish peroxidase (HRP) and Lucifer yellow (LY) in an invertebrate nervous system--HRP fluorescence and LY preservation limit choice of fixative.
The possible application of the combination of horseradish peroxidase (HRP) and Lucifer Yellow CH (LY) for differential retrograde labelling of a relatively large invertebrate nervous system requiring the enzymatic marker to be processed after fixation and sectioning was evaluated. In control experiments an HRP fluorescence induced by glutaraldehyde (GA) fixation was detected and its spectral properties were investigated. This fluorescence, however, does not occur after previous treatment of the tissue with depolymerized paraformaldehyde (PFA) instead of GA. PFA as a fixing agent is also necessary to yield maximum preservation of LY labelling during subsequent HRP histochemistry. Both findings strongly recommend the use of PFA instead of GA as fixative for the combination of HRP and LY. It is shown that the HRP/LY differential labelling technique renders a valid method for the study of the structural interactions at the fibre level of identified neurones in a relatively large invertebrate nervous system, also after retrograde tracing.
Animals↗