Biomedical subjects

G Nagel

Publications and source records attributed to G Nagel.

At least 37 records · Page 2Linked to original sources

PubMed2003

A population-based study on variations in the use of adjuvant systemic therapy on postmenopausal patients with early stage breast cancer.

PURPOSE: To assess adherence to treatment recommendations regarding adjuvant systemic therapy of postmenopausal patients with early stage breast cancer. METHODS: A population-based cohort of women from Eastern Thuringia/Germany with first diagnosis of breast cancer in 1995-2000 was studied. The use of adjuvant therapy was assessed separately for patients with positive and negative nodal status fitting polytomous logistic regression models. RESULTS: Among 396 women with positive lymph nodes and 832 with negative lymph nodes, 92.9% and 87.3% received an adjuvant systemic treatment, respectively. Age, comorbidity, hormone receptor status, histological grading, and additionally, in nodal positives, the number of involved lymph nodes, were associated with treatment patterns. Age had the strongest impact on treatment decision. Older women more often received hormone- or no adjuvant therapy. However, 26.3% of the women with lymph node involvement and positive hormone receptor status received no hormone therapy, whereas 35.7% of women with negative hormone receptor status received hormone therapy. CONCLUSION: The number of patients with adjuvant systemic therapy is high in women with positive and those with negative lymph nodes, reflecting adherence to the recommendations. Better outcome could be expected if hormone therapy was used adequately in receptor positives. Further follow-up is required to monitor the outcome and changes in adherence to treatment recommendations.

Aged↗

PubMed2003

The influence of the dietary intake of fatty acids and antioxidants on hay fever in adults.

BACKGROUND: The objective of the investigation was to explore in a prospective study the associations between dietary intake of fatty acids, antioxidants and hay fever manifestation in adulthood. METHODS: Three hundred and thirty-four hay fever cases with adult onset of clinical symptoms from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort were identified during follow-up and matched with 1336 controls. Dietary intake data were obtained by means of validated food frequency questionnaires. The influence of dietary fatty acid and vitamin intake on hay fever risk was estimated by means of unconditional logistic regression. RESULTS: High intake of oleic acid was positively associated with hay fever [odds ratio (OR): 2.86, 95% confidence intervals (95% CI): 1.22-6.70], whereas high intake of eicosapentaenoic acid was inversely related to hay fever (OR: 0.45, 95% CI: 0.22-0.93). Furthermore, high beta-carotene intake increased the risk of hay fever (OR: 1.69, 95% CI: 1.09-2.63) while increasing intake of vitamin E was a protective factor (OR: 0.38, 95% CI: 0.17-0.85). In grouped analyses, the effects of beta-carotene and vitamin E were mainly observed among women and ex-/current-smokers; in these subgroups, linoleic acid increased the risk of hay fever. CONCLUSIONS: In conclusion, the present results provide further evidence that dietary factors might affect the risk of clinical manifestation of hay fever. However, the effects in smokers and women may suggest different biological mechanisms for the investigated nutrients, which need further research.

Adult↗

PubMed2002

Primary breast cancer therapy in six regions of Germany.

Studies from six regions of Germany (Aachen (W1), Dresden (E1), Jena (E2), Marburg (W2), Munich (W3), and Stuttgart (C1)) have been compared to verify and assess the quality of healthcare using breast cancer as an example. All of the data collection was carried out in comprehensive cancer centres and is population-based, with the exception of C1. Classic prognostic factors and the initial treatment of 8661 women with breast cancer, diagnosed between 1996 and 1998, were examined. Primary therapy, breast conserving therapy (BCT), and the use of subsequent local radiation and/or systemic therapy (chemotherapy or hormonal therapy) were analysed. BCT was performed on 39.3-57.7% of patients. By pT-category, the proportion of BCT in the six regions were as follows: for pTis between 37.8 and 64.3%, for pT1 between 51.7 and 71.5%, for pT2 between 25.9 and 51.1%, for pT3 between 0 and 13.1% and for pT4 between 0 and 15.2%. Multivariate analyses, adjusted for age and biological factors, showed a significant influence of the treating hospital on the mastectomy rate. The use of radiotherapy after BCT (80%) was quite homogeneous in the six regions. The application of radiotherapy after mastectomy, however, varied between 10.4 and 32.2%. In all regions, for premenopausal patients, the use of adjuvant systemic therapy almost reflected the St. Gallen-Consensus recommendations. In contrast, post-menopausal women with positive lymph nodes were not always treated according to these standards. In all regions, age had an influence on the administration of treatment: elderly breast cancer patients received less BCT, less radiotherapy and less adjuvant therapy than recommended in the St. Gallen-Consensus. Feedback of the results was made available to each hospital, providing a comparative summary of patient care that could be used by the participating hospitals for self-assessment and quality-control.

Age Distribution↗

PubMed2001

Expression and NNK reducing activities of carbonyl reductase and 11beta-hydroxysteroid dehydrogenase type 1 in human lung.

The tobacco specific nitrosamine 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), which is found in high amounts in tobacco products, is believed to play an important role in lung cancer induction in smokers. NNK requires metabolic activation by cytochrome P450 mediated alpha-hydroxylation to exhibit its carcinogenic properties. On the other hand, NNK is inactivated by carbonyl reduction to its alcohol-equivalent 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL) followed by glucuronidation and final excretion into urine or bile. Carbonyl reduction and alpha-hydroxylation are the predominant pathways in man, and it has been postulated that the extent of these competing pathways determines the individual susceptibility to lung cancer. Moreover, only a minor part of all habitual smokers develop lung cancer, suggesting the existence of susceptibility genes. Microsomal 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) (EC 1.1.1.146) and cytosolic carbonyl reductase (CR) (EC 1.1.1.184) have been shown to be mainly responsible for NNAL formation in liver and lung. In the present study, we performed comparative investigations of human lung tissue samples from several patients with respect to the expression and activity of 11beta-HSD 1 and carbonyl reductase. We observed varying levels in 11beta-HSD 1 and carbonyl reductase expression in these patients, as revealed by RT-PCR and ELISA. Also, the tissue samples showed a different activity and inhibitor profile for both enzymes. According to our results, variations in the expression and activity of NNK carbonyl reducing enzymes may constitute a major determinant in the overall NNK detoxification capacity and thus may be linked to the great differences observed in the individual susceptibility of tobacco-smoke related lung cancer.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2001

Electrophysiological characterization of specific interactions between bacterial sensory rhodopsins and their transducers.

The halobacterial phototaxis receptors sensory rhodopsin I and II (SRI, SRII) enable the bacteria to seek optimal light conditions for ion pumping by bacteriorhodopsin and/or halorhodopsin. The incoming signal is transferred across the plasma membrane by means of receptor-specific transducer proteins that bind tightly to their corresponding photoreceptors. To investigate the receptor/transducer interaction, advantage is taken of the observation that both SRI and SRII can function as proton pumps. SRI from Halobacterium salinarum, which triggers the positive phototaxis, the photophobic receptor SRII from Natronobacterium pharaonis (pSRII), as well as the mutant pSRII-F86D were expressed in Xenopus oocytes. Voltage-clamp studies confirm that SRI and pSRII function as light-driven, outwardly directed proton pumps with a much stronger voltage dependence than the ion pumps bacteriorhodopsin and halorhodopsin. Coexpression of SRI and pSRII-F86D with their corresponding transducers suppresses the proton transport, revealing a tight binding and specific interaction of the two proteins. These latter results may be exploited to further analyze the binding interaction of the photoreceptors with their downstream effectors.

Animals↗

PubMed2001

The voltage-dependent proton pumping in bacteriorhodopsin is characterized by optoelectric behavior.

The light-driven proton pump bacteriorhodopsin (bR) was functionally expressed in Xenopus laevis oocytes and in HEK-293 cells. The latter expression system allowed high time resolution of light-induced current signals. A detailed voltage clamp and patch clamp study was performed to investigate the DeltapH versus Deltapsi dependence of the pump current. The following results were obtained. The current voltage behavior of bR is linear in the measurable range between -160 mV and +60 mV. The pH dependence is less than expected from thermodynamic principles, i.e., one DeltapH unit produces a shift of the apparent reversal potential of 34 mV (and not 58 mV). The M(2)-BR decay shows a significant voltage dependence with time constants changing from 20 ms at +60 mV to 80 ms at -160 mV. The linear I-V curve can be reconstructed by this behavior. However, the slope of the decay rate shows a weaker voltage dependence than the stationary photocurrent, indicating that an additional process must be involved in the voltage dependence of the pump. A slowly decaying M intermediate (decay time > 100 ms) could already be detected at zero voltage by electrical and spectroscopic means. In effect, bR shows optoelectric behavior. The long-lived M can be transferred into the active photocycle by depolarizing voltage pulses. This is experimentally demonstrated by a distinct charge displacement. From the results we conclude that the transport cycle of bR branches via a long-lived M(1)* in a voltage-dependent manner into a nontransporting cycle, where the proton release and uptake occur on the extracellular side.

Animals↗

PubMed2001

Voltage and Ca(2+) dependence of pre-steady-state currents of the Na-Ca exchanger generated by Ca(2+) concentration jumps.

The Ca(2+) concentration and voltage dependence of the relaxation kinetics of the Na-Ca exchanger after a Ca(2+) concentration jump was measured in excised giant membrane patches from guinea pig heart. Ca(2+) concentration jumps on the cytoplasmic side were achieved by laser flash-induced photolysis of DM-nitrophen. In the Ca-Ca exchange mode a transient inward current is generated. The amplitude and the decay rate of the current saturate at concentrations >10 microM. The integrated current signal, i.e., the charge moved is fairly independent of the amount of Ca(2+) released. The amount of charge translocated increases at negative membrane potentials, whereas the decay rate constant shows no voltage dependence. It is suggested that Ca(2+) translocation occurs in at least four steps: intra- and extracellular Ca(2+) binding and two intramolecular transport steps. Saturation of the amplitude and of the relaxation of the current can be explained if the charge translocating reaction step is preceded by two nonelectrogenic steps: Ca(2+) binding and one conformational transition. Charge translocation in this mode is assigned to one additional conformational change which determines the equilibrium distribution of states. In the Na-Ca exchange mode, the stationary inward current depends on the cytoplasmic Ca(2+) concentration and voltage. The K(m) for Ca(2+) is 4 microM for guinea pig and 10 microM for rat myocytes. The amplitude of the pre-steady-state current and its relaxation saturate with increasing Ca(2+) concentrations. In this mode the relaxation is voltage dependent.

Acetates↗

PubMed2001

Environmental control of invasin expression in Yersinia pseudotuberculosis is mediated by regulation of RovA, a transcriptional activator of the SlyA/Hor family.

Invasin is the primary invasive factor of Yersinia pseudotuberculosis that allows efficient internalization into eukaryotic cells. We investigated invasin expression and found that the inv gene is regulated in response to a variety of environmental signals, such as temperature, growth phase, nutrients, osmolarity and pH, and requires the product of rovA, a member of the SlyA/Hor transcriptional activator family. The rovA gene was found by a genetic complementation strategy that restores temperature regulation of an unexpressed inv-phoA fusion in Escherichia coli K-12. RovA plays a role in the invasion of Y. pseudotuberculosis into mammalian cells and mediates the regulation of invasin in response to all environmental signals analysed. Deletion analysis of the inv promoter region revealed a DNA segment extending 207 bp upstream of the transcriptional start site, which is required for maximal RovA-induced inv transcription. Gel retardation assays showed that RovA interacts preferentially with this promoter fragment and suggested two potential RovA binding sites. Studies with chromosomal gene fusions also demonstrated that rovA follows the same pattern of regulation as invasin, indicating that environmental control of inv expression is mainly mediated by the control of RovA synthesis. Furthermore, we showed that a rovA-lacZ fusion is only slightly expressed in a rovA mutant strain, indicating that a positive autoregulatory mechanism is also involved in rovA expression.

Adhesins, Bacterial↗

PubMed2001

Non-specific activation of the epithelial sodium channel by the CFTR chloride channel.

The genetic disease cystic fibrosis is caused by mutation of the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Controversial studies reported regulation of the epithelial sodium channel (ENaC) by CFTR. We found that uptake of (22)Na(+) through ENaC is modulated by activation of CFTR in oocytes, coexpressing CFTR and ENaC, depending on extracellular chloride concentration. Furthermore we found that the effect of CFTR activation could be mimicked by other chloride channels. Voltage- and patch-clamp measurements, however, showed neither stimulation nor inhibition of ENaC-mediated conductance by activated CFTR. We conclude that the observed modulation of (22)Na(+) uptake by activated CFTR is due to the effect of CFTR-mediated chloride conductance on the membrane potential. These findings argue against the notion of a specific influence of CFTR on ENaC and emphasize the chloride channel function of CFTR.

Animals↗

PubMed2001

Interaction of cations, anions, and weak base quinine with rat renal cation transporter rOCT2 compared with rOCT1.

The rat organic cation transporter (rOCT)-2 was characterized by electrical and tracer flux measurements compared with rOCT1. By applying choline gradients to voltage-clamped Xenopus oocytes expressing rOCT2, potential-dependent currents could be induced in both directions. Tracer flux measurements with seven organic cations revealed similar Michaelis-Menten constant values for both transporters, with the exception of guanidine. In parallel experiments with rOCT2 and rOCT1, inhibition of tetraethylammonium transport by 12 cations, 2 weak bases, corticosterone, and the anions para-amminohippurate, alpha-ketoglutarate, and probenecid was characterized. The IC(50) values of many inhibitors were similar for both transporters, whereas others were significantly different. Mepiperphenidol and O-methylisoprenaline showed an approximately 70-fold lower and corticosterone a 38-fold higher affinity for rOCT2. With the use of these inhibitors together with previous information on cation transporters, experimental protocols are proposed to dissect out the individual contributions of rOCT2 and rOCT1 in intact proximal tubule preparations. Inhibition experiments at different pH levels strongly suggest that the weak base quinine passively permeates the plasma membrane at physiological pH and inhibits rOCT2 from the intracellular side.

Animals↗

PubMed2000

Immunohistochemical detection of estrogen and progesterone receptor in human cornea.

OBJECTIVE: For treatment of postmenopausal keratoconjunctivitis sicca hormone therapy is favored by some clinicians. The likely morphological basis assessing the hormone receptor status in the human cornea has not been performed. Immunohistochemical staining methods provide the opportunity to evaluate the hormone receptor content within the histologic compartments of the cornea. The aim of our study was to assess and localize immunohistochemical hormone receptor staining in the human cornea. METHODS: Formalin-fixed and paraffin-embedded specimens of three pre- and three postmenopausal women were assessed for localization of estrogen receptor (ER) and progesterone receptor (PR) expression with established immunohistochemical hormone receptor staining methods. RESULTS: No nuclear staining reaction was found in the epi- and endothelial layers of the corneas. The stroma of the corneas showed no immunohistochemical staining reaction in all cases. We found cytoplasmatic PR staining of the endothelial layer in two cases. CONCLUSIONS: We found no morphological basis in the human cornea for the use of topical steroid hormone treatment in postmenopausal keratoconjunctivitis sicca. Hormone receptor expression in the conjunctiva or in the lacrimal gland may have an impact in some patients showing relief of symptoms in postmenopausal dry eye syndrome.

Administration, Topical↗

PubMed2000

Mechanism of electrogenic cation transport by the cloned organic cation transporter 2 from rat.

The organic cation transporter 2 (OCT2) is expressed in plasma membranes of kidney and brain. Its transport mechanism and substrates are debated. We studied substrate-induced changes of electrical current with the patch clamp technique after expression of rat OCT2 in oocytes. Activation of current, corresponding to efflux, was observed for small organic cations, e.g. choline. In contrast, the bigger cations quinine and tetrabutylammonium elicited no change in current. However, transport of choline could be inhibited by applying quinine or tetrabutylammonium to the cytoplasmic side. Inhibition of organic cation efflux by quinine was competitive with substrates. Quinine at the inside also inhibited substrate influx from the outside. Current-voltage analysis showed that both maximal turnover and apparent affinity to substrates are voltage-dependent. Substrate-induced currents with organic cations on both membrane sides reversed as predicted from the Nernst potential. Our results clearly identify the electrochemical potential as driving force for transport at neutral pH and exclude an electroneutral H(+)/organic cation(+) exchange. We suggest the existence of an electroneutral organic cation(+) exchange and propose a model for a carrier-type transport mechanism.

Animals↗

PubMed2000

Heterogeneity of 11beta-hydroxysteroid dehydrogenase type 1/microsomal carbonyl reductase (11beta-HSD/CR) in guinea pig tissues. Purification of the liver form suggests modification in the cosubstrate binding site.

11beta-hydroxysteroid dehydrogenase (11beta-HSD) and xenobiotic carbonyl reductase activities were determined in guinea pig tissue microsomes. The data indicate the presence of a NADP(H) dependent form, distinct from the known type I isozyme. Purification of 11beta-HSD-1 from liver microsomes resulted in two distinct peaks, resolved by dye-ligand chromatography, indicating differences in the cosubstrate binding site. Immunoblot analysis using anti 11beta-HSD-1 antibodies reveals the presence of similar structural determinants between the enzyme forms. Both have an apparent molecular mass of 32 kDa, suggesting protein modifications occurring in the type 1 isozyme which account for the differences in chromatographic behaviour.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2000

Voltage and substrate dependence of the inverse transport mode of the rabbit Na(+)/glucose cotransporter (SGLT1).

Properties of the cytoplasmic binding sites of the rabbit Na(+)/glucose cotransporter, SGLT1, expressed in Xenopus oocytes were investigated using the giant excised patch clamp technique. Voltage and substrate dependence of the outward cotransport were studied using alpha-methyl D-glucopyranoside (alphaMDG) as a substrate. The apparent affinity for alphaMDG depends on the cytoplasmic Na(+) concentration and voltage. At 0 mV the K(M) for alphaMDG is 7 mM at 110 mM Na(+) and 31 mM at 10 mM Na(+). The apparent affinity for alphaMDG and Na(+) is voltage dependent and increases at positive potentials. At 0 mV holding potential the outward current is half-maximal at about 70 mM. The results show that SGLT1 can mediate sugar transport out of the cell under appropriate concentration and voltage conditions, but under physiological conditions this transport is highly improbable due to the low affinity for sugar.

Animals↗

PubMed2000

[Salutogenesis].

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Attitude to Health↗

PubMed1999

Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator.

The genetic disease cystic fibrosis is caused by defects in the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR). CFTR belongs to the family of ABC transporters. In contrast to most other members of this family which transport substrates actively across a membrane, the main function of CFTR is to regulate passive flux of substrates across the plasma membrane. Chloride channel activity of CFTR is dependent on protein phosphorylation and presence of nucleoside triphosphates. From electrophysiological studies of CFTR detailed models of its regulation by phosphorylation and nucleotide interaction have evolved. These investigations provide ample evidence that ATP hydrolysis is crucial for CFTR gating. It becomes apparent that the two nucleotide binding domains on CFTR not only diverge strongly in sequence, but also in function. Based on previous models and taking into account new data from pre-steady-state experiments, a refined model for the action of nucleotides at two nucleotide binding domains was recently proposed.

ATP-Binding Cassette Transporters↗

PubMed1999

Interindividual variability in the expression and NNK carbonyl reductase activity of 11beta-hydroxysteroid dehydrogenase 1 in human lung.

The balance between metabolic activation and detoxification is critical in determining the susceptibility to lung cancer upon exposure to the tobacco specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Carbonyl reduction of NNK, followed by glucuronidation, is the main detoxification pathway of this lung carcinogen in humans. Recently, we have identified 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) as microsomal NNK carbonyl reductase in liver and lung. In the present study, the interindividual variability of 11beta-HSD 1 expression and NNK-carbonyl reductase activity was examined in human lung by RT-PCR, Western blot analysis and enzyme activity. Levels of 11beta-HSD 1 mRNA varied over an almost 20-fold range among different subjects. Levels of NNK carbonyl reductase activity in lung microsomes closely resembled the relative amounts of immunoreactive protein as determined by Western blot analysis. In view of the large interindividual differences in the susceptibility of tobacco smoke related lung cancer, we present the first data on the variability of 11beta-HSD 1 expression and NNK carbonyl reduction in human lung.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed1999

Retrobulbar hemodynamics in amaurosis fugax; investigation by color Doppler velocity.

PURPOSE: The aim of the study is to determine blood flow and resistance parameters (Resistance Index-RI, Pulsatility Index-PI) in the retrobulbar arteries of patients suffering from amaurosis fugax. METHODS: Color Doppler velocity was used to measure blood flow velocity and vascular resistance in the ophthalmic artery, central retinal artery and lateral short posterior ciliary artery of 32 involved eyes in their afflictless interval. The patients' mean age was 60.1 years (range 29-85). The age- and sexmatched control group comprised 32 healthy volunteers (32 eyes). RESULTS: There was no significant difference neither in RI nor in PI of amaurosis fugax patients compared to the control group. CONCLUSIONS: We conclude that in almost all cases of amaurosis fugax no local disturbance of blood flow in the afflictless interval is noted. However, increased vessel resistance is noticed in some cases of amaurosis fugax: Giant cell arteritis, intraorbital vascular anomalies, intraorbital tumors. In these cases color Doppler velocity is able to give information on the extent of blood flow disorder and, in particular by the B-mode, the etiology can be assumed.

Adult↗