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Biomedical subjects

C Albrecht

Publications and source records attributed to C Albrecht.

At least 37 records · Page 2Linked to original sources
PubMed2001

Clara-cell hyperplasia after quartz and coal-dust instillation in rat lung.

Bronchiolo-alveolar hyperplasia of type II cells in rat lungs after particle exposure is a well-known preneoplastic lesion. The Clara cell, stem cell of the bronchiolar epithelium and the main carrier of cytochrome P-450 isoenzyme system in the lung, has barely been evaluated with regard to this effect. The aim of this study was to examine Clara-cell hyperplasia after particle exposure and to characterize cell proliferation and its normal function. Female Wistar rats were intratracheally instilled with coal dust samples of variable quartz content, quartz (DQ12), titanium dioxide, or saline solution containing 0.5% Tween 80. After 126-129 wk, all coal mine dust- and quartz-exposed animals developed Clara-cell hyperplasia: up to 0.48% of the total lung area, which was significantly increased compared to titanium dioxide (p <.05) and control (p <.03) animals. Proliferation and hyperplasia of bronchiolar Clara cells by coal dusts was independent of their quartz content. The lack of proliferating cell nuclear antigen staining in most of the hyperplastic Clara cells suggests that following damage of alveolar epithelial cells, Clara cells migrate in and remodulate the alveolar epithelium. After the migration they keep their function in the xenobiotic metabolism, as shown by expansion of CYP2E1 active Clara cells. The minor development of Clara-cell hyperplasia in titanium dioxide-treated rats indicates that this is not a general particle effect, and is possibly due to its lower toxicity to epithelial cells.

Animals↗
PubMed2001

Expression of putative anticancer targets in familial adenomatous polyposis and its association with the APC mutation status.

Several substances interfering with colorectal carcinogenesis may reduce or prevent adenoma formation in familial adenomatous polyposis (FAP), an inherited predisposition to colorectal cancer. This study determined the expression of genes coding for putative anticancer targets (COX-2, iNOS, MMP-7, ODC, PKCbeta, PPARgamma, RXRalpha, RXRbeta, RXRgamma) in FAP patients to provide one of the rationales for the design of chemotherapy and -prevention strategies. Gene expression was assessed by TaqMan analysis in colonic tissue of 9 FAP patients with mutations in the APC gene (APCpos), 5 FAP patients without identified genetic defect (APCneg), and 3 healthy individuals. Among the examined genes, PKCbeta and MMP-7 were most consistently altered in adenoma tissue relative to matched mucosa. Intriguingly, ODC was clearly overexpressed in polyps from APCpos but not APCneg patients. Furthermore, PKCbeta, MMP-7, ODC, and COX-2 as well as all RXRs displayed altered expression in apparently healthy FAP mucosa as opposed to that of healthy individuals. Our data suggests PKCbeta and MMP-7 to be the most suited as anticancer targets among the genes studied.

Adenomatous Polyposis Coli↗
PubMed2000

Muscarinic acetylcholine receptors induce the expression of the immediate early growth regulatory gene CYR61.

In brain, muscarinic acetylcholine receptors (mAChRs) modulate neuronal functions including long term potentiation and synaptic plasticity in neuronal circuits that are involved in learning and memory formation. To identify mAChR-inducible genes, we used a differential display approach and found that mAChRs rapidly induced transcription of the immediate early gene CYR61 in HEK 293 cells with a maximum expression after 1 h of receptor stimulation. CYR61 is a member of the emerging CCN gene family that includes CYR61/CEF10, CTGF/FISP-12, and NOV; these encode secretory growth regulatory proteins with distinct functions in cell proliferation, migration, adhesion, and survival. We found that CYR61, CTGF, and NOV were expressed throughout the human central nervous system. Stimulation of mAChRs induced CYR61 expression in primary neurons and rat brain where CYR61 mRNA was detected in cortical layers V and VI and in thalamic nuclei. In contrast, CTGF and NOV expression was not altered by mAChRs neither in neuronal tissue culture nor rat brain. Receptor subtype analyses demonstrated that m1 and m3 mAChR subtypes strongly induced CYR61 expression, whereas m2 and m4 mAChRs had only subtle effects. Increased CYR61 expression was coupled to mAChRs by both protein kinase C and elevations of intracellular Ca(2+). Our results establish that CYR61 expression in mammalian brain is under the control of cholinergic neurotransmission; it may thus be involved in cholinergic regulation of synaptic plasticity.

Animals↗
PubMed1999

Identification of genes regulated by muscarinic acetylcholine receptors: application of an improved and statistically comprehensive mRNA differential display technique.

In order to identify genes that are regulated by muscarinic acetylcholine receptors, we developed an mRNA differential display technique (DD) approach. By increasing redundancy and by evaluating optimised reagents and conditions for reverse transcription of total RNA, PCR and separation of PCR products, we generated a DD protocol that yields highly consistent results. A set of 64 distinct random primers was specifically designed in order to approach a statistically comprehensive analysis of all mRNA species in a defined cell population. This modified DD protocol was applied to total RNA of HEK293 cells stably expressing muscarinic m1 acetylcholine receptors and cells stimulated with the receptor agonist carbachol were compared to identical but non-stimulated cells. In 81 of 192 possible PCR experiments, 38 differential bands were identified. Sequence analysis followed by northern blot analyses confirmed differentially expressed genes in 19 of 23 bands analysed. These represented 10 distinct immediate-early genes that were up-regulated by m1AChR activation: Egr-1, Egr-2, Egr-3, NGFi-B, ETR101, c- jun, jun -D, Gos-3 and hcyr61, as well as the unknown gene Gig-2. These data show that this improved DD protocol can be readily applied to reliably identify differentially expressed genes.

Base Sequence↗
PubMed1999

Evaluation of autoreceptor-mediated control of [(3)H]acetylcholine release in rat and human neocortex.

In order to assess the autoinhibitory control of endogenous acetylcholine (ACh) in rat and human neocortex, slices of these tissues were prelabelled with [(3)H]choline, superfused continuously and stimulated electrically using various frequencies in the presence or absence of drugs. The autoinhibitory feedback control of [(3)H]ACh release was operative - despite the absence of blockers of ACh esterase - at stimulation frequencies >/= 3 Hz in rat and >/= 6 Hz in human neocortex tissue. At these frequencies the muscarinic antagonist atropine (0.1 microM) disinhibited the release of [(3)H]ACh in both species. Estimation of the biophase concentration of ACh near the autoreceptor in the rat neocortex from concentration-response curves of the muscarinic agonist oxotremorine revealed that at 3 Hz about 25% of the autoreceptors were activated by endogenously released ACh. This estimation is consistent with an increase in [(3)H]ACh release to about 120% of control values by complete blockade of autoreceptors with atropine. The observation that in human neocortical tissue presynaptic autoinhibition of [(3)H]ACh release is operative at stimulation frequencies >/= 6 Hz suggests that selective blockade of autoinhibition may also increase ACh release in the cortex of Alzheimer's disease patients, without additional blockade of the enzyme acetylcholinesterase.

Acetylcholine↗
PubMed1999

Atosiban, an oxytocin receptor blocking agent: pharmacokinetics and inhibition of milk ejection in dairy cows.

Plasma concentrations of the oxytocin receptor blocking agent Atosiban were measured at 2, 4, 10, 15 and 20 min after injection of 5, 10, 20 and 50 micrograms Atosiban/kg body weight in six dairy cows. The half life of Atosiban was 18 min and the total body clearance was 3301 ml/min. Intramammary pressure (IMP) within the teat cistern was measured in six cows before and after i.v. injection of 0 or 20 micrograms Atosiban/kg body weight and repeated injections of 0.2 or 0.5 i.u. oxytocin. IMP was also measured in eleven cows after injection of 0, 10 or 50 micrograms Atosiban/kg body weight: in seven during oxytocin infusions, in four after oxytocin injections in successively increasing dosages (0.05, 0.1, 0.2, 0.5, 1 and 10 i.u.). The occurrence of milk ejection was indicated by a rise in IMP. After injection of 20 micrograms Atosiban/kg body weight, 0.2 i.u. oxytocin did not induce an IMP rise before 48 min, whereas 0.5 i.u. oxytocin induced an IMP rise within 4 min. The time from the start of infusion until the beginning of the IMP rise and the duration of IMP rise during oxytocin infusions both increased, whereas the IMP rise itself was diminished by increasing Atosiban dosages. The amount of injected oxytocin necessary to induce an IMP response increased with increasing Atosiban dosages. Atosiban was shown to have a powerful effect in inhibiting milk ejection in dairy cows.

Animals↗
PubMed1999

Long-term effects on sexual function and fertility after treatment of testicular cancer.

This retrospective study evaluates the types and incidences of sexual disturbances and fertility distress in patients cured from testicular cancer and examines whether there is an effect resulting from different treatment modalities. A self-reported questionnaire was sent to 124 randomly selected patients who were treated at Hanover University Medical School between 1970 and 1993. Ninety-eight patients were included in the study, representing a response rate of 78%. All patients had been in complete remission (CR) for at least 24 months. The median age at diagnosis was 28 years (range 17-44). The median follow-up at the time of study was 12.0 years (range 2.8-25.6). Twenty patients (20%) had been treated for seminomatous and 78 patients (80%) for non-seminomatous germ cell tumours. Treatment included surveillance (7%), primary retroperitoneal lymph node dissection (RPLND) (13%), chemotherapy (CT) (33%), CT + secondary resection of residual retroperitoneal tumour mass (SRRTM) (43%) and infradiaphragmatic radiotherapy (4%). Patients receiving two treatment modalities (CT+SRRTM) reported more frequent an unfulfilled wish for children. Inability of ejaculation was clearly associated with RPLND and SRRTM. Subjective aspects of sexuality, like loss of sexual drive and reduced erectile potential, occurred only in a minority of patients after treatment. No abnormalities were observed concerning the course of pregnancies of partners. In conclusion, sexual dysfunction and infertility are common long-lasting sequelae in testicular cancer survivors affecting approximately 20% of patients. The relative risk for infertility appeared to be elevated for patients treated with the combination of CT+SRRTM. Twenty-one of 40 patients were able to fulfil their wish for children, and no congenital abnormalities were observed in these children.

Adolescent↗
PubMed1999

Time-course analysis of type II cell hyperplasia and alveolar bronchiolization in rats treated with different particulates.

In this study, we compared the morphological reaction patterns in rat lungs following a single intratracheal instillation of 20 mg quartz, 20 mg coal mine dust (15.3% quartz), or 25 mg talc. Control animals received a single dose of 0.5 ml saline solution intratracheally. Investigations by light microscopy, morphometry, and DNA image cytometry were carried out 3, 6, 12, and 18 mo after dust administration. During the investigation period, we observed a temporary increase in the number, area, and proliferative activity of the type II cells, which differed in intensity among the three dusts. After 18 mo, however, type II cells in treated animals did not differ from control animals. On the other hand, the expansion of a multifocal alveolar bronchiolization as putative preneoplastic lesion had progressed enormously by the end of the test (1-3% of the investigated lung area). Consistent with this, the proliferative activity of the epithelial cells in terminal bronchi of the coal mine dust- and quartz-treated animals was enhanced by the end of the 18-mo investigation period, while the reaction to talc was minimal (0.2% of totally investigated lung area). Our data suggest that in bronchiolo-alveolar regions, especially in the epithelium of terminal bronchi, there is an overshoot regeneration after cell damage that leads to an alveolar bronchiolization.

Air Pollutants↗
PubMed1998

Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors.

In order to search for genes that are activated by muscarinic acetylcholine receptors (mAChRs), we used an mRNA differential display approach in HEK293 cells expressing m1AChR. The zinc-finger transcription factor genes Egr-1, Egr-2, and Egr-3 were identified. Northern blot analyses confirmed that mRNA levels of Egr-1, Egr-2, and Egr-3 increased readily after m1AChR stimulation and that a maximum was attained within 50 min. At that time, Egr-4 mRNA was also detectable. Western blots and electromobility shift assays demonstrated synthesis of EGR-1 and EGR-3, as well as binding to DNA recognition sites in response to m1AChR activation. Activation of m1AChR increased transcription from EGR-dependent promoters, including the acetylcholinesterase gene promoter. Activity-dependent regulation of Egr-1 mRNA expression and EGR-1 protein synthesis was also observed in cells expressing m2, m3, or m4AChR subtypes. Increased EGR-1 synthesis was mimicked by phorbol myristate acetate, but not by forskolin, and receptor-stimulated EGR-1 synthesis was partially inhibited by phorbol myristate acetate down-regulation. Together, our results demonstrate that muscarinic receptor signaling activates the EGR transcription factor family and that PKC may be involved in intracellular signaling. The data suggest that transcription of EGR-dependent target genes, including the AChE gene, can be under the control of extracellular and intracellular signals coupled to muscarinic receptors.

Cell Line↗
PubMed1998

Determination of naproxen in liver and kidney tissues by electrokinetic capillary chromatography with laser-induced fluorescence detection.

Pharmacotherapy through the targeting of drugs is a promising new approach that requires adequate analytical methods capable of monitoring the free drug, the drug carrier and metabolites in body fluids and organs. A micellar electrokinetic capillary chromatography (MECC) based assay for analysis of naproxen (NAP) in extracts of hydrolyzed liver and kidney tissue homogenates using salicylate as internal standard and solute detection by laser-induced fluorescence is reported. The assay described uses 100 microliters of hydrolyzed tissue homogenate and has a detection limit of 0.07 microgram/ml. It is shown to be selective, reproducible (at a NAP level of 0.25 microgram/ml, intra-day and inter-day R.S.D. values are 3.73% and 6.39%, respectively), simple and economical (operates with inexpensive separation columns and small amounts of chemicals). It has been successfully applied to the assessment of the total NAP content within liver and kidney tissues of male Sprague Dawley rats that have been treated with NAP conjugated to human serum albumin (the drug targeting carrier) and free NAP. Compared to previously applied techniques, including high-performance liquid chromatography, MECC offers the advantage of having lower running costs and lower consumption of organic solvents.

Animals↗
PubMed1998

Flavonoids and arbuscular-mycorrhizal fungi.

Arbuscular mycorrhizal fungi (AMF) are ancient Zygomycetes forming the most widespread plant-fungus symbiosis. The regulation of this association is still poorly understood in terms of the communication between the two partners. Compounds inside the root and released by the root, such as flavonoids, are hypothesized to play a role in this plant-fungus communication, as already demonstrated in other symbiotic associations (e.g. Rhizobium-leguminoseae). Here we give a general overview of the research concerning this question.

Cell Communication↗
PubMed1998

[3-Dimensional irradiation planning in brain tumors. The advantages of the method and the clinical results].

PURPOSE: Radiotherapy became an important component in the treatment of brain gliomas. The aim of this study is to analyse several advantages of the three-dimensional conformal radiation therapy in comparison with a two-dimensional conventional technique and to present the clinical results of 43 patients with brain gliomas treated according to a three-dimensional planning. PATIENTS AND METHOD: Between January 1994 and December 1995, 43 patients with malignant brain gliomas (WHO III and IV) were treated in our department according to a three-dimensional treatment planning. The patients received a total irradiation dose of 60 Gy, 2 Gy/day, 5 days/week. The rate of survival was analysed in relation with the known prognostical factors: histology, Karnofsky index, age, resection status. In 10 patients a three-dimensional treatment planning was compared with a conventional two-dimensional planning: the volume of the normal brain tissue irradiated to high dose levels (95% isodose) and the normal tissue complication probability (NTCP) for the brain by Kutcher and Lyman were comparatively analysed. RESULTS: The survival rate for the whole group was 14 months. The histology of the tumor, age, Karnofsky index and resection status were important prognostical factors. The three-dimensional planning allows a 15 to 20% reduction in the volume of normal brain tissue irradiated to high dose levels (95% isodose). The NTCP is significantly lower using the three-dimensional technique (range 0.03% to 13%), in comparison with the two-dimensional conventional technique (range 0.1% to 26%). The value of NTCP increases with tumor volume. CONCLUSIONS: Concerning the tumor control and survival rate, the three-dimensional treatment planning shows no advantages compared to the standard conventional methods. The main advantage of the three-dimensional treatment planning is the possibility to spare normal brain tissue. The possibility to integrate mathematical models in the evaluation of the therapy could give this technique new dimensions.

Adolescent↗
PubMed1998

Inhibition of interleukin-4 and interleukin-13 release from immunologically activated human basophils due to the actions of anti-allergic drugs.

Human basophils have recently been shown to rapidly produce and release interleukin (IL-)4 and IL-13 as well as histamine and eicosanoids. Since both IL-4 and IL-13 can initiate and maintain late phase allergic reactions we addressed whether some widely used anti-allergic drugs can inhibit the anti-IgE induced release of these cytokines from enriched human basophils. Basophils were enriched (47-92% purity) by Ficoll density centrifugation followed by elutriation and negative selection of contaminating cells using immunomagnetic beads. Basophils were stimulated with sub-optimal dilutions of anti-IgE in the presence or absence of various drugs and the release of histamine and cytokines were measured after 30 min and 4 h, respectively. The beta-2 agonist salmeterol, the H1-receptor antagonist terfenadine and the phosphodiesterase inhibitor theophylline inhibited the release of IL-4 and IL-13 by more than 50% following 4 h of basophil stimulation with anti-IgE. These drugs also inhibited the release of histamine following 30 min stimulation, although with less efficacy than for IL-4 and IL-13. Short preincubation of basophils with salmeterol or terfenadine before stimulation gave rise to significantly greater inhibition of histamine release but had less effect on the inhibition of cytokine release. The effects of theophylline, however, were not significantly affected by preincubation of the cells with the drug. In contrast to the aforementioned drugs, salbutamol and cetirizine were ineffective at inhibiting both histamine and cytokine release from basophils. These results suggest that a number of anti-allergic drugs may mediate their effects, in part, in reducing late phase allergic responses due to their actions on IL-4 and IL-13 secretion from basophils.

Adrenergic beta-Agonists↗
PubMed1998

Successful radiofrequency current catheter ablation of accessory atrioventricular pathway after tricuspid replacement in Ebstein's anomaly.

A 15-year-old female with Ebstein's anomaly was referred to hospital for radiofrequency (RF) current catheter ablation of her refractory paroxysmal supraventricular tachycardia (PSVT) after tricuspid valve replacement. A surface ECG showed ventricular preexcitation of type B Wolff-Parkinson-White (WPW) syndrome. In a baseline electrophysiological study, two types of PSVT with left and right bundle branch block (LBBB and RBBB) configurations were induced. The LBBB type was antidromic and the RBBB type was orthodromic atrioventricular reciprocating tachycardia (AVRT) with a right posterolateral accessory pathway. RF current was successfully delivered at the posterolateral site above the prosthetic valve (V-delta interval = -30 msec). The patient has been free from arrhythmias during a follow-up period of 9 months. RF current ablation seems to be useful for AVRT patients with corrected Ebstein's anomaly.

Adolescent↗
PubMed1998

Targeting of naproxen covalently linked to HSA to sinusoidal cell types of the liver.

The kinetic behaviour of a naproxen human serum albumin conjugate (Nap23-HSA) was investigated in rats and in isolated perfused rat livers (IPRL), as compared to its active metabolite naproxen-lysine (Nap-lysine) and free naproxen. Through covalently linking the anti-inflammatory drug naproxen to HSA, this drug can be selectively delivered to non parenchymal cells of the liver. Liver endothelial and Kupffer cells play an important role in the pathogenesis of inflammatory liver diseases. Targeting naproxen to these cells might increase its efficacy and reduce the side effects. The altered kinetic properties of Nap23-HSA, after i.v. injection of 22 mg x kg(-1), as compared to an equimolar amount of the uncoupled drug, were demonstrated in vivo by a decrease in the steady state volume of distribution (41 +/- 5 vs. 134 +/- 19 ml x kg(-1)), a decrease in its clearance (0.48 +/- 0.05 vs. 0.63 +/- 0.1 ml x min(-1) x kg(-1)), a shorter plasma half life (60 +/- 11 vs. 152 +/- 44 min) and a sustained biliary excretion. Liver targeting of Nap23-HSA was clearly demonstrated: drug content of the liver 180 min after injection was about 30 times higher for Nap23-HSA as compared to naproxen itself. The IPRL experiments showed that the Vmax of hepatic removal of the conjugate was 40 microg x min(-1) x g liver(-1). With doses below receptor saturation a rapid removal of the conjugate (t1/2 = 6 min) from the perfusion medium was found. In conclusion, this study demonstrates the saturable uptake of Nap23-HSA and its lysosomal degradation in both in vivo and IPRL experiments. Covalently linked naproxen is released as Nap-lysine. This active metabolite accumulates in Kupffer and endothelial cells in which it reaches therapeutic concentrations. Release from these cells leads to rapid uptake by hepatocytes and carrier mediated excretion into bile. Levels of Nap-lysine in bile and plasma reflect the slowest step in its generation: the proteolytic release in endothelial and Kupffer cells.

Animals↗
PubMed1998

Effect of chronic bile duct obstruction and LPS upon targeting of naproxen to the liver using naproxen-albumin conjugate.

Naproxen covalently linked to human serum albumin (NAP-HSA) is efficiently targeted to endothelial and Kupffer cells of the liver and may offer a new therapeutic approach in the treatment of liver disease associated with inflammatory processes. In the present investigation we explored the pharmacokinetic behaviour of targeted and non-targeted naproxen as well as the pharmacokinetic properties of the active metabolite, Naproxen lysine (Nap lysine), in rats rendered fibrotic by bile duct ligation (BDL) for 4 weeks. Furthermore, we studied the effect of endotoxemia, experimentally induced by intravenous injection of 800 microg/kg lipopolysaccaride (LPS) upon the pharmacokinetics of these agents in order to investigate the feasibility of targeting naproxen to non-parenchymal cells in the inflamed and fibrotic liver. Our studies demonstrate that liver disease altered the pharmacokinetic behaviour of the different naproxen compounds. Thus, initial plasma concentrations of NAP HSA and naproxen were markedly lower in BDL rats accompanied by an increase of the volume of distribution during the terminal elimination phase (Vd(beta) BDL vs control 114 +/- 63 vs 50 +/- 7 and 202 +/- 24 vs 115 +/- 11 ml/kg for naproxen and NAP-HSA, respectively). After injection of LPS, no significant change in the pharmacokinetics of NAP-HSA was found whereas the naproxen treated control animals showed an increase in the terminal volume of distribution (176 +/- 34 vs 115 +/- 11 ml/kg) as well as an elevation of the plasma half-life (171 +/- 27 vs 116 +/- 14 min). The feasibility of targeting naproxen to the chronically diseased liver could be clearly demonstrated: 15 min after administration of the conjugate 46% and 55% of the administered dose was found in the liver of CTR and BDL rats, whereas after injection of free naproxen only 5% and 12% of the dose was detected in liver tissue, respectively. We conclude that targeting albumin-linked naproxen to non-parenchymal cells in the liver is still feasible under the pathological conditions induced in the present study. Liver fibrosis induced significant alterations in the pharmacokinetic behaviour of the studied compounds.

Animals↗