Showing papers by "Martin Luther University of Halle-Wittenberg published in 2000"

A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme.

Abstract: Previous uncontrolled clinical trials have shown the in vivo retrovirus (RV)-mediated transduction of glioblastoma cells with the herpes simplex virus thymidine kinase (HSV-tk) gene and subsequent systemic treatment with ganciclovir to be feasible and well tolerated. However, because of continued tumor progression in most patients, the antitumor effect could not be determined using historical controls. Here, we describe a phase III, multicenter, randomized, open-label, parallel-group, controlled trial of the technique in the treatment of 248 patients with newly diagnosed, previously untreated glioblastoma multiforme (GBM). Patients received, in equal numbers, either standard therapy (surgical resection and radiotherapy) or standard therapy plus adjuvant gene therapy during surgery. Progression-free median survival in the gene therapy group was 180 days compared with 183 days in control subjects. Median survival was 365 versus 354 days, and 12-month survival rates were 50 versus 55% in the gene therapy and control groups, respectively. These differences were not significant. Therefore, the adjuvant treatment improved neither time to tumor progression nor overall survival time, although the feasibility and good biosafety profile of this gene therapy strategy were further supported. The failure of this specific protocol may be due mainly to the presumably poor rate of delivery of the HSV-tk gene to tumor cells. In addition, the current mode of manual injection of vector-producing cells with a nonmigratory fibroblast phenotype limits the distribution of these cells and the released replication-deficient RV vectors to the immediate vicinity of the needle track. Further evaluation of the RV-mediated gene therapy strategy must incorporate refinements such as improved delivery of vectors and transgenes to the tumor cells, noninvasive in vivo assessment of transduction rates, and improved delivery of the prodrug across the blood-brain and blood-tumor barrier to the transduced tumor cells.

Multivariate analysis of risk factors for postoperative complications in benign goiter surgery: prospective multicenter study in Germany.

Abstract: Risk factors for postoperative complications of benign goiter surgery have not been investigated systematically. To this end, a prospective multicenter study (January 1 through December 31, 1998) was conducted involving 7266 patients with surgery for benign goiter from 45 East German hospitals. High-volume providers (>150 operations per year) performed 69% (5042/7266), intermediate-volume providers 27% (50–150), and low-volume providers 4% (258/7266) of operations. Among the hospital groups, the pattern of thyroid disease did not vary significantly, but there was a trend that small-volume providers tended to perform more operations for uninodular goiter and high-volume providers treated more patients with Graves' disease and recurrent goiter. Extent of resection (p < 0.0001) and remnant size (multinodular goiter and recurrent goiter, p < 0.001), differed significantly, with total thyroidectomy being performed more often in hospitals with more than 150 operations compared to hospitals with an operative volume of less than 150 procedures per year. Despite the larger extent of resection and smaller remnant size, rates of recurrent laryngeal nerve (RLN) palsy or hypoparathyroidism were not increased. When the logistic regression analyses were fitted to evaluate the impact of risk factors on transient and permanent RLN palsy and hypoparathyroidism, larger extent of resection [relative risk (RR) 1.5–2.1] and recurrent goiter (RR 1.8–3.4) consistently evolved as independent risk factors. With hypoparathyroidism, additional significant factors included patient gender (RR 2.1–2.4), hospital operative volume (RR 0.8–1.5), and Graves' disease (RR 2.8). Unlike parathyroid gland identification during hypoparathyroidism, RLN identification (RR 1.6) significantly (p= 0.01) reduced permanent RLN palsy rates. The multivariate analyses clearly confirmed the pivotal role of routine RLN identification, independent of the extent of the thyroid resection. These findings might help hospitals with lower operative volumes to identify patients at increased risk whom they might consider for specialist care.

Differential Nuclear and Cytoplasmic Expression of PTEN in Normal Thyroid Tissue, and Benign and Malignant Epithelial Thyroid Tumors

Abstract: Germline mutations in PTEN (MMAC1/TEP1) are found in patients with Cowden syndrome, a familial cancer syndrome which is characterized by a high risk of breast and thyroid neoplasia. Although somatic intragenic PTEN mutations have rarely been found in benign and malignant sporadic thyroid tumors, loss of heterozygosity (LOH) has been reported in up to one fourth of follicular thyroid adenomas (FAs) and carcinomas. In this study, we examined PTEN expression in 139 sporadic nonmedullary thyroid tumors (55 FA, 27 follicular thyroid carcinomas, 35 papillary thyroid carcinomas, and 22 undifferentiated thyroid carcinomas) using immunohistochemistry and correlated this to the results of LOH studies. Normal follicular thyroid cells showed a strong to moderate nuclear or nuclear membrane signal although the cytoplasmic staining was less strong. In FAs the neoplastic nuclei had less intense PTEN staining, although the cytoplasmic PTEN-staining intensity did not differ significantly from that observed in normal follicular cells. In thyroid carcinomas as a group, nuclear PTEN immunostaining was mostly weak in comparison with normal thyroid follicular cells and FAs. The cytoplasmic staining was more intense than the nuclear staining in 35 to 49% of carcinomas, depending on the histological type. Among 81 informative tumors assessed for LOH, there seemed to be an associative trend between decreased nuclear and cytoplasmic staining and 10q23 LOH (P = 0.003, P = 0.008, respectively). These data support a role for PTEN in the pathogenesis of follicular thyroid tumors.

Biological activities of lipopolysaccharides are determined by the shape of their lipid A portion

Abstract: Lipopolysaccharide (LPS) represents a major virulence factor of Gram-negative bacteria ('endotoxin') that can cause septic shock in mammals including man. The lipid anchor of LPS to the outer membrane, lipid A, has a peculiar chemical structure, harbours the 'endotoxic principle' of LPS and is responsible for the expression of pathophysiological effects. Chemically modified lipid A can be endotoxically inactive, but may express strong antagonistic activity against LPS, a property that can be utilized in antisepsis treatment. We show here that these different biological activities are directly correlated with the molecular shape of lipid A. Only (hexaacyl) lipid A with a conical/concave shape, the cross-section of the hydrophobic region being larger than that of the hydrophilic region, exhibited strong interleukin-6 (IL-6)-inducing capacity. Most strikingly, a correlation between a cylindrical molecular shape of lipid A and antagonistic activity was established: IL-6 induction by enterobacterial LPS was inhibited by cylindrically shaped lipid A except for compounds with reduced headgroup charge. The antagonistic action is interpreted by assuming that lipid A molecules intercalate into the cytoplasmic membrane of mononuclear cells, and subsequently blocking of the putative signaling protein by the lipid A with cylindrical shape.

Towards industrial ecology: sustainable development as a concept of ecological modernization

Abstract: This paper deals with the key role of ecological modernization in bringing about sustainable development. So far, two strategies of sustainable development have been discussed: sufficiency and effi...

Neonatal end-of-life decision making: Physicians' attitudes and relationship with self-reported practices in 10 European countries.

Abstract: ContextThe ethical issues surrounding end-of-life decision making for infants with adverse prognoses are controversial. Little empirical evidence is available on the attitudes and values that underlie such decisions in different countries and cultures.ObjectiveTo explore the variability of neonatal physicians' attitudes among 10 European countries and the relationship between such attitudes and self-reported practice of end-of-life decisions.Design and SettingSurvey conducted during 1996-1997 in 10 European countries (France, Germany, Italy, the Netherlands, Spain, Sweden, the United Kingdom, Estonia, Hungary, and Lithuania).ParticipantsA total of 1391 physicians (response rate, 89%) regularly employed in 142 neonatal intensive care units (NICUs).Main Outcome MeasuresScores on an attitude scale, which measured views regarding absolute value of life (score of 0) vs value of quality of life (score of 10); self-report of having ever set limits to intensive neonatal interventions in cases of poor neurological prognosis.ResultsPhysicians more likely to agree with statements consistent with preserving life at any cost were from Hungary (mean attitude scores, 5.2 [95% confidence interval {CI}, 4.9-5.5]), Estonia (4.9 [95% CI, 4.3-5.5]), Lithuania (5.5 [95% CI, 4.8-6.1]), and Italy (5.7 [95% CI, 5.3-6.0]), while physicians more likely to agree with the idea that quality of life must be taken into account were from the United Kingdom (attitude scores, 7.4 [95% CI, 7.1-7.7]), the Netherlands (7.3 [95% CI, 7.1-7.5]), and Sweden (6.8 [95% CI, 6.4-7.3]). Other factors associated with having a pro–quality-of-life view were being female, having had no children, being Protestant or having no religious background, considering religion as not important, and working in an NICU with a high number of very low-birth-weight newborns. Physicians with scores reflecting a more quality-of-life view were more likely to report that in their practice, they had set limits to intensive interventions in cases of poor neurological prognosis, with an adjusted odds ratio of 1.5 (95% CI, 1.3-1.7) per unit change in attitude score.ConclusionsIn our study, physicians' likelihood of reporting setting limits to intensive neonatal interventions in cases of poor neurological prognosis is related to their attitudes. After adjusting for potential confounders, country remained the most important predictor of physicians' attitudes and practices.

Screening for high‐grade cervical intra‐epithelial neoplasia and cancer by testing for high‐risk HPV, routine cytology or colposcopy

Abstract: The validity of testing for high-risk types of human papillomavirus (HPV) in cervical cancer prevention programs is undetermined We compared the performance on primary screening of HPV DNA testing, cytology and colposcopy in detecting cervical intra-epithelial neoplasia (CIN) grade 2 or 3 or cancer A cohort of 4,761 women, median age 35 years, was screened by routine cytology, routine colposcopy and testing for high-risk HPV by a PCR-based method Within an 8-month period, women with abnormal findings on cytology or screening colposcopy or in whom high-risk HPV types were detected were referred for colposcopy and biopsy Women negative on all initial screening tests were followed by a second screening examination To correct for work-up bias, the true prevalence of CIN 2 or 3 or cancer was estimated by projection from histologically verified subgroups Cervical biopsies were taken in 364 women (76%), of whom 114 (24%) showed CIN 2 (n = 34) or CIN 3 (n = 71) or cancer (n = 9) High-risk HPV testing achieved bias-corrected performance measures of 894% sensitivity, 939% specificity, 358% positive predictive value and 996% negative predictive value Bias-corrected rates of true- and false-positives by high-risk HPV testing compared to cytology (colposcopy) were about 45 (67) and 191 (74) times higher, respectively The quality of routine cytology was controlled by computer-assisted review, and the observed number of true-positives more than doubled after adding automated review results In middle-aged women, testing for high-risk HPV types, particularly when negative, may be used to increase the screening interval in programs for secondary prevention of cervical cancer

Observation of hot-electron pressure in the vibration dynamics of metal nanoparticles

Abstract: We investigate the vibration dynamics of ellipsoidal silver nanoparticles, using time-resolved optical pump-probe spectroscopy When excited with femtosecond laser pulses, the particles execute anisotropic shape oscillations We show that these vibrations are triggered by the thermal expansion of the optically heated particles The time dependence of the vibrations indicates that this expansion is caused by two mechanisms: The lattice anharmonicity and the extremely large pressure of the hot conduction electrons

Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas.

Abstract: Purpose: To investigate the relationship between tumor oxygenation and the blood hemoglobin (Hb) concentration in patients with squamous cell carcinoma of the head and neck (SCCHN). Methods and Materials: A total of 133 patients with SCCHN underwent pretreatment polarographic pO 2 measurements of their tumors. In 66 patients measurements were also made in sternocleidomastoid muscles. The patients were divided into three groups according to their Hb concentration—severe anemia (Hb Results: No significant difference in tumor oxygenation could be detected between mildly anemic patients and patients with a normal Hb level. However, the tumor oxygenation in the severely anemic group was significantly below that of each of the other two groups ( p 2 . Conclusion: Our data suggest that a low Hb concentration and cigarette smoking contribute to inadequate oxygenation of SCCHN and thus for increased radioresistance. Consequently, Hb correction and abstinence from smoking may significantly improve tumor oxygenation.

Molecular Design of Nonchiral Bent-Core Liquid Crystals with Antiferroelectric Properties

Abstract: Novel bent-core (banana-shaped) liquid crystals without Schiff-base units have been synthesized and investigated by polarized light optical microscopy, differential scanning calorimetry, X-ray scattering, and electrooptical investigations. These molecules are 4-(4-alkylbenzoyloxy)benzoates and 4-(4-alkoxybenzoyloxy)benzoates of resorcinol, 3,4‘-dihydroxybiphenyl, and 4,4‘ ‘-dihydroxy-1,1‘:3‘,1‘ ‘-terphenyl. Three different mesophases were found depending on the molecular structure and the length of the terminal alkyl chains: a rectangular columnar phase, a highly ordered low-temperature mesophase, and an antiferroelectric switchable fluid smectic mesophase designated as SmCPA. The influence of the molecular structure on the occurrence of the SmCPA phase was investigated. The spontaneous polarization of these molecules is quite high (PS = 500−700 nC cm-2) and specially those molecules with long alkyl chains and short bent-core structures have low melting points and broad regions of this switchable mesopha...

Thermodynamic Characterization of Bile Salt Aggregation as a Function of Temperature and Ionic Strength Using Isothermal Titration Calorimetry

Abstract: The critical micellar concentration (cmc) and the demicellization enthalpy ΔHdemic of the primary aggregates of sodium cholate (NaC) and sodium deoxycholate (NaDC) in water and 0.1 M NaCl at pH 7.5 were determined by isothermal titration calorimetry (ITC). The cmc of NaC and NaDC in water and 0.1 M NaCl at pH 7.5 shows a minimum between 295 and 300 K. With increasing ionic strength, the cmc of the bile salts decreases. ΔHdemic is strongly temperature-dependent but shows almost no dependence on the ionic strength. For comparison with other systems, the thermodynamic parameters ΔGdemic and ΔSdemic associated with the demicellization process were calculated using the pseudo-phase-separation model. From the temperature dependence of ΔHdemic, the change in heat capacity ΔCpdemic for the demicellization process was determined. The data obtained for ΔCpdemic are positive and at 298 K have values of 250 J·mol-1·K-1 for NaC and 350 J·mol-1·K-1 for NaDC. These values correspond to changes in the exposed hydrophobic...

Qualitative and quantitative analysis of water‐soluble root exudates in relation to plant species and development

Abstract: The composition of root-derived substances is of great importance for the understanding of processes in the rhizosphere. Therefore, methods allowing a comprehensive collection and chemical analysis of the organic root exudates are necessary. In this study, we compare different methods with regard to their suitability to collect and characterize root exudates. Because the percolation or water logging method failed to quantitatively extract root exudates, a dipping method was developed which allowed an almost complete sampling of coldwater-soluble root exudates. By 14CO2 labeling of the shoots the composition of root exudates was found to be influenced by plant species and growth stage. In comparison to pea plants maize plants had a higher share of carboxylic acids and a lower share of sugars. Younger maize plants exuded considerably higher amounts of 14C labeled organic substances per g root dry matter than older ones. During plant development the relative amount of sugars decreased at the expense of carboxylic acids. The described methods are well suited for the elucidation of the influence of growth factors on root exudation. Qualitative und quantitative Analyse von Wurzelabscheidungen und ihre Abhangigkeit von Wachstumsfaktoren Die Zusammensetzung der Wurzelabscheidungen spielt fur das Verstandnis der Prozesse in der Rhizosphare eine immer grosere Rolle. Deshalb wurden verschiedene Methoden auf ihre Eignung gepruft. Durch eine Perkolation bzw. durch einen Uberstau des Anzuchtsubstrates war eine quantitative Extraktion der Wurzelabscheidungen nicht moglich. Daher wurde eine Eintauchmethode entwickelt, die die weitgehend vollstandige Erfassung der kaltwasserloslichen Wurzelabscheidungen erlaubt. Um die Abhangigkeit der Wurzelausscheidungen vom Pflanzenalter prufen zu konnen, wurden die Pflanzenprosse im interessierenden Entwicklungsstadium mit 14CO2 begast. Die Zusammensetzung der Wurzelabscheidungen hangt sowohl von der Pflanzenart als auch vom Pflanzenalter ab. Im Vergleich zu Erbsenpflanzen zeichneten sich die kaltwasserloslichen Wurzelabscheidungen bei Maispflanzen durch einen hoheren Carbonsaure- und niedrigeren Zuckeranteil aus. Jungere Maispflanzen gaben wesentlich hohere Mengen an 14C-markierten Wurzelabscheidungen je g Wurzeltrockenmasse ab als altere Pflanzen. Im Laufe der pflanzlichen Ontogenese nahm der Zuckeranteil zugunsten des Carbonsaureanteils relativ ab. Die vorgestellte Methode ist gut geeignet, den Einfluss von Wachstumsfaktoren auf die Abgabe organischer Substanzen uber die Wurzel zu erfassen.

Deviations from the area law for supersymmetric black holes.

Abstract: We review modifications of the Bekenstein-Hawking area law for black hole entropy in the presence of higher-derivative interactions. In four-dimensional N = 2 compactifications of string theory or M-theory these modifications are crucial for finding agreement between the macroscopic entropy obtained from supergravity and the microscopic entropy obtained by counting states in string or M-theory. Our discussion is based on the effective Wilsonian action, which in the context of N = 2 supersymmetric theories is defined in terms of holomorphic quantities. At the end we briefly indicate how to incorporate non-holomorphic corrections.

Age-dependent changes of the circadian system.

Abstract: This review summarizes the current knowledge on changes of the circadian system in advanced age, mainly for rodents. The first part is dedicated to changes of the overt rhythms. Possible causes are discussed, as are methods to treat the disturbances. In aging animals and humans, all rhythm characters change. The most prominent changes are the decrease of the amplitude and the diminished ability to synchronize with a periodic environment. The susceptibility to photic and nonphotic cues is decreased. As a consequence, both internal and external temporal order are disturbed under steady-state conditions and, even more, following changes in the periodic environment. Due to the high complexity of the circadian system, which includes oscillator(s), mechanisms of external synchronization and of internal coupling, the changes may arise for several reasons. Many of the changes seem to occur within the SCN itself. The number of functioning neurons decreases with advancing age and, probably, so does the coupling between them. As a result, the SCN is unable, or at least less able, to produce stable rhythms and to transmit timing information to target sites. Initially, only the ability to synchronize with the periodic environment is diminished, whereas the rhythms themselves continue to be well pronounced. Therefore, the possibility exists to treat age-dependent disturbances. This can be done pharmacologically or by increasing the zeitgeber strength. So, some of the rhythm disturbances can be reversed, increasing the magnitude of the light-dark (LD) zeitgeber. Another possibility is to strengthen feedback effects, for example, by increasing the daily amount of activity. By this means, the stability and synchronization of the circadian activity rhythm of old mice and men were improved.

Cap-dependent deadenylation of mRNA.

Abstract: Poly(A) tail removal is often the initial and rate-limiting step in mRNA decay and is also responsible for translational silencing of maternal mRNAs during oocyte maturation and early development. Here we report that deadenylation in HeLa cell extracts and by a purified mammalian poly(A)-specific exoribonuclease, PARN (previously designated deadenylating nuclease, DAN), is stimulated by the presence of an m7-guanosine cap on substrate RNAs. Known cap-binding proteins, such as eIF4E and the nuclear cap-binding complex, are not detectable in the enzyme preparation, and PARN itself binds to m7GTP–Sepharose and is eluted specifically with the cap analog m7GTP. Xenopus PARN is known to catalyze mRNA deadenylation during oocyte maturation. The enzyme is depleted from oocyte extract with m7GTP–Sepharose, can be photocross-linked to the m7GpppG cap and deadenylates m7GpppG-capped RNAs more efficiently than ApppG-capped RNAs both in vitro and in vivo. These data provide additional evidence that PARN is responsible for deadenylation during oocyte maturation and suggest that interactions between 5′ cap and 3′ poly(A) tail may integrate translational efficiency with mRNA stability.

The Function of Plakophilin 1 in Desmosome Assembly and Actin Filament Organization

Abstract: Plakophilin 1, a member of the armadillo multigene family, is a protein with dual localization in the nucleus and in desmosomes. To elucidate its role in desmosome assembly and regulation, we have analyzed its localization and binding partners in vivo. When overexpressed in HaCaT keratinocytes, plakophilin 1 localized to the nucleus and to desmosomes, and dramatically enhanced the recruitment of desmosomal proteins to the plasma membrane. This effect was mediated by plakophilin 1's head domain, which interacted with desmoglein 1, desmoplakin, and keratins in the yeast two-hybrid system. Overexpression of the armadillo repeat domain induced a striking dominant negative phenotype with the formation of filopodia and long cellular protrusions, where plakophilin 1 colocalized with actin filaments. This phenotype was strictly dependent on a conserved motif in the center of the armadillo repeat domain. Our results demonstrate that plakophilin 1 contains two functionally distinct domains: the head domain, which could play a role in organizing the desmosomal plaque in suprabasal cells, and the armadillo repeat domain, which might be involved in regulating the dynamics of the actin cytoskeleton.

The Origin of Soil Organic C, Dissolved Organic C and Respiration in a Long-Term Maize Experiment in Halle, Germany, Determined by 13C Natural Abundance

Abstract: For a quantitative analysis of SOC dynamics it is necessary to trace the origins of the soil organic compounds and the pathways of their transformations. We used the 13 C isotope to determine the incorporation of maize residues into the soil organic carbon (SOC), to trace the origin of the dissolved organic carbon (DOC), and to quantify the fraction of the maize C in the soil respiration. The maize-derived SOC was quantified in soil samples collected to a depth of 65 cm from two plots, one continuous maize' and the other continuous rye' (reference site) from the long-term field experiment Ewiger Roggen' in Halle. This field trial was established in 1878 and was partly changed to a continuous maize cropping system in 1961. Production rates and δ 13 C of DOC and CO 2 were determined for the Ap horizon in incubation experiments with undisturbed soil columns. After 37 years of continuous maize cropping, 15% of the total SOC in the topsoil originated from maize C. The fraction of the maize-derived C below the ploughed horizon was only 5 to 3%. The total amount of maize C stored in the profile was 9080 kg ha -1 which was equal to about 31% of the estimated total C input via maize residues (roots and stubble). Total leaching of DOC during the incubation period of 16 weeks was 1.1 g m -2 and one third of the DOC derived from maize C. The specific DOC production rate from the maize-derived SOC was 2.5 times higher than that from the older humus formed by C3 plants. The total CO 2 -C emission for 16 weeks was 18 g m -2 . Fifty-eight percent of the soil respiration originated from maize C. The specific CO 2 formation from maize-derived SOC was 8 times higher than that from the older SOC formed by C 3 plants. The ratio of DOC production to CO 2 -C production was three times smaller for the young, maize-derived SOC than for the older humus formed by C 3 plants.

Heavy metal-resistant bacteria as extremophiles: molecular physiology and biotechnological use of Ralstonia sp. CH34.

Abstract: In contrast to thermophilic or psychrophilic organisms, heavy metal-resistant bacteria do not supply enzymes that are active under harsh conditions, but are themselves tools for the evaluation and remediation of heavy metal-contaminated environments. Ralstonia sp. CH34 is a gram-negative bacterium with a remarkable set of resistance determinants, allowing this bacterium to live in extreme environments that are heavily contaminated with toxic metal ions. These heavy metal ions are mostly detoxified by inducible ion efflux systems that reduce the intracellular concentration of a given ion by active export. Because all metal resistance determinants in this bacterium are inducible, their regulatory systems can be used to develop biosensors that measure the biologically important concentrations of heavy metals in an environment. Resistance based on metal ion efflux detoxifies only the cytoplasm of the respective cell. Therefore, this resistance mechanism cannot be used directly to develop biotechnological procedures; however, metal ion efflux can protect a cell in a metal-contaminated environment. Thus, the cell can be enabled to mediate biochemical reactions such as precipitation of heavy metals with the carbon dioxide produced during growth or degradation of xenobiotics.

Regulation of the endothelin system by shear stress in human endothelial cells

Abstract: In this study, the effect of shear stress on the expression of genes of the human endothelin-1 system was examined. Primary cultures of human umbilical vein endothelial cells (HUVEC) were exposed to laminar shear stress of 1, 15 or 30 dyn cm-2 (i.e. 0.1, 1.5 or 3 N m-2) (venous and two different arterial levels of shear stress) in a cone-and-plate viscometer. Laminar shear stress transiently upregulates preproendothelin-1 (ppET-1) mRNA, reaching its maximum after 30 min (approx 1.7-fold increase). In contrast, long-term application of shear stress (24 h) causes downregulation of ppET-1 mRNA in a dose-dependent manner. Arterial levels of shear stress result in downregulation of endothelin-converting enzyme-1 isoform ECE-1a (predominating in HUVEC) to 36.2 +/- 8.5 %, and isoform ECE-1b mRNA to 72.3 +/- 1.9 % of static control level. The endothelin-1 (ET-1) release is downregulated by laminar shear stress in a dose-dependent manner. This downregulation of ppET-1 mRNA and ET-1 release is not affected by inhibition of protein kinase C (PKC), or tyrosine kinase. Inhibition of endothelial NO synthase (L-NAME, 500 microm) prevents downregulation of ppET-1 mRNA by shear stress. In contrast, increasing degrees of long-term shear stress upregulate endothelin receptor type B (ETB) mRNA by a NO- and PKC-, but not tyrosine kinase-dependent mechanism. In conclusion, our data suggest the downregulation of human endothelin synthesis, and an upregulation of the ETB receptor by long-term arterial laminar shear stress. These effects might contribute to the vasoprotective and anti-arteriosclerotic potential of arterial laminar shear stress.