Pooled analysis of genotoxicity markers in relation to exposure in the Flemish Environment and Health Studies (FLEHS) between 1999 and 2018.

BACKGROUND: The Flemish Environment and Health Studies (FLEHS) are human biomonitoring surveys running in Flanders since 1999. Additionally to biomarkers of exposure, markers of genotoxicity and oxidative stress have been measured, including the alkaline comet and micronucleus assay in peripheral whole blood cells, and urinary concentrations of 8-oxo-2'-deoxyguanosine (8-oxodG). AIM: Exposure-effect associations were explored in a pooled dataset of nine different cross-sectional FLEHS surveys. Data of adolescents collected in a time frame of about 20 years (1999-2018) were compiled. The aim of the study was to examine whether increased variation in exposure, lifestyle and environmental factors would lead to more powerful and robust exposure-effect associations. MATERIALS & METHODS: The biomarkers were measured in 2283 adolescents in the age range of 14-18 years. Exposure to polycyclic aromatic hydrocarbons [1-hydroxypyrene (1-OHP)], benzene (tt'-muconic acid), metals (arsenic, cadmium, copper, nickel, thallium, lead, chromium), persistent organochlorines and phthalates were assessed in blood or urine. Furthermore, outdoor air levels of particulate matter (PM10 and PM2.5) at the residences of the youngsters were calculated. Pooled statistical analysis was done using mixed models. Study-specific differences in the genotoxicity markers and in the strength/direction of the association were accounted for. This was done by incorporating the random factor 'study' and a random study slope (if possible). The exposure markers were centered around the study-specific mean in order to correct for protocol changes over time. RESULTS: A significant association was observed for the urinary oxidative stress marker 8-oxodG, which was positively associated with 1-OHP (5% increase for doubling of 1-OHP levels, p = 0.001), and with urinary copper (26% increase for doubling of copper levels, p = 0.001), a metal involved in the Fenton reaction in biological systems. 8-oxodG was also associated with the sum of the metabolites of the phthalate di(2-ethylhexyl) phthalate (DEHP) (3% increase for doubling of the DEHP levels, p = 0.02). For those associations, data pooling increased the statistical power. However, some of the associations in the individual surveys, were not confirmed in the pooled analysis (such as comet assay and 8-oxodG vs. atmospheric PM; and 8-oxodG vs. urinary nickel). This may be due to inconsistencies in exposure-effect relations and/or variations in the pollutant mix over time and regions. CONCLUSION: Pooled analysis including a large population of 2283 Flemish adolescents showed that 8-oxodG, a marker of oxidative DNA damage is a valuable marker to assess impact of daily life pollutants, such as PAHs, Cu and the phthalate DEHP.

[More Health in Urban Districts: The Integration of Health Promotion in Urban Development]. / Mehr Gesundheit im Quartier: Wie Gesundheitsförderung in die Stadtteilentwicklung integriert werden kann.

Poverty represents a considerable health risk. As social- and health-related disadvantages are spatially concentrated, municipalities must take up the task of forging a stronger link between urban district development and health promotion than has thus far been the case. Moreover, they must put health promotion as part of urban district development as an item on the agenda. The present contribution illustrates in which ways health promotion in disadvantaged urban districts and its scientific monitoring and evaluation can be successful.

Selective visual dimension weighting deficit after left lateral frontopolar lesions.

The left lateral frontopolar (LFP) cortex showed dimension change-related activation in previous event-related functional magnetic resonance imaging studies of visual singleton feature search with non-brain-lesioned participants. Here, we tested the hypothesis that LFP actively supports changes of attention from the old to the new target-defining dimension in singleton feature search. Singleton detection was selectively slowed in this task when the target-defining dimension changed in patients with left LFP lesions, compared with patients with frontomedian lesions as well as with matched controls without brain lesions. We discuss a potential role of LFP in change detection when the optimal allocation of dimension-based attention is not clearly defined by the task.

Cellular expression of CCK-A and CCK-B/gastrin receptors in human gastric mucosa.

Gastrin stimulates gastric acid secretion in various species, but the role of the structurally related CCK for the peripheral regulation of acid secretion in humans remains controversial. Moreover, species differences in CCK receptor function and expression have been reported. We therefore sought to identify the cellular targets of CCK and gastrin within the human gastric mucosa in situ. Gastric biopsies were collected from 15 patients without gastric disease. Expression of CCK receptor subtypes was detected in individual cells of the gastric mucosa by reverse transcription (RT)-PCR in situ, immunohistochemistry and confocal laser scanning microscopy, using antisera against the CCK-A or CCK-B/gastrin receptor subtype. Both CCK-A and CCK-B receptors were detected in antral and oxyntic mucosa at the mRNA and protein level. In fundic mucosa, CCK-A receptor mRNA and protein mapped to D cells (37.4+/-7.7). Besides, individual chief cells, mucous neck cells and parietal cells (12.3+/-4.7%) expressed CCK-A receptors. CCK-B/gastrin receptor mRNA and protein were detected in parietal cells (57.4+/-11.1%) and in neuroendocrine cells (33.2+/-4.4%) expressing chromogranin A. Furthermore, epithelial cells within the neck of the gastric gland were found to express the CCK-B/gastrin receptor. We conclude that (i) identification of CCK-A receptors on somatostatin producing D cells in humans provide the anatomical basis for a receptor-mediated mode of action of CCK on somatostatin release and (ii) detection of either CCK receptor subtype in the putative stem cell compartment implies a role of CCK in the maintenance of tissue homeostasis in human gastric mucosa.

[Ontogenesis of anesthesia-relevant receptors]. / Ontogenese anästhesierelevanter Rezeptoren.

The particularities in the medical treatment of children, especially those concerning premature infants, new-borns and babies, do not only stem from the immaturity of the organs (kidneys, liver etc.) but also from pharmacokinetic factors which are result of the immaturity of the brain. There are maturation deficits on all levels of transmission, from the nerve with electric transmission to the synapsis with neurotransmitter propagation, even though the whole system is basically laid out. The presented paper concerns itself mainly with the ontogenesis of the receptor-systems, a small part is dedicated to the question of myelination. Number and distribution of the receptors in premature or new-born infants and babies should not only be viewed in the context of the future function in mature humans (i.e. transmission and modification of information) - the receptors themselves are important factors in the maturing process of neuronal pathways, synapses and the differentiation of the neuronal cells themselves. Basically the number of receptors can change as follows: 1. Continuous increase until maturity, 2. Increase to a maximum during maturation with slight or stronger decrease after, 3. High initial number with following distinct decrease, 4. Even number throughout maturation, 5. Passing expression during maturation. The aim of this paper is to present an overview on the ontogenesis of opioid-, NMDA-, GABA-, dopamine-, acetylcholine- and serotoninreceptors. The data derived from animal and human-pharmacological experiments will be used to carefully conclude how the particularities of drug reactions of children (i.e. increased respiratory depression after opioid application in premature and newborn infants, higher incidence of paradox reactions to benzodiazepines etc.) can be explained.

CCK-B/gastrin receptors in human colorectal cancer.

BACKGROUND: Mature amidated gastrin (G17 amide) mediates its effects in the gastrointestinal tract by activating G protein-coupled CCK-B/gastrin receptors. Although trophic actions of gastrin on the gastric mucosa have been well-established, the effect of G17 amide, progastrin and intermediates to colon neoplasia in humans is controversial. While epidemiological evidence from patients with elevated serum gastrin levels related to pernicious anaemia does not support an increased risk for colon cancer, a recent study suggests that prolonged hypergastrinaemia is associated with an increased risk for colon cancer. The extent to which trophic actions of gastrin in colorectal cancer are mediated by functional gastrin receptors remains to be defined. The aim of the present study was to determine CCK-B/gastrin receptor expression, structure, and function in 79 patients with colon cancer. MATERIALS AND METHODS: CCK-B/gastrin receptor cDNAs were isolated from 79 human colorectal cancer specimens and 15 control tissues, subcloned into the eukaryotic expression vector pCR3.1 and subjected to DNA sequence analysis. Wild-type and mutant cDNAs were transiently expressed in COS-7 cells to determine ligand affinities by 125I-labelled CCK-8S competition binding. Activation of the MAP kinase signalling cascade by G17 amide was determined in transfected Colo 320 cells expressing the wild-type or mutant CCK-B/gastrin receptors. Clonal expansion of single cells was quantified in transfected Colo 320 cells. RESULTS: Gastrin mRNA is expressed in 44% of colorectal cancers and in 13% of control tissues. CCK-B/gastrin receptor mRNA is expressed in 38% of colorectal cancers and 13% of normal colonic tissue. Co-expression of gastrin and CCK-B/gastrin receptor message is significantly increased in colorectal cancer specimens (32% vs. 0%). There is no correlation between CCK-B/gastrin receptor expression and disease stage or histological grading. DNA sequence analysis revealed one spontaneous CCK-B/gastrin receptor mutation within the third intracellular loop with an exchange of valine-287 for phenylalanine. Pharmacological characterisation of the 287V --> F CCK-B/gastrin receptor reveals wild-type affinities for G17 amide, glycine-extended gastrin, CCK-8S and L-365,260. Mutation 287V --> F is associated with a loss of gastrin-induced MAPK p44/p42 signalling in Colo 320 cells while clonal expansion from single cells is increased by 53.1 +/- 15.9% when compared to Colo 320 cells expressing wild-type CCK-B/gastrin receptors. CONCLUSIONS: Structural alterations of CCK-B/gastrin receptors may account for increased growth-promoting effects of amidated gastrins in colorectal cancer.

Evidence for a nuclear passage of nascent polypeptide-associated complex subunits in yeast.

The nascent polypeptide-associated complex (NAC) has been found quantitatively associated with ribosomes in the cytosol by means of cell fractionation or fluorescence microscopy. There have been reports, however, that single NAC subunits may be involved in transcriptional regulation. We reasoned that the cytosolic location might only reflect a steady state equilibrium and therefore investigated the yeast NAC proteins for their ability to enter the nucleus. We found that single subunits of yeast NAC can indeed be transported into the nucleus and that this transport is an active process depending on different nuclear import factors. Translocation into the nucleus was only observed when binding to ribosomes was inhibited. We identified a domain of the ribosome-binding NAC subunit essential for nuclear import via the importin Kapl23p/Pselp-dependent import route. We hypothesize that newly translated NAC proteins travel into the nucleus to bind stoichiometrically to ribosomal subunits and then leave the nucleus together with these subunits to concentrate in the cytosol.

[The laryngeal mask in pediatric adenotonsillectomy. A meta-analysis of medical studies]. / Die Larynxmaske bei Adenotonsillektomie bei Kindern. Gefährliche Spielerei oder medizinischer Fortschritt?

Anaesthesia both for adenotomy (AT) and for tonsillectomy (TE) frequently presents a challenge. On one hand, children scheduled for adenotomy often have upper airway infections and are thus at risk of laryngo- and bronchospasm; on the other hand the ENT surgeon and the anaesthetist have to share the "workspace" in the patient's mouth. Since the succinyl choline debate in the early 1990s, the question of the best muscle relaxant has gone hand in hand with that of the most appropriate means of securing the airway. The concept of the laryngeal mask as airway was initially greeted with scepticism. Following several years' use of the mask for this purpose in AT and TE in young children, we report our experience and summarise the literature on this topic. The laryngeal mask represents a safe alternative to intubation, provided there is close cooperation with the ENT surgeon.

Wave number of maximal growth in viscous magnetic fluids of arbitrary depth

An analytical method within the frame of linear stability theory is presented for the normal field instability in magnetic fluids. It allows us to calculate the maximal growth rate and the corresponding wave number for any combination of thickness and viscosity of the fluid. Applying this method to magnetic fluids of finite depth, these results are quantitatively compared to the wave number of the transient pattern observed experimentally after a jumplike increase of the field. The wave number grows linearly with increasing induction where the theoretical and the experimental data agree well. Thereby, a long-standing controversy about the behavior of the wave number above the critical magnetic field is tackled.

Initial characterization of the nascent polypeptide-associated complex in yeast.

The three subunits of the nascent polypeptide-associated complex (alpha, beta1, beta3) in Saccharomyces cerevisiae are encoded by three genes (EGD2, EGD1, BTT1). We found the complex bound to ribosomes via the beta-subunits in a salt-sensitive manner, in close proximity to nascent polypeptides. Estimation of the molecular weight of the complex of wild-type cells and cells lacking one or two subunits revealed that the composition of the complex is variable and that as yet unknown proteins might be included. Regardless of the variability, a certain balance of the subunits has to be maintained: the deletion of one subunit causes downregulation of the remaining subunits at physiological growth temperature. Cells lacking both beta-subunits are unable to grow at 37 degrees C, most likely due to a toxic effect of the alpha-subunit. Based on in vitro experiments, it has been proposed that the function of mammalian nascent-polypeptide associated complexes (NAC) is to prevent inappropriate targeting of non-secretory nascent polypeptides. In vivo, however, the lack of NAC does not cause secretion of signal-less invertase in yeast. This result and the lack of a drastic phenotype of cells missing one, two or three subunits at optimal conditions (28 degrees C, YPD-medium) suggest either the existence of a substitute for NAC or that cells tolerate or 'repair' the damage caused by the absence of NAC.

A prognostic score for postherpetic neuralgia in ambulatory patients.

The main objective was to develop a scoring system for easy use by the physician in daily clinical practice in deciding the appropriate treatment for his herpes zoster patient. Data from 635 patients who did not receive antiviral therapy were included in this analysis. Of these, 131 developed postherpetic neuralgia (PHN). Of the 29 variables tested univariately in this study, 15 showed a significant correlation with the incidence of PHN, but only six proved to contribute to the overall predictive power in the multivariate approach. Using two independent approaches, the model showed a very satisfactory performance in the validation sample. Patients without acute pain rarely developed PHN. In those with acute pain, being female, being over 50 years of age, having more than 50 lesions, having lesions of a hemorrhagic nature, having cranial or sacral localisation of the rash or having pain in the prodromal phase proved to be significant, multivariate factors. An easy-to-use scoring system used in a risk graph is proposed. These data should be useful in the individual treatment decision as well as in the design and analysis of therapeutic trials in herpes zoster.

A cross-cultural study of animal fears.

The present study represents a cross-cultural study of animal fears in which subjects from seven Western and Asian countries were asked to rate their fear of a range of familiar animals. Factor analyses of these ratings in all samples revealed a coherent three factor solution in which animals fell into a fear-irrelevant, fear-relevant (fierce) or disgust-relevant category. The core group of animals making up the disgust-relevant category were similar across cultures. Some views on how a universal disgust-relevant category of feared animals may have developed are discussed.

Demography, symptomatology, and course of disease in ambulatory zoster patients. A physician-based survey in Germany.

This survey summarises the observations of physicians who prospectively recorded clinically relevant data on their patients with an episode of herpes zoster. These included demography of patients, signs and symptoms during the prodromal phase, relevant history, description of disease at the first visit, therapeutic measures and description of disease, and occurrence of postherpetic neuralgia (pain 4-5 weeks after crusting) at the second visit. A total of 2,063 patients were reported to the data management centre. The age distribution resembles that reported in the literature including the notable increase in zoster frequency with advancing age. Almost 20% of the patients, however, were 30 years old or less, and this contrasts markedly with the published literature. Age modifies the frequency of the dermatome afflicted: more cranial and less thoracic manifestations were observed with increasing age. Almost all patients reported symptoms which may be attributed to a prodromal phase, especially pain in the affected dermatome (82%). The incidence of postherpetic neuralgia was 28%. A complicated disease course such as visceral, ocular, or otological involvement, or progression to additional dermatomes was seen in almost 10% of the patients.

Characterization of the N-terminal part of the neutralizing antigenic site I of coxsackievirus B4 by mutation analysis of antigen chimeras.

Coxsackievirus B3 (CVB3) as a potential RNA virus vector for the presentation of foreign antigenic epitopes was further characterized. Insertion mutagenesis of infectious CVB3 cDNA yielded viable antigen chimeras containing variant BC loops of VP1 of coxsackievirus B4 (CVB4). Analysis of three antigen chimeras allowed the mapping of the N-terminal part of the neutralizing antigenic site 1 (N-Ag1) of CVB4 which is located in the BC loop of the structural protein VP1. A significant neutralization of a viable chimera with the deletion of CVB4-specific amino acid Ser-83 at the amino terminus of the VP1 BC loop was obtained with CVB4 serotype-specific polyclonal antisera. This neutralization was reduced after further deletion of the adjacent Ala-84, suggesting that this amino acid either constitutes the beginning of N-Ag1 of CVB4 or is essential for the conformation of the adjacent epitope. In contrast, exchange of amino acid Ser-86 to alanine, in the middle of the BC loop, led to complete loss of reactivity with CVB4-specific antibodies, demonstrating the importance of this residue for binding of CVB4 neutralizing antisera. Furthermore, we observed that manipulations of the VP1 BC loop resulted in increased thermolability of the viable chimeras in comparison to CVB3, although replication efficiencies were similar.

Erythrocyte band 3 protein strongly interacts with phosphoinositides.

85% of the phosphorus coisolated with band 3 protein during separation of the intrinsic proteins of the human erythrocyte membrane by zonal electrophoresis in high concentrations of acetic acid was found to be derived from phosphoinositides, mainly phosphatidylinositol 4,5-bisphosphate. When native band 3 protein and pyrene-labelled phospholipids were present in micelles of the nonionic detergent nonaethyleneglycol lauryl ether, strong resonance energy transfer was observed between the tryptophan residues and phosphatidylinositol 4,5-bisphosphate and, to a smaller degree, phosphatidylinositol 4-phosphate. We conclude that band 3 protein strongly interacts with phosphoinositides, in particular with phosphatidylinositol 4,5-bisphosphate.

[Use of pronouns: formal and functional aspects in the early phases of language development]. / Verweise mit Pronomen: formale und funktionale Aspekte in frühen Phasen des Spracherwerbs.

This article presents findings from empirical studies of the development of the use of pronouns in early child language. This presentation includes discussion of 1) when personal, reflexive, possessive, and indefinite pronominal forms appear in child-initiated contexts, 2) which errors emerge, and 3) which communicative functions utterances with pronouns have in dialogue. A first comparison of German-speaking and (American-)English-speaking children's usage is offered, focussing in particular on the use of the pronominal forms I/ich, you/du, and my/mein. This crosslinguistic comparison reveals differences in the age of first use, but simultaneously suggests similarities in functional characteristics of such usage. The findings are discussed in connection with the question of the development of children's communicative competence.

Mapping of a neutralizing antigenic site of Coxsackievirus B4 by construction of an antigen chimera.

A neutralizing antigenic site of coxsackievirus B4 (CVB4) was identified by construction of an antigen chimera between coxsackievirus B3 (CVB3) and CVB4. This chimera, designated CVB3/4, was constructed by inserting five amino acids of the putative BC loop of the structural protein VP1 of CVB4 into the corresponding loop of CVB3 by site-directed mutagenesis of infectious recombinant CVB3 cDNA. The chimeric cDNA was capable of inducing an infectious cycle upon transfection of permissive host cells. The resulting chimeric virus CVB3/4 was neutralized and precipitated by CVB4 and CVB3 serotype-specific polyclonal antisera, demonstrating that it unifies antigenic properties of both coxsackievirus serotypes. In addition, the chimera elicited antibodies in rabbits which were capable of neutralizing the two coxsackievirus serotypes CVB3 and CVB4. The insertion of the CVB4-specific antigenic site into the BC loop of CVB3 reduces the efficiency of viral replication, resulting in a small-plaque morphology of the virus chimera. In summary, these data give evidence for the presence of a serotype-specific neutralizing antigenic site in the BC loop of VP1 of CVB4 (amino acids 81 to 89). Our findings suggest that the construction of intertypic chimeras can be used as a tool for the identification of antigenic sites of coxsackieviruses. The retained immunogenicity of the mapped CVB4-specific antigenic epitope, when expressed in CVB3, indicates that CVB3 can be used as a RNA virus vector for heterologous antigenic sites.