Vigilance--a state of order or a force that produces order?

The variety of meanings nowadays attached to the notion of "vigilance" essentially mask H. Head's original intentions when he introduced the term more than half a century ago. In an attempt to overcome the obviously existing disturbance in scientific communication, we contrast the new meanings, both with each other and with Head's original conception. We also discuss the importance of "vigilance" as a precursor of a current change of paradigms. We conclude that the original intention of "vigilance" is in line with recently elaborated proposals stressing the self-referential character of living systems. This revised notion of "vigilance" might serve as a conceptual base for empirical research taking self-reference into consideration, and hence for biological research in the true sense of the word.     

Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Summary Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activiy in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m² and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m². At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m² consisted of ocular symptoms (light flashes) accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m²/1 hour was considered the MTD. There were four deaths on study, all considered diseaserelated. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center.The recommended dose for phase II trials derived from our results is 12,550 mg/m²/2 hours. However, with regard to experiences in other phase I studies, the subsequent phase II studies will be performed with a dose of 6,500 mg/m².     

Social relations and smoking behavior: Results from the first MONICA survey Augsburg

Summary This study examines the relationship between various aspects of social relations and the prevalence of smoking, using data from the first MONICA Survey, Augsburg, FRG, 1984/85. Study population of the survey was a two-stage cluster sample of 5312 men and women aged 25 to 64. The response was 79.4%. The measurement of social relations included a modified form of the Syme/Berkman social network scale, as used in the Alameda County Study. Analyses were carried out separately for the total four-level social network index in relation to smoking, and for specific components of that index (marital status, contacts with friends and relatives, activities in informal groups). The results showed for both men and women, that there was a significant association between the social network index and the prevalence of smoking: the more social ties and contacts, the lower the percentage of smokers. The results from multiple logistic regression analyses indicated an effect of social relations on smoking, that is at least partly independent of age, gender and educational level. In general, the findings may contribute to a better understanding of risk groups, and the possible pathways leading from social relations to health and disease.

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Soziale Beziehungen und Rauchverhalten. Ergebnisse der ersten MONICA-Augsburg- Querschnittsstudie

Zusammenfassung Mit Daten der ersten MONICA-Querschnittsstudie Augsburg, 1984/ 85, wurden die Zusammenhänge zwischen verschiedenen Merkmalen des «sozialen Netzwerks» und dem individuellen Rauchverhalten untersucht. Die Studienpopulation umfasste 5312 Männer und Frauen einer zweistufigen Zufallsstichprobe im Alter zwischen 25 und 64 Jahren. Die Teilnahmerate betrug 79,4%. Die sozialen Beziehungen wurden in einem Fragebogen zum Selbstausfüllen mit Hilfe eines «Sozialen Netzwerk Indexes» (SNI) erfasst, der sowohl den Familienstand, die Kontakte zu Verwandten und engen Freunden als auch Aktivitäten in Gruppen und Vereinen beinhaltete. Die Ergebnisse zeigten für Männer und Frauen statistisch signifikante Zusammenhänge zwischen den Gesamtscores des SNI und der Prävalenz des Rauchens: Je mehr soziale Beziehungen und Kontakte, desto geringer war der Anteil Raucher. Die Analysen einzelner Komponenten des SNI ergaben: Es fanden sich keine konsistenten Zusammenhänge zwischen den Aktivitäten in Freizeitclubs und dem Rauchverhalten, jedoch zwischen familiären Beziehungen, Kontakten zu engen Freunden oder Verwandten und der Häufigkeit des Rauchens. Besonders auffallend war der hohe Anteil Raucher bei den geschiedenen oder getrenntlebenden Männern. 70% von ihnen waren Raucher im Vergleich zu 37% der verheirateten Männer. Die entsprechenden Anteile bei den Frauen waren 42% bzw. 22%. Die Ergebnisse der multiplen logistischen Regressionen zeigten einen Effekt der interpersonellen Beziehungen auf das Rauchverhalten, der unabhängig war von den Faktoren Alter, Geschlecht, Bildungsstand und (bei Frauen) von der Erwerbstätigkeit. Die Resultate könnten zu einer besseren Erklärung und Identifizierung von Risiko-Gruppen und damit zu einer erfolgreicheren Bekämpfung des Rauchens beitragen.

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Rapports sociaux et consommation de la cigarette

Résumé Les relations entre les différentes propriétés du «réseau social» et les habitudes individuelles en ce qui concerne la consommation de la cigarette ont été examinées à l'aide des données d'une première étude transversale, faite en région augsbourgeoise, dans le cadre du projet MONICA. L'échantillon aléatoire, divisé en deux étapes, comportait une population de 5312 hommes et femmes âgés de 25 à 64 ans. 79,4% des personnes interrogées participaient à l'enquête. Le recensement des rapports sociaux s'effectuait au moyen d'un questionnaire individuel à «l'Index du Réseau Social» (IRS) qui englobait aussi bien les données sur l'état civil que les sujets relatifs aux contacts sociaux et familiaux. Les résultats ont montré qu'il y avait une correspondance significative entre les valeurs totales du IRS et la prévalence de la consommation de la cigarette. Plus une personne avait de contacts sociaux, moins elle fumait de cigarettes. L'analyse des divers composants du IRS révèle un manque de relations cohérentes entre les activités dans les clubs de loisirs et la consommation de la cigarette. Cependant, la correspondance entre les rapports de famille, les contacts avec amis et parents et la fréquence de la consommation du tabac s'avérait révélatrice. Particulièrement frappant était le taux élevé de fumeurs chez les hommes divorcés ou vivant séparés. 70% d'entre eux étaient fumeurs par rapport à 37% des hommes mariés. Le taux correspondant chez les femmes était de 42% resp. 22%. Les résultats de la régression logistique multiple signalaient un effet des relations interpersonnelles sur la consommation de la cigarette, un effet qui était indépendant des facteurs tels que l'âge, le sexe, le niveau d'instruction et (chez les femmes) des activités professionnelles. Ces résultats pourraient contribuer à une meilleure identification et caractérisation des groupes à risque, et par la suite à combattre d'une manière plus efficace la consommation de la cigarette.

     

Separation of solubilized A2 adenosine receptors of human platelets from non-receptor [3H]NECA binding sites by gel filtration

Summary Human platelet membranes were solubilized with the zwitterionic detergent CHAPS (3-[3-(cholamidopropyl)dimethylammonio]-1-propanesulfonate) and the solubilized extract subjected to gel filtration. Binding of the adenosine receptor agonist [3H]NECA (5-N-ethylcarboxamidoadeno-sine) was measured to the eluted fractions. Two [³H]NECA binding peaks were eluted, the first of them with the void volume. This first peak represented between 10% and 25% of the [³H]NECA binding activity eluted from the column. It bound [³H]NECA in a reversible, saturable and GTP-dependent manner with an affinity of 46 nmol/1 and a binding capacity of 510 fmol/mg protein. Various adenosine receptor ligands competed for the binding of [³H]NECA to the first peak with a pharmacological profile characteristic for the A₂ adenosine receptor as determined from adenylate cyclase experiments. In contrast, most adenosine receptor ligands did not compete for [³H]NECA binding to the second, major peak. These results suggest that a solubilized A₂ receptor-GS protein complex of human platelets can be separated from other [³H]NECA binding sites by gel filtration. This allows reliable radioligand binding studies of the A₂ adenosine receptor of human platelets.Abbreviations CHAPS 3-[3-(cholamidopropyl)dimethylammoniol-l-propanesulfonate - CIA 2-chloroadenosine - CPA N⁶-cyclopentyladenosine - DPX 1,3-diethyl-8-phenylxanthine - NECA 5-N-ethylcarboxamidoadenosine - PAA 2-phenylaminoadenosine - PIA N⁶-phenyhsopropyladenosine - XAC 8-{4-[([{(2-aminoethyl)amino}carbonyl}methyl)oxy]phenyl]-1,3-dipropylxanthine Send offprint requests to M. J. Lohse     

The X-Linked Dystonia-Parkinsonism Syndrome (XDP): Clinical and Molecular Genetic Analysis

Dystonia and parkinsonism are two major representatives of movement disorders. The X-linked dystonia-parkinsonism syndrome (XDP) serves as a model system for the study of both dystonia and parkinsonism since both symptom complexes occur together and are inherited as Mendelian traits with very high penetrance. XDP, which is endemic to the Philippine island of Panay, originated by a single mutation ("genetic founder effect"), thus assuring homogeneity of the disorder at the molecular level. The disease locus, DYT3, has been assigned to the proximal long arm (Xq12-21.1) of the human X chromosome. A strategy is described to isolate this gene by positional cloning. The rationale of this strategy, the major methods involved and technical terms are explained.     

2-Chloro-N6-[3H]cyclopentyladenosine ([3HCCPA) —a high affinity agonist radioligand for A1 adenosine receptors

Summary The tritiated analogue of 2-chloro-N⁶-cyclopentyladenosine (CCPA), an adenosine derivative with subnanomolar affinity and a 10000-fold selectivity for A₁ adenosine receptors, has been examined as a new agonist radioligand. [³H]CCPA was prepared with a specific radioactivity of 1.58 TBq/mmol (43 Ci/mmol) and bound in a reversible manner to A₁ receptors from rat brain membranes with a high affinityK _D-value of 0.2 nmol/l. In the presence of GTP aK _D-value of 13 nmol/l was determined for the low affinity state for agonist binding. Competition of several adenosine receptor agonists and antagonists for [³H]CCPA binding to rat brain membranes confirmed binding to an A₁ receptor. Solubilized A1 receptors bound [³H]CCPA with similar affinity for the high affinity state. At solubilized receptors a reduced association rate was observed in the presence of MgCl₂, as has been shown for the agonist [³H]N⁶-phenylisopropyladenosine ([³H]PIA). [³H]CCPA was also used for detection of A₁ receptors in rat cardio myocyte membranes, a tissue with a very low receptor density. A K_D-value of 0.4 nmol/l and aB _max-value of 16 fmol/ mg protein was determined in these membranes. In human platelet membranes no specific binding of [³H]CCPA was measured at concentrations up to 400 nmol/l, indicating that A2 receptors did not bind [³H]CCPA. Based on the subnanomolar affinity and the high selectivity for A₁ receptors [³H]CCPA proved to be a useful agonist radioligand for characterization of A₁ adenosine receptors also in tissues with very low receptor density.Abbreviations CHA N⁶-cyclopenyadenosine - CPA N⁶-cy-clopentyladen,osine - CCPA 2-chloro-N⁶-cyclopentyladenosine - CCCPA 2-chloro-5-chloro-5-deoxy-N⁶-cyclopentyladenosine; - CHAPS 3-[3-(cholamidopropyl)dimethylammonio]-1-propanesulfonate - DPCPX 8-cyclopentyl-1,3-dipropylxanthine - NECA N-ethylcarboxamidoadenosine - PEI polyethylenimine - PIA N⁶-phenylisopropyladenosine Send offprint requests to K.-N. Klotz at the above address     

Decrease of elastic tissue fibres in stem villus blood vessels of the human placenta during IUGR and IUGR with concomitant pre-eclampsia

In a recent study we described an increase of elastic tissue fibres in blood vessel walls of placental stem villi during pre-eclampsia when compared to uncomplicated pregnancies. Furthermore, the thickness of these blood vessel walls was enhanced in pre-eclampsia. Since it is known that elastic tissue fibres increase in systemic hypertension, it may be assumed that the enhancement of elastic tissue fibres in placental stem villi during pre-eclampsia may be induced by the hypertension. To get further insight into this assumption, we examined the amount of elastic tissue fibres in stem villus blood vessels of placentae of pregnancies complicated by intrauterine growth retardation (isolated IUGR, fourteen cases), a disease without hypertension of the mother and such with pre-eclampsia and concomitant IUGR (IUGR+PE, nine cases). Each study group was compared with uncomplicated pregnancies (twenty-six cases). Unfixed cryostat serial sections were processed for conventional orcein staining and for the demonstration of alpha-actin-immunoreactivity. The intensity of orcein staining of stem villus blood vessel walls was evaluated by a semiquantitative score method. Significant lower intensities of orcein staining were calculated for blood vessel walls of placentae of isolated IUGR (P=0.0007) and IUGR+PE (P=0.0039) when compared to uncomplicated pregnancies each. Additionally, the blood vessel wall thickness of stem villi of isolated IUGR (P=0.0081) and IUGR+PE (P=0.0007) was significantly reduced. In comparison to the above mentioned investigation, our results show that, in contrast to isolated pre-eclampsia, elastic tissue fibres are decreased during pregnancies complicated by IUGR, independently of the occurrence of concomitant pre-eclampsia when compared to uncomplicated pregnancies. From our studies it may be considered that the increase of elastic tissue fibres in placentae of patients with isolated pre-eclampsia may be induced by systemic hypertension. Furthermore, our study underline arguments that IUGR may be an independent disease of the fetus.     

Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration

Communication between leukocytes and endothelial cells is crucial for inflammatory reactions. Paracrine cross-talk and outside-in signaling (via adhesion molecules) have been characterized as communication pathways to date. As leukocytes and endothelial cells express connexins, we considered intercellular communication via gap junctions an intriguing additional concept. We found that gap-junctional coupling between neutrophils and endothelium occurred in a time-dependent, bidirectional manner and was facilitated by adhesion. After blockade of connexins, transmigration of neutrophils through the endothelial layer was enhanced, and the barrier function of cell monolayers was reduced during transmigration. Tumor necrosis factor alpha decreased coupling. In the presence of connexins, transmigration of neutrophils did not alter permeability. Thus, neutrophils couple to endothelium via gap junctions, functionally modulating transmigration and leakiness. Gap-junctional coupling may be a novel way of leukocyte-endothelial communication.     

Innate recognition of bacteria: engagement of multiple receptors

Until recently, consensus was that the mechanism of action of the innate immune system was a simplified one. Current research findings in the field of innate recognition of bacteria suggest that it involves complex associations of receptors depending on cell type and bacterial stimuli, CD14, integrins, Toll-like receptors (TLRs), CD55, ion channels, and activation clusters containing heat shock proteins, chemokine receptor 4 and a plethora of other molecules have been shown to serve as key molecules in bacterial recognition. In this article, we review all the advances in the field and discuss the possibility that the repertoire for recognition of pathogens is defined by the combinational engagement of multiple receptors.     

The influence of surface roughness of titanium on beta1- and beta3-integrin adhesion and the organization of fibronectin in human osteoblastic cells

Mechanisms of cell adhesion and extracellular matrix formation are primary processes in the interaction with the material surface of an implant which are controlled by integrin receptors. The aim of our study was to find out whether beta1- and beta3-integrins of osteoblastic cells sense the surface topography of titanium, and if structural alterations of integrin adhesions were involved in the organization of fibronectin. Pure titanium surfaces were modified by polishing (P), machining (NT), blasting with glass spheres (GB), and blasting with corundum particles (CB) resulting in increasing roughness. Confocal microscopic investigations revealed fibrillar adhesions of beta1- and alpha5-integrins on P, NT, and GB, but on CB with its sharp edges these integrin subunits did not form fibrillar adhesions. beta3 generally appeared in focal adhesions. We observed aligned fibrillar structures of fibronectin on NT not only on the basal site but interestingly, also on the apical cell surface. In contrast, on CB, fibronectin appeared apically clustered. We suggest that this alignment of fibronectin fibrils depends on the directed actin cytoskeleton and in particular, on the capability of the beta1-integrins to form fibrillar adhesions, which is affected by the surface roughness of titanium.