Studies on the Role of the Sympathetic Nervous System in Cirrhosis of the Liver

This thesis is a result of the observation that plasma noradrenaline is increased in cirrhosis with ascites. Three specific questions were addressed: is this increase the result of increased spillover of noradrenaline into plasma (and thus increased activity of the sympathetic nervous system) or of reduced clearance from plasma? What are the implications of sympathetic activation for the various theories of ascites formation? Why does sympathetic overactivity fail to correct the reduced peripheral vascular resistance characteristic of cirrhosis? The kinetics of exogenous tritiated noradrenaline were measured, using an HPLC separation of the radiolabelled noradrenaline in plasma, in 14 cirrhotics with ascites and 13 controls. The cirrhotics had a marked increase in noradrenaline spillover with plasma clearance also slightly increased. Therefore the increased plasma noradrenaline in cirrhosis is due to increased sympathetic activity. Noradrenaline, dihydroxyphenylglycol (DHPG), renin and atrial natriuretic peptide (ANP) were then measured in peripheral venous blood in 41 cirrhotic patients and 34 control patients. Noradrenaline was increased in cirrhotics both with and without ascites, in contrast to renin which was only increased in those cirrhotics with ascites. Therefore sympathetic overactivity in cirrhosis appears to precede the development of ascites. This supports the "underfilling" theory of ascites, which suggests that the effective central intravascular volume is reduced in cirrhosis. The degree of sympathetic activity was shown to parallel the degree of hepatic impairment, and plasma noradrenaline was a useful prognostic indicator in cirrhosis. This may prove of clinical value in assessing the timing of hepatic transplantation. It has been speculated that a deficiency of ANP may contribute to the sodium retention of ascites. In fact plasma ANP was not reduced, but was marginally increased in the presence of ascites. This suggests that ANP is responding appropriately to sodium overload occurring for other reasons. Despite this sympathetic overactivity, patients with cirrhosis demonstrate reduced peripheral vascular resistance and cutaneous vasodilatation. A series of experiments was performed to try to identify the site of this "block" to normal sympathetic vasoconstriction. One theoretical possibility would be an autonomic neuropathy, particularly in alcoholic liver disease. Autonomic function was assessed by a standard battery of parasympathetic and sympathetic tests in 20 cirrhotics and 20 controls. The parasympathetically-mediated heart rate responses to deep breathing, to facial immersion in water and to the Valsalva manoeuvre were all reduced in cirrhotics with severe hepatic impairment. The sympathetically-mediated blood pressure response to isometric exercise was also reduced. However, the absence of clinical evidence of neuropathy in these patients suggested that the changes demonstrated might be a result of impaired vascular responsiveness rather than neuropathic damage. To consider this question, the blood pressure responses to steady state intravenous infusions of noradrenaline and angiotensin II were measured in 20 cirrhotics and 20 controls. Dose response curves were constructed from a minimum of 4 doses using a quadratic fit, allowing calculation of individual PD2O, dose of agent required to raise blood pressure by 20 mmHg. The rise in blood pressure was attenuated to both noradrenaline and angiotensin II in the cirrhotics with severe disease. Therefore the site of the ''block" is distal to the sympathetic nerves. The attenuated response to both sympathetic and non-sympathetic vasoconstrictors could indicate a direct vascular abnormality. Alternatively, there could be parallel desensitisation to the effects of noradrenaline and angiotensin II, both of which are frequently raised in cirrhosis. The question of sympathetic desensitisation was therefore considered in more detail by examining the cardiovascular responses to selective sympathetic agonists in 10 cirrhotics with severe disease and 10 controls, using similar methods to the previous experiment. The blood pressure responses to phenylephrine (an alpha1 agonist) and alphamethylnoradrenaline (an alpha2 agonist) were both impaired in the cirrhotic group, in contrast to the heart rate response to isoprenaline (a beta agonist) which was normal. There is thus no generalised sympathetic desensitisation, but all responses mediated by the peripheral vasculature are impaired, pointing to a defect at this site. Such a defect could involve the adrenergic receptors, by prior occupancy of the receptor site either by the increased circulating noradrenaline or by some catecholamine-like substance (c.f. the "false neurotransmitter" theory) or by "down-regulation" of the receptor number in response to sustained sympathetic overactivity. The alpha1 adrenoceptor on peripheral vessels is inaccessible to study in man, and therefore as a compromise the alpha2 receptors on platelets were studied in 10 cirrhotics and 10 controls. The method involved incubation of the isolated platelets with tritiated yohimbine, measurement of free and bound radioactivity, and calculation of receptor affinity and number by Scatchard analysis. In fact both the number and affinity of the platelet alpha2 receptors were normal, i.e. there was no down-regulation nor receptor site interference. If this reflects the alpha1 adrenoceptor on peripheral vessels, it would suggest a "post-receptor" defect within the vascular smooth muscle cell itself. This probable localisation should assist in the on-going search for the vasodilator(s) responsible for the reduced vascular resistance. Beta adrenoceptors were also assessed, using the beta2 receptor on circulating lymphocytes. The radioligand employed was [131I] iodocyanopindolol. Again, normal receptor number and affinity were demonstrated, which is in keeping with the normal heart rate response to the beta agonist isoprenaline. This study therefore does not support the hypothesis that down-regulation of beta receptors contributes to reduced efficacy of the beta adrenergic antagonist propranolol in variceal haemorrhage in ''decompensated" cirrhosis. The studies described above are in keeping with, but do not provide proof of, the following hypothesis: that in cirrhosis one or more vasodilatory substances accumulate, perhaps due to failure of hepatic inactivation, which act at an intracellular level on the peripheral vasculature. The resulting vasodilatation causes peripheral blood pooling with relative underfilling of the central vascular space. A baroreceptor-mediated increase in sympathetic activity, and possibly other neurohumoral mechanisms, ensues. This sympathetic activation could be one of the factors which cause sodium retention leading to ascites, and ultimately renal vasoconstriction leading to functional renal failure. It appears that the sympathetic nervous system does play a significant role in the complications of cirrhosis of the liver

Quinine and its salts: their solubility and absorbability

The administration of Quinine, although so old and well tried a remedy, is still beset with many difficulties and feelings of uncertainty on the part of the physician regarding the rapidity and certainty of action of a given dose of the alkaloid, by whichever channel that dose is administered. This is due mainly to our want of knowledge regarding the physical, chemical and, in particular, physiologico-chemical peculiarities of Quinine and its salts. The factors influencing the absorption of Quinine from the gastro-intestinal tract have been neglected ; and even the relative therapeutic or prophylactic value of the various methods of administration of Quinine is still unsettled.By many it is assumed that Quinine is absorbed chiefly from the stomach, the intestines taking little or no part in the absorption. Malanin, in 1868, pointed out the insolubility of the compound formed by Quinine and bile acids, and took for granted that, when this alkaloid was administered by the mouth, as much of it as was not absorbed from the stomach became inert on coming in contact with bile in the intestines and was thus eliminated in the faeces. A similar action was ascribed to bile acids by Kerner. Lauder Brunton, on account of the precipitation from a mixture of Quinine and bile acids of this salt, which is sparingly soluble, except in an excess of bile, recommended clearing out the liver by administering an emetic and a cholagotrue purgative before giving Quinine in the treatment of malaria. According to Sollmann, Quinine is fairly readily absorbed from the stomach: Giemsa and Schaumann, however, have come to the conclusion that most of the Quinine given by the mouth is absorbed from the small intestine. Marshall states that most of the Quinine passes into the duodenum: and Dixon is of the opinion that after entering the duodenum Quinine is under ordinary circumstances absorbed rapidly; but, if there is excess of alkali in the duodenum, Quinine is precipitated, forming with the bile acids insoluble salts which are passed unchanged in the faeces.When there is so little agreement regarding the fate of Quinine in the gastro-intestinal tract, it is not surprising to find an explanation of the marked variations in the absorption of Quinine—so often encountered in clinical practice, sometimes even in the same individual and when using the same salt of this alkaloid—wanting, and the reason of the efficacy of a preparation like Warburg’s tincture still shrouded in mystery. Warburg’s tincture has been described as “ merely Quinine concealed in a farrago of inert substances.” To this description Maclean’s (Netley) reply was—“I have never seen a single dose of Quinine given alone to the extent of 9.5 grains sufficient to arrest an exacerbation of remittent fever, much less prevent its recurrence; while nothing is more common than to seethe same quantity of the alkaloid in Warburg’s tincture bring about such results.” According to Sollmann the substances— aloes, rhubarb, camphor, gentian and aromatic substances which are combined with the alkaloid in Warburg’s tincture, “probably aid in the absorption of the Quinine;” and Cushny states that they promote Quinine absorption by acting on the stomach and that capsicum and piperine have a similar reputation as adjuvants in Quinine treatment. The view expressed in the National Dispensatory is that Quinine absorption is hastened by the previous administration of purgatives, of which a combination of rhubarb and aloes acts best.Regarding the relative value of the various methods of Quinine administration, it will suffice in these introductory remarks to refer to only two—oral and hypodermic. Most authors of text-books of pharmacology and therapeutics assume that Quinine given by the hypodermic method is rapidly and effectively absorbed. Cushny recommends this mode of administration in cases of emergency; Sollmann states that by hypodermic injections, deep into the gluteal muscles, rapid action is secured; Binz is of the opinion that absorption is thorough and quick. Many clinicians have expressed similar views. Recent experiments and clinical observations, however, have cast doubt upon the orthodox belief that hypodermic injections of Quinine, as of other medicinal agents, mean more rapid and more concentrated action than is possible with administration by the mouth. In Italy and Germany attempts have been made to solve this problem by laboratory methods. Kleine, on finding a smaller percentage of Quinine eliminated in the mine when the alkaloid was injected subcutaneously than when given by the mouth, came to the conclusion that absorption was less in the former instance and that the hypodermic method was therefore of less therapeutic value than the oral. Mariani made an intramuscular injection into the leg of a rabbit, with a solution of .201 gramme of the bi-hydrochloride of Quinine in one cubic centimetre of water, and from the muscle of the rabbit which was killed seventeen hours after the injection he recovered .1 gramme of anhydrous Quinine or 66.5 percent, of the amount injected. The results of Giemsa and Schaumann agree with those of Kleine they found that after oral administration the amount of Quinine eliminated in the urine was 38.5 per cent, of the dose administered and that after hypodermic injection the amount eliminated was only 19.2 per cent; but they regard this difference in the elimination of Quinine as due not to less absorption, but to a greater destruction of Quinine in the body when administered by hypodermic injection than when given by the mouth. Krom the clinical aspect, the subject has been investigated principally in India. Smythe states that Quinine injected hypodermically is slowly absorbed and is eliminated in the urine for many weeks after administration; and that 20 grains injected into the flanks will protect an individual from malaria for the following month at least. According to Megaw the temperature of patients suffering from malaria takes about twelve hours longer in coming to normal when treatment is by hypodermic injections (bi-hydrochloride of Quinine in doses of 10 grains) than when Quinine is given by the mouth, and consequently that absorption is slower from the subcutaneous connective tissue than from the mucous membrane of the stomach. Scott regards the hypodermic method (intramuscular) as of no special value in the treatment of acute cases of malarial fever, owing to slowness of absorption; but he considers this method particularly useful as a preventive of frequently recurring attacks of ague.The authors of the National Dispensatory acknowledge that the tendency of hypodermic injections to produce “pain, inflammation, gangrene and even fatal tetanus more than counterbalances the advantages of facility of administration and promptness of effect” and recommend that this method of administration should be restricted to cases in which delay would be dangerous. The importance of determining whether or not this “promptness of effect” is really obtained by the hypodermic method is obvious.In an endeavour to throw some light on these debated points regarding the absorption of Quinine, this work has been undertaken. The alkaloid and its salts employed in the various experiments were obtained direct from Merck (Darmstadt) and therefore in unopened bottles

Mobile media practices of young people in «safely digital», «enthusiastically digital», and «postdigital» schools

Wie gehen Schulen gegenwärtig mit mobilen Medien um? Ausgehend von ethnografisch orientierter Feldforschung an Deutschen Auslandsschulen, arbeitet der Beitrag drei Muster schulischer Praktiken im Umgang mit der Smartphone-Nutzung von Jugendlichen heraus: «geschützt-digitale», «enthusiastisch-digitale» und «post-digitale» Praktiken. Anhand von Feldforschungsvignetten aus drei Schulen beschreibt der Beitrag die jeweiligen Muster anschaulich, um nachvollziehbar zu zeigen, wie unterschiedlich Schülerinnen und Schüler durch die Praktiken kontrolliert, geregelt oder befähigt werden, ihre Welt im Bildungskontext zu gestalten. Der Beitrag zeigt, dass die beschriebenen Praktiken gleichzeitig existieren. Sie setzen unterschiedliche (nicht bessere oder schlechtere) institutionelle Prioritäten und unterschiedliche (nicht bessere oder schlechtere) Verständnisse der Mediennutzung von Jugendlichen um. Der Beitrag macht die Spannungen sichtbar, die entstehen, wenn Schulen die Nutzung mobiler Medien von Kindern und Jugendlichen kontrollieren wollen und argumentiert, dass jedes Muster schulischer Praktiken sich selbst untergräbt. Der Beitrag endet mit einer Reflexion der Implikationen der Studienergebnisse für zukünftige Forschung und schulische Praktiken: Die zunehmende Nutzung mobiler Medien in der Schule ist nicht zwingend als Ausdruck von «Fortschritt», «Verbesserung» oder «Modernisierung» zu sehen, sondern wird vielmehr durch die unterschiedlichen Verständnisse von Schule und jungen Menschen hervorgebracht.How do schools today engage with mobile media? Drawing on ethnographically oriented research at German Schools Abroad, this paper teases out three sets of practices regarding young people’s mobile media use: «safe», «enthusiastic», and «postdigital». Presenting vignettes from three schools to illustrate each set of practices, the paper demonstrates how students are differently controlled, guided, and given space to shape their worlds through the practices. The paper highlights that these practices exist simultaneously. They enact different (not better or worse) institutional priorities and different (not better or worse) understandings of young people’s mobile use. The paper also highlights the tensions when schools aim to control young people’s mobile use, arguing that each set of practices undermines itself. It ends by reflecting on the implications for future research and practice if we see increased mobile media use in schools not, as often assumed, as a mark of «progress», «improvement» or «modernity», but instead as emerging from different understandings of school and young people

A Personal Working Model

This paper builds an abductive argument for the existence of a working model personal to each knowledge worker which it bases on long-established cybernetic principles of control and regulation. The paper demonstrates what a working model needs to encompass, notably the individual herself as she crafts her personal work system PWS and her supporting personal information management system PIMS. The essential characteristics of a PIMS are identified. Conceprocity, concept process reciprocity, models are introduced and the example of the first author is used as a means of illustrating a Working Model. An appendix presents further details of the Conceprocity modelling language

Backstaging the teacher: On learner-driven, school-driven and data-driven change in educational technology discourse

As digital technologies become more prominent in schools, and a host of new media products appear in classrooms, critical questions are being asked about the erasure of power and politics in contemporary education. To explore the discourse on digital education, this paper draws on discourse analysis of ethnographic interviews with for-profit and non-profit organizations in the field. It asks (i) what industry insiders describe as driving change in contemporary educational technology (edtech), and (ii) whether new actors/technologies shaping a novel educational hegemony, and if so, what this hegemony looks like. Initial findings suggest that while the teacher was seen as key to driving change in printed educational materials, three different discourses appear when describing change in today’s educational technology. In the first, learners drive change; the focus lies on the individual dimension. In the second, schools drive change; the systemic dimension. In the third, data drive change; the analytics dimension. Linking these three discourses is a shift from “education” to “learning”. The accounts of educational technology simultaneously advocate for improving opportunities for all students, especially weaker or disadvantaged learners, and also strengthen the hegemonic shift across policy and practice towards an instrumental understanding of education. Overall, the paper suggests that power and politics are by no means erased from the edtech industry’s accounts of digital technologies and datafication. The socio-material affordances engineered into the technologies invite particular teaching practices and thus affect power relations in education

Educational publishing: on economic rationality and textbook production

Durch Veränderungen in der Bildungsmedienproduktion (Verfahrenskontrolle, Unternehmenskonzentration, Dezentralisierung) verstärkt sich, so die These, die Rolle der Ökonomisierung in der Bereitstellung von Wissensangeboten für die Schule. Am Beispiel einer ethnographischen Untersuchung zur Produktion eines Schulbuchs wird herausgearbeitet, wie diese Wissensangebote jedoch hoch ambivalent sein können: Das Leitbild des unternehmerischen Selbst wird konstruiert, aber zugleich von einem gesellschaftskritischen Subjektbild "unterbrochen". (DIPF/Orig.)This article highlights central changes in the production of school-based educational media (procedural authorization, corporate consolidation, decentralization). It argues that these changes are strengthening the role of an economic rationality in mediating knowledge for schools. The production of one textbook illustrates how ambivalent this knowledge can be: The ideal of an entrepreneurial self is reproduced, yet simultaneously interrupted by a different, more socially critical subject. (DIPF/Orig.

GLOBAL SUBJECTS: EXPLORING SUBJECTIVATION THROUGH ETHNOGRAPHY OF MEDIA PRODUCTION

Abstract What does it mean to represent events from the Holocaust in a graphic novel? And what if this is done not in the stark design of Art Spiegelman's Maus but in the light ligne claire (known from Tintin)? This paper explores the discursive practices surrounding The Search, a graphic novel produced specifically to teach children and young adults about the Holocaust. It asks how (novel) forms of subjectivation are articulated in the everyday, mundane practices of educational media workers. Drawing on poststructuralist theories of the subject and close micro-analysis of language (and semiotic) practices, the paper presents extracts from ethnographic observations of a team of authors designing teaching and learning materials to accompany The Search. These materials -and their practices of production -are participating in transforming memories of the Holocaust and thus (co)producing forms of globalisation. Findings suggest that while the Holocaust has traditionally been seen as a matter of 'national' responsibility, The Search and its teaching materials invite readers to see it as (global/universal) 'individualised' responsibility. Students are subjectivated as global subjects: Firstly, as universal-ethical subjects and, secondly, as contingency-tolerant subjects. These materials thus constitute a mundane, everyday element shaping new ways of being

Datafied Visibilities: From the Panopticon to the Panspectron in School Practices

Der Beitrag widmet sich den Ambivalenzen, von denen Datenpraktiken in der Schule durchzogen sind. Die Autorinnen nutzen hierfür die Metapher der Sichtbarkeit. Sie zeigen eine dreifache Verschiebung der Sichtbarkeit, wenn digitale Datentechnologien im Unterricht eingesetzt werden. Diese werden mit den Begriffen Panopticon, Panperspicon und Panspectron beschrieben. Dabei werden pädagogische und weitere schulische Praxisformen subtil und beiläufig, aber dennoch weitreichend transformiert. Aufgezeigt wird diese Verschiebung anhand der Analyse eines Interviews mit einer Lehrerin, die vom Einsatz digitaler Technologien in ihrem Schulalltag berichtet.The paper unfolds the ambivalences that permeate data practices in schools. By using the metaphor of visibility, a threefold shift is shown when digital data technologies are used in the classroom. These shifts are described with the terms panopticon, panperspicon and panspectron. In the process, pedagogical and other school practices are transformed in subtle yet far-reaching ways. The argument is demonstrated by analysing an interview with a teacher who reports on the use of digital technologies in her everyday school life