In hierdie studie word die etiologiese verband tussen verstadigde neurologiese integrasie en latere leerproblematiek by kinders met klinies betekenisvolle neonatale bilirubienmetings ondersoek. Resente navorsing dui aan dat kinders met klinies betekenisvolle bilirubienmetings tydens die neonatale fase ‘n groter risiko loop om later verstadigde neurologiese integrasie te vertoon, veral weens die kwesbaarheid van die neonatale brein vir toksiene. Hierdie navorsingsresultate suggereer ‘n verband tussen klinies betekenisvolle neonatale bilirubienmetings en latere leerproblematiek, aangesien spesifieke breinareas wat deur neonatale bilirubien aangetas word ook vaardighede medieer wat belangrik is vir prestasie in sekere leerareas, te wete lees, skryf en reken. Neonatale fisiologiese geelsug is nie altyd met die blote oog sigbaar nie, en derhalwe word simptome soos oormatige slaperigheid en ingekorte behoefte aan voeding dikwels deur onervare moeders geïgnoreer, omdat die baba nie opmerklik “geel” is nie. Verder word neonatale fisiologiese geelsug nie altyd as sodanig gediagnoseer nie, weens verskeie faktore soos ontoereikende primêre gesondheidsorgdienste op die afgeleë platteland, tuisgeboortes en vroeë ontslag van moeders en babas uit klinieke en hospitale, veral gesien in die lig daarvan dat neonatale geelsug piekvlak tussen dag drie en dag sewe bereik. Bilirubienmeting is nie standaard prosedure by afgeleë klinieke nie, en waar ‘n rowwe skatting deur die klinieksuster op ‘n klinies betekenisvolle bilirubientelling dui, word moeders dan dikwels aangeraai om natuurlike fototerapie (sonlig) toe te pas. Verdermeer vind opvolgkonsultasies by ‘n klinieksuster dikwels eers plaas nadat die baba ongeveer een maand oud is, en voorligting aan die moeder rakende moontlike kwesbaarhede wat verband hou met klinies betekenisvolle neonatale bilirubienmetings is gebrekkig. Sodanige ouers kan dus heeltemal onbewus wees van die potensiële skade wat aangerig kan word aan die ontwikkelende brein, en intervensie vind gevolglik nie tydig plaas nie. Betekenisvolle duidinge wat uit hierdie navorsingsprojek mag voortvloei, kan derhalwe benut word ten einde spesifieke kwesbaarhede in kinders met klinies betekenisvolle neonatale bilirubienmetings tydig te kan identifiseer; en hoë-risiko leerders se moontlike latere leerproblematiek deur tydige intervensie tydens die voorskoolse jare te ondervang, voordat pobleme in die grondslagfase manifesteer. ‘n Empiriese ondersoek is uitgevoer waarby 37 deelnemers betrek is. Gebaseer op die resultate van die data-analise en interpretasie van die resultate word die hipotese aanvaar. Relevante aanbevelings met betrekking to praktykverbetering en verdere navorsing word gemaak. ENGLISH: With this study the etiological link between delayed neurological integration, high neonatal bilirubin measures and learning difficulties were investigated. Recent research findings suggest that children with high neonatal bilirubin measures are at a greater risk for delayed neurological integration later on, especially because of the susceptibility of the neonatal brain for toxins. The results of this research project suggest an etiological link between neonatal hyperbilirubinemia and learning difficulties at a later stage, since specific brain-areas which are affected by the bilirubin do mediate skills important for performance in certain learning areas, e.g. reading, writing and arithmetic. It is not always possible to notice neonatal physiological jaundice; hence, inexperienced mothers tend to ignore symptoms like sleepiness and lack of appetite, merely because their babies do not appear “yellowish”. Neonatal physiological jaundice is often misdiagnosed due to various factors like inadequate primary health care services in rural areas, home births and early discharge from hospitals - particularly in light of the fact that jaundice peaks between day three and day seven after birth. Measurement of neonatal bilirubin levels is not a standard procedure at rural clinics, and mothers are often advised to make use of natural phototherapy (sunlight) when the baby appears “yellowish”. Follow-up consultation often occurs when the baby is already one month old; hence mothers often receive inadequate information concerning neonatal hyperbilirubinemia. Parents might therefore be totally unaware of the potential vulnerability and harm to the developing brain, and intervention often does not take place. Significant indicators of this research project can be used to identify well in advance specific vulnerabilities in learners with neonatal hyperbilirubinemia, as well as potentially high-risk learners during the pre-school years, before such vulnerabilities escalate during the foundation phase. An empirical study with 37 participants was conducted. Based on the data analyses and interpretation of the results, the hypothesis was accepted. Relevant recommendations concerning best practice and further research were done. / Thesis (PhD)--University of Pretoria, 2008. / Educational Psychology / unrestricted

Adverse reactions to the antiarrhythmic medication amiodarone are severe, potentially life-threatening, and not rare. One in three patients on long-term therapy experience elevated liver enzymes, and clinically apparent liver toxicity occurs in 1% of patients treated. We report the case of a 76-year-old patient with amiodarone-induced intrahepatic cholestasis and prolonged hyperbilirubinemia despite the discontinuation of the offending agent. Current research hypothesizes that amiodarone leads to hepatic injury both by direct hepatotoxicity and by increasing the likelihood of hepatocytes to create abnormal, toxic metabolites. Increased awareness of such an adverse effect can guide clinicians toward the possible underlying etiologies of prolonged jaundice.

Résumé : L’ictère néonatal, lié à l’hyperbilirubinémie, touche 90% des nouveau-nés prématurés. L’hyperbilirubinémie provoque des troubles neurologiques aigus (somnolence, dystonie, difficultés alimentaires, atteinte de l’audition) et a été reliée à des anomalies du contrôle respiratoire. Ces résultats suggèrent une neurotoxicité de la bilirubine sur le tronc cérébral, qui pourrait aussi affecter les centres déglutiteurs. Le but de cette étude est de tester notre hypothèse selon laquelle l’hyperbilirubinémie altère la déglutition nutritive et la coordination déglutition-respiration chez l’agneau prématuré. 11 agneaux prématurés (nés 14 jours avant terme) ont été randomisés dans un groupe contrôle (n = 6) et un groupe bilirubine (n = 5). À 5 jours de vie, une hyperbilirubinémie modérée (150-250 μmol/L) était induite pendant 17h chez les agneaux du groupe bilirubine. La déglutition était étudiée par l’enregistrement de la pression pharyngée, et la respiration était évaluée par pléthysmographie d’inductance respiratoire et oxymétrie de pouls. L’effet de l’hyperbilirubinémie sur la déglutition nutritive (DN) était évalué pendant une alimentation au biberon standardisée, avec du lait de brebis. Un second enregistrement était réalisé 48h plus tard, après normalisation de la bilirubine. L’alimentation était moins performante (mL/min) dans le groupe bilirubine (p = 0,002) avec des DN moins fréquentes (p = 0,003) et de plus petit volume (p = 0,01). Ces différences n’étaient pas retrouvées à distance de l’hyperbilirubinémie. La coordination déglutition-respiration était également altérée chez les agneaux du groupe bilirubine, indiquée par une tendance à la diminution de la durée de l’inhibition respiratoire pendant les bouffées de DN (p < 0,1), ceci pendant et après l’hyperbilirubinémie. Simultanément, pendant l’alimentation, les agneaux du groupe bilirubine passaient plus de temps en désaturations sévère (< 80%) que ceux du groupe contrôle. Enfin, une diminution de la fréquence respiratoire associée à une augmentation des apnées étaient observées dans les minutes suivant l’alimentation dans le groupe bilirubine (p < 0,05). La déglutition et la coordination déglutition-respiration sont altérées par l’hyperbilirubinémie modérée, chez l’agneau prématuré. La diminution globale d’efficacité de l’alimentation au biberon est associée à une poursuite de la respiration durant les bouffées de DN, ce qui pourrait favoriser les aspirations pulmonaires de lait. / Abstract : Rationale: Jaundice, secondary to hyperbilirubinemia (HB), develops in 90% of preterm newborns. HB induces acute neurological disorders (somnolence, abnormal tone, feeding difficulties, auditory dysfunction) and has been linked to alterations in respiratory control. These findings suggest neurotoxicity in the brainstem that could also affect swallowing centers. This study aims to test our hypothesis that HB impairs nutritive swallowing and swallowing‐breathing coordination in the preterm lamb. Methods: Two groups of preterm lambs (born 14 days prior to term), control (C, n = 6) and hyperbilirubinemia (HB, n = 5) were studied. At day 5 of life, moderate HB (150‐250 μmol/L) was induced during 17 h in HB lambs. Swallowing was assessed via recording of pharyngeal pressure, and respiration was studied by respiratory inductance plethysmography and pulsed oximetry. HB effect on nutritive swallowing was assessed during standardized bottle‐feeding with ewe milk. A second recording was performed 48 hours later, after recovery from hyperbilirubinemia. Results: Swallows were less frequent (p = 0.003) and of smaller volume (p = 0.01) in HB lambs, with a consequent decrease in minute swallowing in HB lambs (p = 0,004). These differences were not found after bilirubinemia was returned to normal. Swallowing‐breathing coordination was also impaired in HB lambs, as indicated by a tendency towards a decrease in % time with respiratory inhibition during bursts of swallows, during and after hyperbilirubinemia. Simultaneously, severe desaturations (< 80%) were longer in HB lambs than in C lambs. Finally, a decreased respiratory rate was observed immediately after feeding (p < 0,05), along with increased apneas duration. Conclusions: Both swallowing and swallowing‐breathing coordination are altered by acute, moderate HB in preterm lambs. The overall decreased efficiency at bottle‐feeding is accompanied by continuation of breathing during bursts of swallows, which may promote lung aspiration.

No description available.

<p>Bilirubin is a degradation product of haem, which is constantly formed in all</p><p>mammals. Increased levels of bilirubin in humans lead to jaundice, a condition</p><p>that is very common during the first days after birth. This neonatal</p><p>jaundice can routinely be treated by phototherapy without any serious side</p><p>effects. During this treatment, bilirubin undergoes a photoreaction to isomers</p><p>that can be excreted. The most efficient photoreaction is the isomerisation</p><p>around a double bond (Z-E-isomerisation), which results in more soluble</p><p>photoproducts.</p><p>The work presented in this thesis shows results of a femtosecond optical</p><p>spectroscopy study, combined with quantum-mechanical investigations, of</p><p>the mechanism of isomerisation of bilirubin. The spectroscopic research was</p><p>conducted with bilirubin in organic solvents, and in buffer complexed by</p><p>human serum albumin. This albumin complex is present in the blood, and</p><p>has thus medical importance. Quantum-chemical calculations (CASSCF) on</p><p>a bilirubin model were used to explain experimental results.</p><p>The fluorescence decay observed with femtosecond spectroscopy shows an</p><p>ultrafast component (~120 fs), which is explained by exciton localisation,</p><p>followed by processes with a lifetime of about 1-3 ps. These are interpreted</p><p>as the formation of a twisted intermediate, which decays with a lifetime of</p><p>10-15 ps back to the ground state, as observed by absorption spectroscopy.</p><p>CASSCF calculations, in combination with the experimental results, suggest</p><p>the ca. 1-3 ps components to be relaxation to the twisted S1 minimum, followed</p><p>by the crossing of a barrier, from where further relaxation takes place</p><p>through a conical intersection back to the ground state.</p><p>Time-dependent DFT calculations were utilised to analyse the absorption</p><p>spectrum of bilirubin. Good agreement with the measured spectrum was</p><p>achieved, and low-lying states were observed, that need further investigation.</p><p>The theoretically obtained CD spectrum provides direct evidence that</p><p>bilirubin preferentially binds to human serum albumin in the enantiomeric</p><p>P-form at neutral pH.</p> / <p>Bilirubin är en nedbrytningsprodukt av hem som ständigt bildas hos alla</p><p>däggdjur. En förhöjd bilirubinkoncentration i den mänskliga kroppen kan</p><p>leda till gulsot, något som är mycket vanligt under de första dagarna efter</p><p>födelsen (neonatal gulsot). Fototerapi används rutinmässigt som säker behandlingsmetod,</p><p>under vilken bilirubin genomgår en fotoreaktion till en</p><p>isomer som kan utsöndras. Den mest effektiva fotoreaktionen är en Z-Eisomerisation,</p><p>vilken leder till lösligare fotoprodukter.</p><p>Arbetet som presenteras i denna avhandling visar resultaten av en kombinerad</p><p>femtosekund optisk-spektroskopisk och kvantmekanisk undersökning</p><p>av mekanismen bakom bilirubins isomerisation. Den spektroskopiska</p><p>studien genomfördes med bilirubin, löst i organiska lösningsmedel och i</p><p>buffert i komplex med humant serumalbumin. Detta albuminkomplex finns i</p><p>blodet, och är därför av medicinskt intresse. Kvantmekanistiska CASSCFberäkningar</p><p>på en bilirubinmodell användes för att förklara de experimentella</p><p>resultaten.</p><p>Det uppmätta fluorescence sönderfallet visar ultrasnabba komponenter</p><p>(~120 fs). Dessa tolkas som excitonlokalisering, som följs av bildandet av</p><p>ett vridet intermediat med en hastighetskonstant på ca. 1 ps-1(beroende på</p><p>lösningsmedlet). Absorptionsmätningar visar att detta intermediat sönderfaller</p><p>tillbaka till grundtillståndet med en livstid på 10-15 ps.</p><p>CASSCF beräkningar, i kombination med de experimentella resultaten, tyder</p><p>på att sönderfallet med livslängden på ca. 1 ps är en relaxation till det</p><p>vridna S1-tillståndet. Reaktionsvägen därifrån antas passera en barriär till en</p><p>konisk genomskärning, som möjliggör snabb relaxation till grundtillståndet.</p><p>Tidsberoende DFT-beräkningar användes för att analysera bilirubins absorptionsspektrum,</p><p>vilket gav bra överensstämmelse med uppmätta data. Dessutom</p><p>hittades ett tillstånd med låg excitationsenergi, som kräver ytterligare</p><p>studier. Med hjälp av det beräknade CD-spectret kunde det visas att bilirubin</p><p>binder till albumin i P-formen vid neutralt pH.</p>

Bilirubin is a degradation product of haem, which is constantly formed in all mammals. Increased levels of bilirubin in humans lead to jaundice, a condition that is very common during the first days after birth. This neonatal jaundice can routinely be treated by phototherapy without any serious side effects. During this treatment, bilirubin undergoes a photoreaction to isomers that can be excreted. The most efficient photoreaction is the isomerisation around a double bond (Z-E-isomerisation), which results in more soluble photoproducts. The work presented in this thesis shows results of a femtosecond optical spectroscopy study, combined with quantum-mechanical investigations, of the mechanism of isomerisation of bilirubin. The spectroscopic research was conducted with bilirubin in organic solvents, and in buffer complexed by human serum albumin. This albumin complex is present in the blood, and has thus medical importance. Quantum-chemical calculations (CASSCF) on a bilirubin model were used to explain experimental results. The fluorescence decay observed with femtosecond spectroscopy shows an ultrafast component (~120 fs), which is explained by exciton localisation, followed by processes with a lifetime of about 1-3 ps. These are interpreted as the formation of a twisted intermediate, which decays with a lifetime of 10-15 ps back to the ground state, as observed by absorption spectroscopy. CASSCF calculations, in combination with the experimental results, suggest the ca. 1-3 ps components to be relaxation to the twisted S1 minimum, followed by the crossing of a barrier, from where further relaxation takes place through a conical intersection back to the ground state. Time-dependent DFT calculations were utilised to analyse the absorption spectrum of bilirubin. Good agreement with the measured spectrum was achieved, and low-lying states were observed, that need further investigation. The theoretically obtained CD spectrum provides direct evidence that bilirubin preferentially binds to human serum albumin in the enantiomeric P-form at neutral pH. / Bilirubin är en nedbrytningsprodukt av hem som ständigt bildas hos alla däggdjur. En förhöjd bilirubinkoncentration i den mänskliga kroppen kan leda till gulsot, något som är mycket vanligt under de första dagarna efter födelsen (neonatal gulsot). Fototerapi används rutinmässigt som säker behandlingsmetod, under vilken bilirubin genomgår en fotoreaktion till en isomer som kan utsöndras. Den mest effektiva fotoreaktionen är en Z-Eisomerisation, vilken leder till lösligare fotoprodukter. Arbetet som presenteras i denna avhandling visar resultaten av en kombinerad femtosekund optisk-spektroskopisk och kvantmekanisk undersökning av mekanismen bakom bilirubins isomerisation. Den spektroskopiska studien genomfördes med bilirubin, löst i organiska lösningsmedel och i buffert i komplex med humant serumalbumin. Detta albuminkomplex finns i blodet, och är därför av medicinskt intresse. Kvantmekanistiska CASSCFberäkningar på en bilirubinmodell användes för att förklara de experimentella resultaten. Det uppmätta fluorescence sönderfallet visar ultrasnabba komponenter (~120 fs). Dessa tolkas som excitonlokalisering, som följs av bildandet av ett vridet intermediat med en hastighetskonstant på ca. 1 ps-1(beroende på lösningsmedlet). Absorptionsmätningar visar att detta intermediat sönderfaller tillbaka till grundtillståndet med en livstid på 10-15 ps. CASSCF beräkningar, i kombination med de experimentella resultaten, tyder på att sönderfallet med livslängden på ca. 1 ps är en relaxation till det vridna S1-tillståndet. Reaktionsvägen därifrån antas passera en barriär till en konisk genomskärning, som möjliggör snabb relaxation till grundtillståndet. Tidsberoende DFT-beräkningar användes för att analysera bilirubins absorptionsspektrum, vilket gav bra överensstämmelse med uppmätta data. Dessutom hittades ett tillstånd med låg excitationsenergi, som kräver ytterligare studier. Med hjälp av det beräknade CD-spectret kunde det visas att bilirubin binder till albumin i P-formen vid neutralt pH.

No description available.

Disease outbreaks continue to be a major problem in the sustainable development of the aquaculture industry. Clinical outbreaks can negatively impact on the welfare of the fish and the economic gain derived from this industry. Jaundice observed as a yellow colouration in the abdominal skin, sclera of the eyes and fin bases is a significant health problem affecting the Vietnamese freshwater catfish industry. This study was designed to investigate jaundice of farmed catfish, Pangasianodon hypophthalmus using several complementary approaches. These included clinical investigations and identification of potential aetiological agents as well as epidemiological analyses to identify farm-based risk factors for this economically devastating condition occurring in the catfish farms of the Mekong Delta. The results of this survey demonstrated that the jaundice was not linked to a single geographical location as affected fish were found widely distributed throughout the five main production areas. Nor was any association found between any weight groupings, feed type or feeding regime applied in the affected farms. The highest prevalence occurred between June to October and fish mortalities ranged from 1 to 10% in the study sites. The duration of this condition was significantly correlated (P &lt; 0.05) to mortality but not to total farm area, depth of pond, stocking density, or amount of water exchanged. The number of fish ponds affected was not as high in the large-scale farms compared to the small-scale farms. The results from the clinical description study showed that the affected fish were suffering a form of jaundice or icterus. Histological examination revealed a number of serious pathologies in the affected fish. Spleenomegaly was associated with the loss of cell structure and connective tissue and the haematopoietic tissue had large areas of necrosis. In the liver, histological changes consisted of vasculitis and multifocal to diffuse hepatocellular necrosis. The presence of haemosiderin was observed in melano-macrophage centres in the spleen and kidney of jaundiced fish. No single pathogen was identified in the jaundiced fish. Myxosporean infection was found in both apparently normal fish and jaundiced fish. However, there was a definite tendency for jaundiced fish to be more heavily infected. Histopathological examination found several changes that could not be ascribed to specific aetiological factors and presume that both groups (jaundiced alone and myxosporean-affected jaundiced fish) have similar lesions. The results of this study would suggest that the parasite identified as M. pangasii was not a primary pathogen associated with the haemolytic jaundice. Neither were the gills myxosporeans associated with the haemolytic jaundice and they may be considered more as a nuisance rather than as primary pathogens in farmed P. hypophthalmus in the Mekong Delta, Vietnam. Univariate analysis of the whole dataset showed several variables were significantly associated with the haemolytic jaundice. However, none of the variables achieved lasting statistical relevance in multivariable models. In conclusion, this study identified a haemolytic jaundice condition affecting farmed P. hypophthalmus in Vietnam, but no single aetiological agent or farm based risk factor was identified with this condition. Several priority areas for further work were identified and include a prospective, longitudinal cohort study to identify further the risk factors associated with the clinical jaundice condition.

Οι ασθενείς με αποφρακτικό ίκτερο έχουν αυξημένη συχνότητα επιπλοκών και θανάτου ιδιαιτέρως μετά από επεμβατικούς διαγνωστικούς ή θεραπευτικούς χειρισμούς. Ο νετερικός βλεννογόνος αποτελεί ανατομικό και λειτουργικό φραγμό ο οποίος περιορίζει εντός του αυλού τα βακτηρίδια και τις ενδοτοξίνες εμποδίζοντας τους την δίοδο στη συστηματική κυκλοφορία και την διασπορά τους. Υπάρχουν όμως παθολογικές καταστάσεις κατά τις οποίες ο εντερικός βλεννογόνος ανεπαρκεί επιτρέποντας την είσοδο στην κυκλοφορία και την διασπορά ενδοτοξινών και ενερικών μικροβίων – το φαινόμενο είναι γνωστό με τον όρο βακτηριακή μετακίνηση (bacterial translocation) – με αποτέλεσμα σηπτικές επιλοκές, ανεπάρκεια πολλαπλών οργάνων και υψηλή θνητότητα. Πειραματικές και κλινικές μελέτες έδειξαν ότι ο αποφρακτικός ίκτερος προκαλεί δυσλειτουργία του βλεννογόνιου εντερικού φραγμού με αποτέλεσμα την ενδοτοξιναιμία και βακτηριακή μετακίνηση που διαδραματίζουν κεντρικό ρόλο στην ανάπτυξη επιπλοκών στους ασθενείς με αποφρακτικό ίκτερο. Η έκθεση στην ενδοτοξίνη είναι σημαντική γιά την ανάπτυξη του ανοσοποιητικού συστήματος του ξενιστή, αλλά όταν εκτεθεί σε υψηλές συγκεντρώσεις τα αποτελέσματα είναι επιβλαβή. Υπό φυσιολογικές συνθήκες ο εντερικός φραγμός εμποδίζει την δίοδο των μικροβίων στο στείρο περιβάλλον της περιτοναικής κοιλότητας, της πυλαίας φλέβας και της συστηματικής κυκλοφορίας. Στο ήπαρ ο πληθυσμός των κυττάρων Kuppfer αποτελεί τον κύριο όγκο του δικτυοενδοθηλιακού συστήματος κι είναι στρατηγικά τοποθετημένος στην συμβολή του συστήματος της πυλαίας για την εξουδετέρωση κι απομάκρυνση ενδοτοξινών και βακτηριδίων της πυλαίας. Λειτουργικές διαταραχές είτε του εντερικού βλεννογόνου είτε των κυττάρων Kuppfer -λόγω κατασταλμένης εκκαθαριστικής ικανότητας εξαιτίας της χολόστασης - έχει ως αποτέλεσμα την διαφυγή ενδοτοξινών και μικροβίων αρχικά στους μεσεντέριους λεμφαδένες, στην πυλαία και στην συνέχεια μέσω της συστηματικής κυκλοφορίας σε απομακρυσμένα όργανα. Ο σκοπός της διατριβής αυτής είναι η επιβεβαίωση και η μελέτη της ενδοτοξαιμίας και βακτηριακής μετακίνησης στο πειραματικό μοντέλο του αποφρακτικού ικτέρου , καθως και η προσπάθεια αποτροπής του φαινομένου μέσω χορήγησης τροφικών κι ανοσοδιεγερτικών παραγόντων και συγκεκριμένα γλουταμίνης κι αργινίνης. Τα αποτελέσματα της παρούσας μελέτης επιβεβαίωσαν την ύπαρξη πυλαίας και συστηματικής ενδοτοξιναιμίας και βακτηριακής μετακίνησης στην εξωηπατική απόφραξη των χοληφόρων. Παρατηρήθηκε επίσης αύξηση της απόπτωσης στον εντερικό βλεννογόνο όπως τεκμηριώθηκε με βάση την μορφομετρική ανάλυση και τις μετρήσεις DNA και πρωτείνης, μηχανισμός που οδηγεί στην περαιτέρω ατροφία του βλεννογόνου πιθανώτατα μέσω διαταραχής στην αναλογία κυτταρικού πολλαπλασιασμού και κυτταρικού θανάτου. Η γλουταμίνη διαδραματίζει σημαντικό ρόλο στον εντερικό μεταβολισμό, δομή και λειτουργία όπως και σε αλλα ταχέως πολλαπλασιαζόμενα κύτταρα Η χορήγησή της φαίνεται να ελαττώνει την ΒΜ και να βελτιώνει την επιβίωση σε αρκετά μοντέλλα σήψης εντερικής προελεύσεως πιθανώς με τροφική δράση στον εντερικό βλεννογόνο και στα κύτταρα του ανοσοποιητικού Η αργινίνη, ειναι σημαντικό αμινοξύ για την λειτουργια των λεμφοκυττάρων και βελτιώνει την κυτταρική απάντηση του ανοσοποιητικού όταν χορηγηθεί τοσο σε ανθρώπους όσο και σε πειραματοζωα. Η αργινίνη όμως, επιπλέον συγκεντρώνει το ενδιαφέρον των μελετητών γιατι αποτελεί πρόδρομο μόριο του μονοξειδίου του αζώτου, μόριο με πολλαπλές λειτουργίες τόσο στην ανοσία και φλεγμονή όσο και στη εντερική διαπερατότητα και βακτηριακή μετακίνηση Η χορήγηση των δύο αυτών ανοσοθρεπτικών αμινοξέων μείωσε την ενδοτοξιναιμία και βακτηριακή μετακίνηση δρώντας πιθανώς τόσο στο ανοσοποιητικό σύστημα όσο και στην ακεραιότητα του εντερικού βλεννογόνου με μείωση της απόπτωσης και στην περίπτωση της γλουταμίνης παράλληλη αύξηση του κυτταρικού πολλαπλασιασμού, όπως αναδείχθηκε στην μέτρηση των μιτώσεων και στην αύξηση του εντερικού DNA και πρωτείνης. Σε περιπτώσεις εξωηπατικής απόφραξης των χοληφόρων έχει παρατηρηθεί σημαντική καταστολή του ανοσοποιητικού συστήματος με επίδραση τόσο στα Τ-κύτταρα όσο και στα κύτταρα Kuppfer. Προηγούμενες αναφορές στη δυσλειτουργία της κυτταρικής ανοσίας εισηγούνται ότι η καταστολή της δραστηριότητας των Τ-κυττάρων έχουν άμεσο αποτέλεσμα στη συστηματική ενδοτοξιναιμία, ενώ η καταστολή του μιτογονικού ερεθίσματος των Τ- κυττάρων συμβαίνει δευτερογενώς ως αποτέλεσμα βακτηριακής μετακίνησης. Στη δική μας μελέτη η χορήγηση των ανοσοθρεπτικών αυτών πεπτιδίων ελάττωσε την βακτηριακή μετακίνηση και βελτίωσε σημαντικά τις ιστολογικές αλλοιώσεις που προκαλεί η εξωηπατική χολόσταση στα πυλαία διαστήματα του ήπατος με πιθανώτερο αιτιοπαθογενετικό μηχανισμό την μείωση της ενδοτοξιναιμίας στην πυλαία φλέβα. Συμπερασματικά τα αποτελέσματα της παρούσας μελέτης επιβεβαιώνουν την ενδοτοξιναιμία και βακτηριακή μετακίνηση στον πειραματικό αποφρακτικό ίκτερο και δείχνουν πως η χορήγηση ανοσοθρεπτικών αμινοξέων όπως η γλουταμίνη και αργινίνη περιορίζουν το φαινόμενο με παράλληλη βελτίωση της ιστολογικής εικόνας τόσο τού ήπατος όσο και του λεπτού εντέρου. / Invasive diagnostic and therapeutic procedures in the presence of obstructive jaundice are associated with a high morbidity and mortality rate, primarily due to septic complications and renal impairement. Bacterial translocation is known as the passage of viable bacteria or endotoxins from the gut to the mesenteric lymph nodes and other organs which may commence or exacerbate the septic state. This study was undertaken to investigate the influence of experimental obstructive jaundice in wistar rats on portal and systematic (aortal) endotoxaemia, on bacterial translocation (ΒΤ) to mesenteric lymph nodes and distant organs, and on liver and ileal histology and apoptosis. In addition, in an attempt for therapeutic intervention we have explored the possible beneficial effect of immunonutrition in obstructive jaundice by administration of glutamine or arginine per os. The amino-acid glutamine although non essential and in abundance, is required as an enterocyte fuel while it seems to possess anabolic properties for the liver, skeletal muscle, intestinal mucosa and the immune system (e.g. lymphocytes, macrophages) and its supplementation has resulted in beneficial clinical outcomes. Glutamine supplements have been used to protect the intestinal mucosa and enhance the immune system. Various authors have postulated that glutamine may prevent or attenuate BT. Arginine plays an important role in many functions including protein synthesis and katabolism. Arginine is important in the function of lymphocytes and improves cellular immune response when administered. In addition it is the sole precursor amino acid in the generation of the immunity-enhancing agent nitric oxide (NO) by NO-synthase. In animals and humans in sepsis plasma L-arginine concentrations are markedly low, may become an indispensable amino acid, and low arginine concentrations are correlated with a worse prognosis. Arginine deficiency was demonstrated in bile duct ligated rats. Dietary L- arginine has been shown to enhance the immune system and wound healing. In obstructive jaundice the absence of intraluminal bile deprives the gut from its bacteriostatic, endotoxin neutralizing and mucosal trophic effect leading to increased intestinal bacterial and endotoxin load together with mucosal atrophy. These alterations promote bacterial and endotoxin translocation into the portal circulation and subsequently, through a decreased clearance capacity of Kupffer cells due to cholestasis, into the systemic circulation. Systemic endotoxaemia activates further a systemic inflammatory response, with dysfunctions of remote organs which in a vicious circle aggrevates the intestinal barrier dysfunction and liver injury. Sevenry-five male Wistar rats were randomly divided in four groups (15 each): I controls, II sham operated, III bile duct ligation (BDL), IV BDL + glutamine (3%in drinking water) and V BDL + arginine (2% in drinking water). Ileal samples for histology, DNA and protein content, liver biopsies, mesenteric lymph nodes (MLN) for cultures, portal and systemic blood samples for endotoxin measurements were obtained 10 days later. Compared to control, a significant increase in contaminated MLN and liver samples and in endotoxaemia was noted in group III (P < 0.01) which was significantly reduced in group IV and V (P < 0.05). Group IV presented also a significantly higher number of mitoses/crypt (M/c) , less apoptotic body counts (as did group V) and a higher DNA content compared to group III (P < 0.05). Liver biopsies from group III displayed typical changes of large duct obstruction that were significantly improved after glutamine or arginine treatment, with decreased ductular proliferation. Two main features highlight the forementioned dual role of the liver in sepsis: the first is the importance of the liver blood supply and particularly the portal flow, which arises from the splachnomesenteric vascular bed, a region especially subject to vasoconstriction and bacterial translocation. The second is the cellular heterogenicity of the liver, which is mainly hepatocytes, Kupffer cells, and endothelial sinusoidal cells. All of these cell types are involved in the immune, anti-infectious, and metabolic responses through multiple cell cross-talk and interactions. We had a beneficial effect on alterations of portal triads in the liver of glutamine or arginine supplemented rats. The mechanisms involved are not fully elucidated but possible explanations could be either the reduction of BT or an immunostimulatory up regulation by administered two immunonutrients. In conclusion, the present study verifies the increased incidence of bacterial and endotoxin translocation in experimental obstructive jaundice. Apoptosis in the small bowel of bile duct ligated rats is also increased. Oral administration of glutamine or arginine was shown to reduce both BT and endotoxaemia, improved histology in the terminal ileum and liver and also decreased apoptosis in the small bowel in extrahepatic experimental jaundice. These findings offer further insight in the pathophysiology of obstructive jaundice and suggest important biological effects of immunonutrition. Understanding the pathophysiology of barrier alterations in obstructive jaundice at the cellular and molecular level will allow novel treatment approaches and a better prognosis for patients in clinical settings.

Thesis (doctoral)--Lund University, 1993. / Added t.p. with thesis statement inserted.