<p>Organ-specific autoimmunity constitutes a large health problem, where both the clinical management and our understanding of the pathogenetic mechanisms need to improve. Women with Addison's disease have abnormally low levels of dehydroepiandrosterone (DHEA), its sulphate ester (DHEA-S) and androgens relative to age, and many patients complain of physical and mental fatigue and low stress tolerance. To define a suitable dose, the effect of oral DHEA replacement was evaluated in women with Addison's disease. </p><p> DHEA was administered for three months to nine women with Addison's disease in either of two doses, 50 mg (n=5) or 200 mg (n=4). A dose of 50 mg restored the DHEA(S) and androgen levels to normal without altering the insulin sensitivity, body composition or serum lipid profile.</p><p> Autoimmune polyendocrine syndrome type I (APS I) is a rare but useful model disorder of autoimmunity, characterised by multiple organ-specific autoimmune manifestations and high-titre autoantibodies and with adrenocortical insufficiency, Addison's disease, as one of its cardinal manifestations. Approximately 10-20% of APS I patients suffer from autoimmune hepatitis, which carries a high mortality, if untreated. The presence of putative antigenic targets in the liver was investigated.</p><p> Cytochrome P4501A2 (CYP1A2) and aromatic L-amino acid decarboxylase (AADC) were identified as hepatic autoantigens with the use of APS I sera for immunofluorescent staining of normal human liver, Western blot of microsomal and cytosol fractions of human liver homogenate, and immunoprecipitation of <i>in vitro</i> transcribed and translated radioactively labelled proteins. The presence of CYP1A2- and AADC-antibodies was significantly correlated to AIH, and CYP1A2 antibodies inhibited enzyme activity <i>in vitro</i>.</p><p><i> In conclusion</i>, a daily replacement dose of 50 mg of DHEA sufficiently restores levels of DHEA, DHEA(S) and androgens in women with Addison's disease, without severe side-effects. We have further identified CYP1A2 and AADC as hepatic autoantigens associated with autoimmune hepatitis in APS I.</p>

Organ-specific autoimmunity constitutes a large health problem, where both the clinical management and our understanding of the pathogenetic mechanisms need to improve. Women with Addison's disease have abnormally low levels of dehydroepiandrosterone (DHEA), its sulphate ester (DHEA-S) and androgens relative to age, and many patients complain of physical and mental fatigue and low stress tolerance. To define a suitable dose, the effect of oral DHEA replacement was evaluated in women with Addison's disease. DHEA was administered for three months to nine women with Addison's disease in either of two doses, 50 mg (n=5) or 200 mg (n=4). A dose of 50 mg restored the DHEA(S) and androgen levels to normal without altering the insulin sensitivity, body composition or serum lipid profile. Autoimmune polyendocrine syndrome type I (APS I) is a rare but useful model disorder of autoimmunity, characterised by multiple organ-specific autoimmune manifestations and high-titre autoantibodies and with adrenocortical insufficiency, Addison's disease, as one of its cardinal manifestations. Approximately 10-20% of APS I patients suffer from autoimmune hepatitis, which carries a high mortality, if untreated. The presence of putative antigenic targets in the liver was investigated. Cytochrome P4501A2 (CYP1A2) and aromatic L-amino acid decarboxylase (AADC) were identified as hepatic autoantigens with the use of APS I sera for immunofluorescent staining of normal human liver, Western blot of microsomal and cytosol fractions of human liver homogenate, and immunoprecipitation of in vitro transcribed and translated radioactively labelled proteins. The presence of CYP1A2- and AADC-antibodies was significantly correlated to AIH, and CYP1A2 antibodies inhibited enzyme activity in vitro. In conclusion, a daily replacement dose of 50 mg of DHEA sufficiently restores levels of DHEA, DHEA(S) and androgens in women with Addison's disease, without severe side-effects. We have further identified CYP1A2 and AADC as hepatic autoantigens associated with autoimmune hepatitis in APS I.

Background: Estrogen has been reported to enhance well-being and quality of life during the climacteric phase. In women with an intact uterus estrogen treatment is always combined with progestins in order to protect the endometrium from hyperplasia and malignancies. However, in certain women the addition of progestins causes cyclicity in negative mood symptoms and physical symptoms similar to those encountered during ovulatory cycles in women with premenstrual dysphoric disorder (PMDD). The ovarian hormones estradiol and progesterone have profound effects on a number of neurotransmitter systems in the brain, such as the gamma aminobutyric acid (GABA) system and the serotonergic system. Progesterone metabolites, such as allopregnanolone and pregnanolone (also referred to as neurosteroids) modify the GABAA receptor in the central nervous system (CNS) and enhance GABAergic inhibitory transmission. Neurosteroid sensitivity in human studies can be studied by saccadic eye movement measurements using pharmacodynamic challenges with pregnanolone. Altered neurosteroid sensitivity has been suggested as a possible contributory factor to the progesterone/progestin-induced adverse mood effects of hormone replacement therapy (HRT). There is also evidence of estrogen treatment affecting the serotonergic system in postmenopausal women, although progestin addition has been less well studied. Aims and method: The aim was to investigate whether the negative mood symptoms experienced during the progestin or progesterone phase of HRT were associated with changes in neurosteroid sensitivity, or changes in platelet serotonin uptake site (transporter) and serotonin2A (5-HT2A) receptor binding. The intention was also to investigate whether hormonal changes during the normal menstrual cycle affect these peripheral serotonergic parameters. Postmenopausal women with climacteric symptoms were given HRT in two randomized, double-blinded, placebo-controlled crossover studies. The women received 2 mg estradiol (E2) continuously during 28- day cycles. Synthetic progestins or natural progesterone were added sequentially during the last 14 days, and compared to a placebo addition. Before treatment, as well as during the last week of each treatment cycle the pharmacodynamic response to pregnanolone was assessed using saccadic eye movement measurements. Throughout the studies daily symptom ratings were made. In the study regarding synthetic progestins, platelet serotonin transporter and 5-HT2A receptor binding were assayed before entering the study, as well as during the last week of each treatment cycle. In the study on reproductive women, blood samples were collected for analysis of platelet serotonin transporter and 5-HT2A receptor binding at six different points in time during the menstrual cycle. Results and conclusion: The addition of synthetic progestins to estrogen treatment increased negative mood symptoms and physical symptoms, whereas positive symptoms decreased. The addition of progestins also increased the sensitivity to pregnanolone. The addition of natural progesterone to estrogen treatment increased the sensitivity to pregnanolone. However, in this study the pregnanolone sensitivity was enhanced also during estrogen treatment. Women expressing cyclicity in negative mood symptoms were more sensitive to pregnanolone than women without symptom cyclicity. Thus, it is evident that mood deterioration during HRT is associated with altered neurosteroid sensitivity. Platelet serotonin transporter and 5-HT2A receptor binding did not change during the different treatment conditions in HRT. Thus, we were unable to explain the negative mood changes of HRT by use of these peripheral serotonergic parameters. In the study on reproductive women however, it was clear that the serotonergic variables did change during the menstrual cycle. Binding to the serotonin transporter was higher in the late follicular phase than in the ovulatory, early luteal or mid-luteal phases. Binding to the 5-HT2A receptor was higher in the early follicular phase and the early luteal phase than in the mid-luteal phase. These findings may provide a link between the ovarian steroids, and the GABAergic and serotonergic neurotransmitter systems, which in turn, could explain part of the specific vulnerability that women have for the development of adverse mood effects during HRT, mood and anxiety disorders and for the deterioration of mood so frequently seen during the luteal phase.

Hintergrund: Die regionale Citrat-Antikoagulation im Rahmen der Nierenersatztherapie hat bei interdisziplinären Intensivpatienten in den letzten Jahren zunehmend an Bedeutung gewonnen. Für Schwerbrandverletzte existieren bislang kaum Untersuchungen zu diesem Verfahren. Ziel dieser Arbeit war es, die kontinuierliche Nierenersatztherapie mit Citrat-Antikoagulation bei Intensivpatienten mit akutem Nierenversagen nach schwerem Verbrennungstrauma im Hinblick auf Praktikabilität, Effektivität und Komplikationshäufigkeit sowie die Stabilität von Elektrolyt- und Säure-Basen-Haushalt und Gerinnung zu untersuchen. Daneben sollten Aussagen zur Prävalenz des akuten Nierenversagens in dieser Patientengruppe und zu dessen Einfluss auf die Letalität getroffen werden. Methode: Im Rahmen einer retrospektiven Untersuchung wurden unter Verwendung von Patientenakten und Patientendatenmanagementsystem (PDMS) Daten von 27 Schwerbrandverletzten (VKOF ≥ 20% oder ABSI ≥ 8) mit akutem Nierenversagen ausgewertet, die zwischen Januar 2004 und Dezember 2009 im Verbrennungszentrum des Klinikums Sankt Georg Leipzig mit einer kontinuierlichen Nierenersatztherapie behandelt wurden. Bei allen Patienten kam ein Dialysegerät Prisma CFM (Gambro Hospal GmbH, Deutschland) mit einer Polyacrylnitril-Filtermembran (AN 69, Filterset M 100) der gleichen Firma zum Einsatz. Standardverfahren war eine kontinuierliche veno-venöse Hämodiafiltration (CVVHDF) im Prädilutionsmodus. Bei 18 Patienten wurde eine regionale Citrat-Antikoagulation als Antikoagulationsverfahren eingesetzt, bei 7 Patienten eine systemische Heparin-Antikoagulation, bei 2 Patienten kamen alternierend beide Verfahren zum Einsatz. Für die 18 Patienten unter regionaler Citrat-Antikoagulation erfolgte eine detaillierte Analyse des akuten Nierenversagens unter Einbeziehung des klinischen Verlaufes, der Laborparameter und der Behandlungsdaten des Nierenersatzverfahrens. Ergebnisse: Die Prävalenz eines akuten Nierenversagens mit Notwendigkeit zur Nierenersatztherapie bei Schwerbrandverletzten betrug 15,5%. Die Sterblichkeitsrate war in der Patientengruppe mit Nierenversagen etwa fünffach erhöht (25,9 vs. 4,8%). Die Letalitätsrate bei den Patienten unter systemischer Heparin-Antikoagulation war bei vergleichbarem Verbrennungsausmaß etwa fünfmal höher als unter regionaler Citrat-Antikoagulation (57,1 vs. 11.1%). Die Nierenersatztherapie wurde im Median nach 6 Tagen begonnen, die mediane Behandlungsdauer pro Patient betrug 7 Tage. Bei Start der CVVHDF wiesen 94,4% der Patienten einen Schockzustand mit Notwendigkeit einer Vasopressortherapie auf, 83,3% zeigten schwere Dysfunktionen in mindestens 3 Organsystemen, der SOFA-score lag im Median bei 14. Bei einer mittleren Citratkonzentration von 3,6 mmol/l Blut im Extrakorporalkreiskauf konnte eine mediane effektive Filterlaufzeit von 67 Stunden erreicht werden. Hypocalcämien (<0,9 mmol/l) fanden sich in 1,1%, Hypercalcämien (>1,3 mmol/l) in 0,4%. Hypernatriämien (<150 mmol) waren mit 0,4% ebenso selten wie metabolische Alkalosen (pH >7,50 und BE >4) mit 0,2%. Im Gesamtdialysezeitraum von 3790 Stunden gab es nur ein Blutungsereignis, die Gerinnungsparameter zeigten bis auf einen passageren Abfall der Thrombozytenzahl keine signifikanten Veränderungen. Die erzielte mittlere Dialysedosis war mit 35,1 ml/kg Körpergewicht/h ausreichend hoch. Neben einer Reduktion der Nierenretentionsparameter Serum-Creatinin und Serum-Harnstoff fanden sich unter dem Nierenersatzverfahren verbesserte Oxygenierungsindices und sinkende SOFA-scores. Keiner der überlebenden Patienten war zum Zeitpunkt der Entlassung dialysepflichtig. Zusammenfassung: Die CVVHDF unter regionaler Citrat-Antikoagulation ist bei Schwerbrandverletzten ein effektives und in Bezug auf Säure-Basen-Haushalt, Elektrolyte und Gerinnung sicheres Verfahren. Neben einer effektiven Elimination harnpflichtiger Substanzen konnten eine exzellente Stabilität von Elektrolyten und metabolischen Parametern sowie eine suffiziente Antikoagulation im Extrakorporalkreislauf mit niedrigem Blutungsrisiko und konstant langen Filterlaufzeiten nachgewiesen werden. Die Prävalenz des akuten Nierenversagens bei Schwerbrandverletzten ist hoch, die Letalität bei Vorliegen des Organversagens vier-bis fünffach erhöht.

Thesis (Ph. D.)--University of Washington, 2003. / Includes bibliographical references (leaves 101-113).

Im Rahmen des demographischen Wandels kommt es zu einem kontinuierlichen Anstieg des Anteils postmenopausaler Frauen an der Weltbevölkerung, so dass die Therapie postmenopausaler Erkrankungen zu einem wichtigen Thema der ärztlichen Behandlung geworden ist. Seit Beginn des 21. Jahrhunderts werden hinsichtlich der klinischen Wirksamkeit und der Sicherheit der Hormonersatztherapie vermehrt Bedenken im Hinblick auf das erhöhte Risiko für das kardiovaskuläre System und Brustkrebs geäußert. Aus diesem Grund rücken alternative Therapieansätze verstärkt in den Mittelpunkt der Forschung. In unterschiedlichen Projekten hat sich hierbei CR als effektives, in der klinischen Praxis anwendbares Medikament gezeigt. Die vorliegende Dissertation setzt sich mit der Wirkung von Subfraktionen der Testsubstanz CR auf die klimakterisch bedingten Veränderungen bzw. Erkrankungen der Skelett- und der Herzmuskulatur auseinander. Vor diesem Hintergrund wurden 100 weibliche, zuvor ovariektomierte Sprague-Dawley-Ratten in 10 Gruppen unterteilt und über einen Zeitraum von 4 Wochen die verschiedenen Substanzen von Cimicifuga racemosa (CR) (Saponin-, S1-, S2-, S3-Fraktion und Rest-, R1-, R2- und R3-Fraktion) oder Östradiolbenzoat (EB) verabreicht. Über denselben Zeitraum wurde eine Kontrollgruppe mit sojafreiem Futter versorgt. Mittels histologischer Untersuchung der Herz- und Skelettmuskulatur wurden die Auswirkungen von EB und den verschiedenen Fraktionen und Subfraktionen aus CR ermittelt und untereinander und mit den Ergebnissen der Kontrollgruppe verglichen. Die Skelettmuskelfaserfläche hat unter dem Einfluss der Saponinfraktion, der S1-Subfraktion, der Restfraktion, der R2-Subfraktion und der EB-Gruppe signifikant im Vergleich zur Kontrollgruppe zugenommen. Eine signifikante Zunahme des elastischen Faseranteils bezogen auf die Skelettmuskelfaserfläche bestand unter dem Einfluss der Saponinfraktion, ihrer S1- und S2-Subfraktion und der R1-Subfraktion als auch der EB-Gruppe im Vergleich zur Kontrollgruppe. Die Kardiomyozytenfläche zeigte einen signifikanten Größenzuwachs im Vergleich zur Kontrollgruppe unter dem Einfluss der Saponinfraktion und all ihrer 3 Subfraktionen als auch der Restfraktion und ihrer 3 Subfraktionen und der EB-Gruppe. Eine signifikante Zunahme des elastischen Faseranteils bezogen auf die Kardiomyozytenfläche bestand unter dem Einfluss der Saponinfraktion, ihrer S1-Subfraktion und der Restfraktion und ihrer R3-Subfraktion als auch der EB-Gruppe im Vergleich mit der Kontrollgruppe. Ableiten lässt sich, dass die Subfraktionen der Saponin- und Restfraktion keine gleichmäßige Wirkung auf die strukturellen Bestandteile von Herz- und Skelettmuskulatur zeigen. Die Ergebnisse sprechen dafür, dass bestimmte Subfraktionen von CR anabol auf die Skelettmuskelfaser- und Kardiomyozytenfläche und die EZM beider Gewebe wirken. Nahezu regelmäßig erweist sich die vor allem Actein und Deoxyactein enthaltende S1-Fraktion als wirksamste Substanzgruppe. Die Wirkungen von CR sind noch Gegenstand der aktuellen Forschung. Eines der Ziele weiterer Untersuchungen sollte die Ermittlung der Kombination der jeweiligen Fraktionen und Subfraktionen oder deren Subsubstanzen sein, um eine bestmögliche osteoprotektive und anabole Wirkung auf Herz- und Skelettmuskulatur und den Knochen zur Linderung oder Beseitigung klimakterischer Beschwerden zu entfalten.

Η τελικού σταδίου χρόνια νεφρική ανεπάρκεια (ΤΣΧΝΑ) είναι η αμετάκλητη απώλεια της νεφρικής λειτουργίας. Όταν η απώλεια της νεφρικής λειτουργίας φτάσει στο σημείο όπου οι νεφροί δεν μπορούν να συντηρήσουν τον ασθενή στην ζωή, τότε απαιτείται θεραπεία υποκατάστασης της νεφρικής λειτουργίας (ΘΥΝΛ). που είναι η αιμοκάθαρση (ΑΜΚ), η περιτοναϊκή κάθαρση, ή η μεταμόσχευση νεφρού. Η ενδονοσοκομειακή ΑΜΚ πραγματοποιείται 3 φορές την εβδομάδα και διαρκεί 3-5 ώρες. Η κατ' οίκον ΑΜΚ λαμβάνει χώρα στο σπίτι του ασθενούς, προσφέροντας ευελιξία στην επιλογή της συχνότητας (3-7 οορές εβδομάδα) και της διάρκειας της συνεδρίας ΑΜΚ (4-10 ώρες). Ειδικότερα η καθημερινή νυχτερινή κατ' οίκον ΑΜΚ, που πραγματοποιείται κατά την διάρκεια του ύπνου, προσφέρει σημαντικά κλινικά οφέλη, δυνατότητα κοινωνικής και επαγγελματικής αποκατάστασης, μείωση της φαρμακοληψίας, ελευθερία στην διατροφή και την πόση, καθώς και βελτίωση στην ποιότητα ζωής των ασθενών. Σύμφωνα με πρόσφατα στοιχεία, περισσότεροι από 10.000 Έλληνες ασθενείς υποφέρουν από ΤΣΧΝΑ και το 74% χρησιμοποιεί την ΑΜΚ ως θεραπεία υποκατάστασης, ενώ παράλληλα υπάρχει αυξανόμενη πίεση στις μονάδες ΑΜΚ, εξαιτίας της μεγάλης προσαύξησης του αριθμού των ασθενών τους. Για το 2004, η Ελλάδα παρουσίασε την μεγαλύτερη συχνότητα νεοεισαχθέντων ασθενών ανά εκατομμύριο πληθυσμού στην ΑΜΚ σε σύγκριση με 24 Ευρωπαϊκές χώρες και κατείχε την 3η θέση παγκοσμίως στην αντίστοιχη συχνότητα σε ΘΥΝΛ, μετά τις ΗΠΑ και την Ιαπωνία. Η κατάταξη της Ελλάδας στην 8η θέση, στην παγκόσμια σύγκριση του επιπολασμού σε ΘΥΝΛ, παρόλο που είναι ευνοϊκότερη, παραμένει πολύ υψηλή, υποδεικνύοντας το μέγεθος του αυξημένου αριθμού ΤΣΧΝΑ στην χώρα μας. Στους παράγοντες που συντελούν στην ύπαρξη του φαινομένου, είναι ο πολύ χαμηλός αριθμός μεταμοσχεύσεων νεφρού στην Ελλάδα, η οποία κατέχει την 20η θέση ανάμεσα σε 24 Ευρωπαϊκές χώρες, για το 2004, καθώς και η αύξηση της επιβίωσης των ασθενών σε ΘΥΝΛ. Η παρούσα διδακτορική διατριβή εστιάζεται στην αποτίμηση τεχνολογίας υγείας της κατ' οίκον αιμοκάθαρσης, στην μελέτη των παραγόντων που επιδρούν την υιοθέτηση της και στην αξιολόγηση της ποιότητας ζωής των αιμοκαθαιρομένων στην Ελλάδα. Συγκεκριμένοι στόχοι της είναι: i) Να εκτιμηθεί, πέρα από την ποιότητα ζωής, η προθυμία των Ελλήνων αιμοκαθαιρομένων να συμμετάσχουν σε πρόγραμμα κατ' οίκον ΑΜΚ και ii) Να διεξαχθεί βιβλιογραφική ανασκόπηση για να αποτιμηθεί αν η κατ' οίκον αιμοκάθαρση είναι πιο αποτελεσματική και με καλύτερο δείκτη κόστους -χρησιμότητας από την ενδονοσοκομειακή, καθώς και να συγκεντρωθούν και να αναλυθούν δεδομένα από την ερευνητική επίσκεψη σε έμπειρα κέντρα κατ' οίκον αιμοκάθαρσης του εξωτερικού. Η συγκέντρωση δεδομένων για την σχετιζόμενη με την υγεία ποιότητα ζωής 146 Ελλήνων αιμοκαθαιρομένων, πραγματοποιήθηκε σε 10 κέντρα ΑΜΚ της Ελλάδας, με ποσοστό απόκρισης 84%. Χρησιμοποιήθηκε το εξειδικευμένο στη νεφροπάθεια εργαλείο KDQOL-SF (που ενσωματώνει το εργαλείο γενικής υγείας SF-36) και ένα συμπληρωματικό ερωτηματολόγιο που συνοδευόταν από ενημερωτικό κείμενο για την* νυχτερινή κατ' οίκον ΑΜΚ, ώστε να συλλεχθούν δημογραφικά δεδομένα και να εκτιμηθεί η προθυμία συμμετοχής σε πρόγραμμα κατ' οίκον ΑΜΚ. Η συμπλήρωση των ερωτηματολογίων έγινε με επιτόπου συνέντευξη. Στην έρευνα συμμετείχαν 99 άνδρες και 47 γυναίκες, με μέση ηλικία 57 +/- 15,7 έτη. Παρόλο που το 61% των ερωτηθέντων ήταν σε παραγωγική ηλικία, μόνο το 23% είχαν παραμείνει στην εργασία τους και οι υπόλοιποι ήταν είτε άνεργοι, είτε σε άδεια ασθενείας, είτε είχαν συνταξιοδοτηθεί λόγω μερικής αναπηρίας, ενώ το 62% των ασθενών δήλωσε ετήσιο εισόδημα μικρότερο από 10.000€. Ο σακχαρώδης διαβήτης ήταν η πιο συχνά εμφανιζόμενη πρωτογενής αιτία νεφρικής ανεπάρκειας (20%) και η πλειοψηφία των ασθενών (73%) τελούν ΑΜΚ για λιγότερα από πέντε χρόνια. Τρεις ασθενείς αναγκάστηκαν να αλλάξουν τόπο διαμονής για να βρίσκονται πιο κοντά στην μονάδα ΑΜΚ, ενώ περίπου το 45% των αιμοκαθαιρομένων διανύουν συνολικά περισσότερα από 40km, 3 φορές την εβδομάδα, για κάθε συνεδρία ΑΜΚ. Από τις κλίμακες του KDQOL-SF, χαμηλότερες τιμές καταγράφηκαν στην εργασία, την σεξουαλική λειτουργία και τον φόρτο της νεοροπάθειας. Η σύγκριση των κλιμάκων SF-36 του δείγματος με τον Ελληνικό γενικό πληθυσμό παρουσίασε στατιστικά σημαντικές διαφορές (p<0,01) σε όλες τις κλίμακες, πλην του σωματικού πόνου. Επίσης, η σύνοψη συνιστωσών ψυχικής υγείας του δείγματος των αιμοκαθαιρουμένων ήταν ελαφρώς χαμηλότερη από του γενικού πληθυσμού, ενώ η σύνοψη συνιστωσών σωματικής υγείας ήταν αρκετά χαμηλότερη. Τα αποτελέσματα του δείγματος της παρούσας έρευνας (Ν=146) συγκρίθηκαν με αντίστοιχο δείγμα Ισπανών ασθενών ΤΣΧΝΑ (Ν=194) που συμπλήρωσαν το ίδιο ερωτηματολόγιο. Το γεγονός ότι και σ" αυτή την σύγκριση δεν εμφανίστηκε στατιστικά σημαντική διαφορά στην κλίμακα του σωματικού πόνου, ενδυναμώνει την εγκυρότητα της μέτρησης και υποδεικνύει ότι οι ασθενείς ΤΣΧΝΑ δεν υπέφεραν σημαντικά από σωματικό πόνο εξαιτίας της ασθένειας τους, σε σημείο τέτοιο, που να έχει αρνητική απήχηση στην αντίληψη τους για την σχετιζόμενη με την υγεία ποιότητα ζωής τους. Διάθεση συμμετοχής στην νυχτερινή κατ’ οίκον ΑΜΚ εξέφρασε το 84% των ασθενών και το 75% για την κατ΄ οίκον ΑΜΚ. Έντονη προθυμία σημειώθηκε στο 53% και το 38% των 146 ερωτηθέντων αντίστοιχα, ενώ διατεθειμένοι να δαπανήσουν κάποιο χρηματικό ποσό για να συμμετάσχουν ήταν το 38%. Στην ερευνητική επίσκεψη σε δύο μεγάλα και έμπειρα κέντρα κατ’ οίκον αιμοκάθαρσης του εξωτερικού, στο Lund και το Helsinki. συγκεντρώθηκαν πολύτιμα δεδομένα που αφορούν στην οργάνωση, την διεξαγωγή, την εμπειρία και την τεχνογνωσία τους. και τα οποία σχετίζονται με την δομή του προγράμματος, οικονομικές εκτιμήσεις, ιατρικά δεδομένα, στατιστικά αποτελέσματα, μεθόδους εκπαίδευσης και τα πιθανά ρίσκα ή προβλήματα που ενδέχεται να ανακύψουν, μαζί με τους τρόπους αποφυγής ή επίλυσης τους. Τα δημογραφικά δεδομένα σε συνδυασμό με το υψηλό κόστος, καθιστούν την ενδονοσοκομειακή αιμοκάθαρση μια από τις πιο δαπανηρές υγειονομικές παρεμβάσεις και διαπιστωμένα την πιο δαπανηρή μεταξύ των υπολοίπων μεθόδων ΘΥΝΛ. Το κόστος της στην Ελλάδα ξεπερνά το 2% των δαπανών της υγείας. Από την ανασκόπηση της παγκόσμιας βιβλιογραφίας, αλλά και από την μελέτη των κέντρων ΑΜΚ της Σκανδιναβίας, επιβεβαιώνεται ότι η κατ’ οίκον και η δορυφορική ΑΜΚ στοιχίζουν λιγότερο και έχουν καλύτερο δείκτη κόστους-αποτελεσματικότητας από την ενδονοσοκομειακή ΑΜΚ. ενώ παράλληλα εμφανίζουν αυξημένη επιβίωση και καλύτερη ποιότητα ζωής. Κατά συνέπεια, η ανάπτυξη αυτών των εναλλακτικών μεθόδων στην Ελλάδα θα μπορούσε να αμβλύνει την αύξηση του προβλεπόμενου συνολικού κόστους των μεθόδων ΘΥΝΛ στο υγειονομικό σύστημα, συμβάλλοντας και στην ανακούφιση από το πρόβλημα της αυξανόμενης πίεσης στις νοσοκομειακές μονάδες ΑΜΚ. αλλά και της έλλειψης του νοσηλευτικού προσωπικού, με την ταυτόχρονη βελτίωση της ποιότητας ζωής των αιμοκαθαιρομένων. Με την κατάλληλη οργάνωση και στελέχωση, η κατ* οίκον ΑΜΚ θα μπορούσε να γίνει εφικτή και στην Ελλάδα, αφού μεγάλη μερίδα ασθενών δηλώνουν πρόθυμοι να συμμετάσχουν, γεγονός που αποτελεί και την βασικότερη προϋπόθεση επιτυχίας ενός τέτοιου προγράμματος. Επιπρόσθετα, με δεδομένο ότι η Ελλάδα παρουσιάζει πολύ υψηλή συχνότητα νεοεισαχθέντων ασθενών ΤΣΧΝΑ, πρέπει να ενταθούν οι προσπάθειες για την συγκράτηση και τον περιορισμό αυτού του φαινομένου, μέσω προγραμμάτων ενημέρωσης και πρόληψης, που μαζί με την μεταμόσχευση παραμένουν οι αποτελεσματικότεροι τρόποι αντιμετώπισης του προβλήματος. / End stage renal failure is the irreversible loss of kidney function. When loss of kidney function reaches the point at which die kidneys fail to support life, then renal replacement therapy (RRT) is required, that is hemodialysis (HD), peritoneal dialysis or renal transplantation. Hospital hemodialysis is conducted 3 times per week and lasts 3-5 hours. Home hemodialysis takes places at patient’s home, offering flexibility in choosing the frequency (3-7 times Week) and the length of the hemodialysis session (4-10 hours). Daily nocturnal home hemodialysis in particular, which is conducted while the patient is asleep, offers significant clinical benefits, the opportunity of social and professional rehabilitation, reduction of drugs, freedom in diet and drinking intake, as well as improvement in patients' quality of life. According to recent records, more than 10.000 Greek patients suffer from end stage renal disease (ESRD) and 74% of them use hemodialysis as replacement therapy, while at die same time there is increasing pressure on hemodialysis units because of the growing number of patients who are receding hemodialysis. In 2004, Greece appeared to have the highest incidence per million population in hemodialysis, in comparison with 24 European countries and the 31 place in die world in the incidence per million population in RRT, after USA and Japan. The rating of Greece in the 8th place of global comparison in prevalence in RRT, although more propitious, remains very high suggesting die extent of the increasing number of ESRD m Greece. Among the factors that contribute to the existence of this phenomenon are the very low numbers of renal transplantation in Greece, which holds the 20th place among 24 European countries m 2004 and the increase of survival of patients on RRT. This doctoral thesis focuses on technology assessment of home HD, the study of the factors that affect its adoption and finally die evaluation of Greek hemodialysis patients' quality of life. The specific objectives are: i) To evaluate the quality of life of Greek hemodialysis patients, as well as their willingness to participate in a home HD program and ii) To conduct a review of the literature in order to assess whether home hemodialysis is more effective and with better cost-utility than hospital hemodialysis and to gather and analyze data taken from the inquiring visit in experienced home hemodialysis units of foreign countries. Data concerning die health related quality of life of 146 Greek hemodialysis patients were gathered from 10 HD units in Greece and the response rate was 84%. The renal disease specific instrument KDQOL-SF was used (which incorporates the general health instrument SF-36), accompanied with an additional questionnaire and an informative leaflet on nocturnal home hemodialysis, in order to gather demographic data and to evaluate the willingness of participation m a home hemodialysis progρam. Questionnaires were completed with on site interview. This study included 99 men and 47 women, with mean age 57 +/- 15,7 years. Although 61% of the participants were in productive age, only 23% were employed and the rest were either unemployed, on sick leave or receiving a disability pension, while 62% of the patients reported annual income less than l0.000 Euros. Diabetes mellitus was the most common primary kidney disease (20%) and the majority of patients were on hemodialysis for less than five years. Three patients were obliged to change place of residence so as to be closer to the hemodialysis unit, while almost 45% of the patients had to navel more than 40km, 3 times per week, for every HD session. The lowest scores in KDQOL-SF scales were found in work status, in sexual functioning and m the burden of kidney disease. The comparison of the SF-36 scales of die study sample with the Greek general population identified statistically significant differences (p<0.01) in all scales, except of the bodily pain scale. Moreover, the Mental Component Summary was slightly worse compared with the general population's, while the Physical Component Summary was quite lower. The results of the present study sample (N=146) were compared with an equivalent sample of Spanish ESRD patients (N=194) who completed the same questionnaire. The fact that m this comparison no statistically significant difference was found in the scale of bodily pain, strengthens the validity of the measurement and suggests that ESRD patients did not experience severe suffering from pain due to their disease that could worsen their perception of health related quality of life. Inclination to participate in nocturnal home HD was expressed by 84% of the patients and by 75% of the patients for home hemodialysis. Strong willingness was reported in 53% of the patients for nocturnal home HD and in the 38% for home HD respectively, while the 38% of the patients were also willing to contribute financially in order to participate. The inquiring visit in two experienced home hemodialysis units in Lund and Helsinki, provided valuable information concerning their organization, their waging, their experience and their know-how. which are related with the structure of the program, economical evaluations, medical data, statistical outcomes, methods of training and potential risks or problems that might emerge, together with advices on how to avoid or solve them. The demographical data in combination with the high cost renders hospital hemodialysis one of the most expensive medical interventions and certainly the most expensive among the other RRT methods. Hemodialysis cost in Greece absorbs more than 2% of total health expenditure. The review of the global literature and the study on the Scandinavian home HD units verified that both home and satellite hemodialysis are less costly and more cost-effective than hospital hemodialysis, while at the same time they present increased survival and better quality of life. Hence, the development of these alternative modalities of dialysis in Greece could mitigate the anticipated net cost increases of RRT to the health system. This could contribute to the alleviation of the increasing pressure on hospital HD units and the nursing shortage, with the simultaneous improvement of hemodialysis patients' quality of life. With the appropriate organization and staff, home hemodialysis could be feasible also in Greece, since big part of the patients are reporting willingness to participate and this fulfils the basic requirement for such a program to succeed. In addition, considering that Greece reports very high incidence, efforts must be intensified in order to restrain and reduce this phenomenon, through informing and prevention programs, which next to renal transplantation are the most effective ways to confront the problem.

No description available.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Natural loss of estrogen occurring in menopausal process may contribute to various health problems many of them possibly related to oxidative stress. Decrease in circulating estrogen levels and increase in follicle stimulating hormone levels (FSH) in menopausal status are related with decrease in bone mineral density. Hormone replacement therapy (HRT) is the most common treatment to attenuate menopausal disturbances and strontium (Sr) and iron (Fe) have been suggested to influence to bone metabolism. The objectives of this study was to evaluate the influence of HRT on the activity of antioxidant enzymes (SOD, CAT, and GPx) and lipid peroxidation (TBARS) in menopausal women and to determine blood strontium and iron levels and their relationship with bone mineral density and biochemical parameters in pre and postmenopausal women with or without HRT. Blood antioxidant enzyme activities were determined in premenopausal (n=18) and in postmenopausal healthy women without (n=21) or with HRT (n=19) (mean ages: 47, 59, and 57, respectively). Whole blood Sr and Fe levels were determined by spectrometric methods (inductively coupled plasma mass spectrometry - ICP-MS and inductively coupled plasma optical emission spectrometry - ICP-OES, respectively) in premenopausal (n=17) and postmenopausal women without (n=20) or with HRT (n=19) (mean ages: 47, 60 and 57 years, respectively). Bone mineral density (BMD) was evaluated at the lumbar spine (BMD L1-L4) and femoral neck (BMD femur) by dual energy X-ray absorptiometry (DEXA). TBARS, CAT, and GPx activity were not significantly different among the groups of study. However, SOD activity was significantly lower in postmenopausal women without HRT (0.68±0.04 U/mg Hb) when compared both to premenopausal women (0.91±0.04 U/mg Hb) and to postmenopausal women with HRT (0.89±0.07 U/mg Hb). SOD activity was positively correlated to the duration of HRT in the postmenopausal groups (r=0.33, p<0.05). Blood Sr and Fe levels in premenopausal (33.66±3.57 µg L-1 and 502.09±19.90 mg L-1, respectively) and postmenopausal women without (31.47±2.58 µg L-1 and 523.65±9.91 mg L-1, respectively) or with HRT (29.74±3.02 µg L-1 and 540.30±20.24 mg L-1, respectively) were not significantly different among study groups. BMD L1-L4 and BMD femur were significantly higher in premenopausal women (1.05±0.23 and 0.84±0.02 g/cm2, respectively) when compared both to postmenopausal women without (0.90±0.37 and 0.75±0.02 g/cm2, respectively) and to postmenopausal women with HRT (0.94±0.04 and 0.74±0.02 g/cm2, respectively). However, BMD had no relationship with blood metal levels, but was negatively influenced by FSH levels (β=-0.47, p<0.01 for BMD L1-L4 and β=-0.42, p<0.01 for BMD femur) and age (r=-0.48, p<0.01 for BMD L1-L4 and r=-0.38, p<0.01 for BMD femur). We concluded that HRT antagonizes the decrease of SOD activity that occurs after menopause, suggesting that HRT may play a beneficial role in the protection against oxidative stress. It was also shown that the physiologic whole blood Sr and Fe levels had no significant effect in BMD or other biochemical parameters in pre and postmenopausal women. BMD decreased with the increased in FSH levels and with aging. / A redução natural nos níveis de estrogênio, que ocorre na menopausa pode contribuir para vários problemas de saúde muitos deles também possivelmente relacionados ao estresse oxidativo. A diminuição dos níveis circulantes de estrogênio e o aumento de hormônio folículo estimulante (FSH) em mulheres na menopausa estão sendo associados à perda óssea. A terapia de reposição hormonal (TRH) é o tratamento mais comum para atenuar os distúrbios menopáusicos e, as concentrações sanguíneas de estrôncio (Sr) e ferro (Fe) têm mostrado influenciar no metabolismo ósseo. Os objetivos deste estudo foram avaliar a influência da TRH na atividade de enzimas antioxidantes (SOD, CAT e GPx) e lipoperoxidação (TBARS); e determinar os níveis de Sr e Fe e sua relação com a densidade mineral óssea (DMO) e parâmetros bioquímicos em mulheres na pré e pós menopausa com e sem TRH. As atividades das enzimas antioxidantes foram determinadas no sangue total de mulheres na pré-menopausa (n= 18) e na pós-menopausa sem (n= 21) e com TRH (n= 19); a idade média dos grupos foi de 47, 59 e 57 anos, respectivamente. As concentrações de Sr e Fe foram avaliadas por espectrofotometria (espectrometria de massas com plasma acoplado indutivamente - ICP-MS e espectrometria de emissão óptica com plasma acoplado indutivamente - ICP-OES, respectivamente), no sangue de mulheres na pré-menopausa (n= 17) e na pós-menopausa sem (n= 20) e com TRH (n= 19), com idade média de 47, 60 e 57 anos, respectivamente. A DMO foi determinada na lombar (L1-L4) e no colo do fêmur por absorciometria de duplo feixe de raios-X (DEXA). Em nosso estudo TBARS, CAT e GPx não foram significativamente diferentes entre os grupos. No entanto, a atividade da SOD foi significativamente menor em mulheres na pós-menopausa sem TRH (0,68±0,04 U/mg Hb) quando comparado com os grupos pós-menopausa com TRH (0,89±0,07 U/mg Hb) e na pré-menopausa (0,91±0,04 U/mg Hb). A atividade da SOD também apresentou correlação positiva com o tempo de TRH (r=0,33; p<0,05) nas mulheres menopausadas. As concentrações de Sr e Fe não diferiram entre as mulheres não menopausadas (33,66±3,57 µg L-1 e 502,09±19,90 mg L-1, respectivamente) e aquelas na pós-menopausa sem (31,47±2,58 µg L-1 e 523,65±9,91 mg L-1, respectivamente) ou com TRH (29,74±3,02 µg L-1 e 540,30±20,24 mg L-1, respectivamente). A DMO da L1-L4 e fêmur foi maior nas mulheres que não estavam na menopausa (1,05±0,23 e 0,84±0,02 g/cm2, respectivamente) quando comparado com os grupos de mulheres na pós-menopausa sem (0,90±0,37 e 0,75±0,02 g/cm2, respectivamente) e com TRH (0,94±0,04 e 0,74±0,02 g/cm2, respectivamente). No entanto, a DMO não apresentou correlação com as concentrações de metais encontradas. A DMO foi negativamente influenciada pelos níveis de FSH (β=-0,47, p<0,01 para DMO L1-L4 e β=-0,42, p<0,01 para DMO fêmur), e pela idade (r=-0,48, p<0,01 para DMO L1-L4 e r=-0,38, p<0,01 para DMO fêmur). Concluiu-se que a TRH antagoniza a diminuição da atividade antioxidante da SOD que ocorre após a menopausa, sugerindo o papel protetor da terapia contra o estresse oxidativo. Também demonstramos que as concentrações sanguíneas de Sr e Fe encontradas não exerceram efeito significativo na DMO e outros parâmetros bioquímicos e não foram influenciadas pela menopausa ou pela TRH em mulheres na pré e pós-menopausa. A diminuição na DMO observada foi em decorrência do aumento nos níveis circulantes de FSH e do processo de envelhecimento.

INTRODUÇÃO. Mulheres pós-menopáusicas apresentam maior risco de desenvolvimento de doença arterial coronariana. Estudos observacionais demonstraram que a terapia de reposição hormonal produz efeitos benéficos no perfil lipídico e na modulação autonômica cardíaca. O aumento da variabilidade da freqüência cardíaca (VFC), até então atribuído à reposição hormonal, não foi testado em estudos randomizados, placebo-controlados, delineados para permitir a comparação entre as duas formas mais utilizadas de reposição hormonal. A VFC de 24 horas calculada pelo método não linear Mapa de Retorno Tridimensional permite avaliar tanto a modulação vagal como a simpática. OBJETIVOS Avaliar a modulação autonômica cardíaca de mulheres pósmenopáusicas através da análise da VFC no domínio do tempo e dos índices do Mapa de Retorno Tridimensional no ECG de 24 horas. Testar a hipótese de que a reposição hormonal contínua, seja com estradiol isolado (TRE), seja com estradiol associado à noretisterona (TRH), por um período de três meses, aumenta a VFC nessas mulheres. MÉTODOS Quarenta mulheres pós-menopáusicas (46 a 63 anos; média = 54,6 ± 4,2) foram randomizadas para um dos três tratamentos, de forma contínua: TRH, estrogenioterapia (TRE) ou placebo, por três meses consecutivos. Previamente, todas as mulheres foram submetidas a exames clínico, ginecológico e laboratorial (glicose, estradiol, HDL, LDL, triglicerídios; mamografia e ultrassonografia transvaginal). O ECG de 24 horas foi gravado em cada paciente, antes e após o tratamento, para calcular os índices da VFC. RESULTADOS Não houve diferença estatisticamente significativa entre os três grupos, após 3 meses de tratamento, nos índices da VFC e do Mapa de Retorno Tridimensional. A TRH diferiu da TRE apenas quanto ao perfil lipídico. A associação com a noretisterona provocou uma redução de 12,4 % no HDL (p = 0,008). CONCLUSÃO Em mulheres pós-menopáusicas, a terapia de reposição hormonal contínua com estradiol, ou com estradiol associado à noretisterona, por um período de 3 meses, não altera a modulação autonômica cardíaca avaliada pela VFC. / Background: Postmenopausal women are at greater risk of coronary heart disease. Observational studies have demonstrated that hormone replacement therapy (HRT) improves lipid profile and cardiac autonomic modulation. The cardioprotective effect attributed to HRT has not been tested in randomized, placebo-controlled trials to compare the two most frequently used regimens. This study evaluates cardiac autonomic modulation in postmenopausal women using time domain indices of heart rate variability (HRV) and indices derived from the three-dimensional return map, and investigates whether continuous HRT for three months, either with estradiol alone (ERT) or with estradiol and norethisterone (HRT), increases HRV in postmenopausal women. Methods: Forty postmenopausal women aged 46 to 63 years were consecutively and randomly assigned to one of three treatment groups: HRT, ERT, or placebo. For all women, clinical, gynecological and laboratory data (glucose, estradiol, HDL, LDL, triglycerides, mammography and transvaginal sonography) were collected. Patients underwent 24-h ECG before and after the treatment to evaluate HRV indices. Results: Time domain indices of HRV as well as indices derived from the threedimensional return map presented no significant changes after interventions. The only significant difference between HRT and ERT groups was in lipid profile. HDL cholesterol levels decreased 12.4% (p = 0.008) for women who used HRT. Conclusion: In postmenopausal women, continuous hormone replacement therapy with estradiol or estradiol with norethisterone for 3 months does not affect cardiac autonomic modulation evaluated by HRV.