Η πορεία μιας οξείας σπειραματικής νόσου προς τη χρόνια νεφρική ανεπάρκεια χαρακτηρίζεται από φλεγμονώδεις διεργασίες που εντοπίζονται αρχικά στο σπείραμα, εν συνεχεία στον ενδιάμεσο χώρο, στα ουροφόρα σωληνάρια και τέλος στα νεφρικά αγγεία. Το πρωταρχικό αίτιο για την έναρξη των διεργασιών αυτών είναι η εναπόθεση ανοσοσυμπλεγμάτων στην περιοχή του σπειράματος και η ενεργοποίηση αντιδράσεων που οδηγούν τελικά στην εμφάνιση σπειραματικής σκλήρυνσης, ίνωσης του διαμέσου ιστού και ατροφίας των ουροφόρων σωληναρίων. Οι διεργασίες αυτές φαίνεται να πυροδοτούνται από κυτταροκίνες, όπως είναι οι ιντερλευκίνες (IL-1, IL-2, IL-6) και να εξελίσσονται περαιτέρω κάτω από την επίδραση αυξητικών παραγόντων, όπως είναι ο Transforming Growth Factor (TGF-β1), Epidermal Growth Factor (EGF) και Insulin-like Growth Factor (IGF-1). Πέραν των διεργασιών όμως αυτών, σημαντικό ρόλο στην ολοκλήρωση της καταστροφής του νεφρώνα, φαίνεται να διαδραματίζει ο ρυθμός απόπτωσης των κυττάρων των ουροφόρων σωληναρίων. Πράγματι η απόπτωση αποτελεί ένα σημαντικό μηχανισμό αποικοδόμησης των κυττάρων που σε συνεργασία με την αναγέννησή τους συμβάλλει στη σταθερότητα όλων των βιολογικών συστημάτων (ομοιόσταση). Ο ρυθμός της απόπτωσης των κυττάρων βρίσκεται σε μια σταθερή σχέση με τον ρυθμό αναγέννησης, έτσι ώστε κάθε βιολογικό σύστημα να παραμένει δομικά και λειτουργικά σταθερό. Οι πρωτεΐνες bax και bcl-2 έχουν αποδειχθεί αξιόπιστοι δείκτες της αποπτωτικής διαδικασίας. Η παρούσα μελέτη έχει σαν στόχο να εξετάσει ποιοτικά και ποσοτικά τη συμμετοχή των αυξητικών παραγόντων (TGF-β1, EGF, IGF-1) και των δεικτών της κυτταρικής απόπτωσης (πρωτεΐνες bax και bcl-2) σε ασθενείς με σπειραματικές βλάβες, παρουσία ιστολογικών αλλοιώσεων διαφορετικής βαρύτητας και κατ’ επέκταση διαταραχή της λειτουργίας του νεφρού. Συμπεριελήφθησαν 76 ασθενείς (44 άνδρες και 32 γυναίκες) στους οποίους, με βάση τα ιστολογικά ευρήματα στις βιοψίες του νεφρικού ιστού, ετέθησαν οι διαγνώσεις: ιδιοπαθής μεμβρανώδης σπειραματονεφρίτιδα (n=26), IgA νεφροπάθεια (n=15), νόσος ελαχίστων αλλοιώσεων (n=12), ταχέως εξελισσόμενη σπειραματονεφρίτιδα (n=11), εστιακή σπειραματοσκλήρυνση (n=7) και νεφρίτιδα του λύκου (n=5). Η μέση χρονική διάρκεια παρακολούθησης των ασθενών ήταν 4 χρόνια. Το είδος και η βαρύτητα των δομικών αλλοιώσεων του νεφρικού ιστού συσχετίσθηκαν με την πορεία της νεφρικής λειτουργίας, αλλά και με παραμέτρους των φλεγμονωδών διεργασιών που προσδιορίσθηκαν ανοσοϊστοχημικά, όπως είναι οι αυξητικοί παράγοντες TGF-β1, EGF και IGF-1, οι μυοϊνοβλάστες (κύτταρα που συμμετέχουν στη διαδικασία ανάπτυξης της ίνωσης) και οι δείκτες της κυτταρικής απόπτωσης (πρωτεΐνες bax και bcl-2). Διαπιστώθηκε, λοιπόν, ότι σε ασθενείς με σπειραματική βλάβη η παρουσία των αυξητικών παραγόντων, των μυοϊνοβλαστών και των δεικτών κυτταρικής απόπτωσης στα σπειράματα, στο διάμεσο χώρο και στα ουροφόρα σωληνάρια είναι έντονη. Μάλιστα αυτή του αυξητικού παράγοντα TGF-β1 των μυοϊνοβλαστών και των πρωτεϊνών bax και bcl-2 είναι εντονότερη σε ασθενείς με σημαντικού βαθμού σπειραματική σκλήρυνση, ίνωση του διάμεσου ιστού και ατροφία των ουροφόρων σωληναρίων. Διαπιστώθηκε επίσης σημαντική συσχέτιση της έκφρασης των παραμέτρων αυτών με τη βαρύτητα των ιστολογικών αλλοιώσεων (r=0.444, p<0.05) και το βαθμό έκπτωσης της νεφρικής λειτουργίας (r= 0.454, p<0.05) ενώ αντίθετα δεν παρατηρήθηκε συσχέτιση με τον τύπο της σπειραματικής βλάβης. Αυξημένος ρυθμός κυτταρικής απόπτωσης παρατηρήθηκε στο νεφρικό ιστό ασθενών με έκπτωση της νεφρικής λειτουργίας κατά τη διάγνωση της νόσου. Συμπερασματικά διαπιστώθηκε ότι : 1) Σε όλους τους ασθενείς, ανεξάρτητα από τον τύπο της σπειραματονεφρίτιδας, εντοπίζονται ανοσοϊστοχημικά αυξητικοί παράγοντες στο σπείραμα, στο διάμεσο ιστό και στα ουροφόρα σωληνάρια και μυοϊνοβλάστες κυρίως στο διάμεσο χώρο. 2) Η ποσοτική έκφραση των αυξητικών παραγόντων και ιδιαίτερα του TGF-β1 φαίνεται να σχετίζεται άμεσα με το βαθμό έκπτωσης της νεφρικής λειτουργίας και τη βαρύτητα των ιστολογικών αλλοιώσεων. 3) Ο ρυθμός της κυτταρικής απόπτωσης είναι ανάλογος της βαρύτητας των ιστολογικών αλλοιώσεων και του βαθμού έκπτωσης της νεφρικής λειτουργίας. / The evolution of an acute glomerular injury towards chronic renal failure is characterized by an inflammatory process that is initially localized in the glomeruli and then in the tubulointerstitial area and vessels of the kidney. The deposition of immune complexes in the glomeruli is the main cause of this process that leads to the development of glomerular sclerosis, interstitial fibrosis and tubular atrophy. In this process various cytokines [interleukins (IL), (IL-1, IL-2, IL-6)] and growth factors [Transforming Growth Factor-β (TGF-β), Epidermal Growth Factor (EGF) and Insulin Growth Factor (IGF-1)] are involved. The phenomenon of cellular apoptosis is implicated in the development of renal scarring. Apoptosis represents the programmed cellular death that is in balance with the generation of cells. The rate of cellular apoptosis is responsible for the preservation of homeostasis in each organism. Various genes and proteins are involved in the regulation of apoptosis within kidney. Bax and bcl-2 proteins represent markers of the apoptotic process since bax is related to an enhanced apoptotic rate whereas bcl-2 provides a survival advantage to renal cells. The aim of this study is to investigate the expression of growth factors (TGF-β1, EGF, IGF-1) and apoptotic markers (bax and bcl-2 proteins) in the renal tissue of patients with various types of glomerulonephritis and to identify any correlation of this expression with the severity of histological injury and with the course of renal function. Seventy six patients (44 males and 32 females) were included in the study. The histological diagnoses were: idiopathic membranous nephropathy (n=26), IgA nephropathy (n=15), minimal changes disease (n=12), rapidly progressive glomerulonephritis (n=11), focal segmental glomerulosclerosis (n=7) and lupus nephritis (n=5). The mean follow-up period was 4 years. The expression of growth factors, apoptotic markers and myofibroblasts (cells that are involved in the development of scarring) in the renal tissue was investigated by immunohistochemical technique and quantitated by morphometric analysis. In the renal tissue of patients with glomerulonephritis presence of growth factors, myofibroblasts and apoptotic markers was identified in the glomeruli and in the tubulointerstitial area. The expression of TGF-β1, myofibroblasts and bax, bcl-2 proteins was particularly severe in patients with glomerular sclerosis, interstitial fibrosis and tubular atrophy. The severity of this expression was related to the degree of histological damage (r=0.444, p<0.05) and that of renal impairment (r=0.454, p<0.05) whereas it was not related to the type of glomerulonephritis. In conclusion, it was found that: 1. Growth factors and myofibroblasts are localized in the glomeruli and in the tubulointerstitial area of patients with glomerulonephritis. 2. The severity of growth factors and in particular that of TGF-β1 expression is related to the degree of renal function impairment and to the severity of histological involvement. 3. The rate of cellular apoptosis in the kidney of patients with glomerulonephritis is also related to the severity of histological involvement and to the degree of renal function imparment.

Insulin-like growth factors (IGF) are known paracrine/autocrine regulators of ovarian development in teleosts. Initial studies investigated the hormonal and intracellular signal cascades involved in regulating the expression of ovarian-derived IGFs in zebrafish (Danio rerio). Quantitative real-time PCR was used to quantify the expression of igf3, igf2a, and igf2b in full grown immature (FG; 0.57-0.65 mm) and mid-vitellogenic (MV; 0.45-0.56 mm) follicles. Addition of the gonadotropin analogue human chorionic gonadotropin (hCG) and the adenylate cyclase activator forskolin increased igf3 expression in FG and MV follicles, but had no effect on igf2a or igf2b expression. The effects of hCG were blocked by the addition of the protein kinase A inhibitor H-89. Pituitary adenylate cyclase activating peptide stimulated a small increase in igf3 expression in FG follicles, while growth hormone and salmon gonadotropin releasing hormone had no effect on igf3, igf2a, or igf2b expression. Treatment with melittin, prostaglandin F2α, and prostaglandin E2 inhibited igf3 and igf2b expression in FG follicles whereas the protein kinase C activators, PMA and A23187, significantly inhibited igf3, igf2a, igf2b expression in FG and MV follicles. Secondary studies investigated the involvement of ovarian-derived IGFs in mediating the ovarian actions of gonadotropins on cell survival and steroidogenesis. Treatment of FG follicles with recombinant human IGF-I, hCG, or forskolin inhibited the induction of caspase-3/7 activity, which was used as a measure of apoptosis. The effects of hCG and forskolin on caspase-3/7 were attenuated by co-treatment with NVP-AEW54, an IGF-I receptor antagonist. hCG increased production of the maturation-inducing steroid 17α, 20β-dihydroxy-4-pregnen-3-one and co-treatment with NVP-AEW541 had no effect. These results suggest there is a high degree of hormonal specificity in regulating IGFs in the zebrafish ovary and the ovarian-derived IGFs, presumably IGF-III, are downstream mediators of gonadotropin-dependent cell survival, but are not involved in gonadotropin-induced steroidogenesis.

Basic fibroblast growth factor (FGF-2) is a trophic molecule involved in a number of functions within the central nervous system (CNS), including a prominent role in the regulation of CNS responses to injury. Prior studies suggest that rats recover differently from injury inflicted to different regions and at different ages throughout development, and that FGF-2 might underlie this phenomenon. This thesis examined whether the functional and structural outcome following bilateral injury to the motor cortex inflicted at postnatal day (P10) could be ameliorated by exogenous administration of a growth factor (FGF-2). Four complimentary studies were conducted that each assessed the role of FGF-2 in mediating recovery from bilateral motor cortex injury inflicted at P10. We found that FGF-2 improves physiological, anatomical, and functional outcome from bilateral lesions to motor cortex at P10. / xiii, 171 p. : ill. ; 28 cm.

Basic fibroblast growth factor (bFGF) has been implicated in the brain's trophic response to injury. This thesis examined the effects of endogenous bFGF on brain plasticity and recovery of behavioral function following cortical injury in adult rats. The first experiment investigated the post-lesion time course of the astrocytic expression of bFGF. Subsequent experiments examined the effects of injury-induced bFGF on neuroonal morphology, cortical morphology, and post-lesion behavioral deficits. Following motor cortex injury, endogenous bFGF prevented neuritic degeneration in layer V pyramidal neurons in Zilles' area Fr2 and promoted recovery of function in the Whishaw Reaching Task. Housing rats in an enriched environment prior to cortical injury enhanced the expression of bFGF but did not increase cortical thickness nor reduce post-lesion behavioral deficits (relative to laboratroy-housed rats). Collectively, these experiments indicate that injury-induced bFGF plays a role in potentiating recovery from brain damage. This implies that bFGF may be beneficial as a treatment following brain injury. / x, 123 p. ; 28 cm.

This thesis examined the role of exogenous basic fibroblast growth factor (FGF-2) in stimulating recovery after early cortical injury. Rats with medial prefrontal cortex (MFC), posterior parietal cortex (PPC), or sham lesions at postnatal day 3 (P3) received one of three variations of FGF-2 treatment: postnatal FGF-2 that was either pre-mixed or prepared daily, or prenatal FGF-2, and tested in adulthood. Behavioral tests used were: 1) the Morris Water task and, 2) the Whishaw Tray Reaching task. The level of functional recovery attained was dependent on FGF-2 preparation and the developmental period. MFC lesion rats showed good recovery but there was a differntial effect of pre and postnatal FGF-2 that appeared to be related to task. PPC rats showed greater recovery after postnatal rather than prenatal treatment. Anatomical changes were restricted to groups with relatively good functional recovery. These findings suggest a multifunctional role of FGF-2 in the injured brain. / xvi, 223 leaves : ill. ; 29 cm.

No description available.

Despite the overwhelming evidence for atrophy of the NGF-dependant Basal Forebrain Cholinergic neurons during aging, there is no persuasive evidence towards a decrease in NGF and/or NGF mRNA content in the brain of aged animals. Previous experiments from our laboratory have shown that NGF is released as a precursor protein and cleaved into the mature form in the extracellular space under the influence of a complex protease cascade. These recent findings have lead us to propose that any alterations in levels and/or activity of this maturation/degradation cascade might affect NGF's biological activity and perhaps lead to cognitive impairments in a subset of aged rats. To investigate this possibility, we measured protein and mRNA levels of the protease cascade players (NGF, pro-NGF, tPA, plasminogen, plasmin, MMP-9, neuroserpin). We found significantly decreased levels of both pro-NGF protein and NGF mRNA, but no difference in the remaining elements of the protease cascade, when comparing aged impaired (Al) to the aged unimpaired (AU) animals. Our second objective was to investigate whether animals trained in the Morris Water Maze would preserve their cognitive status in two additional behavioral paradigms, the Novel Object Location (NOL, spatial memory) and Novel Object Recognition (NOR, nonspatial memory) tasks. We found that both AU and AI animals in the MWM were impaired in the NOL when compared to the young controls, with the AI animals performing significantly worse than the AU in this particular task. In the NOR tasks, AI animals performed significantly worse compared to both young and AU animals. In conclusion, further experiments are required to better understand the implication of the complex protease cascade involved in NGF's maturation and degradation as well as its effect on memory of aged animals. In addition, because the segregation of animals (aged impaired/unimpaired) is a crucial step in aging research, we now have additional behavioral paradigms (NOL/NOR) that confirm the cognitive status of these animals.

The pattern of mucosal blood flow in normal human stomachs, and benign gastric ulcers was assesed with laser Doppler flowmetry and the relationship between a single determination of ulcer blood flow and the systemic level of growth factors was investigated. A significant ascending gradient in mucosal blood flow from the antrum to fundus was demonstrated. Different levels of cellular activity in the regions of the stomach may explain this gradient. In the gastric ulcers that healed on standard medical therapy mucosal blood flow was significantly increased in comparison to normal stomachs. In the ulcers that were refractory to standard medical therapy mucosal blood flow was significantly lower than in normal stomachs and healing ulcers. Higher systemic levels of the growth factor bFGF were demonstrated in healing ulcers compared to non-healing ulcers. Gastric mucosal blood flow can increase in response to the increased metabolic demands of healing, however impairment of this response may be an important factor preventing healing of benign gastric ulcers. It would appear that non-healing of gastric ulcers can be predicted at initial diagnosis by reduced peri-ulcer gastric mucosal blood flow and low blood levels of bFGF. / Thesis (M.Med.Sc.)-University of Natal, Durban, 1999.

Access to abstract permanently restricted to Ball State community only. / School of Physical Education, Sport, and Exercise Science

Since 1975, the extent of catching-up has been very different across Southern regions. Starting from the common arguments of growth theory, the paper wishes to show whether differences in regional income and growth can be attributed to different endowment in human capital, differences in private or public investment level, to structural imbalances, and labour force participation. The investigated panel consists of regional time series for the period 1975 to 1994 and includes NUTS II level regions of Greece, Spain, and the Italian South. Estimation of the impact of the variables on regional income is effected in a dynamic panel data model applying a GMM estimation procedure. The results indicate that the income level of Southern EU regions is largely determined by employment/educational levels and past public investment, while the impact of private investment is not significant. One may follow that EU regional policies should predominately focus on the human factor. Assistance to member countries to upgrade public infra-structures may be continued, but private investment incentives should be curbed. (author's abstract) / Series: EI Working Papers / Europainstitut