Depressive disorders are among the most frequent psychiatric diseases in the Western world with prevalence between 9% and 18%. Poor compliance and inappropriate antidepressant discontinuation invokes long-term morbidity, and appear linked to hippocampal shrinkage. Despite major advances in pharmacological treatment of the illness over the past 3040 years, currently available agents have distinct shortfalls both in clinical efficacy and in maintenance of response. This implies a greater long-term morbidity with significant impact on the patient, the patient's family as well as economic implications to health care managers and providers. The major reason for this state of affairs is our poor understanding of the neurobiology of depression and hence, of antidepressant (AD) action. AD drugs are thus not addressing the crucial neurobiological target underlying the illness, and new strategies and treatments are urgently needed. In recent years, depression has been associated with disturbances in excitotoxic glutamatergic activity, yet this has not been systematically evaluated. While the role of neurotransmitters such as serotonin, noradrenaline and dopamine has been extensively studied, new evidence suggests a role for the unique neurotransmitter nitric oxide (NO). Nitric oxide (NO), is activated by glutamatergic systems in various limbic and other regions of the brain, and has recently also been implicated in anxiety and affective disorders. Of special interest is the putative role of NO in cellular memory, synaptic plasticity and cell survival, all-important processes in the neuropathology and neurodevelopment of depression. Recent clinical studies have provided evidence of the role of the NO-pathway in depression, while preclinical studies have demonstrated the anxiolytic and antidepressant actions of nitric oxide synthase (NOS)-inhibitors. Moreover, NO interacts with other classical transmitters that have a regulatory role on mood, particularly the monoamines, as well as glutamate and gammaaminobutyric acid (GABA). In the current study the role of the NO-cGMP pathway in AD action was investigated, after chronic imipramine (IMI) and after IMI withdrawal, using a learned helplessness paradigm. Behavioural changes, hippocampal NOS activity and cGMP accumulation was determined together with pharmacological manipulation of the NO-cGMP pathway. Chronic IMI, 15 mg/kg/day intraperitoneal (ip) administration induced a pronounced reduction in swim immobility time in the forced swim test (FST), with no effect on horizontal or vertical locomotor activity. These behavioural changes were accompanied by a significant reduction in NOS enzyme activity and cGMP accumulation. In order to confirm the involvement of the NO-cGMP pathway in the AD action of IMI, chronic (3 weeks) IMI treatment was followed by an acute withdrawal of 7 days. Acute withdrawal, after chronic IMI treatment, resulted in a significant increase in swim immobility time and an increase in NOS enzyme activity and cGMP levels. In fact, NOS activity was raised above that of control, not just higher than the effect of chronic IMI. In order to assess the possible role of the NMDA-NO-cGMP pathway in AD withdrawal, the NMDA receptor antagonist, memantine, and the NOS/guanylyl cyclase (GC) inhibitor, methylene blue (MB), were administered during the 7 day IMI withdrawal period. Memantine (5 mg/kg/d ip), during the 7 day IMI withdrawal period, significantly reversed the increase in immobility time evoked after IMI withdrawal. This was accompanied by a significant reduction in NOS enzyme activity and a tendency to decrease cGMP levels. This data confirms that the antidepressant action of IMI, as well as IMI withdrawal, is associated with actions on the NMDA-GIu-NO-cGMP pathway. Particularly. IMI withdrawal evokes an increase in glutamate activity that is responsible for NOS activation. During the 7 day IMI withdrawal period, MB (15 mg/kg/d ip) also significantly reversed the increased immobility time after IMI withdrawal and was accompanied by a tendency to decrease NOS enzyme activity and cGMP levels in the rat hippocampus, however statistical significance was not reached. Although not emphatic, this data implies a possible role of the NO-cGMP pathway in AD action and AD withdrawal. In order to determine whether the observed IMI withdrawal effects on the NO-cGMP pathway may occur through an initial destabilisation in the serotonergic system, the 5-HT2a/2c receptor antagonist, ritanserin (4 mg/kg/d ip), was administered during the IMI withdrawal period. These studies revealed that antidepressant withdrawal evokes an increase in 5-HT2-mediated activity, and that antidepressant-induced NOS activation after withdrawal has its origin in serotonergic hyperactivity. Clearly, this is supportive of a distinct relationship between the NO and serotonergic system in antidepressant response. On its own, ritanserin was found to increase NOS and cGMP levels, yet during IMI withdrawal this response was lost, suggesting that IMI withdrawal alters the response to a 5-HT2a/2c receptor antagonist, which may have major clinical implications. In conclusion, the AD action of IMI, as well as chronic IMI withdrawal, involves actions on the NO-cGMP pathway. Withdrawal of ADS is associated with a loss of AD efficacy together with an increase in release of NO and cGMP. The NMDA antagonist, memantine, and the NOS/GC inhibitor, MB, reversed these responses therefore suggesting that the NMDA-GIu-NO-cGMP pathway may be a new putative target in understanding the neurobiology of AD action. Finally, NOS activation following withdrawal suggest that inappropriate withdrawal during the treatment of depression may mediate neurodegenerative pathology observed in recurrent depression, possibly by severely increased hippocampal NOS activity which is toxic to neurons. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

Tulathromycin is a macrolide antibiotic approved for use in cattle and swine respiratory disease. Extra-label use of tulathromycin occurs in bison and deer and significant interspecies differences in pharmacokinetics warrant specific investigation in these species. This study involved investigation of the pharmacokinetics of tulathromycin in bison and white-tailed deer following a single 2.5 mg/kg bw subcutaneous injection (n=10) of Draxxin (Pfizer Inc.) to provide important information regarding tulathromycin dosage regimens in these species. As well, tulathromycin distribution and depletion in deer muscle and lung tissues following a 2.5 mg/kg bw subcutaneous injection of Draxxin was investigated to obtain pilot information regarding withdrawal time of tulathromycin in deer. For the pharmacokinetic studies, serial blood samples were collected at baseline and up to 25 days post-injection. Pharmacokinetic parameters were estimated using non-compartmental methods. For the tissue pilot study, deer (n = 2 to 3) were slaughtered at 0, 1, 2, 6, 7, and 8 weeks post-injection. A quantitative analytical liquid chromatography-mass spectrometry method for measuring tulathromycin was developed and validated in bison and deer serum and deer lung and muscle according to international guidelines. Samples were processed by solid-phase extraction. Reverse-phase chromatography was performed by gradient elution. Positive electrospray ionization was used to detect the double charged ion [M+2H]+2 at m/z 403.9 and monitored in selected ion monitoring mode. Tulathromycin demonstrated early maximal serum concentrations, extensive distribution, and slow elimination characteristics in deer and bison. In bison, mean Cmax (195 ng/mL) was lower compared to cattle (300 to 500 ng/mL) and half-life (214 hours) longer (cattle, 90 to 110 hours). In deer, mean Cmax (359 ng/mL) is comparable to cattle, but half-life (281 hours) was much longer. Tissue distribution and clinical efficacy studies are needed in bison to confirm extensive distribution of tulathromycin into lung and the appropriate dosage regimen. Tulathromycin was extensively distributed to deer lung and muscle, with tissue levels peaking within 7 to 14 days after injection. Drug tissue concentrations were detected 56 days after treatment, longer than the established withdrawal time of 44 days in cattle. This prolonged drug concentration in the tissue is supportive for the administration of tulathromycin as a single injection therapy for treatment of respiratory disease of deer. While more study is needed to establish a recommended withdrawal time, the long serum and tissue drug half-life and extensive interindividual variability in tissue levels suggests a withdrawal period well beyond 56 days may be required in deer.

No description available.

Chronic ethanol (EtOH) exposure produces neuroadaptations within the NMDA receptor system and alterations in HPA axis functioning that contribute to neurodegeneration during ethanol withdrawal (EWD). Chronic EtOH exposure and EWD, as well as corticosteroids, also promote increased synthesis and release of polyamines, which allosterically potentiate NMDA receptor open-channel time at the NR2B subunit. The current studies investigated effects of 10 day EtOH and corticosterone (CORT) co-exposure on toxicity during EWD in rat organotypic hippocampal slice cultures, and alterations in function and/or density of the NR2B subunit of the NMDA receptor that may mediate CORT-potentiation of toxicity during EWD. We hypothesized that toxicity during withdrawal following EtOH and CORT co-exposure would be greatest in the CA1 region due to increased NMDA NR2B receptor abundance and/or function. Cultures were exposed to CORT (0.01–1 μM) during 10 day EtOH exposure (50 mM) and 1 day EWD. Additional EtOH-naïve cultures were exposed to CORT for 11 days. Propidium iodide (PI) was used to measure toxicity in the CA1, CA3, and DG hippocampal regions. In EtOH-naïve cultures, 11 day exposure to CORT (0.01 – 1 μM) produced modest toxicity and in all regions. Exposure to CORT during EtOH exposure/EWD potentiated CORT-toxicity at all concentrations in the CA1 region. Ifenprodil, an NR2B polyamine site antagonist, significantly reduced toxicity from EtOH and CORT (0.1 μM) co-exposure during withdrawal. Immunohistochemistry and Western blot analyses were conducted for measurement of NR2B immunoreactivity in organotypic cultures, and autoradiography studies were conducted for measurement of polyamine-sensitive NR2B subunits with [3H]ifenprodil. Consistent increases in NR2B subunit protein were not detected with use of any methodology. Additional studies exposed cultures to a membrane impermeable form of CORT (BSA-conjugated CORT; 0.1 μM) with or without EtOH exposure and withdrawal. BSA-CORT exposure did not produce toxicity in any hippocampal region, suggesting that CORT toxicity was not mediated by membrane bound substrates. These data suggest that CORT and EtOH co-exposure result in increased function of polyamine-sensitive NR2B subunits, but this toxicity does not appear dependent on the number of hippocampal NMDA NR2B subunits.

Exposure to ethanol (ETOH) during fetal development results in a range of cognitive/behavioral deficits. There are differences in sensitivity to the effects of ETOH that could be explained by other factors, such as hypoxia. Similar mechanisms of damage underlie both ETOH, more specifically ETOH withdrawal, and hypoxia. Based on this overlap, it was hypothesized that sub threshold levels of these insults may interact to produce increased damage in sensitive brain regions. This study used a rodent organotypic hippocampal slice culture model to investigate the interaction of hypoxia and ETOH withdrawal and to determine possible developmental differences in the sensitivity to these insults. The combination of ETOH and hypoxia produced greater damage in the CA1 and CA3 hippocampal regions, as measured by propidium iodide uptake. Differences in outcome were noted between on postnatal (PND) 2 and PND 8 tissue. ETOH alone caused damage as measured by the neuronal marker NeuN, suggesting the ETOH/hypoxia interaction involves different cell types and that caution should be taken when determining appropriate levels of exposure. This data could explain why some offspring appear more sensitive to ETOH and/or hypoxic challenges during early life.

Depressive disorders are among the most frequent psychiatric diseases in the Western world with prevalence between 9% and 18%. Poor compliance and inappropriate antidepressant discontinuation invokes long-term morbidity, and appear linked to hippocampal shrinkage. Despite major advances in pharmacological treatment of the illness over the past 3040 years, currently available agents have distinct shortfalls both in clinical efficacy and in maintenance of response. This implies a greater long-term morbidity with significant impact on the patient, the patient's family as well as economic implications to health care managers and providers. The major reason for this state of affairs is our poor understanding of the neurobiology of depression and hence, of antidepressant (AD) action. AD drugs are thus not addressing the crucial neurobiological target underlying the illness, and new strategies and treatments are urgently needed. In recent years, depression has been associated with disturbances in excitotoxic glutamatergic activity, yet this has not been systematically evaluated. While the role of neurotransmitters such as serotonin, noradrenaline and dopamine has been extensively studied, new evidence suggests a role for the unique neurotransmitter nitric oxide (NO). Nitric oxide (NO), is activated by glutamatergic systems in various limbic and other regions of the brain, and has recently also been implicated in anxiety and affective disorders. Of special interest is the putative role of NO in cellular memory, synaptic plasticity and cell survival, all-important processes in the neuropathology and neurodevelopment of depression. Recent clinical studies have provided evidence of the role of the NO-pathway in depression, while preclinical studies have demonstrated the anxiolytic and antidepressant actions of nitric oxide synthase (NOS)-inhibitors. Moreover, NO interacts with other classical transmitters that have a regulatory role on mood, particularly the monoamines, as well as glutamate and gammaaminobutyric acid (GABA). In the current study the role of the NO-cGMP pathway in AD action was investigated, after chronic imipramine (IMI) and after IMI withdrawal, using a learned helplessness paradigm. Behavioural changes, hippocampal NOS activity and cGMP accumulation was determined together with pharmacological manipulation of the NO-cGMP pathway. Chronic IMI, 15 mg/kg/day intraperitoneal (ip) administration induced a pronounced reduction in swim immobility time in the forced swim test (FST), with no effect on horizontal or vertical locomotor activity. These behavioural changes were accompanied by a significant reduction in NOS enzyme activity and cGMP accumulation. In order to confirm the involvement of the NO-cGMP pathway in the AD action of IMI, chronic (3 weeks) IMI treatment was followed by an acute withdrawal of 7 days. Acute withdrawal, after chronic IMI treatment, resulted in a significant increase in swim immobility time and an increase in NOS enzyme activity and cGMP levels. In fact, NOS activity was raised above that of control, not just higher than the effect of chronic IMI. In order to assess the possible role of the NMDA-NO-cGMP pathway in AD withdrawal, the NMDA receptor antagonist, memantine, and the NOS/guanylyl cyclase (GC) inhibitor, methylene blue (MB), were administered during the 7 day IMI withdrawal period. Memantine (5 mg/kg/d ip), during the 7 day IMI withdrawal period, significantly reversed the increase in immobility time evoked after IMI withdrawal. This was accompanied by a significant reduction in NOS enzyme activity and a tendency to decrease cGMP levels. This data confirms that the antidepressant action of IMI, as well as IMI withdrawal, is associated with actions on the NMDA-GIu-NO-cGMP pathway. Particularly. IMI withdrawal evokes an increase in glutamate activity that is responsible for NOS activation. During the 7 day IMI withdrawal period, MB (15 mg/kg/d ip) also significantly reversed the increased immobility time after IMI withdrawal and was accompanied by a tendency to decrease NOS enzyme activity and cGMP levels in the rat hippocampus, however statistical significance was not reached. Although not emphatic, this data implies a possible role of the NO-cGMP pathway in AD action and AD withdrawal. In order to determine whether the observed IMI withdrawal effects on the NO-cGMP pathway may occur through an initial destabilisation in the serotonergic system, the 5-HT2a/2c receptor antagonist, ritanserin (4 mg/kg/d ip), was administered during the IMI withdrawal period. These studies revealed that antidepressant withdrawal evokes an increase in 5-HT2-mediated activity, and that antidepressant-induced NOS activation after withdrawal has its origin in serotonergic hyperactivity. Clearly, this is supportive of a distinct relationship between the NO and serotonergic system in antidepressant response. On its own, ritanserin was found to increase NOS and cGMP levels, yet during IMI withdrawal this response was lost, suggesting that IMI withdrawal alters the response to a 5-HT2a/2c receptor antagonist, which may have major clinical implications. In conclusion, the AD action of IMI, as well as chronic IMI withdrawal, involves actions on the NO-cGMP pathway. Withdrawal of ADS is associated with a loss of AD efficacy together with an increase in release of NO and cGMP. The NMDA antagonist, memantine, and the NOS/GC inhibitor, MB, reversed these responses therefore suggesting that the NMDA-GIu-NO-cGMP pathway may be a new putative target in understanding the neurobiology of AD action. Finally, NOS activation following withdrawal suggest that inappropriate withdrawal during the treatment of depression may mediate neurodegenerative pathology observed in recurrent depression, possibly by severely increased hippocampal NOS activity which is toxic to neurons. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

Girls’ withdrawal from school is posing a major challenge to female literacy in Afghanistan. The aim of this research was to examine the influence of Afghan traditions and cultural norms on girls’ school withdrawal by parents or guardians in Khinjan District of Baghlan Province. To achieve this aim the accounts of 12 mothers with daughters pulled out of school were obtained through semi-structured interviews and analyzed via the theoretical lens of Existentialist Feminism and Hofstede’s Cultural Dimensions Model. The findings suggest that in order to address the problem of girls’ withdrawal from school in Khinjan, the informal communication networks that reinforce the tendency of parents/guardians, especially male ones, to withdraw the girls from school should be influenced by communication channels in the district. Grounded on Paulo Freire’s concept of dialogue for liberation, it is recommended that credible members in the community should initiate and engage in a transforming dialogue about education of girls, with Khinjanis.

Šis darbas skirtas savanoriško atsisakymo pabaigti nusikalstamą veiką institutui, kaip specifinei aplinkybei, šalinančiai baudžiamąją atsakomybę, kuri Lietuvos baudžiamojoje teisėje sulaukusi nepagrįstai mažai dėmesio. Šiame darbe šis institutas išnagrinėtas lyginamuoju aspektu, lyginant jo reglamentavimą, teismų praktiką bei doktriną Lietuvoje ir keliose kitose kontinentinėse užsienio šalyse, bet pagrindinai - Vokietijoje – šalyje, turinčioje labiausiai išvystytą pasaulyje baudžiamosios teisės teismų praktiką bei doktriną. Magistrinio darbo tikslas – atskleisti savanoriško atsisakymo pabaigti nusikalstamą veiką instituto turinį, jo probleminius aspektus Lietuvos ir užsienio šalių baudžiamojoje teisėje ir, kiek leidžia šio darbo apimtis, rasti jų sprendimo būdus. Siekiant šių tikslų, darbe išanalizuotas šio instituto tikslingumas, vieta baudžiamosios teisės sistemoje, reglamentavimo ypatumai atskirose šalyse. Didžiausias dėmesys skirtas savanoriško atsisakymo pabaigti nusikalstamą veiką sąlygoms, jų analizei. Taip pat aptartos tokių baudžiamosios teisės institutų kaip aktyvi atgaila ir nepavykęs savanoriškas atsisakymas pabaigti nusikalstamą veiką sąsajos su savanoriško atsisakymo pabaigti nusikalstamą veiką institutu Lietuvos ir užsienio šalių baudžiamojoje teisėje. Didelis dėmesys darbe skirtas Vokietijos teismų praktikai, išsprendusiai daugelį savanoriško atsisakymo pabaigti nusikalstamą veiką instituto probleminių klausimų. / This work is intended to complete the voluntary withdrawal offense Institute , the specific context in which disposes of criminal responsibility , which is the age of criminal law Lithuania unduly little attention. In this paper, the Institute examined a comparative perspective , comparing its regulations , case law and the doctrine of Lithuania and several other onshore foreign countries , but mainly - in Germany - a country with the most developed in the world of criminal law case law and doctrine. Masters aim - voluntary refusal to disclose complete offense Institute content, the problematic aspects of Lithuanian and foreign criminal law and, within the scope of the work to find solutions. To achieve these goals , this paper analyzed the Institute of expediency , place the criminal justice system , regulatory characteristics of individual countries. Focuses on the voluntary withdrawal complete offense conditions of analysis. It also discussed criminal justice institutions such as the active repentance and voluntary waiver failure to complete the interface to the offense of voluntary withdrawal to complete the offense Institute of Lithuanian and foreign criminal law. Great attention to work for the German judicial practice , resolved many of the voluntary withdrawall to complete the offense Institute of problematic issues.

No description available.

Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 6 uppsatser.