Age-related inhibitory effects were investigated during spatial memory performance. In Experiment 1, 15 young (M = 20 years) and 16 old adults (M = 70 years) completed two spatial tasks (i.e., Block Suppression Test, Corsi Block Tapping Test) that differed in need for inhibitory processing. Accuracy differences within each task revealed age-related differences in spatial working memory and between task differences revealed that older adults had difficulty ignoring irrelevant items. Experiment 2 (10 young, 10 old adults) examined whether the distractibility of irrelevant items in the inhibition task (i.e. BST) accounted for the age-related inhibitory effects. Findings were largely consistent with the initial experiment indicating that inhibitory function was affected by adult aging.

Der niedrig dosierte Dexamethason-Suppressionstest (LDDST) wird als Screeningverfahren in der Diagnostik des Cushing-Syndroms angewendet. Allerdings können Faktoren wie die variable Resorption, sowie ein gesteigerter Metabolismus von Dexamethason die Testergebnisse beeinflussen und zu falsch positiven Resultaten führen. Ein falsch positives Testresultat wird hierbei insbesondere bei adipösen Patienten häufiger beobachtet. In der vorliegenden Arbeit wurde daher der Einfluss des Körpergewichts auf das Ergebnis des Dexamethason-Suppressionstestes (DST) untersucht. Hierzu wurden hospitalisierte Patienten und ein aus gesunden Probanden bestehendes Kontrollkollektiv rekrutiert und diese einem regulären LDDST unterzogen. Es konnte gezeigt werden, dass übergewichtige Menschen im Rahmen des DST signifikant niedrigere Dexamethasonwerte erreichen als normalgewichtige Personen. Es ist daher davon auszugehen, dass Unterschiede im Body-Mass-Index (BMI) Einfluss auf die Resorptionsrate und den Metabolismus von Dexamethason nehmen und daraus resultierend die Serum-Dexamethasonspiegel wesentlich verringern können. Diese Prozesse scheinen allerdings keinen nachhaltigen Einfluss auf die Cortisolsuppression im DST zu haben, da die Cortisolwerte nach Dexamethasongabe zwischen adipösen und nicht adipösen Testpersonen nicht signifikant differierten. Diese Ergebnisse belegen, dass ein Zusammenhang zwischen BMI-Unterschieden und der Dexamethasonkinetik im LDDST besteht. Die erniedrigten Dexamethasonspiegel bei übergewichtigen Patienten scheinen hierbei insbesondere durch das wesentlich höhere Verteilungsvolumen und durch Unterschiede im hepatogenen Metabolismus bedingt zu sein. Trotz der erniedrigten Dexamethasonwerte bleibt die Feed-Back-Sensitivität der Hypothalamus-Hypophysen-Nebennieren-Achse (HHNA) auch bei Adipositas erhalten, weshalb der LDDST als zuverlässiges Screeningverfahren bei adipösen Patienten mit Verdacht auf Cushing-Syndrom einzustufen ist.

Made available in DSpace on 2016-04-28T20:18:32Z (GMT). No. of bitstreams: 1 2008 - Pablo Maghelly Correa.pdf: 2175785 bytes, checksum: f499461ebaa5832e5ed7eaeddb46c38a (MD5) Previous issue date: 2008-09-16 / The present study had the participation of twenty dogs from the city of Rio de Janeiro being divided in two groups. The group 1 was formed by ten dogs with behaviors disorders anxiety disorders and aggressiveness and group 2 was formed by ten dogs clinically healthful. Owners of all dogs were interviewed guided by a data form containing opened and closed questions organized in four blocks: general aspects, behavior historical, stereotypic or ritualistic behavior and aggressiveness historical. After being classified as able to participate of the study they were submitted to the high dose dexamethasone suppression test to verify if there was a difference in the hypothalamic-pituitary-adrenal axis among the tested groups. No difference on the basal cortisol could be observed (p<0.05) among the two groups. All the individuals were considered suppressors. Therefore the high dose dexamethasone suppression test did not function as a diagnostic tool to confirm the behavioral problem dogs. / O presente estudo teve a participa??o de vinte c?es da cidade do Rio de Janeiro divididos em dois grupos. O grupo um foi formado por dez c?es com dist?rbios comportamentais transtornos da ansiedade e agressividade e o grupo dois foi formado por dez c?es clinicamente saud?veis. Os propriet?rios de todos os c?es foram entrevistados de forma guiada por question?rio estruturado com perguntas abertas e fechadas organizadas em quatro blocos: aspectos gerais, hist?rico comportamental, comportamentos estereotipados ou ritual?sticos e hist?rico de agressividade. Ap?s todos os animais foram submetidos ao teste de supress?o pela dexametasona em alta dose para verificar se havia diferen?a de funcionamento do eixo hipot?lamo-hip?fise-adrenal entre os grupos testados. N?o houve diferen?a significativa (p<0,05) do cortisol basal entre os grupos testados, sendo tamb?m todos os c?es supressores ao teste. Com isso, n?o foi poss?vel diferenciar animais com e sem dist?rbios comportamentais a partir do teste de supress?o alta pela dexametasona.

There are a number of links between the endocrine system and the nervous system. In this study, the impact of ischemic stroke on the endocrine system was investigated. Elderly volunteers were studied because data regarding the influence of advanced age on endocrine parameters were lacking. Only small differences in pituitary-thyroid and pituitary-adrenal hormone axes were found between two groups of elderly patients, 60 and 80 years of age. The 80-year-old age group had a lower thyrotropin response to thyrotropin releasing hormone (TRH) and a decline in dopamine excretion. Patients with acute ischemic stroke showed a pronounced hypercortisolism studied by the dexamethasone test and urine free cortisol measurements. In multiple regression analyses, postdexamethasone cortisol levels were positively correlated to proximity of the lesion to the frontal pole of the brain and disorientation. Urine cortisol levels were predicted by limb paresis, disorientation and body temperature. High cortisol excretion was associated with a worse functional outcome. Norepinephrine excretion was correlated to urine cortisol levels and to motor impairment. Patients with acute stroke had elevated free thyroxin indices. A paradoxical growth hormone response to TRH was found in the majority of stroke patients. In a multiple regression model disorientation was negatively correlated to thyrotropin response after TRH and positively correlated to prolactin response. Growth hormone response to TRH was associated with extensive paresis. In a cohort study diabetic and non-diabetic patients were prospectively studied after an initial stroke. Diabetes mellitus adversely influenced survival, the risk for a recurrent stroke and myocardial infarction. / <p>S. 1-66: sammanfattning, s. 69-190: 6 uppsatser</p> / digitalisering@umu

Background: Primary aldosteronism (PAL) has emerged as the commonest specifically treatable and potentially curable form of secondary hypertension. With its propensity towards cardiovascular complications above that expected from hypertension alone, PAL is a potentially highly detrimental state which should be detected as early as possible in the course of the disease and treated appropriately. The detection of earlier, milder, normokalaemic forms of PAL using the aldosterone/renin ratio (ARR) as a screening test has significantly enlarged the clinical spectrum of PAL and facilitated identification of a new familial variety (familial hyperaldosteronism type II, FH-II). Unlike familial hyperaldosteronism type I (FH-I), FH-II is not glucocorticoid remediable and is not caused by the CYP11B1/CYP11B2 “hybrid” gene mutation. The genetic defects underlying FH-II have not yet been elucidated and hence, detection of FH-II still involves complicated and time-consuming biochemical screening by ARR testing and confirmation by carefully performed suppression testing such as fludrocortisone suppression testing. Diagnosing PAL by currently available biochemical methods is tedious. Finding a simple and reliable genetic test for FH-II which could be applied to all members of a family with known FH-II and also to apparently sporadic PAL would simplify patient management. A genome-wide search has already demonstrated linkage of FH-II to chromosome 7p22, consistent with this locus harbouring the causative gene/s for FH-II. Three candidate genes [retinoblastoma-associated Kruppel-associated box gene (RBaK, involved in tumorigenesis and cell cycle control), postmeiotic segregation increased 2 (PMS2, involved in DNA mismatch repair and tumour predisposition) and guanine nucleotide-binding protein alpha-12 (GNA12, a transforming oncogene)] within this linked locus have been examined in an attempt to find the causative mutations for FH-II, but no clear causative mutations have so far been found. PAL continues to be a challenging yet rewarding disease to manage. Although much has been learnt about PAL, there are still many areas which have not been explored. PAL considered due to bilateral autonomous production of aldosterone is usually treated medically because unilateral adrenalectomy has been considered ineffective. Since medical treatment may cause adverse effects or fail to control hypertension, defining the role of unilateral adrenalectomy in bilateral PAL is an important clinical issue, but quality outcome data are lacking. The candidate therefore peformed a retrospective study of the efficacy of unilateral adrenalectomy in patients with bilateral PAL. In patients with unilateral PAL, unilateral laparoscopic adrenalectomy has been shown to correct hypokalaemia and lead to cure or improvement in hypertension control. While most studies have focused on clinical and biochemical outcomes, to the candidate’s knowledge, there are no data on the effects of adrenalectomy on quality of life (QOL). Assessing the QOL in patients with unilateral PAL before and after unilateral laparoscopic adrenalectomy (which cured hypokalaemia in all and hypertension in the majority) provided an insight into the degree to which the disease process and/or its treatment affects the life of an individual with PAL. Aims: The overall aims of this thesis were to further explore the genetic basis of FH-II, to examine the role of adrenalectomy in patients with bilateral PAL and the effects of unilateral adrenalectomy on QOL in unilateral PAL as a first step in dissecting out the effects of medical and surgical treatment on QOL in the more common bilateral PAL. In order to address the overall aims, the specific aims of the thesis were (1) to narrow the linked region at 7p22 by phenotyping and genotyping additional FH-II families from Italy, using more closely spaced microsatellite markers at 7p22, and then assess the combined multipoint logarithm of odds (LOD) score for these Italian as well as two Australian and one South American families; (2) to sequence candidate genes in the narrowed linked region for FH-II associated mutations; (3) to assess the role of unilateral adrenalectomy in bilateral PAL and identify predictive parameters; and (4) to assess the quality of life following unilateral adrenalectomy in patients with unilateral PAL. Methods and Results: Two Italian families with FH-II were genotyped using seven closely spaced microsatellite markers at 7p22. All known affected individuals from each of the two Italian families were found to share identical haplotypes for the seven markers, consistent with linkage of the disease locus with the 7p22 region. The multipoint LOD score of the now five known families with FH-II which demonstrate linkage at 7p22, calculated using MERLIN linkage analysis was highly significant at 5.22. Three candidate genes in this linked region were then examined for mutations causing FH-II; the replication protein A 3 (RPA3), zinc finger protein 12 (ZNF12) and glucocorticoid induced transcripts 1 (GLCCI1) genes were selected as they are involved in cell cycle control, and adrenal hyperplasia and adenomas are common in FH-II. Using the method of polymerase chain reaction-sequencing, coding regions, splice sites, proximal promoter, 5’ and 3’ untranslated regions (UTR) were sequenced in affected and unaffected subjects from the 7p22-linked FH-II families. Identified single nucleotide polymorphisms (SNPs) were genotyped to assess significance. For RPA3, four different SNPs were initially found to segregate with the affectation status, that is, they were present in the two affected and not the two unaffected subjects from the largest Australian family (family 1, eight affecteds) with FH-II. However, only two SNPs (rs2024374 G/C and rs17169194 T/G) were further genotyped as that they were in functionally important positions of the gene (that is, in regulatory regions within the promoter and 5’ UTR) and because of the relatively low allele frequency reported in the literature for these two SNPs in controls. Further genotyping of these SNPs was carried out in another six affecteds and four unaffecteds from the same family and a complete segregation of these two SNPs with affectation status was seen in family 1. The G/C mutation rs2024374 in the RPA3 promoter results in the loss of three transcription factor binding sites and creation of one new site. The factors for which the binding sites in the RPA3 promoter and 5’UTR were altered by these two SNPs were involved in regulation of cell differentiation, proliferation and apoptosis. Hence, it is possible that altered activity of the RPA3 promoter and 5’UTR in family 1 could result in predisposition to adrenal hyperplasia or neoplasia, altered ARR and/or hypertension. Genotyping of these SNPs was then carried out in another two pedigrees (families 2 and 3) that showed linkage to 7p22, and in 75 normotensive, non-PAL control subjects. However, neither of these two SNPs segregated with the affectation status in family 2 and 3, and they were present in 30% and 20% of controls, respectively. For ZNF12 and GLCCI1, no evidence of causative mutations was found in the coding regions, splice sites, proximal promoter region and proximal 5’ and 3’ UTR. Between 1984 and 2004, 51 of 684 patients diagnosed with bilateral PAL underwent unilateral adrenalectomy. Forty patients fulfilled the inclusion criteria and were followed for at least 12 (median 56.4) months. Hypertension was cured in 15% and improved in 20%, usually within one year of unilateral adrenalectomy. The proportion with controlled hypertension was significantly (p<0.001) higher after adrenalectomy (65%) than before (25%). Mean systolic (p<0.001) and diastolic (p<0.001) blood pressure, left ventricular mass index (p<0.05) and aldosterone/renin ratio (p<0.001) fell. Serum creatinine independently predicted hypertension cure. From 2007 through 2008, QOL was evaluated prospectively using the internationally validated SF-36 questionnaire before and 3 and 6 months post-operatively in 22 patients [14 males, 8 females; mean age 50.0 ± 2.0 (range 27-69) years] with unilateral PAL who underwent adrenalectomy within the Endocrine Hypertension Centre, Greenslopes and Princess Alexandra Hospitals. Pre-operatively, the SF36 score for each QOL domain was lower for PAL patients than reported for the Australian general population, significantly so for physical functioning (p<0.05), role physical (p<0.001), vitality (p<0.001) and general health (p<0.05). Compared with pre-adrenalectomy, there were significant increments in mean scores at 3 months for physical functioning (p<0.05), role physical (p<0.05), general health (p<0.001), role emotional (p<0.05), social functioning (p<0.05), mental health (p<0.001) and vitality (p<0.001); and at 6 months for physical functioning (p<0.05), role physical (p<0.05), general health (p<0.05), role emotional (p<0.05), mental health (p<0.05) and vitality (p<0.001). Mean SBP and DBP improved significantly (p<0.001), with 86% of these patients cured (BP≤140/90, no drugs) and the remaining 14 % improved. Mean plasma potassium (p<0.001) and renin concentration rose (p<0.01), whereas mean upright plasma aldosterone (p<0.001), aldosterone/renin ratio (p<0.001) and number of antihypertensive agents fell (p<0.001). Conclusion: In the Italian families with FH-II available for study, work by the candidate included in this thesis confirmed linkage of FH-II to chromosome 7p22. The combined multipoint LOD score of 5.22 for the five families showing linkage at 7p22 was highly significant. Linkage to 7p22 in Italian families with FH-II extends the previous positive findings to a third geographical area, bringing greater certainty regarding the importance of this locus in identifying causative mutations. Although no clear causative mutations were found in the three 7p22 candidate genes examined, it is conceivable that the rs2024374 G/C and/or rs17169194 T/G SNPs in RPA3 could act in conjunction with another 7p22 mutation in family 1, resulting in the FH-II phenotype. Examination of the outcome of unilateral adrenalectomy in patients with bilateral PAL suggests that this surgical approach can be beneficial in certain carefully selected patients and should not be automatically excluded as a treatment option. Unilateral adrenalectomy in patients with unilateral PAL has positive impacts not only on clinical and biochemical parameters but also on QOL. The findings of this thesis provide new insights into the genetic basis and therapeutic options and treatment outcomes of PAL and further highlight its importance as a common, genetically based, specifically treatable and potentially curable cause of hypertension and cardiovascular disease. It also points the way to potentially very useful studies in future by exploring longer term effects of unilateral laparoscopic adrenalectomy as treatment for PAL on QOL, to compare unilateral adrenalectomy in those with unilateral versus bilateral PAL, and to compare surgery with specific medical treatment.

Der niedrig dosierte Dexamethason-Suppressionstest (LDDST) wird als Screeningverfahren in der Diagnostik des Cushing-Syndroms angewendet. Allerdings können Faktoren wie die variable Resorption, sowie ein gesteigerter Metabolismus von Dexamethason die Testergebnisse beeinflussen und zu falsch positiven Resultaten führen. Ein falsch positives Testresultat wird hierbei insbesondere bei adipösen Patienten häufiger beobachtet. In der vorliegenden Arbeit wurde daher der Einfluss des Körpergewichts auf das Ergebnis des Dexamethason-Suppressionstestes (DST) untersucht. Hierzu wurden hospitalisierte Patienten und ein aus gesunden Probanden bestehendes Kontrollkollektiv rekrutiert und diese einem regulären LDDST unterzogen. Es konnte gezeigt werden, dass übergewichtige Menschen im Rahmen des DST signifikant niedrigere Dexamethasonwerte erreichen als normalgewichtige Personen. Es ist daher davon auszugehen, dass Unterschiede im Body-Mass-Index (BMI) Einfluss auf die Resorptionsrate und den Metabolismus von Dexamethason nehmen und daraus resultierend die Serum-Dexamethasonspiegel wesentlich verringern können. Diese Prozesse scheinen allerdings keinen nachhaltigen Einfluss auf die Cortisolsuppression im DST zu haben, da die Cortisolwerte nach Dexamethasongabe zwischen adipösen und nicht adipösen Testpersonen nicht signifikant differierten. Diese Ergebnisse belegen, dass ein Zusammenhang zwischen BMI-Unterschieden und der Dexamethasonkinetik im LDDST besteht. Die erniedrigten Dexamethasonspiegel bei übergewichtigen Patienten scheinen hierbei insbesondere durch das wesentlich höhere Verteilungsvolumen und durch Unterschiede im hepatogenen Metabolismus bedingt zu sein. Trotz der erniedrigten Dexamethasonwerte bleibt die Feed-Back-Sensitivität der Hypothalamus-Hypophysen-Nebennieren-Achse (HHNA) auch bei Adipositas erhalten, weshalb der LDDST als zuverlässiges Screeningverfahren bei adipösen Patienten mit Verdacht auf Cushing-Syndrom einzustufen ist.