Made available in DSpace on 2016-06-02T20:19:08Z (GMT). No. of bitstreams: 1 1843.pdf: 1192914 bytes, checksum: 124690357d5fd2c475721de4dd0a5c76 (MD5) Previous issue date: 2008-02-27 / Financiadora de Estudos e Projetos / As lesões musculares são bastante comuns na prática esportiva e na reabilitação ortopédica. A terapia laser de baixa intensidade (TBLI) apresenta bons resultados no tratamento de diferentes afecções que acometem o tecido muscular esquelético, entretanto a fluência utilizada neste tratamento ainda é controversa. Este estudo tem como objetivo verificar os efeitos de diferentes fluências do laser de λ= 830nm no processo de regeneração muscular. Foram utilizados ratos machos Wistar, distribuídos em 8 grupos de 7 animais cada: grupo controle (C); grupos em que os músculos tibial anterior direito (TAD) foram apenas irradiados com laser diodo (λ= 830nm) com fluência de 4J/cm 2 (4J), 8J/cm 2 (8J) e 16J/cm2 (16J); grupo lesão (CL), no qual o músculo foi submetidos à criolesão; grupos em que os músculos TAD foram submetidos à criolesão e tratados com laser diodo (λ= 830nm) com fluência de 4J/cm 2 (L6J), 8J/cm 2 (L8J), 16J/cm2 (L16J). A irradiação teve início 24horas após a lesão por 5 dias consecutivos de forma pontual, sobre a área de lesão. No sexto dia após a lesão, os animais foram eutanaziados. O sangue foi coletado para avaliação dos níveis plasmáticos de NOx-, através da técnica de Griess. A avaliação muscular contou com análises histológicas da área de lesão (Hematolina e Eosina e Fosfatase Ácida). Além disso, a atividadade da COX-2 foi analisada pelas técnicas de Biotin Switch e a atividade e expressão protéica de MMP-2 por técnica de Zimografia e Western Blotting, respectivamente. Os resultados mostraram que houve uma diminuição da área de lesão conforme aumento da fluência do laser (8J/cm2 e 16J/cm2); um aumento nos níveis plasmáticos de NOx- em todos grupos lesados e uma diminuição apenas no grupo L16J em relação aos grupos lesados; a COX-2 foi ativada apenas nos grupos CL e L4J; a atividade da MMP-2 aumentou em todos grupos lesados e a expressão protéica aumentou nos grupos L8J e L16J. Conjuntamente os resultados permitem concluir que as fluências de 8J/cm2 e 16J/cm2 foram as que apresentaram um melhor desempenho na TLBI nos processos que envolvem regeneração do músculo esquelético de ratos. Este estudo trouxe dados importantes para o uso clínico, pois confrontou variáveis importantes como o comportamento de diferentes fluências no processo de regeneração muscular, proporcionando verificar um protocolo de aplicação mais seguro e eficaz.

V této práci se zabýváme metodami pro regresní analýzu výskytu opako- vaných událostí, při které je třeba se vypořádat se závislostí čas· do události v rámci jednoho subjektu. V první části práce se zabýváme možným rozšířením Coxova modelu proporcionálního rizika, který se využívá při analýze cenzoro- vaných dat, pro analýzu výskytu opakovaných událostí. Hlavní část práce je věnována odhadu parametr· v marginálních modelech a jejich asymptotickým vlastnostem. Následně se zabýváme i odhadem parametr· v marginálních mo- delech pro mnohorozměrná cenzorovaná data. Vhodnost použití marginálních model· je zkoumána pomocí simulací. 1

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Os antiinflamatÃrios podem apresentar efeitos diferenciados quanto a eficÃcia terapÃutica, podendo, alguns serem bons analgÃsicos e outros potentes antiinflamatÃrios. Neste estudo, foram avaliados e comparados os efeitos anti-edematogÃnicos de antiinflamatÃrios nÃo esteroidais seletivos COX-2, lumiracoxibe 5mg/Kg, 30mg/Kg, 100mg/Kg, relativamente seletivos, nimesulida 25mg/Kg, meloxicam 30mg/Kg, nÃo seletivos COX, diclofenaco de sÃdio 20mg/Kg, alÃm dos glicocorticÃides dexametasona (3mg/Kg) e hidrocortisona (4mg/Kg), no clÃssico modelo de edema em pata de rato induzido por carragenina (EPICg). Cada grupo com 4 animais, recebia uma hora antes da injeÃÃo subcutÃnea (s.c) intraplantar do estÃmulo inflamatÃrio a dose referente de cada droga a ser testada, sendo que o grupo-controle recebia soluÃÃo salina 0,9%. ApÃs uma hora da administraÃÃo destas doses, 0,1mL de carragenina a 1% era injetada na pata direita de cada animal. O volume da pata edemasiada foi aferido quatro vezes em intervalos de uma hora, em um pletismÃgrafo digital (Ugo Basile Â).O efeito antiedematogÃnico de cada droga testada foi determinado pela comparaÃÃo dos resultados com o grupo-controle atravÃs do teste ANOVA. Dexametasona (3mg/Kg) e diclofenaco (20mg/Kg) foram as drogas com melhor desempenho, com taxa de reduÃÃo significativa do edema, na 3Â hora, em 94,20% e 84,43%, respectivamente. JÃ o lumiracoxibe, nas trÃs concentraÃÃes utilizadas, 5mg/Kg, 30mg/Kg, 100mg/Kg, obteve efeito significativo na reduÃÃo do edema, com 47,49%, 61,21%, 47,76% respectivamente na 3Â hora. Meloxicam, nimesulida e hidrocortisona tambÃm demonstraram eficiÃncia, com taxas de 42,48%, 62,27% e 58,84%, respectivamente. O presente estudo demonstrou que dexametasona (3mg/Kg) e diclofenaco (20mg/Kg) apresentaram potente aÃÃo antiedematogÃnica e que drogas mais seletivas COX-2 nÃo mostraram eficÃcia comparÃvel ao diclofenaco / The anti-inflammatories might present several efects about de therapeutical efficacy being some powerful antiinflammatories, but others act as excellent analgesics. In this study were observed and compared the anti-edematogenic efects of selective COX-2 non-steroidal antiinflammatories, lumiracoxib 5mg/Kg, 30mg/Kg, 100mg/Kg, relatively selected, nimesulide 25mg/Kg, meloxicam 30mg/Kg, non selective COX, diclofenac 20mg/Kg, yet of the glucocorticoids dexamethasone (3mg/Kg) and hydrocortisone (4mg/Kg), on the classic model of the edema on rat paw induced by carrageenan. Each group of four animals got one hour before the subcutaneous injection (sc) of the inflamatory estimulation the dosage of each drug to be tested, being that the control group received saline solution 0.9%. After one hour of the management of those dosages, 0.1% to 1% of carrageenan was injected in the right paw of each animal. The volume of the edema paw was checked four times in between one hour breaks, in a digital pletismograph (Ugo Basile Â).The antiedematogenic effect of each tested drug was determined by the comparission of the results with the control group through the ANOVA test. Dexamethasone (3mg/Kg) and Diclofenac (20mg/Kg) were the drugs with best performance with significative reduction rate of the edema, on the third hour, in 94.20% and 84.43% respectively. But the lumiracoxib on the three concentrations used, 5mg/Kg, 30mg/Kg, 100mg/Kg got significative effect on the reduction of the edema with 47,49%, 61,21%, 47,76% respectively on the third hour. Meloxicam, nimesulide and hydrocortisone also demonstrated eficiency with rates of 42,48%, 62,27% and 58,84% respectively. The current study demonstrated that dexamethasone (3mg/Kg) and diclofenac (20mg/Kg) presented potencial antiedematogenic action and that more COX-2 selective drugs didnât show eficacy comparable to diclofenac

nÃo hà / Esse estudo tem por finalidade avaliar os efeitos de inibidores seletivos da COX (cetorolaco e celecoxibe) e de inibidores nÃo seletivos (indometacina) da COX sobre o transporte ileal de Ãgua e eletrÃlitos em ratos anestesiados. TambÃm se propÃe a avaliar as alteraÃÃes vilo/cripta do Ãleo de ratos tratados com inibidores seletivos e nÃo seletivos da COX-1 e 2 (cetorolaco-inibidor especÃfico da COX-1 na dose de 3mg/Kg, celecoxibe-inibidor especÃfico da COX-2 e indometacina-inibidor nÃo seletivo da COX). Os animais foram tratados per os durante trÃs dias consecutivos com uma das seguintes substÃncias: cetorolaco (3mg/Kg), celecoxibe (10mg/Kg), indometacina (5mg/Kg), cetorolaco + celecoxibe, salina 0,9% ou tampÃo fosfato. Todos os AINES aqui utilizados foram diluÃdos em soluÃÃo salina (Nacl a 0,9%) exceto a indometacina que foi diluÃda em soluÃÃo tampÃo fosfato. ApÃs jejum de 24 horas com livre acesso à Ãgua, os animais foram anestesiados com Uretana (1,2mg /kg corporal, i.p). A seguir realizou-se laparotomia mediana para isolamento do segmento a ser perfundido. CÃnulas foram introduzidas nas extremidades proximal e distal do segmento mediante criaÃÃo de fÃstulas. O segmento isolado e as cÃnulas formaram o circuito que foi perfundido. Para a perfusÃo foi utilizada soluÃÃo modificada de Ringer e FenolsulftaleÃna 50mg/L como marcador nÃo absorvÃvel. O perfusato foi coletado em tubos de ensaio apÃs 40min (03 amostras). TambÃm foram obtidas 3 (trÃs) amostras no inÃcio e no final (03 amostras) do experimento, para determinaÃÃo dos parÃmetros controle. Foram determinadas as diferenÃas entre as amostras controle e as coletas do perfusato quanto aos valores das concentraÃÃes de sÃdio, potÃssio e cloreto (mmol/L). Ao final do experimento, os animais foram sacrificados e o segmento ileal perfundido retirado, sendo imediatamente pesado, depois retirados anÃis distais de aproximadamente 0,5 cm para o histopatolÃgico. Nova mediÃÃo de peso desse segmento foi realizada apÃs o mesmo ser mantido em estufa a 100oC por 48h, de modo a permitir a correÃÃo dos parÃmetros funcionais. A administraÃÃo de cetorolaco aos animais promoveu secreÃÃo ileal de Ãgua, de sÃdio, cloreto e potÃssio. Por outro lado, o tratamento com celecoxib, sozinho ou em associaÃÃo com cetorolaco, bem como o tratamento com indometacina nÃo desencadearam alteraÃÃes significativas na secreÃÃo de Ãgua, sÃdio, cloro e potÃssio, quando comparado com os grupos controles. Em relaÃÃo as alteraÃÃes morfomÃtricas, os tratamentos com celecoxibe sozinho ou em associaÃÃo com cetorolaco, promoveram um aumento da relaÃÃo vilo/cripta. Por outro lado, a administraÃÃo de cetorolaco aos animais nÃo modificou a relaÃÃo vilo/cripta quando comparado com o controle. Por outro lado, no tratamento com indometacina, a administraÃÃo de indometacina apresentou uma diminuiÃÃo na relaÃÃo vilo/cripta, quando comparado com o controle. Baseado nestes dados podemos concluir, que a inibiÃÃo da COX-1 pelo cetorolaco, mas nÃo a inibiÃÃo da COX-2 pelo celecoxib, desencadeia uma alteraÃÃo funcional na secreÃÃo de Ãgua e eletrÃlitos no Ãleo, pois nÃo houve lesÃo do epitÃlio na anÃlise histolÃgica do intestino de ratos tratados com a cetorolaco. / The aim of this study was to evaluate the effects of selective and non-selective COX inhibitors on water and electrolyte transport and the villous/crypt ratio in the ileum of anesthetized rats. Thirty-six animals distributed in 6 groups were treated with 3mg/Kg ketorolac (a selective COX-1 inhibitor), 10mg/Kg celecoxib (a selective COX-2 inhibitor), 5mg/Kg indometacin (a non-selective COX inhibitor),ketorolac+celecoxib, 0.9% saline solution or phosphate buffer for 3 consecutive days. Ketorolac and celecoxib were diluted in 0.9% saline solution, while indometacin was diluted in phosphate buffer. Following 24 hours of fasting with access to water ad libitum, the animals were anesthetized with 1.2mg/Kg urethane i.p. and submitted to median laparotomy to isolate an ileal segment for perfusion. Cannulae were introduced through surgically created fistulas in the proximal and distal extremities of the segment. Perfusion was performed with modified Ringer solution containing 50mg/L phenolsulfonphthalein (a non-absorbable marker). After 40 minutes, 3 samples of perfusate were collected. In addition, 3 control samples were collected at baseline and by the end of the experiment for comparison of sodium, potassium and chloride concentrations (mmol/L). Finally the animals were euthanized, the extremities of the perfused segment were cut off (5-mm rings) for histopathological examination and the segment was weighed. After 48 hours of storage at 100oC, the segment was weighed again in order to correct the functional parameters. The administration of ketorolac promoted secretion of ileal water, sodium, potassium and chlorine. However, treatment with celecoxib alone or with ketorolac, and indomethacin treatment did not induce significant changes in the secretion of water, sodium, potassium and chlorine, when compared with control groups. In the histological evaluation, treatment with celecoxib alone or in combination with ketorolac, induced an increase in villous / crypt ration. On the other hand, ketorolac administration did not change the villous / crypt ration when we compared with the control. Indomethacin treatment induced a decrease in villous / crypt ration compared with the control. Based on these data we can conclude that inhibition of COX-1 by ketorolac, but not COX-2 inhibition by celecoxib, induced a functional change in the ileal water and electrolytes secretion, since there was not epithelial damage in the histological analysis of intestine of rats treated with ketorolac.

The worldwide population of patients with chronic kidney disease (CKD) is growing, with estimated prevalence at 12-15% of adults. Of particular concern are those with late stage CKD, defined as an estimated glomerular filtration rate (eGFR)of less than 30 ml/min/1.73m2, as they are susceptible to the highest risk of adverse outcomes such as progression to end stage kidney disease (ESKD), cardiovascular disease and all-cause mortality (1, 2). As such, late stage CKD patients are often managed in specialized clinics with set clinical targets, standardized education and multi-disciplinary care(3). A key clinical target for therapeutic intervention and prevention of the progression of CKD is blood pressure (BP) reduction(4). Yet, multiple relevant questions remain regarding the strength and nature of association of BP with clinical outcomes in late stage CKD. As the risks of hypotension-related complications are high in late stage CKD, it remains unclear whether strict BP control delays CKD progression in a real world clinic population(5). Furthermore, it is unclear how to appropriately specify the nature of the longitudinal association between BP and clinical outcomes of ESKD and mortality. The overall objective of this thesis is to examine the longitudinal association of BP and adverse clinical outcomes in a cohort of 1203 patients (mean eGFR 17.8 ml/min/1.73m2; mean of 6.7 BP measures per patient) with late stage CKD. In our first paper we examined the association of repeat measures of BP with CKD progression, defined as a decline in eGFR. When modeling eGFR using longitudinal linear regression, we found that its over-time trajectory was non-linear and that this trajectory was modified by BP; thus, we found a significant time-dependant association between BP and eGFR. When modeling time to eGFR decline ≥ 30% using Cox proportional hazards regression with categorized BP specified as a time-dependent exposure, BP was significantly associated with risk of eGFR decline; in particular, extremes of low and high systolic blood pressure (SBP) and high diastolic blood pressure (DBP) significantly increased the risk of eGFR decline. In our second paper, we examined different methods of modelling longitudinal BP and its association with time to mortality and ESKD. We found that elevations in SBP and DBP, in particular, when expressed as current (most recent visit), lag (previous visit), and cumulative exposure were significantly associated with increased risk of ESKD while low SBP (current, lag and cumulative exposure) was significantly associated with increased risk of mortality. Baseline BP measures were not statistically significantly associated with any outcomes. In patients with more moderate ranges of SBP (121-140) or DBP (60-85) at baseline, a subsequent rise to >160 or > 85 respectively, was associated with an increased risk of ESKD. Thus, longitudinal BP measures in late-stage CKD are significantly associated with adverse outcomes and convey important information beyond baseline BP measures.

The diploma thesis is focused on process stability and capability assessment. It describes certain types of control charts, basic capability indices as well as Box-Cox transformation. The practical part of the study is concerned with applying control charts on generated data and consequently on real data. By this, it focuses on comparing various methods of estimating sample standard deviation and on the impact of non-compliance with the assumption of normal distribution of process variable on process stability and capability assessment.

Einleitung: Die Mucositis enoralis stellt die bedeutendste und schwerwiegendste frühe Nebenwirkung bei der Strahlentherapie fortgeschrittener Kopf-Hals-Tumoren dar. Sie führt häufig zu einer Unterbrechung der Behandlung, mit der Folge einer reduzierten Tumorheilungschance. Des Weiteren wirkt sie sich nachteilig auf die Lebensqualität aus, erhöht das Risiko später Nebenwirkungen und Infektionen und stellt einen erheblichen Kostenfaktor dar. Trotz umfangreicher experimenteller und klinischer Untersuchungen wurde bisher keine allgemein anerkannte Strategie zur Prophylaxe oder Therapie der Mucositis enoralis klinisch etabliert. Die Blockade der Cyclooxygenase-2 (COX-2), welche in einer Reihe von Tumoren überexprimiert wird, wird in der Kombination mit einer Strahlentherapie diskutiert. Außerdem kommen COX-2-Inhibitoren als entzündungshemmende Medikamente therapiebegleitend zum Einsatz. C-Jun und NF-kB p50 sind Transkriptionsfaktoren, die möglicherweise in der Pathogenese der radiogenen Mukositis eine wichtige Rolle spielen. Ziel der Untersuchungen: Ziel der vorliegenden Arbeit ist es, die Wirkung von Celecoxib, einem selektiven COX-2-Inhibitor, auf die Strahlenreaktion der oralen Mukosa (Zellzahl, Epitheldicke) und die epitheliale Expression von c-Jun und NF-kB p50 im etablierten Tiermodell der Schleimhaut der Zungenunterseite der Maus zu untersuchen. So soll festgestellt werden, ob eine Interaktion zwischen den begleitenden Entzündungsreaktionen und der eigentlichen epithelialen Strahlenreaktion besteht. Material und Methoden: In vorangegangenen Untersuchungen wurden die Schnauzen von Mäusen des Stammes C3H/Neu mit 5x3 Gy/Woche über 2 Wochen (Tag 0-4, 7-14) bestrahlt (200 kV Röntgenstrahlung). In einer weiteren Versuchsgruppe erhielten die Tiere täglich an den Tagen 0 bis 13 25 mg/kg/Tag Celecoxib oral per Schlundsonde. Im vierzehntägigen Untersuchungszeitraum wurden täglich jeweils 5 Mäuse je Versuchsgruppe getötet, deren Zungen entnommen und fixiert. In diesem Zustand wurde das Material von der Autorin dieser Arbeit übernommen. Mit Hilfe eines Zählrasters wurden in den vorliegenden Untersuchungen die Zellzahl, die Epitheldicke und die Expression von c-Jun und NF-kB p50 im Epithel der Zungenunterseite der unbehandelten Kontrolle (n = 5), während alleiniger Bestrahlung, sowie nach Bestrahlung und Gabe von Celecoxib manuell erfasst. Aufgrund der geringen Tierzahlen pro Untersuchungszeitpunkt (n = 5) und Versuchsgruppe wurde auf eingehende statistische Analysen verzichtet. Die vorliegende Arbeit beschränkt sich auf eine beschreibende Darstellung des Verlaufs der Einzelparameter über den Gesamtzeitraum. Ergebnisse: Das unbehandelte Epithel besteht aus 402 ± 11 Zellen, wobei 281 ± 8 Zellen der Germinativ- und 121 ± 4 Zellen der funktionellen Schicht angehören. Die Dicke des Gesamtepithels beträgt 68 ± 3 μm. Davon nehmen Germinativ- und Keratinschicht je 15 ± 1 μm und die funktionelle Schicht 38 ± 4 μm ein. Im Kontrollepithel wird c-Jun von 81 % der Zellen der funktionellen und von 80 % der Zellen der Germinativschicht exprimiert, wobei die funktionelle Schicht scheinbar eine größere Färbeintensität aufweist. NF-kB p50 wird von 79 % der Epithelzellen exprimiert, wobei eine stärkere Expression in der Germinativschicht zu beobachten ist. Bei alleiniger fraktionierter Bestrahlung verringert sich die Zellzahl innerhalb der ersten Woche auf 68 % des Kontrollwertes und bleibt anschließend trotz weiterer Bestrahlung weitestgehend konstant. Der größere Anteil an Zellen geht dabei in der funktionellen Schicht verloren. Die Epitheldicke nimmt in der ersten Bestrahlungswoche bis auf 113 % zu und liegt in der folgenden Woche im normalen bis subnormalen Bereich. Die epitheliale c-Jun-Expression nimmt unmittelbar nach Bestrahlungsbeginn zu und liegt anschließend während des gesamten Beobachtungszeitraums über dem Kontrollbereich. Während der gesamten Bestrahlung liegt die Färbeintensität der funktionellen Schicht weiterhin über derer der Germinativschicht. Auch bei NF-kB p50 nimmt die Färbeintensität in der ersten Bestrahlungswoche zu und bleibt anschließend erhöht. Der Anteil NF-kB p50 exprimierender Zellen ist in der Germinativschicht scheinbar größer als in der funktionellen Schicht. Unter zusätzlicher Celecoxibgabe liegen die Zellzahlen vom 6.-12. Tag des Beobachtungszeitraums vermutlich unterhalb derjenigen bei alleiniger Bestrahlung. Dieser Effekt ist besonders innerhalb der Germinativschicht sichtbar. Der Anstieg der Epitheldicke in der ersten Bestrahlungswoche fällt bei zusätzlicher Celecoxibtherapie stärker aus. Im weiteren Verlauf sind kaum Differenzen zu verzeichnen. Die epitheliale Färbeintensität von c-Jun unterscheidet sich kaum von den alleinig bestrahlten Tieren. Bei NF-kB p50 ist dies mit Ausnahme einer scheinbar geringeren Expressionsintensität am 8. und 13. Beobachtungstag ebenso. Schlussfolgerungen: Bei der frühen Strahlenreaktion der Mundschleimhaut werden c-Jun und NF-kB p50 verändert exprimiert. Celecoxib reduziert im Vergleich zur alleinigen Bestrahlung die Zellzahl und verstärkt die Zunahme der Epitheldicke. Es hat keinen Einfluss auf die Expression von c-Jun und NF-kB p50. Somit ist die Regulation der Aktivität von c-Jun und NF-kB p50 unabhängig von der Aktivität von COX-2 erfolgt.

The fuel consumption of a seagoing vessel is, through a combination of Box-Cox transforms and principal component analysis, reduced to a univariatefunction of the primary principle component with mean model error −3.2%and error standard deviation 10.3%. In the process, a Latin-hypercube-inspired space partitioning sampling technique is developed and successfully used to produce a representative sampleused in determining the regression coefficients. Finally, a formal optimisation problem for minimising the fuel use is described. The problem is derived from a parametrised expression for the fuel consumption, and has only 3, or 2 if simplified, free variables at each timestep. Some information has been redacted in order to comply with NDA restrictions. Most redactions are either names (of vessels or otherwise), units, andin some cases (especially on figures) quantities. / <p>Presentation was performed remotely using Zoom.</p>

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Alzheimer's disease (AD), the most common form of dementia, is a chronic neurodegenerative disease. The HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) gene is expressed in human brain and may play a role in the pathogenesis of neurodegenerative disorders. Till now, no previous study has reported the association of the HACE1 gene with the risk and age at onset (AAO) of AD; while few studies have checked the proportional hazards assumption in the survival analysis of AAO of AD using Cox proportional hazards model. In this study, we examined the associations of 14 single nucleotide polymorphisms (SNPs) in the HACE1 gene with the risk and the AAO of AD using 791 AD patients and 782 controls. Multiple logistic regression model identified one SNP (rs9499937 with p = 1.8×10) to be associated with the risk of AD. For survival analysis of AAO, both classic Cox regression model and Bayesian survival analysis using the Cox proportional hazards model were applied to examine the association of each SNP with the AAO. The hazards ratio (HR) with its 95% confidence interval (CI) was estimated. Survival analysis using the classic Cox regression model showed that 4 SNPs were significantly associated with the AAO (top SNP rs9499937 with HR=1.33, 95%CI=1.13-1.57, p=5.0×10). Bayesian Cox regression model showed similar but a slightly stronger associations (top SNP rs9499937 with HR=1.34, 95%CI=1.11-1.55) compared with the classic Cox regression model. Using an independent family-based sample, one SNP rs9486018 was associated with the risk of AD (p=0.0323) and the T-T-G haplotype from rs9786015, rs9486018 and rs4079063 showed associations with both the risk and AAO of AD (p=2.27×10 and 0.0487, respectively). The findings of this study provide first evidence that several genetic variants in the HACE1 gene were associated with the risk and AAO of AD.