Parkinson disease (PD) is the second most common neurodegenerative disease worldwide, with estimates suggesting that PD prevalence and incidence will increase with aging populations. Therapeutic options and clinical guidelines for PD have significantly changed over the past 15 years; however, pharmacoepidemiology data in PD are lacking, especially regarding adverse effects of non-ergot dopamine agonists (DAs) and outcomes associated with anticholinergic burden. The objectives of this doctoral research are threefold: 1) examine patterns of antiparkinson drug use in relation to clinical guideline publication, drug availability, and emerging safety concerns; 2) determine whether PD patients treated with non-ergot DAs are at increased risk of adverse cardiovascular or cerebrovascular outcomes; and 3) determine whether anticholinergic burden is associated with adverse outcomes in PD. Specific research questions were investigated using epidemiological methods and electronic health data from Cerner Health Facts®, an electronic medical record database that stores time-stamped patient records for more than 300 Cerner subscribing facilities across the United States. Findings from this work are reported in a series of manuscripts, all of which have been published. Key findings include: 1) DA use began declining in 2007, from 34% to 27% in 2012. The decline followed publication of the American Academy of Neurology’s practice parameter refuting levodopa toxicity, pergolide withdrawal, and pramipexole label revisions; 2) heart failure was the only adverse cardiovascular or cerebrovascular outcome that demonstrated a significant association with non-ergot DA use, mainly pramipexole; and 3) anticholinergic burden in PD was associated with the diagnosis of fracture and delirium, and significantly increased the risk of emergency department visit and readmission post inpatient discharge. Reported antiparkinson prescribing trends suggest that safety and best practice information may be communicated effectively in PD. Although findings warrant replication, individuals with PD and independent risk factors for or a history of heart failure may benefit from limited use of pramipexole. Similarly, individuals with PD may benefit from substituting non-PD medications with anticholinergic effects for equally effective non-anticholinergic agents. Additional pharmacovigilance studies are needed to better understand health risks and the impact of population health interventions in PD.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13192号 / 論医博第2156号 / 新制||医||1030(附属図書館) / (主査)教授 中山 健夫, 教授 松村 由美, 教授 川村 孝 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Esophageal and biliary stents are indwelling devices used in the treatment of selected gastrointestinal and biliary disorders. Stenting is accepted as a standard procedure for palliation of malignant obstruction of the esophagus and biliary system. Review of the early and late complications associated with these devices is made with emphasis on the clinical and radiographic features. A suggested approach to diagnosis and treatment recommendations are made for each complication that the emergency department physician may encounter.

Indiana University-Purdue University Indianapolis (IUPUI) / External apical root resorption (EARR) is a common complication of orthodontic treatment. Genetic factors account for approximately 50% of the variation in EARR. Data have indicated variation in histological root resorption associated with orthodontic force (RRAOF) among different inbred strains of mice. Differences in expression of RANKL and OPG were investigated in two strains of mice with different susceptibility to RRAOF using irnmunohistochemistry. Increased localization of RANKL was detected in the tissues surrounding the root of the susceptible strain compared to the resistant strain and the controls. In contrast, increased localization of OPG was found in the tissues surrounding the roots in the resistant A/J strain compared to the susceptible DBA/2J strain. We conclude that differences in the expression of these key bone resorption mediators play a role in determining RRAOF susceptibility. Changes in serum TRAP 5b level in response to orthodontic force were investigated among female A/J, DBA/2J and BALB/cJ mice. The three strains differed in their TRAP positive cell numbers as well as their serum TRAP 5b level at baseline and when treated. A significant increase in the serum TRAP 5b level with treatment was only detected in the RRAOF susceptible DBA/2J strain, and not in RRAOF resistant strains. Our analysis indicates that differences in osteoclast/odontoclast activity play a role in susceptibility to RRAOF that is genetically determined. Serum TRAP 5b levels have a potential role in screening for individuals with greater susceptibility to root resorption. RRAOF was determined for male and female mice of the A/J, DBA/2J and BALB/cJ strains, as well as A/J x DBA/2J and A/J x BALB/cJ crosses. Sex differences were observed among the BALB/cJ strain only, with females more resistant to RRAOF when compared to males. Fis from the A/J x BALB/cJ cross were resistant suggesting that the A/J have dominant resistance alleles, while Fis from the A/J x DBA/2J cross had RRAOF intermediate between their parental A/J and DBA/2J mice, suggesting a polygenic trait. We concluded that the mode of inheritance of RRAOF in mice was polygenic in nature.

Indiana University-Purdue University Indianapolis (IUPUI) / According to one theory of root resorption, occlusal trauma during orthodontic tooth movement damages the cementum covering the root dentin. The body detects the exposed dentin and seeks to remove it, and the result is root resorption. This experiment will explore an aspect of this theory by quantifying the amount and location of damage in mechanically fatigued teeth. Nine dog mandibles were sectioned at the mandibular symphysis. Each half was mounted in orthodontic resin with the incisors upright and exposed. The block was inserted into a jig and placed into a servohydraulic mechanical testing machine. The left central incisor was fatigue loaded with a 2Hz, 10-90 N sinusoidal force for 100,000 cycles (approximately 14 hours). The right central incisor served as the control. Both specimens were scanned with a micro-CT unit, stained with basic fuchsin, and then sectioned along the sagittal plane. Because the experimental and control specimens were stained before sectioning, only microdamage due to the loading process would be evident in the sections. Microdamage which occurred during the sectioning process would not be stained. Central sections through the long axes of the samples were examined for the presence of microdamage with a light microscope and a micro-CT unit. Based on preliminary findings, two types of staining patterns were measured and recorded. The first was called "diffuse stain" and consisted of large stained areas in the dentinal tubules. Diffuse stain was not associated with any visible features at the dentinocemental junction. The second type of staining pattern was called "stained defects." Stained defects were stained irregularities at the dentinocemental junction. For statistical analysis, the roots were divided into buccal-cervical, buccal-middle, buccal-apical, lingual-cervical, lingual-middle, and lingual-apical regions. Comparisons between the fatigued and non-fatigued teeth for differences in area, length, and depth were made under the generalized estimating equation (GEE) framework applied to normally-distributed data. Because the measurements were not normally distributed, a rank transformation of the measurements was performed before conducting the analyses. Comparisons between the fatigued and non-fatigued teeth for differences in presence or absence of stain or defects were made using Cochran-Mantel-Haenszel tests. Repeatability of the measurements was assessed using intraclass correlation coefficients (ICCs), paired t-tests, and Bland-Altman plots. The ICC's ranged from 0 .85 to 1.00, thus making the repeatability of the measurements generally very good. The statistical analysis showed there were no significant differences between the experimental and control teeth for stained defects or diffuse staining for length, depth, or area measurements. However, analyses comparing the distribution of stained defects and diffuse stain within the control and experimental specimens showed significant differences in the distribution of stained defects within the experimental specimens. In the experimental specimens, the stained defects were distributed in a gradient, with the most in the apical region and progressing to the least amount in the cervical region. In the control specimens, there was only a difference in the stained defects between the cervical and apical regions. This distribution is consistent with the biomechanical model which shows increasing stress moving from the cervical region towards the apex. These results show that the test and control specimens differed in how the stained defects were distributed throughout the root, even though there were no differences in the amount of staining between the control and experimental specimens. Whole tooth and histologic slides were scanned with the micro-CT unit, but the dentinocemental junction could not be delineated enough to make any measurements. No data could be collected regarding microdamage in this area using the micro-CT unit. It was recommended that future studies use a tomography unit with better resolution, use a larger samples size, employ a contrast agent when trying to visualize microdamage with the micro-CT unit, and incorporate a way to measure the intensity of the staining in addition to the location and size.

No description available.

Os efeitos tóxicos decorrentes da exposição ambiental e ocupacional ao benzeno são amplamente descritos na literatura. Seus produtos de biotransformação fenólicos, entre os quais os compostos hidroxilados como FE e hidroquinona HQ, são indutores importantes de efeitos citotóxicos e genotóxicos responsáveis pela toxicidade ao sistema imune. No entanto, a contribuição de cada metabólito e os mecanismos envolvidos não estão completamente esclarecidos. Desta forma, o presente trabalho teve por objetivo estudar a capacidade da resposta inflamatória em ratos expostos à HQ, ao FE, ou a ambos simultaneamente (HQ+FE). Para tanto, ratos Wistar machos foram expostos aos agentes químicos por período de tempo prolongado (doses diárias de 5 ou 10mg/kg; i.p.; com 5 doses/semana no período de 17 ou 23 dias). Animais controles receberam o veículo pela mesma via. As respostas inflamatórias foram induzidas 24 horas após a última dose administrada. Foram avaliadas a resposta inflamatória inespecífica, decorrente da instilação intranasal de LPS de Salmonella abortus e a resposta inflamatória específica em animais previamente sensibilizados e desafiados pela OVA. Na resposta inflamatória inespecífica, as exposições à HQ e à HQ+FE provocaram redução acentuada no influxo de leucócitos para o pulmão inflamado, pelo menor número de leucócitos no LBA e pela atividade enzimática da MPO reduzida no tecido pulmonar. O efeito não é dependente de modificações no número de leucócitos circulantes nem de alterações nas expressões de moléculas de adesão nos leucócitos circulantes (L-selectina e β2 integrina) e no endotélio pulmonar (ICAM-1 , VCAM-1 e PECAM-1) envolvidas na interação leucócito-endotélio. Na vigência de resposta inflamatória específica, as exposições à HQ, FE ou HQ+FE reduziram significativamente a migração de leucócitos para o LBA e para o tecido pulmonar. Da mesma forma que a RI induzida pelo LPS, não foram detectados alterações nos número de leucócitos circulantes e na expressão de moléculas de adesão. No entanto, os resultados obtidos em ensaios de anafilaxia passiva cutânea e reação anafilática in vitro mostraram que o efeito é dependente, pelo menos em parte, da menor concentração de imunoglobulinas anafiláticas circulantes e, consequentemente, da menor habilidade de desgranulação mastocitária. Em conjunto, os dados obtidos demonstram que as exposições à HQ, ao FE ou à HQ+FE prejudicam a migração de leucócitos para o foco de lesão na vigência de respostas inflamatórias de origem inata ou adquirida. / The toxic effects of the ambiental and occupational exposures to benzene is widely described in the literature. Phenolic hydroxylated compounds obtainded from its biotransformation, such as phenol (PHE) and hydroquinone (HQ), induce important of cytotoxic and genotoxic effects responsible for the immunotoxicity. However, the role of each metabolite and mechanisms of toxicity are unknown. Then, the present work aimed to study the inflammatory response in rats exposed to HQ, PHE, ar both simultaneously (HQ+PHE). Male Wistar rats were exposed to they chemical agents for extended period of time (5 or 10mg/kg/day; ip.; during 17 or 23 days; 2 days intervals each 5 doses). Control animais received the vehicle. Inflammatory reactions were induced 24 hours after the last dose by they intranasal instillation of lipopolysaccharide of Salmonella aborlus (non-specific response) or by inhalation of ovalbumin in animals previously sensitized to the same antigen (specific response, produced by anaphylactic immunoglobulins). Animais exposed to HQ or HQ/PHE presented reduced n,3umbers of PMN and MN cells in the bronchoalveolar lavage fluid (BALF) and lesser myeloperoxidase (MPO) activity in the pulmonary tissue. The reduced influx of leukocytes is not dependent oh alterations on the numbers of circulating leukocytes either adhesion molecules expressions on leukocytes (L-selectin or β2 integrin) and on lung microvascular endothelium (ICAM-1, V CAM-1 or PECAM-1) responsible for leukocyte-endothelial interactions. On the other hand, rats exposed to ali schedules of exposures presented reduced numbers of leukocytes in the BALF and lesser MPO activity in the pulmonary tissue after an antigenic stimulus. As shown to inflammation induced by LPS, no alterations on circulating leukocyte numbers and adhesion molecules expressions were detected. However, the impaired leukocyte migration to the inflamed lung may be dependent, at last in part, on reduced levels of circulating anaphylactic antibodies, as detected by passive cutaneous anaphylaxis test, and by consequent reduced ability of mast cell desgranulation, evidenced by in vitro trachea contraction. Together, our data show that HQ and PHE exposure differently affect the specific and non-specific ínflammatory reactions.

Vascular access-related bloodstream infection (BSI) is frequent among patients undergoing hemodialysis increasing significantly their morbidity and mortality. Studies assessing centre- and patient-predictors of BSI have had inadequate sample size and follow-up time. The aims of this project are: to describe the incidence rates; and to determine patient- and centre-level predictors of BSI in a cohort of incident hemodialysis patients treated in teaching or community hospitals, and in First Nation dialysis units. The rates of BSI in our population were lower than those observed in other settings. Central venous catheters were the most important risk factor for BSI and their use in our study was much higher than recommended. Some variability in BSI rates was found among centres, but no centre-related variable was found to be associated with the risk of BSI. Effort to reduce catheter use in hemodialysis patients may significantly reduce the risk of BSI in this patient population.

Magistro baigiamojo darbo tikslas – retrospektyviai išnagrinėti veterinarijos farmakologinio budrumo sistemos vykdymą Lietuvoje nuo 2004 iki 2013 metų. Siekiant nurodyto tikslo buvo iškelti tokie uždaviniai: susipažinti su prieinama moksline literatūra lietuvių ir anglų kalbomis, išanalizuoti veterinarijos farmakologinio budrumo organizavimą ir atitinkamus teisės aktus, reglamentuojančius veterinarijos farmakologinį budrumą; atlikti Lietuvos veterinarijos farmakologinio budrumo dešimties metų analizę, už budrumą atsakingoje institucijoje; įvertinti veterinarijos farmakologinio budrumo sistemos efektyvumą Lietuvoje; išsiaiškinti problemas, lemiančias tokius rezultatus. Pirmajame darbo skyriuje yra nagrinėjama veterinarijos farmakologinio budrumo samprata, su tuo susiję teisės aktai, reguliavimas ir vykdymas Lietuvoje. Antrame skyriuje atlikus tyrimą gauti rezultatai parodė, kad Lietuvoje vykdomo veterinarijos farmakologinio budrumo sistema yra menka, gaunamas pranešimų skaičius yra vos keli pranešimai per metus. Prieita išvados, kad Lietuvoje vykdomo veterinarijos farmakologinio budrumo efektyvumas yra labai blogas. Nustatyta viena iš pagrindinių priežasčių, lemiančių tokį rezultatą – menkas visuomenės ir veterinarų praktikų aktyvumas ir nenoras pranešti apie pastebėtas nepalankias veterinarinių vaistų reakcijas. Darbo apimtis 32 puslapis, darbe yra 4 lentelės ir 2 paveikslai, buvo panaudoti 25 literatūros šaltiniai. / Master’s final thesis aims was to perform the retrospective analysis of veterinary pharmacovigilance system in Lithuania in the period from 2004 to 2013. To achieve this objective, the below goals were stated: to analyse available scientific literature in the Lithuanian and English languages concerning topic; to reveal veterinary pharmacovigilance concept; to analyse Lithuanian legislation governing veterinary pharmacovigilance; to make analysis of veterinary pharmacovigilance for the period of 10 years in the institutions in charge; to evaluate efficiency of veterinary pharmacovigilance system in Lithuania; to find out the problems leading to such results. The first part of the thesis analyses the concept of veterinary pharmacovigilance and the related legislation governing and implementing it in Lithuania. In the second part of the thesis the obtained results are presented that showed that the system of veterinary pharmacovigilance in Lithuania is weak. Only a few cases have been reported within a year. It suggests that efficiency of veterinary pharmacovigilance system in Lithuania is equal to zero. One of the main reasons responsible for poor results has been found i.e. unwillingness of the society and veterinary practicians to report detected reactions to veterinary medications. Volume of master thesis 32 pages, with 4 tables and 2 pictures. 25 references have been used.

Os efeitos tóxicos decorrentes da exposição ambiental e ocupacional ao benzeno são amplamente descritos na literatura. Seus produtos de biotransformação fenólicos, entre os quais os compostos hidroxilados como FE e hidroquinona HQ, são indutores importantes de efeitos citotóxicos e genotóxicos responsáveis pela toxicidade ao sistema imune. No entanto, a contribuição de cada metabólito e os mecanismos envolvidos não estão completamente esclarecidos. Desta forma, o presente trabalho teve por objetivo estudar a capacidade da resposta inflamatória em ratos expostos à HQ, ao FE, ou a ambos simultaneamente (HQ+FE). Para tanto, ratos Wistar machos foram expostos aos agentes químicos por período de tempo prolongado (doses diárias de 5 ou 10mg/kg; i.p.; com 5 doses/semana no período de 17 ou 23 dias). Animais controles receberam o veículo pela mesma via. As respostas inflamatórias foram induzidas 24 horas após a última dose administrada. Foram avaliadas a resposta inflamatória inespecífica, decorrente da instilação intranasal de LPS de Salmonella abortus e a resposta inflamatória específica em animais previamente sensibilizados e desafiados pela OVA. Na resposta inflamatória inespecífica, as exposições à HQ e à HQ+FE provocaram redução acentuada no influxo de leucócitos para o pulmão inflamado, pelo menor número de leucócitos no LBA e pela atividade enzimática da MPO reduzida no tecido pulmonar. O efeito não é dependente de modificações no número de leucócitos circulantes nem de alterações nas expressões de moléculas de adesão nos leucócitos circulantes (L-selectina e β2 integrina) e no endotélio pulmonar (ICAM-1 , VCAM-1 e PECAM-1) envolvidas na interação leucócito-endotélio. Na vigência de resposta inflamatória específica, as exposições à HQ, FE ou HQ+FE reduziram significativamente a migração de leucócitos para o LBA e para o tecido pulmonar. Da mesma forma que a RI induzida pelo LPS, não foram detectados alterações nos número de leucócitos circulantes e na expressão de moléculas de adesão. No entanto, os resultados obtidos em ensaios de anafilaxia passiva cutânea e reação anafilática in vitro mostraram que o efeito é dependente, pelo menos em parte, da menor concentração de imunoglobulinas anafiláticas circulantes e, consequentemente, da menor habilidade de desgranulação mastocitária. Em conjunto, os dados obtidos demonstram que as exposições à HQ, ao FE ou à HQ+FE prejudicam a migração de leucócitos para o foco de lesão na vigência de respostas inflamatórias de origem inata ou adquirida. / The toxic effects of the ambiental and occupational exposures to benzene is widely described in the literature. Phenolic hydroxylated compounds obtainded from its biotransformation, such as phenol (PHE) and hydroquinone (HQ), induce important of cytotoxic and genotoxic effects responsible for the immunotoxicity. However, the role of each metabolite and mechanisms of toxicity are unknown. Then, the present work aimed to study the inflammatory response in rats exposed to HQ, PHE, ar both simultaneously (HQ+PHE). Male Wistar rats were exposed to they chemical agents for extended period of time (5 or 10mg/kg/day; ip.; during 17 or 23 days; 2 days intervals each 5 doses). Control animais received the vehicle. Inflammatory reactions were induced 24 hours after the last dose by they intranasal instillation of lipopolysaccharide of Salmonella aborlus (non-specific response) or by inhalation of ovalbumin in animals previously sensitized to the same antigen (specific response, produced by anaphylactic immunoglobulins). Animais exposed to HQ or HQ/PHE presented reduced n,3umbers of PMN and MN cells in the bronchoalveolar lavage fluid (BALF) and lesser myeloperoxidase (MPO) activity in the pulmonary tissue. The reduced influx of leukocytes is not dependent oh alterations on the numbers of circulating leukocytes either adhesion molecules expressions on leukocytes (L-selectin or β2 integrin) and on lung microvascular endothelium (ICAM-1, V CAM-1 or PECAM-1) responsible for leukocyte-endothelial interactions. On the other hand, rats exposed to ali schedules of exposures presented reduced numbers of leukocytes in the BALF and lesser MPO activity in the pulmonary tissue after an antigenic stimulus. As shown to inflammation induced by LPS, no alterations on circulating leukocyte numbers and adhesion molecules expressions were detected. However, the impaired leukocyte migration to the inflamed lung may be dependent, at last in part, on reduced levels of circulating anaphylactic antibodies, as detected by passive cutaneous anaphylaxis test, and by consequent reduced ability of mast cell desgranulation, evidenced by in vitro trachea contraction. Together, our data show that HQ and PHE exposure differently affect the specific and non-specific ínflammatory reactions.