Introduction: Stavudine is a commonly used drug in paediatric antiretroviral treatment (ART) regimens. Due to toxicity concerns, however, the drug abacavir has replaced stavudine in first-line paediatric regimens inmany countries.Wedescribe the frequency of stavudine toxicity in children receiving ART at a treatment clinic in Soweto, South Africa. Methods: Data on patient characteristics and outcomes of ART were collected from a cohort of 2222 HIV-infected children initiating ART between 2004 and 2008 when stavudine-containing regimenswere routinely recommended. At several time-points after treatment initiation, we estimate the proportion of children where an attending clinician discontinued stavudine due to lipodystrophy, pancreatitis, lactic acidosis or peripheral neuropathy. Factors associated with stavudine-related toxicities were identified. Results: At ART initiation, most children had advanced disease. The majority initiated an efavirenz/lamivudine/stavudine regimen (n¼1422), and 76% of children remained on their initial ART regimen after a median 19.9 months of ART. Replacement of stavudine due to drug toxicity occurred at a rate of 28.8 per 1000 child years on treatment (95% confidence interval¼23.6–35.2). Rates of toxicity increased with treatment duration (in their first year of ART stavudine was replaced in 0.5% of children, but after 3 years stavudine had been changed to abacavir in 12.6% of children). Toxicity was more common in older children and in girls. Lipodystrophy accounted for 87 of 96 toxic events. Conclusion: Stavudine-associated toxicity resulting in single-drug substitution was uncommon in this cohort, though its frequency increased steadily with ART duration, especially with lipodystrophy. Where drug options are limited, stavudine remains a relatively well tolerated and effective option for children.

Estudos sugerem que a suplementação de creatina pode atenuar a resistência à insulina, embora sejam escassas evidências que atestem a segurança desse suplemento. Diante disso, esse estudo teve como objetivo investigar a eficácia e segurança da suplementação de creatina em diabéticos do tipo 2. Foi conduzido um estudo clínico, randomizado, duplo-cego, controlado por placebo. Ao longo de três meses, os pacientes foram submetidos a treinamento físico e suplementação de creatina (CR) ou placebo (PL). No período basal e após a intervenção, os indivíduos realizaram avaliações de controle glicêmico, perfil lipídico, capacidade física, composição corporal e efeitos adversos. Além disso, os voluntários foram submetidos à biópsias musculares, para análises da expressão proteica e translocação de GLUT-4, e espectrometria de fósforo para determinação dos conteúdos intramusculares de fosforilcreatina. Após a intervenção, as concentrações intramusculares de fosforilcreatina foram maiores no grupo CR (diferença estimada entre as médias: 23,6 mmol/Kg músculo úmido; p = 0,03). Esse grupo também apresentou menores concentrações de hemoglobina glicada quando comparado ao grupo PL (diferença estimada entre as médias: -1,1%; p = 0,004). Os testes de tolerância oral à refeição demonstraram menores valores de glicemia de jejum e pós-prandial (momentos 30 e 60 minutos) no grupo CR versus PL. A expressão proteica de GLUT-4 não foi diferente entre os grupos, porém o aumento na translocação dessa proteína foi significantemente superior no grupo CR (p = 0,03). Não houve diferenças significantes entre os grupos para a insulinemia, perfil lipídico, concentrações séricas de peptídeo C, composição corporal, condicionamento aeróbio, força e função musculares. A suplementação de creatina não provocou deterioração nas funções renal e hepática. Os demais efeitos adversos relatados também não foram diferentes entres os grupos. Desta forma, concluímos que a suplementação de creatina aliada ao treinamento físico é uma estratégia terapêutica segura e efetiva em melhorar o controle glicêmico em diabéticos do tipo 2. Número de registro no domínio Clinicaltrials.com: NCT00992043 / Some studies have suggested that creatine supplementation may attenuate insulin resistance, but whether this supplement is safe remains uncertain. In light of this, the aim of this trial was to investigate the efficacy and safety of creatine supplementation combined with exercise training in patients with type II diabetes. A randomized, double-blind, placebo-controlled, clinical trial was conducted. The patients were submitted to exercise training and received either creatine (CR) or placebo (PL) for 12 weeks. At baseline and after the intervention, glycemic control, lipid profile, physical capacity, body composition, and adverse effects were assessed. Moreover, muscular biopsies were performed to determine the muscle GLUT-4 content and the GLUT-4 translocation, and muscle phosphorylcreatine was assessed by using magnetic resonance spectroscopy. After the intervention, muscle phosphorylcreatine content was higher in the CR group (estimated difference of means: 23.6 mmol/Kg wet muscle; p = 0.03). The CR group also presented decreased glycosylated hemoglobin when compared to the PL group (estimated difference of means: -1.1%; p = 0.004). The oral meal tolerance tests revealed reduced fasting and postprandial glycemia (30 and 60 minutes) in the CR versus the PL group. The muscle GLUT-4 content was similar between groups, but the increase in GLUT-4 translocation was significantly superior in the CR group when compared to the PL group (p = 0.03). In addition, No significant differences between groups were observed for insulinemia, lipid profile, serum peptide C concentration, body composition, aerobic conditioning, strength, and muscle function. Cr supplementation provokes no deleterious effects on kidney and liver functions. The reported adverse effects were similar between groups. Thus, we concluded that creatine supplementation is safe and capable of improving glycemic control in type 2 diabetic patients. ClinicalTrials.gov registration number: NCT00992043

Na prática clínica, é comum a associção de vários fármacos para o tratamento de patologias crônicas. Entretanto, agumas associações podem ter respostas indesejáveis para o paciente que resultam desde a ineficácia do tratamento medicamentoso até eventos adversos graves. As interações medicamentosas (IM) são exemplos de eventos adversos com medicamentos e para sua ocorrência contam-se fatores relacionados ao paciente, medicamento e com a prescrição. Quanto aos fatores de risco relacionados ao paciente, algumas populações, são mais vulneráveis as IM, tais como: idosos, pacientes submetidos à procedimentos cirúrgicos, em unidades de terapia intensiva e imunodeprimidos. Desta forma, esta investigação foi conduzida com o objetivo de analisar as potenciais interações medicamentosas em pacientes de uma Unidade de Terapia Intensiva do Hospital Universitário do Ceará. A análise dos prontuários ocorreu nos meses de julho e agosto de 2007. A população do estudo foi composta por todos os pacientes hospitalizados na UTI por mais de seis dias nos meses de junho de 2006 a junho de 2007. Após os critérios de inclusão, foram selecionados 102 pacientes, destes, 74 (72,5%) apresentaram 311 potenciais interações medicamentosas. Quanto as características sócio demográficas e clínicas dos pacientes, verificou-se que as IM ocorreram com maior frequências nos pacientes do sexo femino 47 (64%), na faixa etária dos 63 a 72 anos 17 (23%), com tempo de permanência na UTI por um periodo de seis a dez dias 42 (56,7%) e em portadores de doenças do aparelho circulatório 115 (25,2%). Quanto ao númemero de medicamentos, os pacientes que apresentaram interações medicamentosas receberam mais do que o dobro de medicamentos comparado aos pacientes sem IM. A Classe medicamentosa mais frequente no estudo foi a dos medicamentos do Aparelho digestivo e metabolismo 474 (25,7%), entretanto, as IM foram mais frequntes entre os medicamentos do Sistema Nervoso 124 (40%). Dentre estes destacam-se o midazolam 65 (20,8%) e o fentanil 21 (6,7%). Verificou-se que dos 1845 medicamentos analisados, 1140 (61,8%) foram aprazados para o mesmo horário, destes 844 (74%) apresentaram potencial para interações medicamentosas, sendo o horário das 6 horas o que concentrou maior número de medicamentos administrados. Dentre as vias de administração de medicamento, a via intravenosa foi a via mais freqüente no estudo 1151 (62,3%). Quanto as IM, verificou-se que a associação do midazolam com o fentanil 45 (14,5%) e midazolam com o omeprazol 19 (6,1%), foram as IM mais freqüentes no estudo. Quanto a classificação das IM identificou-se que: 150 (48,2%) apresentaram perfil farmacocinético; 173 (55,4%) de início demorado; 170 (54,7%) de moderada gravidade; 189 (60,6%) apresentaram boa documentação científica. O manejo clínico mais freqüente no estudo foi Observar sinais e sintomas com 221 (47,9%) das recomendações. Salienta-se que 80% das ações para minimizar ou até evitar os efeitos indesejáveis das IM podem ser realizados pelo enfermeiro. No entanto, para que as intervenções ocorram de fato é importante que o enfermeiro tenha conhecimento quanto aos mecanismos farmacológicos das interações medicamentosas, bem como seus fatores precipitantes. / In clinical practice, it is common to associate several drugs for the treatment of chronic pathologies. However, some associations may cause undesirable conditions that may result in inefficacy of drug therapies and serious adverse events. Drugs interaction is a kind of adverse event, whose occurrence has relation with factors involving characteristics of patients, drugs, and prescriptions. With respect to patients, some populations are more vulnerable to drugs interaction, such as that ones including aged people, people submitted to surgery procedures, people hospitalized in intensive care units. Thus, this investigation has analysed potential drugs interactions in an intensive care unit of the teaching hospital in Ceará-Brazil. The analysis of the prescription sheets have been made between July and August 2007, including all patients that stayed hospitalized for more than six days between June 2006 and July 2007. 102 patients have been selected after to apply the inclusion criteria. Among them, 74 (72,5%) have been exposed to potential drugs interactions. With respect to sociodemographic and clinical characteristics of the patients, most of the drugs interaction has occurred with female 47 (64%), with age between 63 and 72 years old 17 (23%), with a hospitalized period in the range of six to ten days 42 (56,7%), and with patients with heart and circulatory failures 115 (25,2%). The patients exposed to potential drugs interaction have received twice more drugs than the other patients. The most frequent class of drugs in drugs interaction are those related to the digestive system and metabolism. However, drugs interactions have been more frequent between drugs for the Nervous System 124 (40%), such as midazolam 65 (20,8%) and fentanil 21 (6,7%). Among the 1845 evaluated drugs, 1140 (61,8%) have been scheduled to be applied administration. Among them, 844 (74%) have presented potential drugs interaction. Most of them have been scheduled to 6am. The intravenous way has been the most frequent form of administration of drugs in the study 1151 (62,3%). The most frequent associations have been midazolam with fentanil 45 (14,5%) and midazolam with omeprazol 19 (6,1%). With respect to classification of drugs interaction, 150 (48,2%) present farmacokinetic profile; 173 (55,4%) present delayed beginning; 170 (54,7%) present moderate severity; 189 (60,6%) have presented good scientific documentation. The most frequent clinical handling has been to observe signals and symptoms, with 221 (47,9%) recommendations. It is important to emphasize that 80% of preventive procedures to avoid undesirable effects of drugs interactions can be performed by nursing staff. For that, nurses must have knowledge about pharmacological mechanisms of drugs interactions, as well as their causes.

Nesta pesquisa foi avaliada a incidência e a severidade da mucosite oral em pacientes que foram submetidos à adequação bucal previamente ao Transplante de Medula Óssea. Foi realizado exame clínico e radiográfico dos pacientes portadores de Leucemia Mielóide Crônica que estavam se preparando para o transplante. Após a avaliação inicial dos pacientes foram realizados os tratamentos odontológicos necessários para a remoção de quaisquer focos de infecção bucal. Todos os pacientes receberam o mesmo tipo de condicionamento quimioterápico e de profilaxia para Doença do Enxerto-Contra-Hospedeiro. Todos os pacientes receberam adequação bucal e foram avaliados durante o período de internação hospitalar para o transplante pelo mesmo Cirurgião Dentista. Os resultados mostraram que a mucosite grau 0 foi encontrada em 5 pacientes (14,29%), grau 1 em 8 pacientes (22,85%), grau 2 em 17 pacientes (48,57%), grau 3 em 3 pacientes (8,57%) e grau 4 em 2 pacientes (5,71%). Estes dados sugerem que a adequação bucal realizada previamente ao Transplante de Medula Óssea reduziu a severidade da mucosite oral, salientando a importância da presença do Cirurgião Dentista na equipe multidisciplinar em um serviço de Transplante de Medula Óssea. / The aim of this research was to evaluate the incidence and the severity of the oral mucositis in patients submitted to dental treatment before the Bone Marrow Transplantation. Clinical and radiographical examination was performed in patients with Chronic Myeloid Leukemia who would be submitted to transplantation. After patient’s initial evaluation, dental treatment was performed in order to remove any site of oral infection. All patients received the same chemotherapy conditioning regimen and the Graft-versus-host-disease prophylaxis. All patients received oral care during the hospital intern period and were evaluated by the same dentist. The results showed that 5 patients (14,29%) presented level 0 of oral mucositis, 8 patients (22,85%) presented level 1 of oral mucositis were, 17 patients (48,57%) presented level 3 of oral mucositis and 2 patients (5,71%) presented level 4 of oral mucositis. These data suggest that oral care and dental treatment previous to the Bone Marrow Transplantation reduced the severity of oral mucositis and emphasizes the importance of the Dentist as a member of a multidisciplinary team in a Bone Marrow Transplantation unit.

Novilhas Holandesas (n=35) foram vacinadas e distribuídas em grupos de acordo com os adjuvantes presentes nas vacinas comerciais contra BVDV e BoHV-1: Halum (hidróxido de alumínio, n=9), Oleosa (emulsão oleosa, n=10), Prezent A (composto saponina, n=10) e Salina (controle, n=6). As reações locais e sistêmicas foram avaliadas às zero horas (h), seis, 24, 48, 72 e 168h pós-vacinal. A produção de anticorpos (ACs) foi mensurada nos dias da vacinação (D0), D21 e D42. Capítulo 1 O objetivo deste estudo foi avaliar a resposta inflamatória sistêmica em novilhas vacinadas contendo diferentes tipos de adjuvantes. O número de hemácias (P=0,009) e hemoglobina (P=0,028) foram maiores no grupo Prezent A após a 2a dose. Os teores de ferro foram maiores no grupo controle após 1ª e 2ª dose (P=0,000; 0,000). Em geral, no leucograma os grupos vacinados apresentaram decréscimo nos números de leucócitos (P=0,001) em 2ª dose, neutrófilos (%) (P=0,000; 0,000) em ambas aplicações e monócitos (%) (P=0,010) após 1ª dose. Os linfócitos (%) apresentaram aumento gradual após as duas doses (P=0,031; 0,000), observando-se menores proporções nos grupos Prezent A e Oleosa. Basófilos (%) após 2ª dose (P=0,012) e eosinófilos (%) (P=0,000; 0,000) foram mais reativos nos grupos Prezent A e Halum entre 24 e 72h. As novilhas Prezent A apresentaram maiores valores (P=0,000; 0,000) haptoglobina às 24 e 48h em relação aos demais grupos após a 1ª e 2ª dose. Em geral, a produção de EROs foi suprimida nas novilhas vacinadas em relação ao controle após 1a dose (P=0,018) e entre 24 à 168h após a 2a dose (P=0,002). Capítulo 2 O objetivo desta pesquisa foi avaliar os efeitos adversos associados às reações locais e sistêmicas, assim como verificar a reposta imune humoral induzida pelas vacinas. A reatividade local foi mais intensa no grupo Oleosa após a 1a dose (P=0,000), em contrapartida o grupo Prezent A após a 2a dose foi mais reativo (P=0,000). A temperatura retal foi elevada em Prezent A entre 0 a 24h em 1a dose (P=0,000). O escore de Doença Respiratória Bovina foi mais intensa no grupo Prezent A e Oleosa às 48 horas (P=0,0024). Os ACs contra BVDV foram detectados apenas em D42, observando-se médias semelhantes entre Prezent A (log2=5) e Halum (log2=5). A soroconversão foi maior em Halum (78%) em comparação ao Prezent A (40%) e oleosa (10%). Em relação ao BoHV-1, observou-se títulos e soroconversão em D21 nos grupos Halum (log2=3; 67%) e Prezent A (log2=1; 80%). No D42 verificou-se uma maior intensidade de resposta para Prezent A (log2= 6; 100%), seguido de Halum (log2=4; 100%) e Oleosa (log2=3,0; 60%). Os dados permitem concluir que a vacina contendo o adjuvante oleoso e Prezent A ocasionaram maior reatividade local, porém a Prezent A induziu maior resposta inflamatória sistêmica. A produção de ACs contra o BVDV e BoHV-1 foi mais intensa na vacina com hidróxido de alumínio e Prezent A. Estudos futuros são necessários para demonstrar os efeitos benéficos da resposta inflamatória sistêmica do Prezent A sobre a resposta imune adquirida mediada por células do tipo Th1. / Dairy heifers (n=35) were vaccinated and distributed according to adjuvants present in commercial vaccines against BVDV and BoHV-1: Halum (n=9), Oil (n=10), Prezent A (n=10) and Saline (n=6). The local and systemic reactions were evaluated at zero hours (h), 6, 24, 48, 72 and 168h post-vaccination. The production of antibodies (ABs) was measured at vaccination days (D0), D21 and D42. Chapter 1 The objective of this study was to evaluate the inflammatory systemic response in vaccinated heifers with products that contained different types of adjuvants. The numbers of red blood cells (P=0.009) and hemoglobin (P=0,028) were higher in Prezent A after the 2nd dose. The iron were higher in saline group after 1st and 2nd dose (P=0.000; 0.000). In leukogram, vaccinated groups showed a decrease in total leukocytes (P = 0.001) at 2nd dose, neutrophils (%) (P = 0.000; 0.000) in both applications and monocytes (%) (P = 0.010) . Lymphocytes (%) presented gradual increase after received two doses (P = 0.031; 0.000), showing smaller proportions in Prezent A and Oil groups. Basophils (%) after 2nd dose (P = 0.012) and eosinophils (%) (P = 0.000; 0.000) were more reactive in Prezent A and Halum groups between 24 and 72h. Prezent A group presented higher values (P = 0.000; 0.000) of haptoglobin at 24 and 48h compared to the other groups after the 1st and 2nd doses. In general, ROS production was suppressed in vaccinated heifers relative to control after the 1st dose (P = 0.018) and 24 to 168h after the 2nd dose (P = 0.002). Chapter 2 The objective of this research was to evaluate the adverse effects associated with local and systemic reactions as well measure humoral immune response induced by reproductive vaccines containing different adjuvants. Local reactivity was more intense in Oil group after the 1st dose (P = 0.000), in contrast, Prezent A group presented higher reactivity after the 2nd dose. Rectal temperature was higher in Prezent A between 0 and 48 hours in the 1st dose. Bovine Respiratory Disease score was higher in Prezent A and Oil groups at 48h (P=0.002). ABs against BVDV were detected only at D42, observing the similar averages between Prezent A (log2=5) and Halum (log2=5). The seroconversion was higher in Halum (78%) compared to Prezent A (40%) and oil (10%). The titers and seroconversion against BoHV-1 at D21 were observed in Halum (log2 = 3; 67%) and Prezent A (log2 = 1; 80%) groups. At D42 a higher response was observed for Prezent A (log2 = 6, 100%), followed by Halum (log2 = 4, 100%) and Oil (log2 = 3.0, 60%). The data allow to conclude that the vaccine containing oil adjuvant and Prezent A caused greater local reactivity, but Prezent A induced a greater systemic inflammatory response. The production of ABs against BVDV and BoHV-1 was more intense in Halum vaccine and Prezent A. Future studies are needed to demonstrate the beneficial effects of the systemic inflammatory response of Prezent A on the acquired Th1 cell-mediated immune response.

O objetivo desta pesquisa foi identificar os efeitos adversos relatados por cirurgiões-dentistas (CD) e correlacioná-los com o uso de equipamentos motores. Trata-se de um estudo seccional, não experimental com análise quantitativa dos dados. O estudo foi realizado com 247 CD de Ribeirão Preto-SP. Na coleta dos dados, foi utilizado um questionário auto-aplicável composto por questões agrupadas em: questões sócio-demográficas, relativas a efeitos adversos (musculoesqueléticos, nervosos e vasculares), prática profissional e questões sobre o uso de equipamentos motores. Os dados foram analisados por meio de medidas de distribuição (freqüência), análise bivariada (Teste qui-quadrado e Exato de Fisher) e análise multivariável (Regressão logística). Os efeitos indesejáveis relatados pelos sujeitos e considerados mais intoleráveis foram: dor (67,65%), limitação de amplitude de movimento (7,84%) e parestesia / formigamento (6,86%). As regiões do corpo mais acometidas foram: pescoço, ombros e membros superiores direitos, perfazendo 76,8% das queixas. Os preditores estatisticamente significativos para os efeitos indesejáveis relatados em mãos foram sexo (RC = 0,513, p = 0,056) e pausa entre os atendimentos (RC = 0,514, p = 0,022). O equipamento mais utilizado foi o motor de alta rotação (94,7%), seguido pelos de baixa rotação com contra-ângulo (82,2%) e baixa rotação com peça reta (62,8%). Concluiu-se que embora os CD apresentassem sintomatologia característica de exposição a equipamentos motores que emitem vibração, estes sintomas não são suficientes para confirmar que os equipamentos motores são prejudiciais a sua saúde e que são fatores de risco para a ocorrência de LER/DORT. Os resultados deste estudo oferecem subsídios importantes para a conscientização do cirurgião-dentista sobre sua prática de trabalho e a necessidade de cuidar de sua saúde e levanta questionamentos que possibilitarão a realização de futuras investigações pela equipe multidisciplinar de Saúde do Trabalhador. / This study aimed to identify adverse effects reported by dental surgeons (DS) and correlate them to the use of motor equipment. We carried out a non experimental cross-sectional research with quantitative data analysis. The study involved 247 DS who work in Ribeirão Preto, Brazil. A self-applied questionnaire was used to assess the professionals. This instrument consisted of four parts, asking sociodemographic questions, questions about reported (muscle-skeletal, nervous and vascular) adverse effects, professional practice and questions related to motor equipment use. Data were analyzed through distribution (frequency) measures, bivariate analysis (chi-square and Fisher?s exact test) and multivariate analysis (logistic regression). Within the described undesirable effects, the ones these professionals considered most intolerable are pain (67.65%), movement range limitation (7.84%) and paresthesia/tingling (6.86%). The most affected body regions were neck, shoulders and right superior limbs, corresponding to 76.8% of complaints. The reported predictors statically significant for the undesirable effects on hands were gender (RC = 0,513, p = 0,056) and pause between appointments (RC = 0,514, p = 0,022). These professionals most frequently used high-speed rotating equipment (94.7%), followed low-speed rotation equipment with contra-angle (82.2%) and low-speed rotation equipment with a straight piece (62.8%). Although the symptoms these professionals present are characteristic of exposure to vibrating motor equipment, these symptoms are not sufficient to confirm that motor equipments cause damage to health and are factors of risk to the occurrence of RSI and WMSD. The results of this study offer important support to the consciousness of the Dental Surgeon about his(er) practice and the need to care of his(er) health and raises questions that can give rise to further research by the multidisciplinary team on the worker?s health.

Sun Qiang. / "December 1999." / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (p. 119-139). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

吸煙是引起骨質疏鬆症的因素之一。臨床研究清楚表明吸煙者的骨密度降低，但其他干擾因素可能掩蓋了吸煙對骨頭的不良效果。使用動物模型用以研究吸煙和骨質疏鬆症之間是否有直接的因果關係與它潛在的機制是有必要的。為此，我們使用年輕和雌激素耗盡的小鼠作被動吸煙模型以及小鼠成骨細胞和破骨細胞株來作研究。 / 年輕的Balb/c小鼠暴露於2%或4% (v/v)的香煙煙霧中，代表中度和重度吸煙的人。骨代謝生物標誌物明顯增加，4%吸煙組在14週後股骨的微觀結構4%顯著下降，這相等於人類吸煙12年。此外，雌性Balb/c小鼠進行4%吸煙和/或卵巢切除術(OVX)。吸煙+OVX組增加血清中骨轉換指標水平。4%吸煙組的股骨生長板較薄。μ-CT數據進一步表明，相對骨體積(BV / TV)和結構模型指數(SMI)在吸煙組有顯著影響，而且在吸煙+ OVX組上有更大程度的影響。 / 在細胞研究中使用氯仿(CSE)和乙醇的香煙提取物(ESE)。CSE抑制小鼠細胞株RAW 264.7形成破骨細胞，並刺激小鼠成骨細胞株的分化和功能。這個與體內研究矛盾的結果暗示直接從煙霧中提取的化學成分並不是引起骨質疏鬆的元兇。影響骨代謝的很可能是其他從煙霧中生成的活性代謝物和一些吸煙引起的內源性激素物質。在吸煙引起的骨質流失中，這些代謝物或內源性物質可能是非常重要的。 / 有見及此，4%吸煙小鼠的血清用以研究其對成骨細胞和破骨細胞活動的影響。吸煙小鼠血清顯著降低在成骨細胞中鹼性磷酸酶(ALP)活性和鈣沉積，一些成骨細胞標記基因和蛋白表達均下降，而且 Wnt/β-catenin信號通路下調。此外，吸煙小鼠血清顯著增加形成破骨細胞的數量，組織蛋白酶K的基因和蛋白表達增加，在NF-κB和p-38 MAPK信號傳導途徑的信號分子表達增加。 / 總而言之，大量吸煙可能影響年輕小鼠和雌激素耗竭小鼠的骨代謝和微結構，通過類似的行動機制，人類也可能有同樣的骨疾病風險。這項研究揭示了吸煙導致的骨質疏鬆症在青少年和絶經後婦女的發病機制。這也給我們線索如何預防和治療與吸煙有關的骨骼疾病。這項研究還傳達了一個明確的信息：在年輕時應開始應控制吸煙。 / Cigarette smoking is one of the risk factors for osteoporosis. Clinical studies clearly showed that smokers have lower bone mineral density, but other confounding factors could mask the adverse actions of smoking on bones. Animal models are warranted to study the direct causal relationship between cigarette smoking and osteoporosis, and also the underlying mechanisms. In this regard, we used a mouse passive smoking model in both young and estrogen depleted mice, and the mouse osteoblast and osteoclast cell lines. / Young Balb/c mice were exposed to 2 or 4% (v/v) of cigarette smoke, similar to moderate or heavy smoking respectively in humans. Biomarkers for bone turnover were increased and bone microstructure of femur was significantly deteriorated after 4% smoking for 14 weeks which is similar to cigarette smoking for 12 years in humans. Furthermore, the effects of heavy smoking on ovariectomized mice were also investigated. Female Balb/c mice were subjected to 4% cigarette smoking and/or ovariectomy (OVX). Cigarette smoking together with OVX further increased the levels of bone turnover markers in serum. Femur growth plate was thinner in the 4% smoking group when compared to those in the SHAM- and OVX-operated groups. Micro-CT data further indicated that the relative bone volume (BV/TV) and structural model index (SMI) were significantly affected in the smoking groups, and to a greater extent in the 4% smoking + OVX group. / Chloroform (CSE) and ethanol smoke extracts (ESE) were used in cell studies. CSE suppressed the formation of osteoclasts, and stimulated the differentiation and function of mouse osteoblasts. These findings are contradictory to those found in in vivo study implying that chemical components directly extracted from cigarette smoke are not the culprits in causing bone disorder in animals. It is likely that other active metabolites from cigarette smoke and some endogenous hormonal substances released by cigarette smoking could affect bone metabolism. These active metabolites together with the endogenous bone hormones are perhaps crucial in smoking-induced bone loss in the body. / In view of this hypothesis, sera from 4% smoking mice were used to investigate their effects on osteoblast and osteoclast activities. It was found that the alkaline phosphatase (ALP) activity and calcium deposition in osteoblast were reduced significantly by the sera from smoking mice. Gene and protein expressions of some osteoblast markers were also decreased. The downregulation of Wnt/β-catenin signaling pathway was observed after the treatment with the serum obtained from the 4% smoking group. Moreover, the number of osteoclasts being formed was increased significantly by the smoking mouse serum. Cathepsin K gene and protein expressions were also induced. The increased expressions of the signaling molecules including NF-κB and p-38 MAPK were also observed. / In conclusion, heavy cigarette smoking could deteriorate bone metabolism and microstructures in young female and also estrogen depleted mice. The same kind of risk in bone disease may also apply to humans through similar mechanisms of action. This study sheds light in understanding the pathogenesis of smoking-induced bone disorders in teenagers and also postmenopausal women. It also gives us clues how to prevent and treat smoking related bone diseases. This study also conveys a clear message that cigarette smoking control should be started in young ages. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chan, Lok Yi Ruby. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 182-207). / Abstracts also in Chinese. / Chan, Lok Yi Ruby.

Wong Yin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves [110]-126). / Abstracts in English and Chinese. / ABSTRACT --- p.VI / ACKNOWLEDGEMENTS --- p.X / GLOSSARY --- p.XI / Chapter CHAPTER 1 --- INTRODUCTION AND LITERATURE REVIEW --- p.1 / Chapter 1.1 --- Sudden infant death syndrome --- p.1 / Chapter 1.1.1 --- Definition --- p.1 / Chapter 1.1.2 --- Epidemiology of sudden infant death syndrome --- p.1 / Chapter 1.1.3 --- Pathologic findings --- p.5 / Chapter 1.1.4 --- Theories of causation --- p.6 / Chapter 1.1.5 --- Associations of SIDS with temperature and hyperthermia --- p.8 / Chapter 1.1.6 --- Associations of sudden infant death syndrome with infection --- p.11 / Chapter 1.1.7 --- Association of sudden infant death syndrome with sleep state --- p.13 / Chapter 1.2 --- Overview of cytokines --- p.15 / Chapter 1.2.1 --- Definition --- p.15 / Chapter 1.2.2 --- Classification of cytokines --- p.15 / Chapter 1.2.3 --- Biological activities --- p.16 / Chapter 1.2.4 --- Cytokines and temperature --- p.20 / Chapter 1.2.5 --- Cytokines and infection --- p.22 / Chapter 1.2.6 --- Cytokines and smoking --- p.23 / Chapter 1.2.7 --- Cytokines and sleep/arousal --- p.23 / Chapter 1.3 --- Hypothesis and aims of the study --- p.27 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.28 / Chapter 2.1 --- Overview of methods in piglet experiments --- p.28 / Chapter 2.2 --- Pilot study design --- p.30 / Chapter 2.2.1 --- Study Groups --- p.30 / Chapter 2.2.2 --- Temperature controller --- p.33 / Chapter 2.2.3 --- PowerLab system --- p.34 / Chapter 2.2.4 --- Experimental set up --- p.36 / Chapter 2.2.5 --- Provisional ethical approval --- p.36 / Chapter 2.3 --- Problems and results of pilot experiments --- p.37 / Chapter 2.3.1 --- What is baseline body temperature of neonatal rat? --- p.38 / Chapter 2.3.2 --- What type of anaesthesic agent to use? --- p.39 / Chapter 2.3.3 --- What dose of ketamine to use? --- p.40 / Chapter 2.3.4 --- Dilution of ketamine --- p.41 / Chapter 2.3.5 --- Temperature calibration --- p.41 / Chapter 2.3.6 --- What is optimal neonatal rat age to use? --- p.44 / Chapter 2.3.7 --- Which method of blood collection to use? --- p.45 / Chapter 2.3.8 --- What method to raise body temperature? --- p.47 / Chapter 2.3.9 --- Summary results --- p.48 / Chapter 2.4 --- Final study design --- p.49 / Chapter 2.4.1 --- Study animal --- p.49 / Chapter 2.4.2 --- Final Study Groups --- p.50 / Chapter 2.4.3 --- Final ethical approval --- p.56 / Chapter 2.4.4 --- Muramyl dipeptide --- p.56 / Chapter 2.4.5 --- Recalibration of Temperature Controller --- p.57 / Chapter 2.4.6 --- Data collection --- p.58 / Chapter 2.4.7 --- Blood collection and Storage --- p.58 / Chapter 2.4.8 --- Study timetable --- p.59 / Chapter 2.5 --- Cytokines analysis --- p.59 / Chapter 2.5.1. --- Methods of Quantitative Enzyme Immunoassay --- p.59 / Chapter 2.5.2 --- Base theories of Enzyme-linked immunosorbent assay (ELISA) --- p.60 / Chapter 2.5.3 --- Procedure for cytokines assay --- p.61 / Chapter 2.6 --- Histology --- p.65 / Chapter 2.6.1. --- Macroscopic --- p.65 / Chapter 2.6.2. --- Microscopic --- p.65 / Chapter 2.7 --- Data handling and statistical analysis --- p.66 / Chapter CHAPTER 3 --- RESULTS --- p.67 / Chapter 3.1 --- Group (body weight) characteristics --- p.67 / Chapter 3.2 --- Serum concentration of IL- 6，IL-1 β --- p.69 / Chapter 3.3 --- Temperature --- p.78 / Chapter 3.4 --- Mortality rate --- p.80 / Chapter 3.5 --- Cardio-respiratory parameters --- p.85 / Chapter 3.6 --- Macroscopic findings at postmortem --- p.87 / Chapter 3.7 --- Histology --- p.91 / Chapter CHAPTER 4 --- DISCUSSION --- p.96 / Chapter 4.1 --- Study Model --- p.96 / Chapter 4.11 --- Core temperature of newborn rat --- p.95 / Chapter 4.12 --- Temperature calibration --- p.97 / Chapter 4.13 --- Respiratory and pulse rate measurements --- p.93 / Chapter 4.14 --- Measurement of sleep state --- p.99 / Chapter 4.2 --- Animal age and weight --- p.99 / Chapter 4.3 --- Cytokines response to heating --- p.101 / Chapter 4.4 --- Cytokine response to MDP --- p.104 / Chapter 4.5 --- "Hyperthermia, MDP and mortality" --- p.106 / Chapter 4.6 --- Further study --- p.107 / Chapter CHAPTER 5 --- CONCLUSION --- p.109 / Chapter 5.1 --- Small animal model of hyperthermia --- p.109 / Chapter 5.2 --- Hyperthermia and MDP elicit cytokine response --- p.109 / Chapter 5.3 --- Hyperthermia and MDP increase mortality rate --- p.109 / REFERENCES --- p.110 / APPENDICES --- p.A / Appendix 1: Experimental record --- p.A / Appendix 2 : Planned Study Timetable --- p.C / Appendix 3: PowerLab System --- p.E

Sam Sze Wing. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 156-184). / Abstracts in English and Chinese. / Publications based on work in this thesis --- p.ii / Abstract --- p.iii / Acknowledgements --- p.vii / Chapter 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Corticosteroids --- p.2 / Chapter 1.1.1 --- Chemical Structure of Steroids --- p.3 / Chapter 1.1.2 --- Biosynthesis of Endogenous Corticosteroids --- p.3 / Chapter 1.1.2.1 --- Regulation of Cortisol synthesis and negative feedback system --- p.4 / Chapter 1.1.3 --- Biological Significance of Corticosteroids --- p.5 / Chapter 1.1.3.1 --- Involvement of corticosteroids as anti-inflammatory drugs --- p.6 / Chapter 1.1.3.2 --- Eicosanoid biosynthesis --- p.7 / Chapter 1.1.3.3 --- Lipoxygenase pathway --- p.9 / Chapter 1.1.3.4 --- Side-effects of prolonged use of corticosteroids --- p.9 / Chapter 1.2 --- Organisation of the Emetic Reflex --- p.11 / Chapter 1.2.1 --- Motor Pathway of Emetic Reflex --- p.12 / Chapter 1.2.1.1 --- Retching and vomiting --- p.12 / Chapter 1.2.1.2 --- Nausea --- p.13 / Chapter 1.2.2 --- Components of the Emetic Reflex --- p.14 / Chapter 1.2.2.1 --- The vomiting centre (VC) --- p.15 / Chapter 1.2.2.2 --- Area postrema (AP) / Chemoreceptor trigger zone (CTZ) --- p.15 / Chapter 1.2.2.3 --- The nucleus tractus solitarius (NTS) --- p.17 / Chapter 1.2.2.4 --- Gastrointestinal tract and vagus nerves --- p.17 / Chapter 1.2.2.5 --- Neurotransmitter receptors --- p.18 / Chapter 1.3 --- Chemotherapy-Induced Emesis --- p.19 / Chapter 1.3.1 --- Cancer as a cause of mortality in Man --- p.20 / Chapter 1.3.2 --- Chemotherapeutic Agents --- p.20 / Chapter 1.3.2.1 --- Different classes --- p.20 / Chapter 1.3.2.2 --- Emetogenic potential --- p.21 / Chapter 1.3.3 --- Cisplatin-Induced Emesis --- p.23 / Chapter 1.3.3.1 --- Unfavourable effects associated with chemotherapy-induced nausea and emesis --- p.24 / Chapter 1.3.3.2 --- Anticipatory nausea and vomiting --- p.24 / Chapter 1.3.3.3 --- Profile of cisplatin-induced emesis --- p.25 / Chapter 1.3.4 --- Animal Models of Cisplatin-Induced Acute and Delayed Emesis --- p.26 / Chapter 1.3.5 --- Mechanisms and Pathways Involves in Chemotherapy-Induced Emesis --- p.28 / Chapter 1.3.6 --- Anti-Emetic Drugs for the Treatment of Chemotherapy-Induced Emesis --- p.31 / Chapter 1.3.6.1 --- 5-HT3 receptor antagonists --- p.31 / Chapter 1.3.6.2 --- Dopamine receptor antagonists --- p.33 / Chapter 1.3.6.3 --- Benzodiazepines --- p.35 / Chapter 1.3.6.4 --- Cannabinoids --- p.35 / Chapter 1.3.6.5 --- Antihistamines and anticholinergics --- p.35 / Chapter 1.3.6.6 --- NK1 receptor antagonists --- p.37 / Chapter 1.3.6.7 --- Corticosteroids --- p.38 / Chapter 1.3.6.8 --- Multi-agent anti-emetic regimens --- p.39 / Chapter 1.4 --- Motion-Induced Emesis --- p.41 / Chapter 1.4.1 --- Incidence --- p.42 / Chapter 1.4.2 --- Mechanisms and Pathways Involved in Motion Sickness --- p.43 / Chapter 1.4.2.1 --- Importance of the vestibular apparatus --- p.44 / Chapter 1.4.2.2 --- Importance of the area postrema --- p.45 / Chapter 1.4.2.3 --- The nucleus tractus solitarius --- p.46 / Chapter 1.4.2.4 --- Hormone and neurotransmitters --- p.46 / Chapter 1.4.3 --- Animal models in Motion-Induced Emesis --- p.47 / Chapter 1.4.4 --- Anti-Emetic Drugs for the Treatment of Motion Sickness --- p.48 / Chapter 1.4.4.1 --- Anticholinergics --- p.49 / Chapter 1.4.4.2 --- Antihistamines --- p.49 / Chapter 1.4.4.3 --- Non-selective muscarinic and histamine receptor antagonists --- p.51 / Chapter 1.4.4.4 --- Sympathomimetics --- p.51 / Chapter 1.4.4.5 --- NK1i receptor antagonists --- p.51 / Chapter 1.4.4.6 --- 5-HT1A agonists --- p.52 / Chapter 1.4.4.7 --- 5-HT2 receptor agonist --- p.52 / Chapter 1.4.4.8 --- Arginine vasopressin (AVP) antagonists --- p.53 / Chapter 1.4.4.9 --- Opioid receptor agonists --- p.53 / Chapter 1.4.4.10 --- Dexamethasone and hormone levels --- p.54 / Chapter 1.4.4.11 --- Other anti-emetic drugs --- p.55 / Chapter 1.5 --- Aims of the Studies --- p.56 / Chapter 2 --- Methods --- p.59 / Chapter 2.1 --- Cisplatin-Induced Emesis Studies --- p.60 / Chapter 2.1.1 --- Animals --- p.60 / Chapter 2.1.2 --- Induction and Measurement of Emesis --- p.60 / Chapter 2.1.3 --- The Effects of Corticosteroids on Cisplatin-Induced Acute and Delayed Retching and Vomiting --- p.63 / Chapter 2.1.4 --- "The Effects of Dexamethasone (1 mg/kg, i.p.) Administered as an Intervention Treatment on an Established Delayed Retching and Vomiting Response Induced by Cisplatin" --- p.63 / Chapter 2.1.5 --- The Effects of Cortrosyn Depot (Tetracosactrin) on Cisplatin-Induced Acute and Delayed Retching and Vomiting --- p.63 / Chapter 2.1.6 --- The Effects of Metyrapone on Cisplatin-Induced Acute and Delayed Retching and Vomiting --- p.64 / Chapter 2.1.7 --- The Effects of Indomethacin on Cisplatin-Induced Acute and Delayed Retching and Vomiting --- p.64 / Chapter 2.1.8 --- "The Effects of DFU and L-745,337 Administered as an Intervention Treatments on an Established Delayed Retching and Vomiting Response Induced by Cisplatin" --- p.64 / Chapter 2.1.9 --- "The Effects of MK-886 (L-663,536) on Cisplatin-Induced Acute and Delayed Retching and Vomiting" --- p.65 / Chapter 2.1.10 --- The Effects of a Combination of Indomethacin and MK-886 on Cisplatin- Induced Acute and Delayed Retching and Vomiting --- p.65 / Chapter 2.1.11 --- Statistical Analysis --- p.66 / Chapter 2.2 --- Motion-Induced Emesis Studies --- p.67 / Chapter 2.2.1 --- Animals --- p.67 / Chapter 2.2.2 --- Measurement of Emesis --- p.67 / Chapter 2.2.3 --- Induction of Emesis in Motion-Naive Suncus murinus: Effects of Glucocorticoids --- p.68 / Chapter 2.2.4 --- Induction of Emesis in Motion-Sensitive Suncus murinus: Effects of Dexamethasone --- p.70 / Chapter 2.2.5 --- Preparation of Serum --- p.72 / Chapter 2.2.6 --- Measurement of Serum Cortisol by Enzyme-Linked Immunoassay (ELISA) --- p.72 / Chapter 2.2.6.1 --- Immunoassay kit --- p.72 / Chapter 2.2.6.2 --- Assay procedures --- p.73 / Chapter 2.2.7 --- Measurement of Serum Adrenocorticotrophin (ACTH) by Radioimmunoassay (RIA) --- p.75 / Chapter 2.2.7.1 --- Immunoassay kit --- p.75 / Chapter 2.2.7.2 --- Assay procedures --- p.76 / Chapter 2.2.8 --- Statistical Analysis --- p.79 / Chapter 3 --- Results --- p.81 / Chapter 3.1 --- Cisplatin-Induced Emesis --- p.82 / Chapter 3.1.1 --- General Profile of Emesis Induced by Cisplatin --- p.82 / Chapter 3.1.2 --- Antagonism of Cisplatin-Induced Emesis by Corticosteroids --- p.82 / Chapter 3.1.3 --- "The Effect of Dexamethasone (1 mg/kg, i.p.) Administered as an Intervention Treatment on an Established Delayed Retching and Vomiting Response Induced by Cisplatin" --- p.84 / Chapter 3.1.4 --- The Effect of Cortrosyn Depot (Tetracosactrin) on Cisplatin-Induced Acute and Delayed Retching and Vomiting --- p.85 / Chapter 3.1.5 --- The Effect of Metyrapone on Cisplatin-Induced Acute and Delayed Retching and Vomiting --- p.85 / Chapter 3.1.6 --- "The Effect of Indomethacin, DFU and L-745,337 on Cisplatin-Induced Acute and Delayed Retching and Vomiting" --- p.86 / Chapter 3.1.7 --- The Effect of MK-886 on Cisplatin-Induced Acute and Delayed Retching and Vomiting --- p.88 / Chapter 3.1.8 --- The Effect of Combination of Indomethacin and MK-886 on Cisplatin- Induced Acute and Delayed Retching and Vomiting --- p.89 / Chapter 3.2 --- Motion-Induced Emesis --- p.91 / Chapter 3.2.1 --- General Effect of Motion on Serum Cortisol and ACTH Levelsin Motion Naive Suncus murinus --- p.91 / Chapter 3.2.2 --- The Effect of Glucocorticoids on Motion-Induced Emesis and Cortisol and ACTH Levels in Motion-Naive Male Suncus murinus --- p.92 / Chapter 3.2.2.1 --- Effect of dexamethasone --- p.92 / Chapter 3.2.2.2 --- Effect of betamethasone --- p.93 / Chapter 3.2.2.3 --- Effect of methylprednisolone --- p.93 / Chapter 3.2.3 --- The Effect of Glucocorticoids on Motion-Induced Emesis and Cortisol and ACTH Levels in Motion Naive Female Suncus murinus --- p.94 / Chapter 3.2.3.1 --- Effect of dexamethasone --- p.94 / Chapter 3.2.3.2 --- Effect of betamethasone --- p.95 / Chapter 3.2.3.3 --- Effect of methylprednisolone --- p.95 / Chapter 3.2.4 --- The Effect of Dexamethasone on Motion-Induced Emesis and Cortisol and ACTH Levels in Motion-Sensitive Suncus murinus --- p.96 / Chapter 3.2.4.1 --- Effect of dexamethasone on male motion-sensitive animals --- p.97 / Chapter 3.2.4.2 --- Effect of dexamethasone on female motion-sensitive animals --- p.97 / Chapter 4 --- Discussion --- p.131 / Chapter 4.1 --- "Cisplatin (5 mg/kg, i.p.)-Induced Emesis in Control Animals" --- p.132 / Chapter 4.2 --- Anti-Emetic Action of Corticosteroids in the Ferret --- p.133 / Chapter 4.3 --- Metyrapone Study --- p.138 / Chapter 4.4 --- Cortrosyn Depot Study --- p.139 / Chapter 4.5 --- Role of Cycloxygenase --- p.141 / Chapter 4.6 --- Role of 5-Lipoxygenase --- p.143 / Chapter 4.7 --- Duel Inhibition of Cycloxygenase and 5-Lipoxygenase --- p.144 / Chapter 4.8 --- Anti-Emetic Potential of Glucocorticoids in Suncus murinus --- p.145 / Chapter 4.9 --- General Summary --- p.149 / Appendix I --- p.152 / Appendix II --- p.154 / References --- p.156