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Chan, Wai Kiu. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 233-256). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract and appendix also in Chinese.

目的：本研究主要目的是建立預測模型來判定矽肺發生的累積風險從而推薦適宜的胸片照射年限並從而評估常規監測和推薦監測策略的成本效益。此外，本研究還評價了常規診斷和驗證性診斷的符合度以及在驗證性診斷中邀請的三位專家之間的符合度。 / 方法：總計有3492男性接塵工人在1964年1月1日到1974年12月31日期間進入本隊列並隨訪至2008年12月31日。不同閱片專家根據中國最新塵肺病診斷標準 （GBZ70-2009））分別閱片總計9084張。對專家之間閱片結果的兩兩比較和兩種診斷結果的比較均采用Cohen’s Kappa檢驗。應用三種篩選方法（強制所有變量同時進入模型，後退逐步篩選，以及Least Absolute Shrinkage and Selection Operator (LASSO)篩選。LASSO模型作為最優模型，以分數量表的方式來表達。根據分數，把工人分成高、中、低危險組，並估計這三組不同危險水平工人的累積危險度。運用0.1% 累積危險度來判定不同危险的工人及不同期別的矽肺病人的射線照射年限。多狀態Markov模型用於計算矽塵暴露工人不同狀態的年轉移概率，並應用Markov成本效益分析方法來估計每獲得一個生命年的成本效益。 / 結果：截至2008年底，本矽塵暴露隊列共計發現298例矽肺病人（累計發病率為8.53%），死亡1347例（死亡比例為38.57%）。本研究發現常規診斷和驗證性診斷有很好的符合度 （Kappa值為0.89， 95%可信區間為0.88-0.91）。基於LASSO模型的分數量表具有很好的診斷識別能力 （ROC曲線下面積為0.83， 95%可信區間為0.81-0.86）。根據0.1%累積危險度標準，我們判定低危險組工人第一次射線照射的時間為第11年，推薦每兩年隨訪一次；中等危險組工人和高危險組工人的第一次射線照射時間分別為第11年和第5年，推薦每年隨訪一次。矽肺病人未晉級到三期以前均一年隨訪一次。矽塵暴露工人的年轉移概率為：從健康狀態向疑似病例轉移的概率為0.0198，從疑似病例向一期矽肺轉移的概率為0.038，從一期矽肺向二期矽肺轉移的概率為0.0516，從二期矽肺向三期矽肺轉移的概率為0.059，從三期矽肺向死亡轉移的概率為0.18。在1964到2008年間，診斷一例矽肺病例平均花費醫療成本為21853.11美元，非醫療成本為5993.30美元。模擬10,000矽塵暴露工人在未來40年按照當前的狀態轉移概率，應用常規的職業健康檢查為手段獲得一個生命年的成本效益為43.60美元，應用推薦的職業健康檢查為手段獲得一個生命年的成本效益為46.99美元。 / 結論：本研究在最優預測模型的基礎上為不同矽肺危險度的矽塵暴露工人首次提供了科學的證據來判定射線照射的適宜年限，亦為未來矽塵暴露工人的職業健康監測提供了科學理論依據，雖然本研究推薦的監測策略獲得同常規策略相類似的成本和效益。 / Objectives: The primary objective was to develop prediction models for determining the optimal intervals of chest radiographic surveillance for workers exposed to silica dust; the second primary objective is to assess the cost per case identification and compare the cost per life year gained under routine medical surveillance program with that under the recommended program for workers exposed to silica dust in China. In addition, the inter-rater agreement amongst three invited radiologists on rereading the chest radiographs and the agreement between the original diagnoses of silicosis (from routine reports) and the verified diagnoses reassessed by the three experts were also evaluated. / Methods: A total of 3492 male workers exposed to silica dust in an iron ore during the period 1964 - 1974 were recruited into this retrospective cohort study. All cohort members were followed up through the end of 2008 to observe the occurrence of silicosis and overall profile of mortality. All 9084 chest X-ray films were reread by three radiologists who had been qualified as experts at the national level according to the Chinese National Diagnostic Criteria of Pneumoconiosis (GBZ70-2009). The diagnosis of silicosis made by the panel of these three invited experts was referred to the “verified diagnosis“. Cohen’s Kappa test was used to test inter-rater agreements of three invited readers on chest radiographs and the agreement on the diagnosis of silicosis obtained from routine medical surveillance (i.e., the original routine diagnosis) was compared with those verified by the 3 qualified readers (i.e., the verified diagnosis). The multivariate Cox’s proportional hazard regression models were developed to predict the silicosis occurrence based on three selection approaches entry of all predictors at the same time, backward stepwise selection, and Least Absolute Shrinkage and Selection Operator (LASSO) selection. The LASSO model showed the best model fit which was thus regarded as the final model for predicting a score chart. / Based on this practically used score chart, we then classified workers into three groups of different risk levels of silicosis (low, moderate, and high). We estimated the cumulative risk of silicosis over years of follow-up for these three groups of workers at different risk levels. We used 1 per thousand of cumulative risk for developing silicosis as a “benchmark“ to determine the intervals of radiologic surveillance for workers with different risks of silicosis. Multi-state Markov model was used to calculate the transition probabilities of different states of silicosis and the analysis on cost and effectiveness was performed. / Results: By the end of 2008, the cumulative incidence rate of silicosis was 8.53% (298 silicosis cases) and a total of 1347 deaths (38.57%) were observed. / Good inter-rater agreements were observed amongst three invited radiologists for rereading all the chest films. Kappa value for the agreement between the original diagnoses and the verified diagnoses was 0.89 (95% confidence interval [95%CI], 0.88-0.91). / The model with the best fit was LASSO Cox model which showed a good discrimination with an area of 0.83 (95%CI, 0.81-0.86) under the receiver operating characteristic (ROC) curve. We classified workers into 3 risk groups according to the score chart obtained from the LASSO Cox model, and found the observed probabilities matched well to the predictions. According to 1 per thousand “benchmark“, we can determine that the initial interval of radiographic surveillance for workers in the low risk group was 11 years and a subsequent biyearly examination was recommended. The initial examination interval was 11 years and 5 years respectively for workers in the middle and high risk group, and then a yearly examination was recommended. For patients with silicosis, an annual radiological surveillance program was recommended regardless of the stage of pneumoconiosis. / According to results from multi-state model, we estimated that the yearly transition probability was 0.0198 for silica dust exposed workers from healthy state to the suspected silicosis cases (sojourn time = 47 years), 0.0338 from suspected silicosis cases to silicosis stage one (sojourn time = 23 years), 0.0516 from silicosis stage one to stage two (sojourn time = 9 years), 0.059 from silicosis stage two to stage three (sojourn time = 6 years), and 0.18 from silicosis stage three to death (sojourn time = 5 years). / During the period 1964 to 2008, the average direct medical cost spent on identifying one silicosis case was US$ 21853.11 and the non-medical cost for identifying one case was US$ 5993.30 per case. The estimated medical cost regarding per life year gained was US$ 43.60 under the routine medical surveillance program and it would be US$ 46.99 if the newly recommended surveillance program is adopted. / Conclusion: This study is the first to provide scientific evidence on determining the optimal intervals of radiographic surveillance for workers at different risk levels of silicosis based on the ‘best’ prediction model. Although our study revealed similar cost and effectiveness for using the recommended occupational health examination strategy compared with the routine program, this study is the first to provide scientific theory for guiding evidence-based occupational medical surveillance on workers exposed to silica dust in the world. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chen, Minghui. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 195-210). / Abstract also in Chinese. / Abstract (English) --- p.i / Abstract (Chinese) --- p.v / Acknowledgements --- p.vii / List of contents --- p.ix / List of tables --- p.xv / List of figures --- p.xviii / List of main abbreviations --- p.xx / Chapter Section I --- Introduction and Literature Review --- p.1 / Chapter Chapter 1 --- Introduction --- p.2 / Chapter Chapter 2 --- Literature Review of Medical Examination, Prediction model and Economic Evaluation in Silicosis --- p.7 / Chapter 2.1 --- The aims of this literature review --- p.7 / Chapter 2.2 --- Search strategies and selection criteria --- p.7 / Chapter 2.3 --- Searching results --- p.8 / Chapter 2.4 --- Critical appraisal criteria and quality of selected studies --- p.9 / Chapter 2.4.1 --- Critical appraisal criteria --- p.9 / Chapter 2.4.2 --- Quality of selected studies --- p.10 / Chapter 2.5 --- Overview of effectiveness of chest radiography in medical surveillance of silicosis for workers exposed to silica dust --- p.15 / Chapter 2.5.1 --- Occupational medical surveillance for workers exposed to silica dust --- p.15 / Chapter 2.5.2 --- Comparison of CT or HRCT and chest radiography --- p.16 / Chapter 2.5.3 --- Comparison of digital radiography (DR) and chest radiography --- p.17 / Chapter 2.5.4 --- Other tests to be relevant to silicosis diagnosis --- p.23 / Chapter 2.5.5 --- The effectiveness of chest radiography in medical surveillance and diagnosis of silicosis --- p.24 / Chapter 2.5.6 --- Comparison between the ILO Classification and the Chinese Diagnostic criteria of pneumoconiosis --- p.25 / Chapter 2.6 --- Overview of application of prediction model in silicosis and a review on methodology in prediction model --- p.32 / Chapter 2.6.1 --- Application of prediction model in occupational diseases --- p.32 / Chapter 2.6.2 --- Overview of application of predicting model in pneumoconiosis including silicosis in China in recent 10 years --- p.34 / Chapter 2.6.3 --- Development of prediction model and the applications from practical perspectives --- p.35 / Chapter 2.7 --- A review on economic evaluation in occupational diseases and the screening interval analyses --- p.42 / Chapter 2.7.1 --- An overview on economic evaluation in pneumoconiosis --- p.42 / Chapter 2.7.2 --- Overview of economic evaluation in occupational health and safety and screening interval analyses --- p.44 / Chapter 2.7.3 --- Overview for methodology of performing CEA --- p.45 / Chapter 2.8 --- Research gaps were found from this literature review --- p.52 / Chapter Section II --- Objectives and Methods --- p.53 / Chapter Chapter 3 --- General aims and objectives --- p.54 / Chapter 3.1 --- General aims --- p.54 / Chapter 3.2 --- Primary objectives --- p.54 / Chapter 3.3 --- Secondary objective --- p.54 / Chapter Chapter 4 --- Methodology and Research Plans --- p.55 / Chapter 4.1 --- Study Design --- p.55 / Chapter 4.2 --- The cohort --- p.55 / Chapter 4.3 --- Follow-up --- p.58 / Chapter 4.4 --- Data Collection --- p.58 / Chapter 4.4.1 --- Baseline information --- p.58 / Chapter 4.4.2 --- Diagnosis of silicosis and the verification --- p.59 / Chapter 4.4.3 --- Occupational hygiene monitoring data --- p.60 / Chapter 4.4.4 --- Cost data of medical examination --- p.61 / Chapter 4.5 --- Data Entry and Data Analyses --- p.62 / Chapter Section III --- Results and Discussions --- p.65 / Chapter Chapter 5 --- Description of the cohort --- p.66 / Chapter 5.1 --- Cohort recruitment --- p.66 / Chapter 5.2 --- Baseline characteristics --- p.69 / Chapter 5.3 --- Change of respirable silica dust concentration over time --- p.71 / Chapter 5.5 --- Occurrence of silicosis --- p.73 / Chapter 5.5.1 --- Basic characteristics of silicosis patients --- p.73 / Chapter 5.5.2 --- Trend of silicosis occurrence with calendar year --- p.78 / Chapter 5.5.3 --- Trend of silicosis occurrence with age of entering the cohort --- p.78 / Chapter 5.5.4 --- Trend of silicosis occurrence with cumulative exposure to respirable silica dust --- p.78 / Chapter 5.6 --- Survival distribution at different respirable silica dust exposure levels --- p.79 / Chapter 5.7 --- A summary of the results in Chapter 5 --- p.82 / Chapter Chapter 6 --- Agreement between the routine diagnosis of silicosis and the verified ‘new panel’ diagnosis --- p.83 / Chapter [Summary] --- p.83 / Chapter 6.1 --- Background --- p.85 / Chapter 6.2 --- Methodology --- p.86 / Chapter 6.2.1 --- The routine and the verified diagnosis of silicosis --- p.86 / Chapter 6.2.2 --- Inter-rater agreement --- p.87 / Chapter 6.3 --- Results --- p.89 / Chapter 6.3.1 --- Technical quality of chest X-ray films --- p.89 / Chapter 6.3.2 --- Inter-rater agreement amongst readers --- p.89 / Chapter 6.3.3 --- Agreement between the routine and the verified diagnosis of silicosis --- p.93 / Chapter 6.3.4 --- Agreement of the progression of silicosis between the routine and verified diagnosis --- p.95 / Chapter 6.4 --- Discussion --- p.97 / Chapter Chapter 7 --- Developing prediction model for determining the optimal intervals of chest radiographic examinations for workers at different risks of silicosis --- p.100 / Chapter [Summary] --- p.100 / Chapter 7.1 --- Background --- p.102 / Chapter 7.2 --- Methods --- p.104 / Chapter 7.2.1 --- The cohort and outcome determination --- p.104 / Chapter 7.2.2 --- Developing prediction models for silicosis --- p.107 / Chapter 7.2.3 --- Coding of Predictors --- p.113 / Chapter 7.3 --- Results --- p.118 / Chapter 7.3.1 --- Model Specifications --- p.118 / Chapter 7.3.2 --- Stepwise Selection and LASSO selection --- p.119 / Chapter 7.3.3 --- Model Validations: Stability and Optimism --- p.119 / Chapter 7.3.4 --- Model Presentations --- p.126 / Chapter 7.3.5 --- Cut-off point of follow up year for determining examination intervals --- p.130 / Chapter 7.4 --- Discussions --- p.136 / Chapter Chapter 8 --- Transition probabilities of multi-states for workers with silica dust exposure --- p.141 / Chapter [Summary] --- p.141 / Chapter 8.1 --- Background --- p.143 / Chapter 8.2 --- Methodology of multi-state model --- p.145 / Chapter 8.2.1 --- Survival data and multi-state model --- p.145 / Chapter 8.2.2 --- Markov model and transition states --- p.151 / Chapter 8.2.3 --- Model assessment --- p.153 / Chapter 8.3 --- Results --- p.154 / Chapter 8.3.1 --- Initial values specification and estimates of intensity matrix --- p.154 / Chapter 8.3.2 --- Transition probability matrix, mean sojourn times, and survival situation --- p.159 / Chapter 8.3.3 --- Observed and expected prevalence of each state for Model assessment --- p.163 / Chapter 8.4 --- Discussion --- p.165 / Chapter Chapter 9 --- Cost effectiveness analysis of occupational medical surveillance for workers exposed to silica dust --- p.168 / Chapter [Summary] --- p.168 / Chapter 9.1 --- Background --- p.170 / Chapter 9.2 --- Methodologies --- p.171 / Chapter 9.2.1 --- Costs and effectiveness --- p.171 / Chapter 9.2.2 --- Cost per silicosis identification estimation in the iron ore during 1964 to 2008 --- p.172 / Chapter 9.2.3 --- Cost effectiveness analysis in the Markov model --- p.173 / Chapter 9.3 --- Results --- p.176 / Chapter 9.3.1 --- Cost estimation and cost per silicosis identification in the iron ore cohort --- p.176 / Chapter 9.3.2 --- Cost effectiveness analysis in the Markov model --- p.181 / Chapter 9.4 --- Discussion --- p.187 / Chapter Section IV --- Conclusions and Implications --- p.191 / Chapter Chapter 10 --- Conclusions, implications, and recommendations --- p.192 / Chapter 10.1 --- Conclusions --- p.192 / Chapter 10.2 --- Implications and recommendations --- p.193 / Reference list --- p.195 / Chapter Appendix I --- Chest Radiographic Imaging of Different Diagnostic Criteria for Pneumoconiosis in China --- p.211 / Chapter Appendix II --- Diagnosis Stages among Different Diagnostic Criteria for Pneumoconiosis in China --- p.212 / Chapter Appendix III --- Publications in journals and international conferences during the PhD study --- p.213 / Chapter Supplement I --- Syntax for test proportionality of Cox model in R survival package and LASSO model in R penalized package --- p.215 / Chapter Supplement II --- Guideline of applying the prediction model in practice --- p.216 / Chapter Supplement III --- Syntax for multi-state model in R msm package --- p.221 / Chapter Supplement IV --- An example for cost estimation of adjusting inflation and exchanging --- p.222 / Chapter Supplement V --- Cost estimation of workers, suspected silicosis cases and silicosis patients in the iron ore during 1964 - 2008 --- p.223 / Chapter Supplement V (Continued) --- Cost estimation of workers, suspected silicosis cases and silicosis patients in the iron ore during 1964 - 2008 --- p.224 / Chapter Supplement VI --- Number of deaths for all cause of death in the iron ore cohort until 2008 --- p.225 / Chapter Supplement VII --- Decision tree of Markov model in the study --- p.226 / Chapter Supplement VII (Continued) --- Decision tree of Markov model in the study --- p.227

Introdução. As hemisferectomias são cirurgias utilizadas há décadas para se tratar epilepsias refratárias à medicação anticonvulsivante. Embora o controle das crises seja satisfatório, a morbidade, per e pós-operatória, ainda é considerada um importante fator limitante à sua utilização. Dessa maneira, compreender as complicações mais comuns do procedimento, e os fatores que as influenciam, é essencial para se estabelecer o melhor uso para a técnica. Métodos. Foram coletados dados de 30 pacientes, operados por seis cirurgiões no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período entre 1980 e 2003. Foram realizadas 11 hemisferectomias com a abordagem de Rasmussen, três hemisferectomias anatômicas, nove hemisferectomias funcionais extraventriculares e sete hemisferotomias. Foram estudados cinco grupo de pacientes de acordo com a fisiopatologia da doença de base: Dezesseis pacientes eram portadores de Síndrome de Rasmussen, dois da Síndrome de Sturge-Weber, quatro de malformações corticais, dois de lesões sequelares e seis de cistos porencefálicos. Os fatores de morbidade foram avaliados dentro de rês perspectivas: 1- da doença de base; 2- da técnica utilizada; e 3- do fator humano. Resultados. Nossos dados mostraram ausência de diferença estatisticamente significativa entre as técnicas cirúrgicas empregadas nos itens: tempo cirúrgico; tempo de internação na unidade de terapia intensiva; queda da hemoglobina; volume de hemoderivados transfundidos e febre no pós-operatório. Presença de leucograma acima de 15.000 leucócitos/mm3 no pós-operatório imediato foi associada a estadias mais longas na unidade de terapia intensiva A média diária de temperatura dos pacientes, mostrou temperaturas acima de 38º C entre o terceiro e sexto dia pós-operatório. Pacientes com hemimegalencefalia apresentaram temperaturas mais elevadas quando comparados com os portadores de cistos porencefálicos. Doenças com maior manto cortical contribuíram para aumentar o tempo cirúrgico, embora o fator humano tenha sido decisivo nesse item. Ao comparar nossos achados com os da literatura, vimos que os pacientes submetidos à hemisferectomia anatômica apresentaram no pós-operatório temperaturas mais elevadas e reação inflamatória liquórica mais intensa que os submetidos a técnicas de desconexão hemisférica, no entanto, a importância desse dado necessita ser estabelecida. Conclusões: O principal fator de morbidade nas hemisferectomias é a doença de base, assim, os dados presentes na literatura, incluindo nossa casuística, não nos permite concluir que uma técnica seja superior à outra ou que as técnicas desconectivas sejam melhores que as ressectivas / Hemispherectomy has been the treatment of choice in some sorts of refractory epilepsies for decades. Although surgery results in satisfactory control of seizures, its morbidity remains a major concern. Thus, understanding most common complications, as well as the factors that contribute to it, becomes an essential step to learn the limits on technique applications. Methods. Hospital charts from 30 patients operated on by six different surgeons at the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo from 1980 to 2003 were reviewed. Eleven functional hemispherectomies using Rasmussen approach, three anatomical hemispherectomies, nine extraventricular functional hemispherectomies, and seven hemispherotomies were included in this study. Sixteen patients presented with Rasmussen Syndrome, two Sturge-Weber Syndrome, four cortical malformations, two hemispheric lesions, and six porencephalic cysts. Morbidity was evaluated from three different perspectives 1- background disease, 2- employed technique, and 3- human factor. Results: our data presented no statistical difference among the employed techniques regarding 1- surgical time, 2- intensive care unit time, 3- per and postoperative fall of hemoglobin, 4- blood transfusion volume, and 5- postoperative axilar temperature variation. Patients that presented over 15,000 leucocytes per mm3 stayed longer at the intensive care unit, regardless of the surgical technique employed. Daily average temperatures varied around 38 degrees Celsius from the third to the sixth postoperative day. Patients with hemimegalencephaly had higher postoperative axilar temperatures when compared to those with porencephaly. Thicker cortical mantle contributed to increase surgical time, though human factor also showed to be important in this item. Comparing data from this study and the literature disclosed that patients undergoing anatomical hemispherectomies presented an inflammatory response in the cerebrospinal fluid more evident than those submitted to cerebral disconnection, although the importance of this finding is still elusive. Conclusions: The main factors of morbidity in the hemispherectomy are the background disease and patient\'s peculiarities, therefore, it is not reasonable to infer that there is a superior technique or that hemisphere disconnection is better than removal

Hin-Chung Chu. / Thesis submitted in: July 2002. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 281-306). / Abstracts in English and Chinese. / Cover (English & Chinese version) --- p.I / 中文封面 --- p.II / Abstract (English version) --- p.III-IV / 中藥不良反應論文摘要 --- p.V / Acknowledgements --- p.VI / Abbreviations --- p.VII-VIII / Publication in press --- p.IX / Content --- p.X-XV / Lists of Table --- p.XVI / Chapter Chapter 1 --- Introduction --- p.1-3 / Chapter Chapter 2 --- Chinese herbal medicines used in Hong Kong. --- p.4-15 / Chapter 2.1 --- Overview --- p.4-5 / Chapter 2.2 --- The Policy In Hong Kong -- Past And Present --- p.5-1 / Chapter 2.3 --- The Preparatory Committee on Chinese Medicine (PCCM) --- p.7-8 / Chapter 2.4 --- The Chinese Medicine Council of Hong Kong --- p.8-10 / Chapter 2.5 --- Development of Standards --- p.10 / Chapter 2.6 --- Development of Centres of Good Clinical Practice --- p.10-11 / Chapter 2.7 --- Establishment of a Good System of Education and Training --- p.11 / Chapter 2.8 --- Investigation of Suspected Herbal Toxicity Cases --- p.12-13 / Chapter 2.8.1 --- Herbal Safety Surveillance --- p.13-14 / Chapter 2.9 --- Conclusion --- p.14-15 / Chapter Chapter 3 --- Herbal medicines used in other countries --- p.16-45 / Chapter 3.1 --- Overview --- p.16 / Chapter 3.2 --- China --- p.16-19 / Chapter 3.3 --- Macau --- p.22-23 / Chapter 3.4 --- Taiwan --- p.23-26 / Chapter 3.5 --- Japan --- p.27-30 / Chapter 3.6 --- Singapore --- p.30-31 / Chapter 3.7 --- Australia --- p.31-34 / Chapter 3.8 --- Others Asian countries --- p.35 / Chapter 3.9 --- USA --- p.35-39 / Chapter 3.10 --- United Kingdom --- p.39-41 / Chapter 3.11 --- Europe --- p.41-43 / Chapter 3.12 --- Germany --- p.43-45 / Chapter Chapter 4 --- Adverse reaction -- General Aspect --- p.46-63 / Chapter 4.1 --- Overview --- p.46 / Chapter 4.2 --- Traditional Chinese medicine --- p.47-49 / Chapter 4.2.1 --- Compound Prescriptions to Reduce Toxicity --- p.50 / Chapter 4.2.2 --- Processing Of Chinese Herbs --- p.50-51 / Chapter 4.2.2.1 --- The Aims of Herbal Drug Processing --- p.51-52 / Chapter 4.2.2.2 --- The Methods of Herbal Drug Processing --- p.52 / Chapter 4.2.2.3 --- External processing (simple treatment by trimming) --- p.52-53 / Chapter 4.2.2.4 --- Water processing --- p.53-54 / Chapter 4.2.2.5 --- Fire processing --- p.54 / Chapter 4.2.2.6 --- Water-fire processing --- p.54-55 / Chapter 4.2.2.7 --- Other methods --- p.55 / Chapter 4.3 --- Practical Problem in Traditional Chinese Medicine --- p.55-57 / Chapter 4.4 --- Evaluation of herbal adverse reactions --- p.57 / Chapter 4.4.1 --- Type A reactions --- p.57 / Chapter 4.4.2 --- Type B reactions --- p.58 / Chapter 4.4.3 --- Type C reactions --- p.58 / Chapter 4.4.4 --- Type D reactions --- p.58 / Chapter 4.5 --- Chinese Proprietary medicine --- p.58-59 / Chapter 4.6 --- Potential Risks for Herbal Adverse Reaction --- p.59 / Chapter 4.6.1 --- Misidentification --- p.59-60 / Chapter 4.6.2 --- Lack of standardisation --- p.60 / Chapter 4.6.3 --- Contamination --- p.60 / Chapter 4.6.4 --- Incorrect preparation / dosage --- p.60 / Chapter 4.6.5 --- Excessive dosage --- p.60-61 / Chapter 4.6.6 --- Individual errors --- p.61 / Chapter 4.6.7 --- Individual response --- p.61 / Chapter 4.6.8 --- Unqualified Herbal Practitioner with Wrong Prescription --- p.61-62 / Chapter 4.6.9 --- Interaction with Western medicine --- p.62 / Chapter 4.6.10 --- Prolonged Usage --- p.62 / Chapter 4.6.11. --- Coexisting disease --- p.62-63 / Chapter 4.7 --- Conclusion --- p.63 / Chapter Chapter 5 --- "Substitution, Adulteration or Misusing with Toxic Herbs" --- p.64-84 / Chapter 5.1 --- Overview --- p.64-65 / Chapter 5.2 --- Adulteration by Guijiu --- p.65-68 / Chapter 5.3 --- Anticholinergic reactions Caused by <Yangjinhua> --- p.69-74 / Chapter 5.4 --- Overdosage --- p.74 / Chapter 5.4.1 --- Overdose of Aconitine --- p.74-78 / Chapter 5.4.2 --- Overdose of Liquorice ('Gancao') --- p.78-80 / Chapter 5.4.3 --- Overdose of <Chansu> --- p.80 / Chapter 5.5 --- Misusing - Personal abuse --- p.80 / Chapter 5.5.1 --- <Banmao> --- p.80-81 / Chapter 5.6 --- Discussion --- p.81-84 / Chapter 5.7 --- Conclusion --- p.84 / Chapter Chapter 6 --- Chinese Patent Medicine - General Aspect --- p.85-112 / Chapter 6.1 --- Chinese Patent Medicine --- p.85 / Chapter 6.1.1 --- Introduction --- p.85-87 / Chapter 6.1.2 --- Herbal Injection and Infusion --- p.87-88 / Chapter 6.1.2.1 --- Variety & Processing --- p.88 / Chapter 6.1.2.2 --- Stabilization --- p.88-89 / Chapter 6.1.2.3 --- The Molecular Size --- p.89-90 / Chapter 6.1.3 --- Adverse Reactions Caused by Chinese Proprietary Medicines --- p.90 / Chapter 6.1.3.1 --- Aconitine poisoning --- p.90 / Chapter 6.1.3.2 --- Nan Lien Chui Fong Toukuwan' --- p.90-91 / Chapter 6.1.3.3 --- Jin Bu Huan' --- p.91 / Chapter 6.1.3.4 --- Baoyingdan' --- p.91 / Chapter 6.1.4 --- Heavy metals in CPM --- p.91 / Chapter 6.1.5 --- The Necessarity to Develop Randomise Herbal Clinical Trial. --- p.91-92 / Chapter 6.1.6 --- Recommendation --- p.92-93 / Chapter 6.1.7 --- Conclusion --- p.93-94 / Chapter 6.2 --- Adulteration by synthetic therapeutic substances --- p.95-104 / Chapter 6.2.1 --- The Experiences in China --- p.91-99 / Chapter 6.2.2 --- The Experiences in Hong Kong --- p.99-101 / Chapter 6.2.3 --- The Experience in Taiwan --- p.101-102 / Chapter 6.2.4 --- Discussion --- p.102-104 / Chapter 6.3 --- Oil of Wintergreen (Methyl salicylate) --- p.104-112 / Chapter 6.3.1 --- Overview --- p.104-111 / Chapter 6.3.2 --- Prevention --- p.111-112 / Chapter Chapter 7 --- Adverse effects of Ginseng. --- p.113-123 / Chapter 7.1 --- Overview --- p.113 / Chapter 7.2 --- Botany --- p.113-114 / Chapter 7.3 --- Pharmacological Effects --- p.114-115 / Chapter 7.4 --- Adverse reaction of Ginseng --- p.115 / Chapter 7.4.1 --- Overdosage --- p.115-116 / Chapter 7.4.2 --- Substitution with cheaper and more toxic herbs --- p.116-121 / Chapter 7.5 --- Drug - herb Interaction --- p.121-122 / Chapter 7.6 --- Conclusion --- p.123 / Chapter Chapter 8 --- Herbal Medicines With Cardiovascular Adverse Reactions --- p.124-123 / Chapter 8.1 --- Overview --- p.124 / Chapter 8.2 --- Hypertension --- p.124 / Chapter 8.3 --- Atherosclerosis --- p.124-125 / Chapter 8.4 --- Arrhythmias --- p.125-126 / Chapter 8.5 --- Cardic Failure --- p.126 / Chapter 8.6 --- Angia Pectoris --- p.126 / Chapter 8.7 --- Thromboembolic Disorders --- p.126-127 / Chapter 8.8 --- Discussion --- p.127-128 / Chapter 8.8.1 --- Herbal Medicine Used in Cardiovascular System --- p.131 / Chapter 8.8.1.1 --- Ginseng --- p.131-133 / Chapter 8.8.1.2 --- Ma huang (Ephedra sinica) --- p.133-136 / Chapter 8.8.1.3 --- Yellow oleander (Thevetia neriifolia) --- p.136-137 / Chapter 8.8.1.4 --- Stephania tetrandra --- p.137-138 / Chapter 8.8.1.5 --- Danshen (Salvia miltiorrhiza) --- p.138 / Chapter 8.8.1.8 --- Ginkgo biloba --- p.138-140 / Chapter 8.8.1.9 --- Dong Quai (Angelicae Sinensis) --- p.140-141 / Chapter 8.8.1.10 --- Licorice (Glycyrrhiza Glabra) --- p.141-143 / Chapter 8.8.1.11 --- Berberine --- p.143 / Chapter 8.8.2 --- Potential Problem Caused by Chinese Proprietary Medicine --- p.143-144 / Chapter 8.9 --- Other Herbal Adverse Effects And Drug Interaction --- p.144-145 / Chapter 8.10 --- Conclusion --- p.145 / Chapter Chapter 9 --- Review of the Adverse Reactions to herbal treatments of Obesity --- p.146-150 / Chapter 9.1 --- Overview --- p.146 / Chapter 9.2 --- Combined With Unknown medication --- p.146-147 / Chapter 9.3 --- Dietary Supplements and Herbal Preparations --- p.147-149 / Chapter 9.4 --- Conclusion --- p.149-150 / Chapter Chapter 10 --- Adverse Effects of CHM used for Diabetes --- p.151-159 / Chapter 10.1 --- Introduction --- p.151 / Chapter 10.2 --- Traditional Chinese medicine used in Diabetes --- p.151 / Chapter 10.3 --- Adverse Reaction of Alternative Diabetic Treatment --- p.152-158 / Chapter 10.4 --- Conclusion --- p.159 / Chapter Chapter 11 --- Review of Herbal Hepatotoxicity --- p.160-194 / Chapter 11.1 --- Introduction --- p.160-161 / Chapter 11.2 --- Drug-induced hepatic injury --- p.161-163 / Chapter 11.3 --- Types of Liver Injury --- p.163 / Chapter 11.3.1 --- Pyrrolizidine alkaloid (PA) --- p.163 / Chapter 11.4 --- Hepatotoxicity Herbs --- p.163 / Chapter 11.4.1 --- Tripterygium wilfordii --- p.163-164 / Chapter 11.4.2 --- Rhizoma Discoreae Bulbiferae --- p.164-165 / Chapter 11.5 --- Consumption of Insect herbs --- p.165 / Chapter 11.6 --- Hepatotoxicity Cause by Chinese Proprietary Medicine --- p.165-166 / Chapter 11.6.1 --- Jin Bu Huan --- p.166-168 / Chapter 11.6.2 --- Chi R Yun (Breynia officinalis) --- p.168 / Chapter 11.6.3 --- Sho-saiko-to --- p.168-169 / Chapter 11.6.4 --- Shou-Wu-Pian --- p.169-171 / Chapter 11.7 --- Importance of Drug-Herb and Herb-Herb Interactions --- p.171-172 / Chapter 11.8 --- Diagnosis of Herbal Hepatotoxicity --- p.172-173 / Chapter 11.9 --- Recomandation --- p.173-174 / Chapter 11.10 --- Conclusion --- p.175 / Table --- p.176-180 / Chapter Chapter 12 --- Review of Herbal Nephropathy --- p.181-194 / Chapter 12.1 --- Introduction --- p.181 / Chapter 12.2 --- Aristolochia acids (AA) --- p.181-183 / Chapter 12.2.1 --- Intoxication of Aristolochia in Worldwide --- p.183-184 / Chapter 12.2.2 --- Morphological findings --- p.184-185 / Chapter 12.2.3 --- Carcinogenic --- p.185-187 / Chapter 12.3 --- MuTong (Aristolochia manshuriensis) --- p.187-188 / Chapter 12.4 --- Ma-dou-ling (Fructus Aristolochiae) --- p.188 / Chapter 12.5 --- Tripterygium wilfordii --- p.188-189 / Chapter 12.6 --- Gastrodia Elata --- p.189 / Chapter 12.7 --- Licorice (Glycyrrhiza glabra) --- p.190-191 / Chapter 12.8 --- Hippocampus (Sea Horse) --- p.191 / Chapter 12.9 --- Milabris Phanalerata --- p.191-192 / Chapter 12.10 --- Chinese Proprietary Medicine --- p.192-193 / Chapter 12.11 --- Conclusion --- p.193-194 / Chapter Chapter 13 --- Adverse Reaction of Herbal Medicine in Dermatology. --- p.195-217 / Chapter 13.1 --- Overview --- p.195-196 / Chapter 13.2 --- Chinese Herbal Medicine Used in Psoriasis --- p.196 / Chapter 13.2.1 --- Tripterygium wilfordii --- p.197 / Chapter 13.2.2 --- Radix Angelicae pubescentis and Radix Angelicae dahuricae --- p.197-198 / Chapter 13.2.3 --- Radix macrotomiae seu Lithospermi Injection --- p.198 / Chapter 13.3 --- Chinese Herbal Decoction For Atopic Dermatitis --- p.198-200 / Chapter 13.3.1 --- Tea Extracts --- p.200-201 / Chapter 13.4 --- Potential Adverse Effect with Herbal Medicine --- p.201 / Chapter 13.4.1 --- Allergic skin reactions --- p.201-202 / Chapter 13.4.2 --- Stevens-Johnson syndrome --- p.202 / Chapter 13.4.3 --- Photosensitization --- p.202-204 / Chapter 13.4.4 --- Pellagra --- p.204 / Chapter 13.4.5 --- Hepatotoxic Effects --- p.204-205 / Chapter 13.4.6 --- Others Adverse Reaction --- p.205 / Chapter 13.4.7 --- Potential Adverse Reaction Caused by Interactions --- p.205 / Chapter 13.5 --- Potential Adverse Reaction Caused by Contamination of Herbal Product --- p.206 / Chapter 13.5.1 --- Herbal creams adulterated with corticosteroids --- p.206-207 / Chapter 13.5.2 --- Arsenic dermatoses --- p.207 / Chapter 13.5.3 --- Mercury poisoning --- p.207-208 / Table --- p.208-211 / Chapter 13.6 --- Dermatological Adverse Reaction Caused by Herbs --- p.211 / Chapter 13.7 --- Contact Dermatitis Caused by CPM --- p.211-212 / Chapter 13.7.1 --- Liushenwan' --- p.211-212 / Chapter 13.7.2 --- Heiguiyou' --- p.212 / Chapter 13.7.3 --- 101 Hair Regrowth Liniment' --- p.212-213 / Chapter 13.7.4 --- Zhenggushui' --- p.213 / Chapter 13.7.5 --- Tiedayaoiing' --- p.213-214 / Table --- p.214-215 / Chapter 13.8 --- Non-dermatological adverse effects of systemic herbal treatments used for dermatological conditions --- p.215-216 / Chapter 13.9 --- Conclusion --- p.216-217 / Chapter Chapter 14 --- "Chinese Herbal Medicine in Pregnancy, Infants & Children," --- p.218-229 / Chapter 14.1 --- Overview --- p.218-219 / Chapter 14.2 --- Asian Cultures for Pregnancy --- p.219-223 / Chapter 14.3 --- Teratogenic Herbs --- p.224-225 / Chapter 14.4 --- Chinese proprietary medicines --- p.225 / Chapter 14.4.1 --- "“Tse Koo Choy""" --- p.225-226 / Chapter 14.4.2 --- "“Lu Shen Wan""" --- p.226 / Chapter 14.4.3 --- "“Po Ying Pills""" --- p.226-227 / Chapter 14.4.4 --- """Jin Bu Huan Toxicity"" in Children" --- p.227 / Chapter 14.6 --- Topical Preparations --- p.227-228 / Chapter 14.7 --- Dietary supplement --- p.228-229 / Chapter 14.8 --- Conclusion --- p.229 / Chapter Chapter 15 --- Heavy metals poisoning in traditional Chinese medicines. --- p.230-251 / Chapter 15.1 --- Introduction --- p.230-232 / Chapter 15.2 --- LEAD --- p.232 / Chapter 15.2.1 --- Overview --- p.232 / Chapter 15.2.2 --- Poisoning Cases of Boa Ning Dan --- p.233-235 / Chapter 15.2.3 --- Lead Poisoning in Worldwide --- p.235-238 / Chapter 15.3 --- MERCURY --- p.238 / Chapter 15.3.1 --- Overview --- p.238-239 / Chapter 15.3.2 --- Cinnabar --- p.239-240 / Chapter 15.3.3 --- Presentation --- p.240-241 / Chapter 15.3.4 --- Poisoning Cases --- p.241-242 / Chapter 15.4 --- ARSENIC --- p.242 / Chapter 15.4.1 --- Overview --- p.242-243 / Chapter 15.4.2 --- Arsenic toxicity --- p.243-244 / Chapter 15.4.3 --- The toxicologic mechanisms of inorganic arsenic --- p.244-246 / Chapter 15.4.4 --- Poisoning Cases --- p.246 / Chapter 15.4.5 --- Discussion --- p.247-248 / Chapter 15.5 --- Conclusion --- p.248 / Table --- p.249-251 / Chapter Chapter 16 --- Herb - Drug Interactions --- p.252-269 / Chapter 16.1 --- Overview --- p.252-254 / Chapter 16.2 --- Effects of Herb-drug interactions --- p.255 / Chapter 16.2.1 --- Gastrointestinal system --- p.255-256 / Chapter 16.2.2 --- Cardiovascular system --- p.256 / Chapter 16.2.3 --- Central nervous system --- p.257 / Chapter 16.2.4 --- Endocrine system --- p.257 / Chapter 16.3 --- Reason regard to herb-drug interactions --- p.257 / Chapter 16.3.1 --- Lack of Knowledge About Herbs --- p.257 / Chapter 16.3.2 --- Mislabelling or Adulteration --- p.258 / Chapter 16.3.3 --- Lack of Patient Communication About Use of Botanicals --- p.258 / Chapter 16.3.4 --- Lack of Practitioner Knowledge About Potential Interactions --- p.258 / Chapter 16.4 --- Metabolism of Herb-Drug Interaction --- p.258-259 / Chapter 16.5 --- Pharmacologic Interactions --- p.259-260 / Chapter 16.5.1 --- Interaction with Antibiotics --- p.260 / Chapter 16.5.2 --- Interaction with Nonsteroidal Anti-inflammatory Drugs --- p.260-261 / Chapter 16.5.3 --- Interaction with Sedatives --- p.261-262 / Chapter 16.5.4 --- Interaction with Anticoagulants --- p.262-263 / Chapter 16.5.5 --- Interaction with Anti-hypertensives and Diuretics --- p.263 / Chapter 16.5.6 --- Interaction with Spironolactone --- p.264 / Chapter 16.5.7 --- Interaction with Corticosteroids and Cyclosporine --- p.264-265 / Chapter 16.5.8 --- Interaction with Estrogen Replacement Therapy --- p.265 / Chapter 16.5.9 --- Interactions Between Natural Product and Drug --- p.265-266 / Chapter 16.6 --- Herb-to-Herb Interactions --- p.266-267 / Chapter 16.7 --- Conclusion --- p.268-269 / Chapter Chapter 17 --- Recommendation --- p.270-264 / Chapter 17.1 --- Overview --- p.270 / Chapter 17.2 --- The need to evaluate the clinical effectiveness of traditional Chinese medicine --- p.270-271 / Chapter 17.3 --- For the Pharmaceutical Industries --- p.211-212 / Chapter 17.4 --- For the physicians & patient --- p.272-274 / Conclusion --- p.274 / Chapter Chapter 18 --- Conclusion --- p.275-280 / Chapter Chapter 19 --- Reference --- p.281-306

O Tacrolimus é uma potente droga imunossupressora introduzida no transplante cardíaco no início da década de 90. Pacientes com rejeição refratária ou intolerância à ciclosporina podem responder à terapia de resgate com o tacrolimus. Os objetivos deste estudo foram: avaliar a evolução clínica das crianças submetidas ao transplante cardíaco que necessitaram da conversão de ciclosporina para tacrolimus por rejeição refratária, tardia ou efeitos adversos de difícil controle; avaliar a incidência de rejeição após a conversão para o tacrolimus e comparar a sobrevida dos pacientes em uso de tacrolimus e ciclosporina. Realizou-se estudo coorte, observacional, prospectivo, em 28 crianças submetidas ao transplante cardíaco no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e que foram submetidas à conversão da ciclosporina ao tacrolimus, no período de julho de 1999 a dezembro de 2009. Avaliou-se a incidência de episódios de rejeição e a sobrevida após a conversão. Realizou-se, também, a comparação entre os pacientes em uso de tacrolimus e os pacientes que permaneceram em uso de ciclosporina submetidos ao transplante cardíaco no mesmo período. A idade média no momento do transplante foi de 5,3 anos, e no momento da conversão de 8,2 anos. As causas de conversão foram efeitos adversos em 50% dos pacientes, rejeição tardia em 32% e rejeição refratária em 18%. O tempo médio de conversão e seguimento foram 36 meses e 74 meses, respectivamente. Observou-se resolução completa dos episódios de rejeição refratária e melhora dos efeitos adversos em todos os pacientes. A taxa de incidência (x100) de episódios de rejeição antes da conversão foi de 7,98 e após a conversão foi de 2,11 (p=0,0001). A taxa de episódios de infecção antes da conversão foi de 5,89 e após a conversão 4,18 (p=0,023). Pela análise das complicações pré e pós-conversão ao tacrolimus, não se evidenciou diferença estatisticamente significativa em relação a incidência de tumor, insuficiência renal, hipertensão arterial sistêmica, dislipidemia, litíase biliar, diabetes melito, anemia, alterações neurológicas, hirsutismo e hiperplasia gengival. Houve maior prevalência da doença vascular do enxerto após conversão para tacrolimus (p=0,004). Ao se comparar os pacientes com tacrolimus e os com ciclosporina, identificou-se diminuição significativa na taxa de incidência de episódios de rejeição (p=0,001), e na taxa de incidência de episódios de infecção (p=0,002), nos pacientes em uso de tacrolimus. Os pacientes convertidos ao tacrolimus apresentaram menor incidência de complicações neurológicas, hirsutismo e hiperplasia gengival, porém maior prevalência de anemia. Em relação à sobrevida, observou-se uma mortalidade de 25% nos pacientes em uso de tacrolimus, após um período médio de conversão de sessenta meses. Três óbitos foram secundários à rejeição, dos quais apenas um, no primeiro ano de transplante. Evidenciou-se menor sobrevida nos pacientes em uso de ciclosporina. O estudo clínico das crianças submetidas ao transplante cardíaco e que necessitaram de conversão do esquema de imunossupressão permitiu concluir que o tacrolimus foi eficaz como terapia de resgate para rejeição refratária e constitui opção terapêutica como droga imunossupressora de manutenção na faixa etária pediátrica / Tacrolimus is a potent calcineurin inhibitor that was introduced in heart transplantation therapy in the early 1990s. Organ transplant recipients with refractory rejection or intolerance to conventional immunosuppressant may respond to rescue therapy with tacrolimus. The aim of this study was to evaluate the clinical outcome of children undergoing heart transplantation who required conversion from a cyclosporine to a tacrolimus-based immunosuppressive regimen due to refractory rejection, late rejection or cyclosporine intolerance. We performed a prospective observational cohort study in 28 children who underwent cardiac transplantation at the Heart Institute (InCor) University of São Paulo Medical School and who required conversion from July 1999 to December 2009. The clinical outcome of the patients was evaluated after tacrolimus conversion. We also compared the patients on tacrolimus to the patients who remained on cyclosporine, and who had undergone heart transplantation during the same period. The mean age at the time of transplantation was 5.3 years and 8.2 years at the time of conversion. The causes of conversion were adverse side effects in 50% of patients, late rejection in 32% and refractory rejection in 18%. The mean time from heart transplant to conversion was 36 months and the mean follow-up period was 74 months. We observed complete resolution of refractory rejection episodes and adverse side effects in all patients. The incidence rate (x100) of rejection episodes before and after conversion was 7.98 and 2.11, respectively (p = <0.0001). The rate of infectious episodes before conversion was 5.89 and after conversion was 4.18 (p = 0.023). There was no statistically significant difference in relation to tumor, renal failure requiring dialysis, systemic arterial hypertension, dyslipidemia, gallstones, diabetes mellitus, anemia, neurological complications, hirsutism and gingival hyperplasia after conversion. A significant incidence of cardiac allograft vasculopathy after conversion to tacrolimus was found (p = 0.004). When comparing patients on tacrolimus to patients on cyclosporine, there was a significant decrease in the incidence of rejection (p = 0.001), and infectious episodes (p = 0.002) in patients using tacrolimus. Patients converted to tacrolimus when compared to patients on cyclosporine had lower neurological complications, hirsutism and gingival hyperplasia, but higher prevalence of anemia. There was a 25% mortality rate in patients using tacrolimus after a mean period of 60 months after conversion. Three deaths were secondary to rejection, and only one in the first year after transplant. Patients using tacrolimus showed greater survival rate when compared to patients taking cyclosporine. The clinical outcome of children undergoing heart transplantation and who required conversion of immunosuppressive regimen allowed us to conclude that tacrolimus is effective as rescue therapy for refractory rejection and is a therapeutic option in pediatric patients

O Tacrolimus é uma potente droga imunossupressora introduzida no transplante cardíaco no início da década de 90. Pacientes com rejeição refratária ou intolerância à ciclosporina podem responder à terapia de resgate com o tacrolimus. Os objetivos deste estudo foram: avaliar a evolução clínica das crianças submetidas ao transplante cardíaco que necessitaram da conversão de ciclosporina para tacrolimus por rejeição refratária, tardia ou efeitos adversos de difícil controle; avaliar a incidência de rejeição após a conversão para o tacrolimus e comparar a sobrevida dos pacientes em uso de tacrolimus e ciclosporina. Realizou-se estudo coorte, observacional, prospectivo, em 28 crianças submetidas ao transplante cardíaco no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e que foram submetidas à conversão da ciclosporina ao tacrolimus, no período de julho de 1999 a dezembro de 2009. Avaliou-se a incidência de episódios de rejeição e a sobrevida após a conversão. Realizou-se, também, a comparação entre os pacientes em uso de tacrolimus e os pacientes que permaneceram em uso de ciclosporina submetidos ao transplante cardíaco no mesmo período. A idade média no momento do transplante foi de 5,3 anos, e no momento da conversão de 8,2 anos. As causas de conversão foram efeitos adversos em 50% dos pacientes, rejeição tardia em 32% e rejeição refratária em 18%. O tempo médio de conversão e seguimento foram 36 meses e 74 meses, respectivamente. Observou-se resolução completa dos episódios de rejeição refratária e melhora dos efeitos adversos em todos os pacientes. A taxa de incidência (x100) de episódios de rejeição antes da conversão foi de 7,98 e após a conversão foi de 2,11 (p=0,0001). A taxa de episódios de infecção antes da conversão foi de 5,89 e após a conversão 4,18 (p=0,023). Pela análise das complicações pré e pós-conversão ao tacrolimus, não se evidenciou diferença estatisticamente significativa em relação a incidência de tumor, insuficiência renal, hipertensão arterial sistêmica, dislipidemia, litíase biliar, diabetes melito, anemia, alterações neurológicas, hirsutismo e hiperplasia gengival. Houve maior prevalência da doença vascular do enxerto após conversão para tacrolimus (p=0,004). Ao se comparar os pacientes com tacrolimus e os com ciclosporina, identificou-se diminuição significativa na taxa de incidência de episódios de rejeição (p=0,001), e na taxa de incidência de episódios de infecção (p=0,002), nos pacientes em uso de tacrolimus. Os pacientes convertidos ao tacrolimus apresentaram menor incidência de complicações neurológicas, hirsutismo e hiperplasia gengival, porém maior prevalência de anemia. Em relação à sobrevida, observou-se uma mortalidade de 25% nos pacientes em uso de tacrolimus, após um período médio de conversão de sessenta meses. Três óbitos foram secundários à rejeição, dos quais apenas um, no primeiro ano de transplante. Evidenciou-se menor sobrevida nos pacientes em uso de ciclosporina. O estudo clínico das crianças submetidas ao transplante cardíaco e que necessitaram de conversão do esquema de imunossupressão permitiu concluir que o tacrolimus foi eficaz como terapia de resgate para rejeição refratária e constitui opção terapêutica como droga imunossupressora de manutenção na faixa etária pediátrica / Tacrolimus is a potent calcineurin inhibitor that was introduced in heart transplantation therapy in the early 1990s. Organ transplant recipients with refractory rejection or intolerance to conventional immunosuppressant may respond to rescue therapy with tacrolimus. The aim of this study was to evaluate the clinical outcome of children undergoing heart transplantation who required conversion from a cyclosporine to a tacrolimus-based immunosuppressive regimen due to refractory rejection, late rejection or cyclosporine intolerance. We performed a prospective observational cohort study in 28 children who underwent cardiac transplantation at the Heart Institute (InCor) University of São Paulo Medical School and who required conversion from July 1999 to December 2009. The clinical outcome of the patients was evaluated after tacrolimus conversion. We also compared the patients on tacrolimus to the patients who remained on cyclosporine, and who had undergone heart transplantation during the same period. The mean age at the time of transplantation was 5.3 years and 8.2 years at the time of conversion. The causes of conversion were adverse side effects in 50% of patients, late rejection in 32% and refractory rejection in 18%. The mean time from heart transplant to conversion was 36 months and the mean follow-up period was 74 months. We observed complete resolution of refractory rejection episodes and adverse side effects in all patients. The incidence rate (x100) of rejection episodes before and after conversion was 7.98 and 2.11, respectively (p = <0.0001). The rate of infectious episodes before conversion was 5.89 and after conversion was 4.18 (p = 0.023). There was no statistically significant difference in relation to tumor, renal failure requiring dialysis, systemic arterial hypertension, dyslipidemia, gallstones, diabetes mellitus, anemia, neurological complications, hirsutism and gingival hyperplasia after conversion. A significant incidence of cardiac allograft vasculopathy after conversion to tacrolimus was found (p = 0.004). When comparing patients on tacrolimus to patients on cyclosporine, there was a significant decrease in the incidence of rejection (p = 0.001), and infectious episodes (p = 0.002) in patients using tacrolimus. Patients converted to tacrolimus when compared to patients on cyclosporine had lower neurological complications, hirsutism and gingival hyperplasia, but higher prevalence of anemia. There was a 25% mortality rate in patients using tacrolimus after a mean period of 60 months after conversion. Three deaths were secondary to rejection, and only one in the first year after transplant. Patients using tacrolimus showed greater survival rate when compared to patients taking cyclosporine. The clinical outcome of children undergoing heart transplantation and who required conversion of immunosuppressive regimen allowed us to conclude that tacrolimus is effective as rescue therapy for refractory rejection and is a therapeutic option in pediatric patients

It is now generally acknowledged that particulate air pollution can cause respiratory symptoms and that indoor dust particles may be associated with mucous membrane irritation and odour annoyance. One reason for this may be that dust particles adsorb large quantities of gases and other volatile compounds. It is therefore important to be able to determine the chemical compounds adsorbed onto indoor dust particles. In this thesis, a new technique was developed that can analyse chemical compounds in indoor dust particles in a simple yet accurate way. In its basic configuration, it comprises a one stage thermal desorption oven, a gas flow cell with a miniaturized GC column, and a nitrogen-flushed photo diode array (PDA) detector for fast UV spectra recording. The dust sample is thermally desorbed in the oven and the released compounds are flushed onto the GC column by means of a carrier gas stream; the separated compounds are then registered by the PDA detector and identified by their characteristic gas-phase UV spectra. Using this set-up, a number of volatile organic as well as inorganic compounds were identified in indoor dust particles, e.g. nitric oxide, ammonia, hydrogen sulphide, pyridine, 2-furaldehyde, 2-methylfuran, and isoprene. Moreover, acrylate monomers were identified in dust samples from a secondary school with problems due to powdering floor polish. An instrumental set-up with higher performance was achieved by interfacing the gas flow cell to a capillary GC column. When airborne indoor dust samples were analysed by this system and by GC-MS under similar conditions of thermal desorption (150 °C) and GC separation, the two analytical systems were found to be complementary. GC-UV together with GC-MS was thus demonstrated to be considerably more powerful than GC-MS alone for the analysis of volatile organic compounds (VOC) in indoor dust. When airborne dust samples from damp (n=9) and control (n=9) residences were analysed for VOC and microorganisms, identifications made by culture and microscopy of the major moulds found, i.e. Aspergillus, Cladosporium and Penicillum, coincided with the identification of VOC known to be produced by these species. A number of additional VOC were also found, some of which may be irritating to the skin, eyes or respiratory tract if present at higher concentrations. Quantitative GC-UV analysis of indoor dust from 389 residences in Sweden showed that the VOC found at the highest concentrations were saturated aldehydes (C5-C10), furfuryl alcohol, 2,6-di-tert-butyl-4-methylphenol, 2-furaldehyde, and benzaldehyde. Alkenals were also found, notably 2-butenal (crotonaldehyde), 2-methyl-propenal (methacrolein), hexenal, heptenal, octenal, and nonenal. GC-UV was also applied (together with GC-MS) to determine VOC in dust from residences of 198 children with symptoms of asthma and/or allergy (cases) and from residences of 202 children without symptoms (controls). The mean concentration of nicotine was found to be significantly higher in dust from case residences, while the mean concentrations of hexane, nonanal, octane, 2-pentylfuran and tridecanol were significantly higher in dust from control residences. In a stepwise logistic regression model, nicotine, hexanal, furfuryl alcohol, nonane, butanol, and octenal showed increased relative risks, expressed as odds ratios comparing cases with controls. By contrast, benzaldehyde, nonanal, butenal, hexane, tridecanol, and pentylfuran showed decreased relative risks. These findings point to the possibility that not only environmental tobacco smoke but also other emissions in the indoor environment may be linked to the increased prevalence of asthma and/or allergy in children. It is concluded that GC-UV may be used as an alternative or complement to GC-MS for measuring chemicals in indoor dust, thus improving the survey and control of human exposure to particle-bound toxicants and other chemicals. / Copyright Agreement: Figure 3 included in the PDF file abowe is the exclusive property of SAGE Publications (http://www.sagepublications.com/), or its licensors and is protected by copyright and other intellectual property laws. The download of the file(s) is intended for the User's personal and noncommercial use. Any other use of the download of the Work is strictly prohibited. User may not modify, publish, transmit, participate in the transfer or sale of, reproduce, create derivative works (including coursepacks) from, distribute, perform, display, or in any way exploit any of the content of the file(s) in whole or in part. Permission may be sought for further use from Sage Publications Ltd, Rights and Permissions Department, 1 Oliver's Yard, 55 City Road, London EC1Y 1SP Fax: +44 (020) 7324-8600. By downloading the file(s), the User acknowledges and agrees to these terms.

Myelin and oligodendrocytes (OLGs) are the apparent targets of the immune-mediated injury that underlies the development of multiple sclerosis (M8). Recovery from M8 clinical relapses likely reflects remyelination attributed to recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), rather than to new process formation by previously myelinating OLGs. Newly emerging M8-directed immuno-modulatory therapies (statins and FTY720) can readily cross the blood-brain barrier and have been shown to impact signaling pathways implicated in cytoskeletal regulation, differentiation, migration, and survival; these are cellular events presumably important for myelin integrity and remyelination. / Statins inhibit the production of cholesterol (concentrated in the myelin membrane) and isoprenoids (post-translational attachments regulating the functions of proteins such as the Rho GTPases). We showed that treatment of human and rodent-derived OPCs with lipophilic statins induced an initial process extension associated with enhanced differentiation and impaired spontaneous migration, whereas prolonged treatment induced process retraction and cell death. Rodent and human mature OLGs demonstrated similar cytoskeletal and survival responses. Chronic simvastatin therapy of mice inhibited remyelination following demyelination induced by the OLG toxin, cuprizone, attributed to a block in OPC differentiation and consequent decrease in mature OLGs. Even fully myelinated animals treated with simvastatin over the long-term demonstrated a decrease in myelin in the brain by maintaining oligodendroglial cells in the pre-OLG state and preventing continual replacement of mature OLGs. / FTY720 is an agonist of G-protein-coupled receptors S1P1, 3, 4, and 5, that are associated with distinct receptor isotype-selective activation of Rho GTPases. In human OPCs, FTY720 could induce initial S1P3/5-dependent process retraction associated with an inhibition of differentiation, and subsequent S1P1-dependent process extension. Mature OLGs showed a dose-dependent cyclic modulation of process extension and retraction was observed over time. Both human OPCs and OLGs were rescued by FTY720 under death-promoting environments. Both cell types also demonstrated a cyclic and reciprocal modulation of S1P1 and S1P5 mRNA levels, reflected in the recurring receptor isotype-dependent functional responses over time. Studies using organotypic cerebellar slice cultures demonstrated that FTY720 did not impact myelin integrity under basal conditions, yet accelerated remyelination following lysolecithin-induced demyelination. Both treatment regimens were associated with an extension of OPC and mature OLG processes. / Our observations demonstrate that drug concentrations used to modulate immune function can have differential dose and time-dependent effects on OPCs, OLGs, as well as on myelin and remyelination processes. Our findings indicate the need to monitor the effects of putative immuno-modulatory therapies on myelin-related processes in MS patients.