Colorectal cancer (CRC) is one of the most common malignancies worldwide. However, adjuvant chemotherapeutic agents exhibit poor accumulation in the tumor mass and frequently result in serious side effects due to nonspecific damage to normal organs. Therefore, the development of more selective anticancer drugs with targeted delivery to tumor sites is the current trend in cancer therapies. Among these sites, tumor neovasculature is an attractive target for anticancer agents. It is because tumor growth is largely limited by blood supply which is dependent on the extent of angiogenesis in the tumor. / Experimental analysis suggested that TCP-1 phage and synthetic TCP-1 peptide specifically homed to colorectal cancer tissues and co-localized with the tumor vasculature. Moreover, TCP-1 peptide also recognized the vasculature of human colorectal cancer specimens. Subsequently, the homing abilities of TCP-1 phage were extensively tested in other cancer models. Results showed that TCP-1 peptide could also target the vasculature of orthotopic gastric cancer induced by human colon cancer cell line (MKN45) in BALB/c nude mice. Meanwhile, TCP-1 phage exhibited binding activity to colorectal cancer cells such as colon 26 and SW1116. TCP-1 peptide could carry a pro-apoptotic peptide into these cells and markedly enhanced its pro-apoptotic action. / In summary, we have used the phage display technology to isolate two unique peptides TCP-1 and TCP-2, which targeted the vasculature of orthotopic colorectal cancer and also recognized the vasculature of human colorectal cancer. Moreover, they could deliver fluorescein or pro-apoptotic peptide only to the tumor vasculature but not to other normal tissues, for imaging detection and targeted therapy. In conclusion, both TCP-1 and TCP-2 may have significant clinical applications as carriers in diagnostic imaging and ligand-mediated targeted therapy for human colorectal cancer. / Similarly, TCP-2 phage or its peptide also targeted specifically the orthotopic colorectal cancer, and co-localized with the tumor vasculature in mice. Meanwhile, TCP-2 peptide recognized the vasculature of human colorectal cancer specimens. FITC-labeled TCP-2 peptide could also be used to detect cancer tissues in tumor-bearing mice. / To identify specific ligands targeting the tumor neovasculature, in vivo phage display technology has been extensively used. Several dozens of peptides homing to normal or diseased vasculature have been identified through this technology. However, these peptides target mainly the tumors growing at distant sites but not at the primary organ, thus limiting their clinical application. To obtain specific peptides targeting the neovasculature of colorectal cancer growing in situ, we established an orthotopic colorectal cancer model in normal BALB/c mice by using syngeneic colon cancer cells (colon 26). Subsequently, in vivo phage display technology was utilized to isolate peptides which specifically recognized the vasculature of the cancer. Four peptides (termed TCP-1, 2, 3, 4) were enriched more than once after four-round selections. Further investigation disclosed that TCP-1 and TCP-2 phages had relatively stronger binding abilities to cancer tissues among the four phage clones. They were chosen for further study. / We further demonstrated that TCP-1 could serve as a carrier for image detection and drug delivery. FITC-labeled TCP-1 could specifically produce a strong fluorescence signal in the tumors after intravenous injection into the orthotopic tumor-bearing mice. Moreover TCP-1, when conjugated with a pro-apoptotic peptide, could also specifically induce apoptosis of tumor vasculature in vivo. / Li, Zhijie. / Adviser: Cho Chiltin. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 194-221). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Lee, Ching Ching. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 90-103). / Abstracts in English and Chinese. / Acknowledgments --- p.i / Abstract --- p.ii / 論文摘要 --- p.iv / Table of Contents --- p.vi / List of Tables --- p.x / List of Figures --- p.xi / Chapter Chapter 1 --- Introduction / Chapter 1.1. --- Quinolone Antimicrobial Agents --- p.1 / Chapter 1.1.1. --- Development --- p.1 / Chapter 1.1.2. --- Mode of action --- p.3 / Chapter 1.1.3. --- Mechanisms of resistance to quinolones --- p.4 / Chapter 1.1.3.1. --- Target genes mutations --- p.4 / Chapter 1.1.3.2. --- Decreased intracellular quinolone accumulation --- p.5 / Chapter 1.1.3.3. --- Plasmid-mediated quinolone resistance --- p.6 / Chapter 1.2. --- Plasmid-mediated Quinolone Resistance Genes (qnr) --- p.8 / Chapter 1.2.1. --- Discovery of qnrA genes --- p.8 / Chapter 1.2.2. --- Discovery of qnrS genes --- p.9 / Chapter 1.2.3. --- Discovery of qnrB genes --- p.10 / Chapter 1.2.4. --- Discovery of qnrC genes --- p.11 / Chapter 1.2.5. --- Discovery of qnrD genes --- p.12 / Chapter 1.2.6. --- Origins of qnr genes --- p.12 / Chapter 1.2.7. --- Qnr proteins and mode of action --- p.14 / Chapter 1.2.8. --- Epidemiology and quinolones resistance activity of qnr genes --- p.16 / Chapter 1.2.9. --- Epidemiology of fluoroquinolone-resistant Enterobacteriaceae --- p.17 / Chapter 1.2.10 --- Multidrug-resistant in extended-spectrum-B-lactamase- and AmpC-producing Enterobacteriaceae --- p.19 / Chapter 1.3. --- Background of Study --- p.20 / Chapter 1.4. --- Objectives of Study --- p.21 / Chapter Chapter 2 --- Materials & Methods / Chapter 2.1. --- Study Design --- p.22 / Chapter 2.2. --- Antimicrobial Susceptibility Testing --- p.24 / Chapter 2.2.1 --- Bacterial isolates --- p.24 / Chapter 2.2.2. --- Screening for ESBL and AmpC production by disk diffusion test --- p.24 / Chapter 2.2.3. --- Determination of minimal inhibitory concentrations (MICs) --- p.25 / Chapter 2.3. --- "Detection of qnrA, qnrB and qnrS Genes by Multiplex PCR" --- p.27 / Chapter 2.3.1. --- Total DNA preparation --- p.27 / Chapter 2.3.2. --- "Multiplex PCR assay for qnrA, qnrB and qnrS genes detection" --- p.27 / Chapter 2.3.3. --- Agarose gel electrophoresis --- p.29 / Chapter 2.4. --- "Detection of TEM-, SHV-, CTX- and PMAmpC Type B-Lactamase Genes by PCR" --- p.30 / Chapter 2.5. --- PCR Assays for Further Genotypic Characterization Purpose --- p.32 / Chapter 2.5.1. --- PCR assay to amplify qnrB genes --- p.32 / Chapter 2.5.2. --- PCR assay to amplify qnrS genes --- p.33 / Chapter 2.5.3. --- "PCR assays for genotypic characterizations of the co-existed blaTEM, blaSHV, blaCTX-M and PMAmpC genes of all qnr-positive isolates" --- p.33 / Chapter 2.5.3.1. --- Genotypic characterizations of the co-existed bla-TEM and genes --- p.33 / Chapter 2.5.3.2. --- PCR assays to amplify the co-existed blaCTX_M genes --- p.33 / Chapter 2.5.3.3. --- PCR assay to amplify the co-existed PMAmpC genes --- p.34 / Chapter 2.5.4. --- Sequencing reaction --- p.36 / Chapter 2.5.4.1. --- Purification of PCR product and sequence determination --- p.36 / Chapter 2.5.4.2. --- Sequence analysis --- p.37 / Chapter 2.6. --- Collection of Clinical Data --- p.38 / Chapter 2.6.1. --- Demographics and clinical data --- p.38 / Chapter 2.6.2. --- Definitions --- p.38 / Chapter 2.6.3. --- Data analysis --- p.40 / Chapter Chapter 3 --- Results / Chapter 3.1. --- Bacterial Isolates --- p.41 / Chapter 3.2. --- "Demographics, Medical History, Clinical Features and Clinical Outcomes of Patients" --- p.42 / Chapter 3.3. --- Antimicrobial Susceptibility Testing --- p.44 / Chapter 3.4. --- Detection of qnr Genes --- p.48 / Chapter 3.4.1. --- "Detection of qnrA, qnrB and qnrS genes by multiplex PCR" --- p.48 / Chapter 3.5. --- Detection of ESBLs --- p.49 / Chapter 3.5.1. --- Detection of TEM- and SHV-type ESBLs --- p.49 / Chapter 3.5.2. --- Detection of CTX-M- type ESBLs --- p.51 / Chapter 3.6. --- Detection of PMAmpC Genes --- p.52 / Chapter 3.6.1. --- Detection of PMAmpC genes --- p.52 / Chapter 3.7. --- "The Distribution of qnr and bla Genes for TEM, SHV, CTX-M and PMAmpC" --- p.53 / Chapter 3.8. --- The Characteristics of qnr Isolates --- p.54 / Chapter 3.8.1. --- Genotypes of qnrB and qnrS --- p.54 / Chapter 3.8.2. --- Antimicrobial susceptibility of qnr isolates --- p.58 / Chapter 3.9. --- "The Associations of qnr Genes with Other Bacterial Resistance Genotypes, and the Clinical Characteristics and Outcomes of Patients" --- p.62 / Chapter 3.9.1. --- "Univariate analysis of the associations of qnr genes with other bacterial resistance genotypes, and the clinical characteristics and outcomes of patients" --- p.62 / Chapter 3.9.2. --- "Multivariate analysis of the associations of qnr genes with other bacterial resistance genotypes, and the clinical characteristics and outcomes of patients" --- p.65 / Chapter 3.9.2.1. --- "Multivariate analysis of the associations of qnr genes with other bacterial resistance genotypes, and the clinical characteristics of patients" --- p.65 / Chapter 3.9.2.2. --- "Multivariate analysis of the associations of mortality with qnr genes, bacterial resistance genotypes and other clinical characteristics of patients" --- p.66 / Chapter Chapter 4 --- Discussion / Chapter 4.1. --- Prevalences and Susceptibility of ESBL and PMAmpC in Bacteraemic Enterobacteriaceae Isolates --- p.67 / Chapter 4.2. --- Epidemiology of Plasmid-mediated Quinolone Resistance (qnr) Genes --- p.69 / Chapter 4.3. --- Genotypes of qnr-positive Isolates --- p.72 / Chapter 4.4. --- Antimicrobial Susceptibility of qnr-positive Isolates --- p.75 / Chapter 4.5. --- "The Associations of qnr Genes with Other Bacterial Resistance Genotypes, and the Clinical Characteristics of Patients" --- p.79 / Chapter 4.6. --- "The Associations of Mortality with qnr Genes, Bacterial Resistance Genotypes and Other Clinical Characteristics of Patients" --- p.80 / Chapter 4.7. --- Clinical Importance and Clinical Implications of qnr Genes --- p.82 / Chapter 4.8. --- Limitations of the Current Study --- p.85 / Chapter 4.9. --- Future Studies --- p.87 / Chapter 4.10. --- Conclusions --- p.89 / References --- p.90

Wong, Ka Yee. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 177-189). / Abstracts in English and Chinese; includes Chinese. / Abstract --- p.i / 摘要 --- p.iii / Acknowledgements --- p.v / Table of Contents --- p.vii / List of Appendices --- p.xi / List of Tables --- p.xii / List of Figures --- p.xiv / Abbreviations --- p.xvi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General Introduction --- p.1 / Chapter 1.2 --- Background to the study --- p.2 / Chapter 1.2.1 --- Epidemiology of cancer --- p.2 / Chapter 1.2.1.1 --- Incidence and mortality in the World --- p.2 / Chapter 1.2.1.2 --- Incidence and mortality in Hong Kong --- p.4 / Chapter 1.2.2 --- Prevalence of Traditional Chinese Medicine (TCM) --- p.5 / Chapter 1.2.3 --- Prevalence of Traditional Chinese Medicine (TCM) in cancer --- p.6 / Chapter 1.2.4 --- Development of TCM in Hong Kong --- p.7 / Chapter 1.3 --- Theoretical rationale of the study --- p.8 / Chapter 1.4 --- Significance of the study --- p.11 / Chapter Chapter 2 --- Literature Review --- p.13 / Chapter 2.1 --- Introduction --- p.13 / Chapter 2.2 --- The concept of Advanced Cancer --- p.13 / Chapter 2.2.1 --- Pathology of Advanced Cancer --- p.14 / Chapter 2.2.1.1 --- Metastatic Cancer --- p.14 / Chapter 2.2.2 --- Sign and Symptoms of Advanced Cancer --- p.19 / Chapter 2.2.3 --- Diagnosis of Advanced Cancer --- p.19 / Chapter 2.2.4 --- Current Treatment for Advanced Cancer --- p.21 / Chapter 2.2.5 --- Limitation of Current Treatments --- p.24 / Chapter 2.3 --- Diagnosis and Treatment by TCM of Advanced Cancer --- p.26 / Chapter 2.3.1 --- (Advanced) Cancer from the TCM perspectives --- p.26 / Chapter 2.3.2 --- Diagnosis by TCM of Advanced Cancer --- p.27 / Chapter 2.3.3 --- Treatment by TCM of Advanced Cancer --- p.28 / Chapter 2.4 --- Current Evidences about the Clinical Effectiveness of TCM on Cancer Patients --- p.29 / Chapter 2.5 --- The concept of Health-related Quality of Life (HRQOL) --- p.35 / Chapter 2.5.1 --- The importance of HRQOL to cancer patients --- p.35 / Chapter 2.5.2 --- HRQOL instruments --- p.37 / Chapter 2.5.2.1 --- EORTC QLQ-C30 --- p.38 / Chapter 2.5.2.2 --- SF-36 --- p.39 / Chapter 2.6 --- Summary of Literature Review --- p.40 / Chapter 2.7 --- The research questions --- p.41 / Chapter 2.8 --- Research Hypotheses --- p.42 / Chapter 2.9 --- The design of TCM protocol --- p.42 / Chapter Chapter 3 --- Methodology --- p.45 / Chapter 3.1 --- Introduction --- p.45 / Chapter 3.2 --- Protocol --- p.45 / Chapter 3.2.1 --- Study Design --- p.46 / Chapter 3.2.2 --- Selection of Participants --- p.46 / Chapter 3.2.2.1 --- Inclusion criteria --- p.48 / Chapter 3.2.2.2 --- Exclusion criteria --- p.49 / Chapter 3.2.3 --- Sample size calculation --- p.50 / Chapter 3.2.4 --- Setting --- p.51 / Chapter 3.2.5 --- Interventions --- p.51 / Chapter 3.2.5.1 --- Treatment --- p.51 / Chapter 3.2.5.2 --- Medication and dose/dosage --- p.52 / Chapter 3.2.5.3 --- Treatment Assignment --- p.55 / Chapter 3.2.5.4 --- Concurrent Medications --- p.56 / Chapter 3.2.6 --- Procedure and Methods --- p.56 / Chapter 3.2.6.1 --- Informed Consent --- p.56 / Chapter 3.2.6.2 --- Documentation --- p.57 / Chapter 3.2.6.3 --- Assessment Procedure --- p.57 / Chapter 3.2.7 --- Outcome Measurements --- p.62 / Chapter 3.2.7.1 --- Survey Questionnaire --- p.62 / Chapter 3.2.7.2 --- Quality of life (QOL) instruments --- p.62 / Chapter 3.2.7.3 --- Global Ratings --- p.64 / Chapter 3.2.7.4 --- Physical Examination and Laboratory tests --- p.65 / Chapter 3.2.8 --- Safety Considerations --- p.66 / Chapter 3.2.8.1 --- Adverse Events (AE) --- p.66 / Chapter 3.2.8.2 --- Serious Adverse Event (SAE) --- p.66 / Chapter 3.2.8.3 --- Causality Assessment --- p.67 / Chapter 3.2.9 --- Ethical consideration --- p.68 / Chapter 3.2.10 --- Data Collection --- p.69 / Chapter 3.3 --- Data analysis --- p.69 / Chapter 3.4 --- Expected Outcomes of Study --- p.71 / Chapter Chapter 4 --- Results --- p.72 / Chapter 4.1 --- Study Progress --- p.72 / Chapter 4.2 --- The Participants --- p.72 / Chapter 4.3 --- Clinical characteristics and Socio-demographics of Participants --- p.75 / Chapter 4.4 --- Main Outcome - Quality of Life --- p.78 / Chapter 4.4.1 --- QLQ-C30 --- p.79 / Chapter 4.4.1.1 --- Scoring and Transforming of items into scales --- p.79 / Chapter 4.4.1.2 --- Changes of Individual Scale at Different Visits --- p.80 / Chapter 4.4.1.3 --- Clinical significance of Scales --- p.98 / Chapter 4.4.2 --- SF-36 --- p.104 / Chapter 4.4.2.1 --- Scoring and Transforming of items into scales --- p.104 / Chapter 4.4.2.2 --- Changes of Individual Scale at Different Visits --- p.104 / Chapter 4.4.2.3 --- SF-36 Summary Scales --- p.113 / Chapter 4.4.3 --- Correlation of QLQ-C30 and SF-36 --- p.115 / Chapter 4.5 --- Measurement of Physical examination --- p.117 / Chapter 4.5.1 --- Body Weight --- p.117 / Chapter 4.6 --- Measurement of Laboratory Blood tests --- p.118 / Chapter 4.6.1 --- "Comparison of CBC, RFT, LFT and LD" --- p.118 / Chapter 4.6.2 --- Tumor Markers --- p.120 / Chapter 4.7 --- Adverse Events and Serious Adverse Events --- p.121 / Chapter 4.8 --- Global Ratings --- p.123 / Chapter 4.8.1 --- Global Rating 1 - Severity of Disease --- p.123 / Chapter 4.8.2 --- Global Rating 2 - Global Disease Status --- p.124 / Chapter 4.8.2.1 --- Change in Global Disease Status --- p.125 / Chapter 4.8.2.2 --- Agreement between RCMP and clinician --- p.125 / Chapter 4.8.2.3 --- Patients' perception after treatment --- p.126 / Chapter 4.9 --- Distribution of TCM patterns and Chinese herbal medicines --- p.127 / Chapter 4.10 --- Survival Rate --- p.132 / Chapter 4.11 --- Conclusion --- p.133 / Chapter Chapter 5 --- Discussion --- p.135 / Chapter 5.1 --- Conclusion on findings --- p.135 / Chapter 5.2 --- Baseline profile of participants --- p.137 / Chapter 5.3 --- Feasibility of TCM on advanced cancer patients --- p.139 / Chapter 5.3.1 --- Recruitment of Participants --- p.139 / Chapter 5.3.2 --- Compliance of participants to the study schedule --- p.140 / Chapter 5.4 --- Health-related Quality of Life --- p.142 / Chapter 5.5 --- Safety of TCM --- p.149 / Chapter 5.6 --- Chinese medicine practitioner vs Western medicine doctor --- p.150 / Chapter 5.7 --- TCM pattern differentiation and treatment --- p.151 / Chapter 5.8 --- Implication of study --- p.154 / Chapter 5.8.1 --- Clinical implication --- p.154 / Chapter 5.8.2 --- Policy implication --- p.154 / Chapter 5.9 --- Limitations of the study --- p.155 / Chapter 5.10 --- Recommendations for further studies --- p.157 / Chapter 5.11 --- Overall Conclusion --- p.158 / Appendices --- p.160 / References --- p.177

Wong Kin Yee. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 151-166). / Abstracts in English and Chinese. / Chapter (I) --- ABSTRACT (IN ENGLISH) --- p.i / Chapter (II) --- Abstract (in Chinese) --- p.iv / Chapter (III) --- ACKNOWLEDGEMENTS --- p.vii / Chapter (IV) --- PERSONAL CONTRIBUTION TO THE WORK --- p.ix / Chapter (V) --- PUBLICATIONS --- p.x / Chapter (VI) --- TABLE OF CONTENTS --- p.xi / Chapter (VII) --- List of Abbreviations --- p.xvi / Chapter (VIII) --- LIST OF FIGURES --- p.xx / Chapter (IX) --- LIST OF TABLES --- p.xxii / Chapter Section 1: --- GENERAL INTRODUCTION / Chapter CHAPTER 1 --- General Introduction of Atopic Dermatitis --- p.1-8 / Chapter 1.1. --- Definition of Atopic Dermatitis --- p.1 / Chapter 1.2. --- Epidemiology and Classification --- p.3 / Chapter 1.3. --- Factors Provoking Flares of AD / Chapter 1.3.1. --- Genetics --- p.5 / Chapter 1.3.2. --- "Allergens-Food Allergens, Aeroallergens and Autoallergens" --- p.6 / Chapter 1.3.3. --- Microbial Colonization: Staphylococcus Aureus (S. aureus) --- p.7 / Chapter CHAPTER 2 --- Measurements of AD Severity and Quality of Life Impairment --- p.9-14 / Chapter 2.1. --- Scoring of Atopic Dermatitis severity and the SCORing Atopic Dermatitis (SCORAD) Index --- p.9 / Chapter 2.2. --- Quality of life Measurement --- p.10 / Chapter 2.3. --- The Children's Dermatology Life Quality Index --- p.11 / Chapter CHAPTER 3 --- Management of AD --- p.15-19 / Chapter 3.1. --- Current Management of AD and Their Drawbacks --- p.15 / Chapter 3.2. --- Traditional Chinese Herbal Medicne (TCHM) / Chapter 3.2.1. --- General Principle of TCHM --- p.17 / Chapter 3.2.2. --- Side Effects of Using TCHM --- p.18 / Chapter 3.2.3. --- Literature Reviews of TCHM Use in Treating AD --- p.18 / Chapter CHAPTER 4 --- The Pentaherbs Formula for AD Treatment --- p.20-26 / Chapter 4.1. --- Pilot study: Pentaherbs Capsule as Treatment Option of AD Children --- p.20 / Chapter 4.2. --- Literature Review: Nature of Five Herbs / Chapter 4.2.1. --- PHF as Treatment Option of AD under TCHM Concepts --- p.22 / Chapter 4.2.2. --- PHF as Treatment Option of AD from Modern Research Literature --- p.22 / Chapter CHAPTER 5 --- Pathobiology of Atopic Dermatitis --- p.27-40 / Chapter 5.1. --- Nature of Complexity of Pathogenesis --- p.27 / Chapter 5.2. --- Skin barrier-impairment of epidermal barrier --- p.28 / Chapter 5.3. --- Biphasic T cell response in skin of AD --- p.29 / Chapter 5.4. --- Nature of Immunoglobulin-E and its Role in Atopic Dermatitis --- p.32 / Chapter 5.5. --- Innate Immunity Defect in AD --- p.33 / Chapter 5.6. --- Role of Superantigen in Pathogenesis of AD --- p.35 / Chapter 5.7. --- "Cytokines, Chemokines and Inflammatory Mediators in Pathogenesis of Atopic Dermatitis" / Chapter 5.7.1. --- Proinflammatory Cytokines --- p.37 / Chapter 5.7.2. --- Th1/Th2 Cytokines --- p.37 / Chapter 5.7.3. --- Chemokines --- p.38 / Chapter 5.7.4. --- Pruritus Mediators --- p.39 / Chapter Section 2: --- CLINICAL TRIAL OF PENTAHERBS / Chapter CHAPTER 1 --- Objective --- p.41 / Chapter CHAPTER 2 --- Materials and Methods (RCT) --- p.42-51 / Chapter 2.1. --- Materials / Chapter 2.1.1. --- SCORAD worksheet --- p.42 / Chapter 2.1.2. --- CDLQI questionnaire --- p.42 / Chapter 2.1.3. --- Allergic Rhinitis Score (ARS) --- p.43 / Chapter 2.1.4. --- ELISA Assay Kits --- p.43 / Chapter 2.1.5. --- EDTA blood collestion tubes --- p.43 / Chapter 2.2. --- Methods / Chapter 2.2.1. --- Design --- p.45 / Chapter 2.2.2. --- Intervention --- p.45 / Chapter 2.2.3. --- Treatment / Chapter 2.2.3.1 --- The Pentaherbs Formula --- p.45 / Chapter 2.2.3.2 --- Randomization --- p.48 / Chapter 2.2.3.3 --- Concomitant Treatment in Study Period --- p.48 / Chapter 2.2.4. --- Participants --- p.49 / Chapter 2.2.5. --- Outcome Measures --- p.50 / Chapter 2.2.6. --- Statistical Analysis --- p.50 / Chapter CHAPTER 3 --- Results (RCT) --- p.52-67 / Chapter 3.1. --- Demographics --- p.52 / Chapter 3.2. --- Drug Compliance --- p.55 / Chapter 3.3. --- Efficacy / Chapter 3.3.1. --- SCORAD Score --- p.56 / Chapter 3.3.2. --- Quality of Life Score --- p.56 / Chapter 3.3.3. --- Duration and Amount of CS Usage --- p.59 / Chapter 3.3.4. --- Amount of Antihistamine Usage --- p.61 / Chapter 3.3.5. --- Allergic Rhinitis Score --- p.61 / Chapter 3.3.6. --- Blood chemistry and Haematology --- p.63 / Chapter 3.3.7. --- Plasma TARC and BDNF level --- p.63 / Chapter 3.4. --- Tolerability --- p.65 / Chapter Section 3: --- IN VITRO STUDY OF PENTAHERBS / Chapter CHAPTER 1 --- Objectives and Study Design --- p.68 / Chapter CHAPTER 2 --- Materials and Methods (In vitro Study) --- p.69-86 / Chapter 2.1. --- Materials for in vitro study / Chapter 2.1.1. --- Preparation of the Water Extracts of PHF Capsules --- p.69 / Chapter 2.1.2. --- Endotoxin Assay --- p.69 / Chapter 2.1.3. --- Cell isolation and culture ofPBMC / Chapter 2.1.3.1 . --- Cell Isolation from Human Peripheral Blood --- p.70 / Chapter 2.1.3.2. --- Culture of Peripheral Blood Mononuclear Cells --- p.70 / Chapter 2.1.4. --- Trypan Blue Exclusion Assay --- p.72 / Chapter 2.1.5. --- [3H]-Thymidine incorporation Assay --- p.72 / Chapter 2.1.6. --- Supernatant Collection and ELISA --- p.72 / Chapter 2.1.7. --- RNA Extraction and RT-PCR / Chapter 2.1.7.1. --- Reagents for RNA Extraction --- p.73 / Chapter 2.1.7.2. --- Reagents for Reverse Transcription --- p.73 / Chapter 2.1.7.3. --- Reagents for Polymerase Chain Reaction --- p.74 / Chapter 2.1.7.4. --- Reagents for Gel Electrophoresis --- p.74 / Chapter 2.2. --- Methods / Chapter 2.2.1. --- Isolation and Culture PBMC / Chapter 2.2.1.1. --- Isolation of PBMC --- p.76 / Chapter 2.2.1.2. --- Culture of Isolated PBMC --- p.76 / Chapter 2.2.1.3. --- PHA/SEB Treatment --- p.77 / Chapter 2.2.2. --- Preparation of PHF Water Extracts and Endotoxin Level / Chapter 2.2.2.1. --- Hot Water Extraction --- p.78 / Chapter 2.2.2.2. --- Limulus Amebocyte Lysate Assay --- p.78 / Chapter 2.2.3. --- Study on the Cytotoxic and Mitogenic Effects of PHF on PBMC / Chapter 2.2.3.1. --- Trypan Blue Exclusion Assay --- p.80 / Chapter 2.2.3.2. --- [3H]-Thymidine Incorporation Assay --- p.80 / Chapter 2.2.4. --- Study on the Effect of PHF on PBMC Inflammatory Mediator Production / Chapter 2.2.4.1. --- Determination of Inflammatory Mediator Expression Levels by ELISA --- p.82 / Chapter 2.2.4.2. --- Semi-quantification of Inflammatory Mediator mRNA Levels by RT-PCR --- p.83 / Chapter 2.2.5. --- Statistical Analysis --- p.86 / Chapter CHAPTER 3 --- Results(In vitro) --- p.87-114 / Chapter 3.1. --- preparation of PHF Water Extracts and Endotxin Level --- p.87 / Chapter 3.2. --- Cytotoxicity Effect of PHF on PBMC --- p.88 / Chapter 3.3. --- Mitogenicity Effect of PHF on PBMC --- p.93 / Chapter 3.4. --- Effects of PHF on Expression of Inflammatory Mediators from PBMC Following Mitogen (PHA) Stimulation / Chapter 3.4.1. --- Effects of PHF on mRNA Expression of Inflammatory Mediators from PHA-stimulated PBMC --- p.98 / Chapter 3.4.2. --- Effects of PHF on Secretion of Inflammatory Mediators from PHA-stimulated PBMC --- p.101 / Chapter 3.5 --- Effects of PHF on Expression of Inflammatory Mediators from SEB-stimulated PBMC / Chapter 3.5.1. --- Effects of PHF on mRNA Expression of Inflammatory --- p.106 / Chapter 3.5.2. --- Effescts of PHF on secretion of inflammatory Mediatorsfrom SEM-Stimulated PBMC --- p.109 / Chapter 3.6. --- Summarization of Effects of PHF on Expression of Inflammatory Mediators from PHA- and SEB-stimulated PBMC / Chapter 3.6.1. --- Mitogen (PHA) Stimulation --- p.114 / Chapter 3.6.2. --- Superantigen (SEB) Stimulation --- p.114 / Chapter Section 4: --- DISCUSSIONS / Chapter CHAPTER 1 --- Discussions on RCT of PHF --- p.115-122 / Chapter 1.1. --- Clinical Efficacy and Tolerability of PHF for Treatment of Children AD: a RCT study / Chapter 1.2. --- Efficacy of PHF for Treatment of Children with AD --- p.117 / Chapter 1.3. --- Safety and Tolerability of PHF Use for Treatment of Children with AD --- p.119 / Chapter 1.4. --- Rounding up --- p.121 / Chapter CHAPTER 2 --- Discussions on In vitro Immunomodulatory Activities of PHF --- p.123-130 / Chapter 2.1. --- General Effects of PHF on PBMC --- p.123 / Chapter 2.2. --- Effects of PHF on Inflammatory Mediators Expression in PBMC --- p.124 / Chapter CHAPTER 3 --- Limitations of the Present Study --- p.131-132 / Chapter Section 5: --- CONCLUSIONS AND FUTURE PROSPECTS / Chapter CHAPTER 1 --- Conclusions --- p.133 / Chapter CHAPTER 2 --- Future Prospects --- p.134-135 / Chapter Section 6: --- APPENDICES / Appendix1 --- p.137 / Appendix2 --- p.142 / Appendix3 --- p.149 / Chapter Section 7: --- BIBLIOGRAPHY --- p.151-166

A adesão ao tratamento medicamentoso é um importante fator determinante no sucesso terapêutico. A adesão do paciente pode ser influenciada por fatores diversos, ligados à doença, ao tratamento, ao paciente, às condições sociais e econômicas, como também, relacionada ao sistema de saúde que o atende. Ainda que existam inúmeros estudos sobre a adesão ao tratamento em portadores com doenças crônicas, são escassas as investigações sobre este tema nas doenças inflamatórias intestinais. O presente trabalho teve o objetivo de avaliar a adesão ao tratamento medicamentoso e os possíveis fatores que a influenciam, em pacientes portadores de doenças inflamatórias intestinais (DII): doença de Crohn (DC) e retocolite ulcerativa (RCU), do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP), da Universidade de São Paulo. Como controles, foram investigados pacientes portadores de pancreatite crônica e insuficiência pancreática (PC), com medicação fornecida pelo hospital, tal como os pacientes portadores de DII. Foram também investigados pacientes portadores de afecções digestivas variadas (ADV), grupo no qual a medicação prescrita não era fornecida pelo hospital. Por meio de estudo transversal e indireto, foi realizada entrevista estruturada para avaliar a adesão de 110 pacientes, que foram caracterizados como apresentando maior ou menor grau de adesão. Esta classificação foi baseada no cotejo entre os dados do prontuário e os informados pelo paciente em entrevista, considerando a afirmação do paciente que usava a medicação e que conhecia o nome da droga em uso. Utilizou-se, também, o teste de Morisky, que permite avaliar o padrão de comportamento do paciente em relação ao uso diário do medicamento. Este teste consiste de quatro perguntas padronizadas relacionadas ao esquecimento, descuido com o horário de tomada do medicamento, percepção de efeitos colaterais e ausência de sintomas. Na análise dos medicamentos utilizados pelo paciente, foram observadas as seguintes proporções de pacientes classificados como menos aderentes: 15,4% em pacientes portadores de DC, 13,3% na RCU, 8,4% na PC e 16,6% nos pacientes do grupo ADV. Porém, o teste de Morisky mostrou as seguintes proporções de menos aderentes: 50% de pacientes portadores de DC, 63,3% na RCU, 54,2% na PC e 63,4% na ADV. Não houve diferenças estatisticamente significativas, entre os grupos de pacientes, tanto na análise dos medicamentos utilizados pelo paciente como pelos resultados do teste de Morisky. Em análise univariada, nenhum dos fatores demográficos, sociais, clínicos ou referentes ao tratamento medicamentoso apresentou relação estatisticamente significativa, comum a todos os grupos, que indicasse influência sobre a adesão ao tratamento. Apesar do alto grau de adesão, de acordo com a análise dos medicamentos utilizados, detectou-se alto percentual de não-adesão ao tratamento medicamentoso ligado ao comportamento habitual e independente do diagnóstico, ou do acesso gratuito aos medicamentos. Isto pode indicar a existência de um padrão específico de comportamento dos usuários do serviço, o que sugere a necessidade de maior atenção dos profissionais de saúde para o problema, bem como medidas de educação do paciente quanto ao uso dos medicamentos. / Compliance to drug therapy is an important factor determining a successful treatment. Patient compliance may be influenced by various factors related to the disease, to treatment, to the patient himself, to his socioeconomic condition, as well as to the health system. Although many studies have assessed compliance to treatment in patients with chronic diseases, few investigations are available in inflammatory bowel diseases (IBD). The objective of the present study was to assess compliance to drug therapy in patients with IBD - Crohn’s disease (CD) and ulcerative colitis (UC), seen at the University Hospital, Faculty of Medicine of Ribeirão Preto (HCFMRP), University of São Paulo, Brazil. Patients with chronic pancreatitis (CP) and pancreatic insufficiency who received free medication supplied by the hospital, like the IBD patients, were used as controls. Patients with various digestive affections (VDA) whose prescribed medication was not supplied by the hospital were also investigated. In a transverse and indirect study, a structured interview was applied to assess the compliance of 110 patients, who were characterized as presenting a higher or lower degree of compliance. This classification was based on a comparison of data in the medical records to the information provided by the patient in the interview, considering the patient’s statements that he/she actually used the medication and was capable of produce correctly its name. The Morisky test was also used to assess the behavioral pattern of the patient regarding the daily use of the medication. This test consists of four standardized questions that evaluate forgetfulness, carelessness regarding the time when the medication should be taken, the perception of side effects, and the absence of symptoms. In the analysis of patient statements on medication in use, the proportions of patients regarded as less compliant were as follows: 15.4% of patients with CD, 13.3% of those with UC, 8.4% of those with CP, and 16.6% of those with VDA. However, the Morisky test revealed the following proportions of less compliant patients: 50% of patients with CD, 63.3% of those with UC, 54.2% of those with CP, and 63.4% of those with VDA. No statistically significant differences were observed between the four groups regarding evaluation according to either the analysis of patient statements or the results of the Morisky test. Univariate analysis revealed that none of the demographic, social, or clinical factors or the variables related to drug therapy showed statistically significant relationships, common to all groups, that would indicate their influence on compliance to treatment. Despite the high degree of compliance evaluated by patient statements on medication in use, a high degree of noncompliance to treatment linked to habitual behavior was detected. Those findings were independent on either disease type or free access to medication. This may indicate the existence of a specific behavioral pattern common to the local health system users, which suggests the need for better consideration of the problem on the part of the health professionals, as well as the need for measures of patient education regarding medication use.

Viruses are a major threat to humans due to their unique adaptability, evolvability and  capability to control their hosts as parasites and genetic elements. HIV/AIDS is the third largest cause of death by infectious diseases in the world, and drug resistance due to the viral mutations is still the leading cause of treatment failure. The flaviviruses, such as Dengue virus (DEN) and Japanese encephalitis virus (JEV), represent other major cause of morbidity and mortality, and the areas where these viruses are endemic are spreading rapidly. No curative therapy for any flavivirus could be made available as yet. The first part of this thesis focuses on the HIV-1 drug resistance caused by mutations in a major HIV drug target, the HIV-1 reverse transcriptase (RT) as a response to the largest class of clinically used anti-retrovirals, the NRTIs. A robust proteochemometric model was created to analyse the complex mutation patterns in RT drug resistance. The model identified more than ten frequently-occurring mutations, each conferring at least two-fold decrease in susceptibility for one or several NRTIs. Using our prediction server (hivdrc.org), the model can be applied to propose optimum combination therapy for patients harbouring mutated HIV variants. The second part of the thesis encompasses studies on a promising drug target, the NS2B(H)-NS3pro, in two flaviviruses, namely the dengue virus (DEN) and Japanese encephalitis virus (JEV). Functional determinants of DEN NS2B(H)-NS3pro were identified by site-directed mutagenesis. Further, peptide inhibitors were designed using proteochemometrics (PCM) and statistical molecular design (SMD), synthesized and assayed on DEN proteases, which resulted in some novel peptides with low micromolar or sub-micromolar inhibitor activity. The very poorly characterised JEV NS2B(H)-NS3pro  was cloned, purified and the kinetic parameters of this attractive drug target were determined for a series of model substrates and inhibitor. The results identified the role in target-ligand interaction of different residues on specific positions in the target (NS2B(H)-NS3pro) and ligands (substrates/inhibitors). Overall, the findings in this thesis contribute to rational antiviral drug discovery and therapy.

En esta tesis se presenta un estudio bibliométrico sobre la producción nacional e internacional acerca de los avances terapéuticos del asma en el periodo 1955-2005, ambos años inclusive. El análisis cuantitativo nos ha permitido comprobar las principales leyes bibliométricas (Price, Bradford y Lorcka) y la información relacionada con la autoría y procedencia de los trabajos, la distribución geográfica de los artículos y su relación con el grado de desarrollo (medido por el PIB per cápìta) de cada país . El bloque occidental y sobre todo el mundo anglosajón obtienen el mayor nº de publicaciones. El estudio también se correlaciona con la producción no solo neta sino con la producción científica en nº de artículos por millón de habitantes. A nivel nacional, los artículos publicados sobre el tema en el Índice Médico Español muestran que la comunidad con mayor producción científica es Cataluña.Se ha hecho también un análisis de los principios activos más estudiados, con una predominio claro de los betamiméticos y esteroides. Se ha llevado a cabo una lectura crítica de un grupo seleccionado de revisiones sistemáticas valorado mediante un cuestionario específicos desarrollado por el grupo CASPe. / This thesis presents a bibliometric study of national and international research papers concerning advances in the treatment of asthma during the period 1955-2005. Quantitative analysis techniques allowed us to review the main bibliometric laws (Price, Bradford and Lodka) and information relating to the authorship and origin of the studies, along with the geographical distribution of articles and their relationship to the degree of development as measured by the per capita Gross Domestic Product of the country in which they were carried out. The largest number of publications appeared in Western countries, most notably in the Anglo-Saxon world. In addition to a correlation between number of studies and economic productivity, our analysis found a relationship between scientific production in particular and the number of articles published per million inhabitants. On the national level, the articles published on this topic in the Indice Médico Español (Spanish Medical Index) in dicate that Catalonia is the autonomous community with the highest scientific production.In addition, we conducted an analysis of the most commonly studied pharmacological principles and found a clear predominance of betamimetics and steroids. We also carried out a critical appraisal of a selected group of systematic reviews evaluated by means of specific questionnaires developed by the CASP (Critical Appraisal Skills Program) group.

Multiple modulating genes and environmental factors have been implicated in the pathogenesis of high-altitude pulmonary edema (HAPE). However, at the present time, there exists an incomplete understanding of the molecular mechanisms and pathways which underlie constitutional susceptibility. Genome-wide measurements of gene expression in peripheral blood mononuclear cells (PBMCs) were performed using microarray technology. Comparison of gene expression profiles of HAPE-susceptible and resistant individuals resulted in the identification of several previously undescribed candidate genes. RhoA and Rho-kinase (ROCK), regulators of vascular smooth muscle contraction, were differentially regulated in the HAPE-susceptible cohort, as compared to both HAPE-resistant patients with acute mountain sickness (AMS+) and healthy controls (p=0.0014; p=0.0020). Furthermore, biological pathways involving RhoA and Rho-kinase were strongly upregulated in subjects with HAPE. These findings represent the first description of the RhoA/Rho-kinase signaling pathway in HAPE. Currently, few pharmacologic therapies have been demonstrated to be effective in the prevention and treatment of HAPE. The results of this study provide early evidence that Fasudil, a selective Rho-kinase inhibitor, may represent a novel therapeutic intervention effective in the prevention and/or treatment of high-altitude pulmonary edema.

Thesis (M.S.P.H.)--University of South Florida, 2009. / Title from PDF of title page. Document formatted into pages; contains 114 pages. Includes bibliographical references.

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