Thesis (M. Med. Sc.)--University of Hong Kong, 2008.

M.Tech. (Homoeopathy) / Atopic dermatitis (atopic eczema) is a chronic, relapsing, allergic inflammatory skin disease (Hauk, 2008). The prevalence of atopic dermatitis has increased significantly over the past few decades, with highest rates of 45 – 64% occurring amongst preschool children (Butler, 2009), and 40% amongst older children and adults (Manjra, 2005). This increase in prevalence is attributed to environmental factors such as microbial exposure and poor nutrition, which can all lead to atopic dermatitis (Schnopp, 2006). The quality of life of patients suffering from atopic dermatitis and their family members are significantly affected (Manjra, 2005). Atopic dermatitis is characterized by active skin lesions that are red, flaky, dry and itchy and in children commonly occurs in the flexural areas of the body (Fölster-Hols et al., 2007, Schnopp, 2006). Conventional treatment potions for atopic dermatitis are associated with adverse effects in children (Kalicharan et al., 2005). Homoeopathic remedies may offer an alternative option for this condition. This study aimed to assess the effect of a homoeopathic complex consisting of Graphites 6cH, Histaminum 9cH, Psorinum 6cH and Sulphur 6cH, on atopic dermatitis in children. All the participants of the study received the homoeopathic complex. The atopic dermatitis was evaluated using the SCORAD index (Scoring of Atopic Dermatitis) (Appendix F) and the Children’s Dermatology Life Quality Index (CDLQI) (Appendix E). Thirty four participants who met the inclusion and exclusion criteria were recruited to participate in this pre-test – post-test single group study by means of advertisements (Appendix A) placed in and around primary schools in the Gauteng area (with relevant permission given) and in the local newspaper. Participants were also recruited via word of mouth. Once participants were accepted into the study they were allocated into the treatment group which received the homoeopathic complex containing Graphites 6cH, Histaminum 9cH, Psorinum 6cH and Sulphur 6cH. The study was completed over a four week period. The percentage of the area affected, the intensity of the symptoms, the pruritus and the loss of sleep as well as the quality of life of the participants suffering from atopic dermatitis were aspects of the condition evaluated on a weekly basis. The results for the CDLQI showed improvements in the participant’s perception of itching/ pain of the affected area, as well as their quality of sleep. These improvements were shown to have occurred gradually over the study period. There were however no statistically significant changes noted in the mental and emotional quality of life of the participants.

Indiana University-Purdue University Indianapolis (IUPUI) / Atopic dermatitis (AD) is a pruritic, chronic inflammatory skin disease with a lifetime prevalence of 10-20% in children and 1-3% in adults, worldwide. In the past three decades, prevalence of the disease has increased by two to three-fold in industrialized countries, with higher incidences in urban regions compared to rural regions. Mice with an activating mutation in STAT6, known as STAT6VT, constitutively express STAT6 in T-cells. Our preliminary data suggests significant differences between the STAT6VT transgenic mice from WT littermate controls treated with SLS. These findings correlate with evidence that there are abnormalities in the barrier function between these mice

Dermatological conditions affect between 15 to 25% of canines. Canine Atopic Dermatitis (CAD) is one of the most prevalent of these conditions and is a chronic inflammatory disorder with a wide array of causes and triggers and no known cure. Symptoms of this condition can be persistent and often lead to significant discomfort, leading many owners to seek preventative care in an attempt to avoid expensive veterinary care and discomfort in their dogs. Sebaceous Adenitis (SA) is another skin condition, which while less common, is also a disorder of the inflammatory pathways and affects keratin production in the coats of dogs. It has more persistent symptoms and requires rigorous grooming care to prevent its onset, and as a result is the cause for euthanasia in many of the breeds which it affects. Similar to CAD, owners of dogs with SA seek preventative care to avoid flares of the conditions that are often coupled with secondary infections that perpetuate the skin’s poor condition. Due to the overwhelming variety and misleading advertising that currently exists in the dog food market, one key element to preventative treatment that is confusing to many owners is manipulation of the diet. Research has demonstrated that certain dietary components may be important. These include increased protein composition, supplementation of vitamins A, D, and E, essential fatty acid supplements, and the use of probiotics and prebiotics. Increasing the proportion of dietary protein to total energy intake allows for greater consumption of amino acids, which can be utilized to renew epidermal cells, including hair follicles. It is speculated that Vitamin A supplementation may slow down the rate of hyperkeratinization seen in SA as it attenuates epithelial cell turnover. Supplementation with vitamin E has been found to improve pruritus in CAD and acts as an anti-inflammatory in areas which are affected by a loss of sebum, as seen in SA. It may also act to improve antibody responses in hypersensitivity reactions, which are exaggerated immunologic responses to allergens, seen in CAD. It is known that an increase in dietary vitamin D enhances immunomodulatory roles that lead to its ability to reduce lesions in both CAD and SA. Essential fatty acids (FA), of which two are omega-3 and omega-6 FA, are useful supplements for dogs with CAD, as they may affect mediators of inflammation specific to inflammatory skin disorders. Additionally, supplementation with essential FA may replenish a factor lacking in an impaired skin barrier. The breakdown in the epithelial barrier leads to increased cutaneous permeability and decreased membrane fluidity. It is important to balance the more pro-inflammatory effects of omega-6 FA with the anti-inflammatory effects of omega-3 FA. Two balanced sources of these essential fatty acids that often appear in the literature are evening primrose and borage oils, which supply gamma linoleic acid (GLA), a less inflammatory omega-6 FA. Probiotics/prebiotics aid in repairing possible issues observed in the gut-skin axis seen in AD though the strains which provide benefits are not consistent in the literature. In summary, there are promising developments on the treatment of CAD and SA through diet, although extensive research is needed to validate these studies and clarify the results prior to usage by the general public.

No description available.

Lam Man Ching. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 101-114). / Abstracts in English and Chinese; appendices also in Chinese. / Chapter Chapter 1 --- Introduction and Literature Review / Chapter 1.1 --- General introduction of atopic dermatitis --- p.1 / Chapter 1.1.1 --- Definition and its nature --- p.1 / Chapter 1.1.2 --- Epidemiology and prevalence of atopic dermatitis --- p.1 / Chapter 1.1.3 --- Factors and triggers related to high risk of atopic dermatitis --- p.3 / Chapter 1.2 --- Pathogenesis of atopic dermatitis --- p.5 / Chapter 1.2.1 --- Nature of complexity of pathogenesis --- p.5 / Chapter 1.2.2 --- Role of T-helper cell in atopic dermatitis and its paradigm model --- p.5 / Chapter 1.2.3 --- Nature of immunoglobulin-E and its role in atopic dermatitis --- p.6 / Chapter 1.2.4 --- Chemokines in pathogenesis of atopic dermatitis: CTACK and TARC --- p.7 / Chapter 1.2.5 --- Role of antimicrobial peptides and innate immunity --- p.8 / Chapter 1.3 --- Measurements of atopic dermatitis severity and related quality of life impairment --- p.9 / Chapter 1.3.1 --- Scoring of atopic dermatitis severity and the SCO Ring Atopic Dermatitis Index --- p.9 / Chapter 1.3.2 --- Quality of life measurement --- p.9 / Chapter 1.3.3 --- The Children's Dermatology Life Quality Index (CDLQI) --- p.10 / Chapter 1.4 --- Pruritus in atopic dermatitis and its underlying mechanisms --- p.11 / Chapter 1.4.1 --- Introduction to pruritus --- p.11 / Chapter 1.4.2 --- Difference between pruritus and pain --- p.11 / Chapter 1.4.3 --- Pathogenesis and neuronal pathways of pruritus --- p.12 / Chapter 1.4.4 --- Neurogenic itch --- p.13 / Chapter 1.4.5 --- Role of histamines in pruritus of AD --- p.14 / Chapter 1.4.6 --- Substance-P --- p.14 / Chapter 1.4.7 --- Brain-derived neurotrophic factor and other recent mediators in pruritus --- p.15 / Chapter 1.5 --- "Scratching, nocturnal scratching and sleeping behavior in atopic dermatitis subjects and related research progress" --- p.16 / Chapter 1.5.1 --- Overview --- p.16 / Chapter 1.5.2 --- "Interrelationship between pruritus, scratching and sleep disturbance" --- p.17 / Chapter 1.5.3 --- Current methodologies in nocturnal scratching and sleep quality measurement --- p.18 / Chapter Chapter 2 --- Objectives --- p.25 / Chapter Chapter 3 --- Methodologies and Materials / Chapter 3.1 --- Validation of a new methodology /device --- p.27 / Chapter 3.1.1. --- Device selection --- p.27 / Chapter 3.1.2 --- Study design --- p.27 / Chapter 3.1.3 --- Validation of the Digitrac with laboratory markers --- p.29 / Chapter 3.1.4 --- Factor and statistical analysis --- p.31 / Chapter 3.2 --- Application of Digitrac in traditional Chinese herbal medication (TCHM / TCM) clinical trial --- p.32 / Chapter 3.2.1 --- Current AD treatment using corticosteroids and their drawbacks --- p.32 / Chapter 3.2.2 --- Recent trend on TCM treatment --- p.32 / Chapter 3.2.3 --- Study plan --- p.33 / Chapter 3.2.4 --- "Validation with laboratory markers, Staphylococcus aureus infection and statistical analysis" --- p.35 / Chapter 3.3 --- Application of Digitrac in a trial of 0.1% tacrolimus ointment in treatment of atopic dermatitis --- p.37 / Chapter 3.3.1 --- Topical immunomodulators as a treatment approach of AD --- p.37 / Chapter 3.3.2 --- Mechanism of tacrolimus in suppressing AD and pruritus --- p.37 / Chapter 3.3.3 --- Study plan --- p.39 / Chapter 3.4 --- Further application of Digitrac in pruritus of other medical fields --- p.41 / Chapter Chapter 4 --- Results and Discussions / Chapter 4.1 --- Digitrac validation --- p.52 / Chapter 4.1.1 --- General demographic background data --- p.52 / Chapter 4.1.2 --- Wrist activities --- p.53 / Chapter 4.1.3 --- Laboratory markers and factor analysis --- p.54 / Chapter 4.1.4 --- Interpretation of results --- p.55 / Chapter 4.1.5 --- Drawbacks of the validation --- p.58 / Chapter 4.1.6 --- Summary --- p.59 / Chapter 4.2 --- Digitrac in traditional Chinese herbal medication clinical trial --- p.68 / Chapter 4.2.1 --- General information --- p.68 / Chapter 4.2.2 --- "SCORAD, wrist activities and CDLQI" --- p.69 / Chapter 4.2.3 --- Laboratory findings --- p.70 / Chapter 4.2.4 --- Interpretation of results --- p.71 / Chapter 4.2.5 --- Safety of TCM use --- p.73 / Chapter 4.2.6 --- Summary --- p.74 / Chapter 4.3 --- Tacrolimus clinical trial --- p.81 / Chapter 4.4 --- Application of Digitrac in other areas of study --- p.90 / Chapter 4.4.1 --- Pemphigoid gestationis case study --- p.90 / Chapter 4.4.2 --- T-cell lymphoma case study --- p.92 / Chapter Chapter 5 --- Further Discussions and Conclusion --- p.98 / References --- p.101 / Appendices --- p.116

No / Background  Interleukin (IL)-33 is a member of the IL-1 family and has been implicated in Th2-driven allergic diseases such as atopic dermatitis (AD) and asthma. The principal Th2 cytokine IL-4, found highly expressed in acute allergic eczema, is known to downregulate human β-defensin 2 (hBD2) expression in human keratinocytes and this is associated with superinfection in patients with AD. Objectives  To investigate the effect of IL-33 on the expression of hBD2 in human keratinocytes. Methods  hBD2 production by stimulated keratinocytes was measured by enzyme-linked immunosorbent assay. Results  Our results showed that serum is a very potent inducer of hBD2 and 2·5% human serum was much more potent in inducing hBD2 than 20 ng mL−1 of tumour necrosis factor-α. Interestingly, serum from patients with AD showed an impaired ability to induce hBD2 in normal keratinocytes. IL-33 significantly downregulated serum-induced hBD2. The downregulatory capacity of IL-33 was found to be 1·5- to 2-fold weaker compared with IL-4. Conclusions  Our data suggest that IL-33 can significantly contribute to the decreased expression of hBD2 in acute eczematous reaction clinically characterized by spongiosis and oozing – thus indicative for contact of the epidermis with serum components.

Introduction: Staphylococcus aureus skin infection is an almost ubiquitous feature of patients with atopic dermatitis (AD). TLR1, 2 and 6 are important in immune sensing of these bacteria. The aim of this study was to determine whether defects in TLR1, 2 and/or 6 expression/function may explain the propensity to infection in humans and the NC eczema mouse model. Methods: Fibroblast cell lines from severe AD, nonatopic controls, and mouse embryonic fibroblasts (MEFs) from the NC, MSM/Ms wild-type strain and a 3T3 control strain TLR1, 2 and 6 expression were measured by qPCR and FACS. IL-6, TNF-α, TSLP and IL-33 production was measured by qPCR and ELISA at baseline and after stimulation with LPS, HKSA and a live strain of Staphylococcus aureus that produced only SEB. Results: No differences were found in either TLR expression or function in human fibroblasts derived from patients and controls. The MSM/Ms MEFs expressed significantly more TLR1 and 2, as well as exhibited high inflammatory profile after stimulation comparing with 3T3 and the NC MEFs. Live Staphylococcus aureus, but not HKSA, LPS or SEB, was a potent stimulus for the Th2-inducing cytokines (TSLP and IL-33), and induce cell death. Cytokines levels were found to be similar in AD and NC MEFs when compared to healthy controls. Conclusion: Eczema in both the human and NC mouse is not associated with abnormalities in fibroblasts TLR1, 2, and 6. Live, but not killed Staphylococcus aureus or its enterotoxin, is a potent inducer of TSLP and IL-33 in both species.

Atopic asthma is a complex disease process that has a significant social, personal and economic burden across all ages. Leukotriene-receptors are involved in the cascade of inflammation that may result in symptoms of atopy and asthma. Two leukotriene receptors have been identified in the lung. The cysteinyl leukotriene receptor 1 and cysteinyl leukotriene receptor 2 genes (i.e., CYSLTR1 and CYSLTR2) have been sequenced, and a number of single nucleotide polymorphisms (SNPs) within these genes have been identified.The purpose of this study was to: (1) Determine the relationship between CYSLTR1 genotypes, CYSLTR2 genotype, atopy, elevated IgE level, and eosinophilia, (2) Determine the relationship between CYSLTR1 genotypes, CYSLTR2 genotype, asthma, and atopic asthma, and (3) Determine the degree of interaction between CYSLTR2 genetic variation and gender in atopic asthma.Nested within two sub-studies of the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) study, a prospective longitudinal cohort, 853 individuals were entered into this study. Study criteria included Non-Hispanic white adults, who consented to genetic testing in the two sub-studies. Tagging SNPs of the CYSLTR1 and CYSLTR2 genes were genotyped. Serum IgE status and eosinophilia were obtained from existing dataset. Questionnaires collected in the parent study were used to obtain demographic and clinical data.SNP rs321006 in the CYSLTR1 gene was associated with atopy among Non-Hispanic white women. Assuming a recessive model, among female Non-Hispanic white adults, the odds of having rs321073 CC genotype was 5.82 times higher among those with atopic asthma than those without atopic asthma. No gene by gender interaction was found between SNP of interest in CYSLTR2 and atopic asthma. Genetic association of SNPs rs321006 with atopy and rs321073 with atopic asthma are novel findings to date.Implications for nurses, clinicians, and scientists include better understanding of associations of these genetic variations with asthma, atopy, and atopic asthma that can generate further inquiry into other mechanisms of atopic asthma. These novel genetic associations with atopy and atopic asthma may have the potential for personalized medicine that might afford patients with appropriate treatment based on their genotype.

Over the past four years, a previously unrecognised family of innate effector cells has been identified. Their comprehensive functional capabilities range from lymphoid organogenesis, tissue remodelling, wound healing, immune protection and homeostasis to contribution to inflammation and allergic responses. Here we investigate the presence and function of type 2 innate lymphoid cells (ILC2) in the skin. We show that human ILC2 are resident in human skin and express RORA and GATA3, and skin homing receptors. ILC2 further infiltrate the skin after allergen challenge, where they produce the type 2 cytokines IL-5 and IL-13. Skin-derived ILC2 express the IL-33 receptor ST2, which is up-regulated during activation. Signalling via IL-33 induces type 2 cytokine and amphiregulin expression, and increases ILC2 migration. Atopic dermatitis (AD) is a chronic inflammatory skin disorder. Current evidence suggests that both skin barrier dysfunction and immune system abnormalities, particularly those of a type 2 phenotype, contribute to disease pathogenesis. We demonstrated that ILC2 are enriched in lesional skin biopsies from atopic patients and show higher expression of cytokine receptors, reflecting an activated phenotype. Down-regulation of E-cadherin is characteristic of filaggrin insufficiency, a cardinal feature of AD. Interestingly, E-cadherin binding to KLRG1 on human ILC2 dramatically inhibits IL-5 and IL-13 production. ILC2 may contribute to increases in type 2 cytokine production in the absence of the inhibitory E-cadherin ligation through this novel mechanism of barrier sensing. CRTH2, a receptor for prostaglandin D₂ (PGD₂), is expressed by human ILC2. However, the function of CRTH2 in these cells is unclear. We sought to determine the role of PGD₂ and CRTH2 in human ILC2 and compare it with that of the established ILC2 activators IL-25 and IL-33. PGD₂ binding to CRTH2 induced ILC2 migration and production of type 2 cytokines IL-4, IL-5, IL-13 and release of other pro-inflammatory cytokines IL-3, IL-8, IL-9, IL-21, GM-CSF, and CSF-1 in a dose-dependent manner. ILC2 activation through CRTH2 also upregulated the expression of IL-33 and IL-25 receptor subunits (ST2 and IL-17RA) suggesting a synergistic role. The effects of PGD₂ on ILC2 could be mimicked by the supernatant from activated human mast cells and inhibited by a CRTH2 antagonist. Therefore, PGD₂ can be considered as an important and potent activator of ILC2 through CRTH2 mediating strong inflammatory responses. Cell surface interaction mechanisms that activate ILC2 function are unknown. We observed the expression of NKp30 on ILC2 ex vivo and after culture. Using quantitative PCR we confirmed that ILCs express NKp30c splice variant, an immune-modulatory isoform. Incubation of ILC2 with the NKp30 ligand B7H6 and tumour cell lines expressing this protein induced production of type 2 cytokines. This interaction can be inhibited by NKp30 blocking antibodies. We further established that activation of NKp30 induces the canonical pathway of NFƙB signalling. Overall the work in thesis shows for the first time that ILC2 are resident in human skin and infiltrate rapidly after allergen challenge and in AD lesional skin. We have defined cytokine and lipid mediators that contribute to migration and activation of ILC2 and shown that KLRG1 and NKp30 act as inhibitory and activatory receptors respectively. The work defines novel pathways for barrier sensing and cutaneous inflammation, and identifies potential new targets for therapeutic intervention.