203 research outputs found

    ADC 11(4)

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    Diagnosis and treatment of patients with undefined autoinflammatory diseases

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    Sterile inflammation characterizes a heterogeneous group of primary immunodeficiency disorders named autoinflammatory diseases (AID). Less than 30% of AID patients are molecularly defined. To increase the diagnostic rate and treatment outcome in patients with undefined AID, "omics" technologies, as the next-generation sequencing and mass spectrometry, and clinical data registries analysis are applied. During the last three years, I described patients with undefined and known rare AID (i.e. RAS-associated autoimmune leukoproliferative disease and SAMD9L-associated AID), the first 100 genes and related pathways associated with AID, the actin-related AID, the syndrome of undifferentiated recurrent fever (SURF) and the proteomic signature of monocytes in hereditary recurrent fever. Furthermore, I analyzed the efficacy of the interleukin 1 inhibitors in systemic juvenile idiopathic arthritis, cryopyrin associated periodic syndrome and refractory hyperferritinemic syndromes. Finally, I developed a metadata registry called MeRITA in order to increase the interoperability and data sharing among clinical registries of the European Reference Network on Rare Immunological Disorders (ERN-RITA)

    Post-transcriptional mechanisms in type XVII collagen synthesis

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    In chapter 1 we started with making an inventory of type XVII collagen directed research during the last three decades; on its role in normal healthy tissue and even more on its role in the pathogenesis in a range of diseases. We concluded that, although these studies have provided much information about type XVII collagen, certain aspects are still misunderstood. Most studies confirmed the main function of type XVII collagen: anchoring of the basal keratinocytes to the basement membrane. Several observations, however, suggests that type XVII collagen may have other additional functions as well. Also fundamental information on the transcription of the COL17A1 gene and the translation to type XVII collagen is lacking. Main enigmas include the unknown function of the shedding of type XVII collagen, the deregulated expression of type XVII collagen in squamous cell carcinogenesis, and the function of the alternative splicing of the COL17A1 3'Untranslated Regions (UTR). Considering the established involvement of the untranslated regions of mRNA in various protein expression related mechanisms, we choose to mainly focus on exploring the function the 3'UTR and the primary characterisation of the still unknown 5'UTR. By studying COL17A1 transcript levels in Hemidesmosomal Epidermolysis Bullosa (HEB) patients with various phenotypes, we tried to find answers on what transcript levels are minimally needed to provide good anchoring of the epidermis and what is the relation of the mRNA level with the HEB skin phenotype. These answers will also be important for studies aimed at gene correction as therapy for Epidermolysis Bullosa. In chapter 2 we characterised the COL17A1 5'UTR and we demonstrated that the 5'UTR is, like the 3'UTR, also alternatively spliced. RACE and RPA experiments demonstrated the presence of six different 5'UTRs, all with different start points, of which two major transcripts accounted for 75% of the total COL17A1 expression. The finding of two major transcripts also at the 5' end raised the question if each of the major 5'UTR was connected to a particular 3'UTR. In long template PCR experiments this hypothesis could not be confirmed, so we conclude that both 5' ends are equally shared by the two alternative 3'UTRs. Moreover, motif analysis of the sequence upstream of the translation start site showed the existence of several transcription motifs. These transcription motifs may be important in regulating type XVII collagen expression, not only in normal homeostasis but also under conditions where synthesis has to be shut down. For instance, when keratinocytes differentiate and leave the basal layer, and under conditions where increased expression –often accompanied by a strong cytoplasmic presence- is observed as in wound healing and carcinogenesis. Chapters 3 and 4 were dedicated to the function of alternative splicing of the COL17A1 3'UTR. We investigated whether the alternative splicing is connected with the translation of the ORF, either in a quantitative way and/or in directing its subcellular localisation. In the first of these two chapters we transfected several cell types with different luciferase-COL17A1-3'UTR constructs to investigate translation levels, and in separate experiments we blocked transcription to investigate transcript stability. We showed that when the long variant 3'UTR was cloned behind the coding region of a reporter gene increased reporter gene translation levels were observed in comparison to constructs containing the short variant 3'UTR. The mRNA stability experiments revealed that this is probably caused by decreased stability of the short variant transcript. In the subsequent chapter we again transfected cells with COL17A1-3'UTR constructs, but now we used a GFP-reporter vector that enabled us to localise the subcellular site of translation products. Moreover, we investigated the subcellular location of original COL17A1 transcripts in cultured keratinocytes and in skin by double fluorescent in situ hybridisation (FISH) experiments. We demonstrated that GFP-protein translated from transcripts containing the long variant 3'UTR is mainly observed near the nucleus, whereas GFP-protein translated via the short 3'UTR transcript localises more randomly. Through double colour FISH we showed that it is the 3'UTR that is responsible for the targeting of the two major COL17A1 mRNA transcript to distinct subcellular compartments as the distribution of these transcripts mimics the distribution of the GFP protein. We hypothesise that conserved stretches in the unique insert of the COL17A1 3'UTR are responsible for these mechanisms. The conclusion arising from these experiments is that keratinocytes have the ability to shift type XVII collagen expression, both the level and the site of translation, by differential splicing of the COL17A1 gene. In this way, cells may be able to alter type XVII collagen translation very specifically and such a mechanism may also be active in the shift in type XVII collagen expression observed in wound healing and carcinogenesis. That type XVII collagen is translated at more than one location evokes the question whether the resulting populations of protein have different destinations, and what relation exists with the incorporation of the individual hemidesmosome components into the emerging hemidesmosomal complex. In skin we found by FISH COL17A1 mRNA expression in basal and first suprabasal layers. Visualisation of type XVII collagen by immunofluorescence confirmed that the protein was indeed found in basal and suprabasal keratinocytes. Besides a linear staining parallel to the basement membrane, we observed a granular pattern similar to that observed in our experimental cell studies. These granules are the first observations of the ‘birth’ of the type XVII molecule in skin. Due to the absence of hemidesmosomes in suprabasal layers the question is raised what function type XVII collagen has in the suprabasal layer. In chapter 5 we investigated the COL17A1 mRNA levels in a panel of HEB patients whom all had mutations leading to PTC on both alleles. We also investigated if the lower transcript levels were due to nonsense mediated mRNA decay (NMD) by blocking the protein translation and thus the synthesis of NMD components. COL17A1 mRNA levels in keratinocytes of HEB patient appeared severely decreased, not only compared to normal keratinocytes, but also with other genetic diseases. Furthermore we observed a possible polar effect in NMD, and this is the first time this was demonstrated in a series of patients. The most intriguing observation in this study was that keratinocytes of patients with the mild subtype of nH-HEB, localized atrophic benign Epidermolysis bullosa (LABEB), in which the PTC was removed by exon skipping, still had low COL17A1 mRNA levels. Other mechanisms than NMD must thus be active since NMD is elicited by PTCs. Despite the low mRNA levels these patients had a mild phenotype. We concluded that the best way to predict the phenotype of an HEB patient is to examine the presence of the different epitopes of type XVII collagen. Patients, whom express the full-length molecule at a detectable level in skin, have milder phenotypes than patients with no detectable expression of full-length type XVII collagen. Loss of also the full-length epitopes leads to the more severe HEB subtype generalized atrophic benign epidermolysis bullosa (GABEB) phenotype.

    Common Allergens in Foot Dermatitis attributable to Footwear

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    INTRODUCTION: Contact dermatitis is classified into two groups: irritant contact dermatitis and allergic contact dermatitis. Irritant contact dermatitis is more frequent and occurs in anyone exposed to an irritant for a sufficient duration and concentration. In contrast allergic contact dermatitis is a T cell mediated immunological reaction, occurs only when the skin in previously sensitized person is reexposed to that allergen. The etiology can be related to several factors acting singly or in combination. Contact eczema may also be characterized into endogenous conditions like atopic or exogenous causes such as contact dermatitis. (both allergic and irritant contact dermatitis). Foot dermatitis is one of the common problems seen by the dermatologist. It causes discomfort and embarrasment to the patients. Although the majority of the Indian population used to walk barefoot, the trend has changed with more adopting some protective footwear. As a result increasing numbers of dermatitis attributable to footwear present to the dermatologist. There are 4 major factors which influence footwear dermatitis, namely allergy, atopy, friction, and occlusion. The clinical presentation of foot wear dermatitis has varied presentation from region to region and with time .The prevalence in South India is 11.7% as compared to 3-6% from abroad3,4,5 Leather, rubber & adhesives have been reported to be the most common allergen. Most of the incriminating allergens can be identified by patch testing. Irritant reactions have to be differentiated and usually fade by the second reading. The diagnosis of contact allergens by patch testing gives the clinician a distinct advantage in the subsequent management of the patient & improves the prognosis by avoidance of the possible sources of the allergen. In the market a variety of footwear is available from different manufacturers who do not furnish a list of the constituents. Incorporating the list of constituents of footwear would help sensitized patients to select those without the culprit allergens. AIMS & OBJECTIVES: 1. To identify the common allergens in foot dermatitis attributable to footwear. 2. To prepare handouts with information on the possible household and occupational sources of the incriminating allergens other than those in the Indian Standard Series (ISS). MATERIALS AND METHODS: This study was conducted over the period of 16 months from April 2013 to August 2014 in the department of Dermatology PSGIMSR Coimbatore Tamilnadu. During this period total number of 40 patients with foot dermatitis attending the outpatient departments were included in this study. An informed consent was taken from all the patients. Patients details were recorded in the proforma (age, occupation, duration of illness, site of initial lesion, extent of involvement, type of footwear, seasonal variations, association with atopy). In patients showing extensive scaling/suspecting fungal infections KOH. Skin scraping was carried out in addition to patch testing. In patients with family history or personal history of atopy serum IgE was done. In case of purulent discharge from the lesions pus culture sensitivity was sent to rule out concomitant bacterial infections. Past treatment history (topical/systemic) was also recorded. The Clinical signs and symptoms like itching with oozing, scaling, pustules, erythema, vesicles, purpura, hyperpigmentation, depigmentation, lichenification were recorded. Area of involvement was recorded as symmetrical/ asymmetrical lesions, dorsum of the foot, dorsum of the toe, plantar surface, heel and sparing of instep/flexures. Inclusion criteria: Investigation of patients with eczematous eruptions mainly over the foot. Exclusion criteria: 1. pregnant and lactating mother, 2. patient with exfoliative dermatitis, 3. patients on systemic immunosuppressants and high dose oral steroids. CONCLUSIONS: Foot eczema is one among the many common dermatological disorders that is seen in dermatology outpatient departments. The most common morphological pattern was dry scaly plaque. Patch testing has played an important role in identifying patients with footwear dermatitis as all patch positive (30 out of 40) patients showed sensitivity to one or more of the allergens in the footwear series. Instep involvement, an uncommon presentation in footwear dermatitis, was seen in a single patch test negative patient who was an atopic with raised IgE. The 3 common allergens include nickel, chromate and NN DPG. Although nickel and chromate have remained the commonest allergens in the past, the rubber allergen NN DPG has emerged as a common sensitizer. Earlier reports have detected MBT to be the common allergen in rubber. This could be related to the increasing use of NN Diphenylguanidine in the processing of rubber. Sometimes patch testing with foot wear series may yield negative results; in this situation it would be advisable to include pieces of patients own footwear for testing. Sometimes the specific needs to be released from the footwear prior to testing by sophisticated processes like ultrasonication. HPLC (high pressure liquid chromatography) may isolate the individual components of the particular footwear and patch testing with these may sometimes yield a positive result. This study has enabled the compilation of data related to household and occupational exposure of the allergens in the footwear series in the form of pamphlets for distribution to the patients both in English and Tamil. This would help to educate patients on allergen avoidance for freedom from disease

    Occupational exposure to inorganic nickel.

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    "This report presents the criteria and the recommended standard based thereon which were prepared to meet the need for preventing impairment of health from occupational exposure to inorganic nickel. The criteria document fulfills the responsibility of the Secretary of Health, Education, and Welfare under Section 20(a)(3) of the Occupational Safety and Health Act of 1970 to ". . .develop criteria dealing with toxic materials and harmful physical agents and substances which will describe...exposure levels at which no employee will suffer impaired health or functional capacities or diminished life expectancy as a result of his work " experience. The National Institute for Occupational Safety and Health (NIOSH), after a review of data and consultation with others, formalized a system for the development of criteria upon which standards can be established to protect the health and to provide for the safety of employees exposed to hazardous chemical and physical agents. The criteria and recommended standard should enable management and labor to develop better engineering controls and more healthful work practices and should not be used as a final goal. These criteria for a standard for inorganic nickel are part of a continuing series of criteria developed by NIOSH. The proposed standard applies to the processing, manufacture, and use of inorganic nickel as applicable under the Occupational Safety and Health Act of 1970. The standard was not designed for the population-at-large, and any extrapolation beyond occupational exposures is not warranted. The standard is intended to (1) protect against injury from inorganic nickel, (2) be measurable by techniques that are valid, reproducible, and available to industry and official agencies, and (3) be attainable with existing technology. However, it will only substantially reduce the risk of developing nickel-related cancers and minimize the risk of developing dermatitis. Ingestion and inhalation of, and dermal exposure to, nickel are common, since nickel is present in air, soil, water, food, and household objects. Although nickel is commonly found in the air, it is present in higher concentrations where there is environmental pollution as a result of the burning of fossil fuels or the processing of nickel. The recommended standard for inorganic nickel is based on the conclusion that these substances are carcinogenic. An excess number of deaths from lung cancer and nasal cancer has been observed in nickel refinery workers. After review of the relevant data, it was concluded that a substantial portion of those excess deaths was caused by exposure to airborne nickel compounds. It might be reasoned from the limited animal data that only nickel subsulfide is a carcinogen; or the interpretation might be made, based on some epidemiologic studies. that only one stage of nickel refining presents a risk of cancer. In addition, it might be concluded from limited data on human exposures and environmental concentrations that the safe threshold level of exposure to nickel compounds is greater than the recommended environmental limit. Should sufficient evidence be developed to demonstrate that any of these is a correct interpretation or that some nickel compounds are not carcinogenic, the recommended standard for inorganic nickel will be considered for revision. The available evidence indicates that workers can be adversely affected by skin contact with nickel, particularly when it is in solution. Because of the ubiquity of nickel in the nonoccupational environment, some individuals may develop a sensitivity to nickel regardless of precautions taken in the workplace. The standard cannot protect these individuals from developing recurrent dermatitis when occupationally exposed to inorganic nickel. However, it will greatly reduce the risk of unsensitized workers becoming sensitive to nickel in the course of their employment. Even though there is considerable information about occupational health problems associated with inorganic nickel, several major areas require further research. Epidemiologic studies are needed to determine the risk of developing nickel-related cancers in occupations which have not been adequately studied, eg, welding, plating, and refining nickel oxide ore; inhalation experiments in suitable animal species are needed to supplement these studies. Both animal and human studies are needed to ascertain whether the limited information on reproductive effects has any relevance to human exposure. Animal studies are needed to characterize the acute and chronic toxicities of the many nickel compounds for which insufficient information is available. The health effects of occupational exposure to nickel carbonyl are not discussed in this document, nor have the effects of simultaneous exposure to nickel and cadmium been reviewed herein. The effects ,of nickel carbonyl are discussed in "Special Occupational Hazards Review and Control Recommendations for Nickel Carbonyl" and the effects of cadmium are discussed in the "Criteria for a Recommended Standard--Occupational Exposure to Cadmium." Two other reviews of nickel provide additional information on its toxicity. The International Agency for Research on Cancer (IARC) prepared monographs on nickel and nickel compounds in 1973 [1] and 1976 [2], in which evidence for the carcinogenicity of all nickel compounds was considered. The Committee on Medical and Biologic Effects of Environmental Pollutants of the National Academy of Sciences published in 1975 a comprehensive review (NAS-NRC report) [3] of nickel which also included nickel carbonyl." - NIOSHTIC-2CurrentPrevention and ControlEnvironmental Healt

    Paediatric atopic dermatitis and treatment adherence: Exploring factors contributing to topical corticosteroid phobia as a contributor to poor treatment adherence

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    Atopic dermatitis (AD), also known as eczema or atopic eczema, is the most common chronic inflammatory dermatosis (skin condition) affecting paediatric patients in the western world. There continues to be a rapid rise in incidence of this condition worldwide with a doubling of prevalence in children under age five years in the past 30 years. It also remains one of the most treatable with correct management. Topical corticosteroids (TCS), which have a topical anti-inflammatory action, remain central to this management. However, parent and patient poor adherence to prescribed treatment plans often leads to less effective control of their AD. A review of the literature demonstrated that one of the commonly cited contributing factors to treatment non-adherence in paediatric AD is a fear or anxiety regarding the use of TCS, a condition termed ‘TCS phobia’ (Chapter 2). Although moderate to severe atopic dermatitis is disabling and highly disruptive for patients and their families, TCS phobia is a significant barrier to effective treatment. This thesis presents a body of work that aims to identify the sources of information or misinformation about the safety and efficacy of TCS, as well as assessing the impact of this information on parents’ and patients’ perception on the long term use of TCS to manage their AD. Previous research has identified that parents of children with AD highlight the role of family and friends, the Internet, pharmacists and general practitioners as key sources of information that contribute to fear and anxiety towards using TCS to manage AD. This can create conflicting information leading to confusion and ultimately poor or non-adherence to prescribed treatment plans. This is especially the case when the conflicting information comes from different members of the multidisciplinary treatment team. A multidisciplinary treatment team incorporates health care professionals from different disciplines who provide a specific service and associated health information to the patients, and in the setting of AD in Australia includes general practitioners, dermatologists, and pharmacists. Therefore, it is important to investigate the knowledge and attitudes of these health professionals about the safety and efficacy of TCS that forms the advice provided to parents and patients in paediatric AD. This is because treatment adherence is directly related to risk/benefit of treating a condition as well as the perception of disease severity. If the perceived risks associated with treatment, such as TCS in paediatric AD, out way the perceived benefits or perceived disease severity, then there is significant risk of treatment non-adherence. A consensus statement and systematic review of the adverse effects arising from the use of TCS in children with atopic dermatitis was performed (Chapter 3). The aim of the consensus meeting was to identify the potential and perceived adverse effects and systematically review the literature for each. Dermatologists play a key role as clinical educators around the use, safety and efficacy of TCS. A cross-sectional survey of all Australian dermatologists was performed to assess their attitudes towards the use and safety of TCS in paediatric AD (Chapter 4). Close to half (44%) of the 455 dermatologists in Australia completed the survey (n=198). Nearly all responders prescribed potent or super-potent TCS in the management of paediatric AD. The most common side-effect cited by over two-thirds of the respondents was peri-orificial dermatitis with only a minority (6%) citing cutaneous atrophy. Most dermatologists stated that pharmacists were the most common source of misinformation leading to TCS phobia. Of the respondents, 75% strongly agreed that TCS do not cause skin atrophy when used appropriately and under clinical supervision. Furthermore, 77% agreed or strongly agreed that the words ‘use sparingly’ should be removed from pharmacist labels on TCS prescriptions. This study indicates that dermatologists comfortably manage paediatric AD with potent or super-potent TCS and believe that TCS do not cause skin atrophy in paediatric AD. This is in keeping with the current up to date literature on the safety and efficacy of TCS in this setting and represents the baseline against which other healthcare professionals should refer to when providing advice about the treatment of paediatric AD. Parents and dermatologists commonly cite conflicting information provided by pharmacists on the safety and efficacy of TCS in paediatric AD as contributing to TCS phobia and serving as a major impediment to treatment adherence. Consequently, a study was conducted to assess pharmacists’ beliefs and information on the safety of TCS in paediatric AD treatment (Chapter 5). A cross-sectional survey to assess attitudes and knowledge on the use of TCS in paediatric AD was completed by Australian pharmacists (n=292) who attended a continuing professional development conference. The mean response rate for each question was 86% of the 292 surveyed. Of the responders, 64% recognised that treatment non-adherence was a major reason for treatment failure in paediatric AD. Only a quarter (27%) of the pharmacists would instruct parents/patients to apply TCS until the eczema is clear. Over half (54%) of the responders indicated they would instruct patients to use TCS sparingly. Nearly half (46%) of the responders believed that cutaneous atrophy was the commonest side-effect from use and over half (56%) indicated that side-effects would occur, even if used appropriately. This study demonstrated the existence of significant knowledge gaps about the use and safety of TCS in paediatric AD in Australian pharmacists. Furthermore, their advice to patients potentially contributes to poor treatment adherence because of this misinformation which can contribute to the fear and anxiety around using TCS. Parents cite general practitioners and pharmacists as a source of information that contributes to TCS phobia which can in turn affect treatment adherence. The previous study demonstrated the knowledge gap amongst Australian pharmacists. Therefore, a study was conducted to assess general practitioners’ beliefs and information on the safety of TCS in paediatric AD treatment (Chapter 6). A cross-sectional survey was performed on Australian general practitioners (n=257) participating in continuing professional development programs. Over a third (40.7%) instruct parents to apply TCS for two weeks or less. Nearly half (47.7%) instruct parents to apply TCS sparingly or with the smallest amount possible. Furthermore, nearly a third (30.2%) reported skin atrophy as the most common TCS side effect. Therefore, this study demonstrates that advice from their general practitioner may carry unintentional risk messages contributing to a fear and anxiety about using TCS and ultimately can lead to treatment non-adherence. The studies in chapters 4 to 6 demonstrate the potential for conflicting advice from healthcare professionals in a patient’s multi-disciplinary treatment team. However, an investigation was needed to assess the actual impact of the advice from healthcare professionals on patients and parents’ perception of the safety and efficacy of TCS in AD. Furthermore, it is important to assess the advice provided by pharmacists and general practitioners as related to and reported by patients and parents of patients using TCS on a long-term basis for AD (Chapter 7). A multi-centre cross-sectional survey was performed on a total of 123 adult patients and 78 parents (n=201). Of the total respondents, three quarters (76.6%) reported consistently (“Often” or “Always”) receiving one or more message(s) regarding TCS “risk” from a general practitioner (GP) and/ or pharmacist (n=192). Respondents reported being told to “try natural or complementary and alternative therapies before resorting to the use of TCS” significantly more often by pharmacists than by GPs (p=0.039). This study demonstrates that high rates of consistently delivered messages about TCS “risk” from GPs and pharmacists do affect patient/parent understanding about TCS safety. This “risk” messaging can contribute to fear and anxiety about using TCS and may lead to treatment non-adherence. Chapters 4 to 7 provide evidence that conflicting information from different healthcare professionals in the multi-disciplinary treatment team leads to the delivery of negative risk messaging to parents and patients with AD. This contributes to TCS phobia and can lead to poor treatment outcomes due to non-adherence. However, non-health professional such as parents, family and friends, and the Internet are others sources of knowledge about AD and its treatment. This was also investigated. The perception of TCS safety in the management of AD is influenced by family/friends of the patient or parent of children with AD. This means these are another potential source of misinformation on TCS which can negatively impact perceptions of TCS safety. A multicentre cross-sectional survey of patients (aged >18years old) and parents of patients (aged <18years old) with a history of a chronic inflammatory dermatosis was performed to assess information they receive from family/friends and the Internet about TCS use (Chapter 8). A total of 123 patients and 78 parents completed the survey (n=201). Parents/Patients reported that they were more likely to be informed by the Internet “[having] my [child’s] skin condition means that [I/he/she] will need to use topical corticosteroids” (p <0.001) and that “inflamed skin conditions will improve with the topical corticosteroids” (p = 0.007). On the other hand, family/friends were more likely to recommend parents/patients “try nonprescription creams/ointments before resorting to the use of prescription topical corticosteroids” (p = 0.014). This study highlights that high rates of messages about TCS ‘risk’ from family/friends and the Internet may affect patient/parent understanding about TCS safety. Furthermore, this may contribute to treatment non-adherence. Chapters 3 to 8 have demonstrated external influence that can deliver negative biases that contribute to fear and anxiety about TCS use and ultimately lead to non-adherence in the treatment of paediatric AD. However, a parent’s perception of disease severity, representing an ‘internal’ influence bias, can contribute to whether or not they treat their child’s AD. If a parent assesses their child’s AD to be less severe than it actually is, they are much more likely to undertreat and more likely to be non-adherent with the prescribed management plan. A study was performed comparing parent reported disease severity compared to physician assessed disease severity (Chapter 9). A prospective cohort study recruited fifty paediatric patients and their caregivers from an outpatient dermatology clinic. Two clinicians completed ratings on the Eczema Area and Severity Index (EASI) tool and caregivers completed ratings on the Self-Administered EASI (SA-EASI) and Dermatology Quality of Life Index (DLQI) tools. EASI scores between clinicians were compared and there was good inter-clinician reliability (p = 0.351 ). There was a strong, positive statistically significant correlation between EASI and SA-EASI (r = 0.865, p= <0.01). The EASI score mean was statistically significantly higher than the SA-EASI mean (p = <0.001) for a given patient. This study looked to establish a discrepancy between clinician and caregiver perception of atopic dermatitis severity. It showed that caregivers significantly underestimate the severity of their child’s atopic dermatitis. This provides the clinician with a greater understanding into poor treatment compliance commonly observed in clinical practice and highlights a need to provide parents with a greater understanding of their child’s disease. By establishing the severity of the eczema to the caregiver, the clinician is empowered to provide education about the expectations surrounding treatment, allowing greater insight into noncompliance. This can facilitate an approach to the fears and misconceptions that caregivers may have. Overall, the studies in this thesis contribute to an awareness of the sources of negative risk or misinformation about the safety and efficacy of TCS in the setting of paediatric AD. Furthermore, it demonstrates the direct impact of this information on patients and parents. These findings provide the basis for education programs to help educate the healthcare professional members of the multi-disciplinary treatment team. It is through consistent positive messaging from these healthcare professionals that patients and parents will be better equipped and supported to combat the negative risk messaging from non-healthcare professional sources such as family, friends and the Internet. Ultimately, this has the capacity to positively impact treatment adherence and outcomes for both the patient with AD and their entire family unit

    ADC 11(4)

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    Effect of glucocorticoids on the anti-cancer activity of chemotherapeutic agents in oral squamous cell carcinoma (OSCC) cells

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    Glucocorticoid hormones, such as hydrocortisone, are produced in the adrenal cortex and exert pleiotropic effects in peripheral tissues by regulating the expression of up to 10% of genes that are associated with broad spectrum of metabolic processes. In addition to the adrenal‐derived steroids, it is now recognised that peripheral tissues, such as the epidermis, may also act as steroidogenic organs. Recently has been shown that oral keratinocytes regulate the local concentration of active steroids as well as synthesize hydrocortisone de novo following stimulation with adrenocorticotropin hormone (ACTH). Synthetic corticosteroids are routinely administered during the treatment of several diseases, including pre-malignant and malignant conditions, particularly to alleviate side effects of chemotherapy. However, recent evidence suggests that corticosteroids may have tumour-promoting effects, particularly in epithelial neoplasms. The aim of this thesis was to assess the influence of the recently characterized tumor-associated glucocorticoid (GC) system on both cell proliferation and migration, and on the efficacy of chemotherapeutic agents in the treatment of oral squamous cell carcinoma (OSCC). The chemotherapeutic agents used in the present study were 5-fluorouracil (5-FU), an established drug for OSCC treatment and doxorubicin (DOXO), a potential candidate for the treatment of OSCC.Five different human malignant oral keratinocyte cell lines were selected: H314 / H357 / H400 / BICR16 / BICR56. The cell lines were treated with 5ÎŒM DOXO, 5 ÎŒg/mL 5-FU, 0,5 ÎŒg/mL Hydrocortisone (HC), 10 nM Adrenocorticotropic hormone (ACTH), 10 ÎŒM 5-pregnen-3-beta-ol- 20-one-16-alfa-carbonitrile (PCN) (a Glucocorticoid Receptor antagonist), 25 ÎŒM Fasentin (a novel inhibitor of glucose uptake that interacts with GLUT1), and 10 ÎŒM WZB-117 (an inhibitor of basal glucose transport; specific GLUT1 inhibitor). The cell lines were tested with both high (4.5 g/L) and low (1g/L) glucose mediums. Moreover in vitro wound healing assays were performed using the H357 human carcinoma cell line to assess cell migration. The literature review performed showed, in contrast to previous thought, how increased levels of autocrine, paracrine, and exogenous cortisol are important to tumor progression, as well as the expression of enzymes regulating the levels of tumor-derived cortisol. In the experimental part of the project we have clearly demonstrated, for the first time, the importance of cortisol on oral cancer cells ability to survive, migrate, and interestingly combat the effectiveness of chemotherapeutic agents. This effect would appear to be glucose dependent. Finally, Doxorubicin shows promise for the treatment of oral cancer. In conclusion, glucocorticoids promote oral carcinoma cell proliferation and migration implying an increase in cell invasiveness. This has important implications on the pharmacological use of glucocorticoids, as topical and systemic preparations, for the treatment of a wide variety of oral conditions and in combination with chemotherapy
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