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Thesis--Københavns Tandlaegehøjskole. / At head of title: From the Department of Oral Diagnosis, Royal Dental College, Copenhagen, Denmark. Includes bibliographical references (p. 198-217) and index.

Thesis--Københavns Tandlaegehøjskole. / At head of title: From the Department of Oral Diagnosis, Royal Dental College, Copenhagen, Denmark. Includes bibliographical references (p. 198-217) and index.

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.

Periocular malignancy represents an increasing burden and currently requires disfiguring surgery in an attempt to cure patients. Basal cell carcinoma (BCC) is the commonest cancer worldwide and morphoeic BCC (mBCC) is an aggressive subtype. Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition that often requires blinding surgery to prevent mortality, especially in the pagetoid subtype. MBCC has a high risk of local recurrence compared to the more indolent nodular subtype reflected by a different set of driver genes including FLNB and HECTD4. Surrounding mBCC stroma is abnormal, containing mutations in EPHA3 and GLI3. Four common dysregulated pathways detected using both whole exome and RNA sequencing for mBCC were; 'hedgehog (Hh) signalling pathway', 'BCC', 'Natural killer cell mediated cytotoxicity' and 'Fc Epsilon RI signalling pathway'. Hh mutational profile for nodular BCC was not reflected in the RNA and protein expression. In contrast, Hh overexpression is seen in the tumour and stroma of morphoeic tissue with the latter potentially being partly responsible for its aggressive nature and risk of recurrence that may warrant removal to prevent recurrence. SGC has a low overall mutational burden, no UV signature and defective mismatch repair signature. Driver genes included TP53, RB1 and the dynein family is a novel driver possibly involved in chromatid segregation as marked chromosomal instability was demonstrated on copy number analysis. Correlation of whole exome and RNA sequencing data demonstrated upregulated 'cell cycle', 'ubiquitin mediated proteolysis' and 'wnt signalling'. Subtype analysis of pagetoid and nodular SGC revealed the histone gene cluster family as important to both. Oncomir hsa-miR-21 was overexpressed in both and loss of hsa-miR-199a occurs in pagetoid. Increased protein expression of HIST1H2BD was seen in both subtypes as was Hh expression. These novel SGC findings support a chromosomally unstable cancer with the ability to invade extracellular matrix.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

The skin of mammals contains sebaceous glands (SGs) which are attached to the hair follicle (HF), and their best known function is to release sebum onto the skin surface via the HF canal. It has long been known that these two entities of the pilosebaceous unit are interconnected, but the extent to which the two ‘control’ one another was less clear. The current project set out to investigate the impact of the HF cycle on the SG. It was found that in a depilation- induced HF cycle, SG morphology altered drastically, with an increase in SG area (P<0.001), number of sebocytes (P<0.001), and individual sebocyte area (P<0.001) occurring after HF depilation. In SGs attached to a spontaneously cycling HF, none of the above was observed, indicating that spontaneous HF cycling does not affect SG morphology, whereas anagen induction by depilation is associated with altered SG morphology, likely as a result of HF trauma. Diacylglycerol acyltransferase 1 (DGAT1) is an enzyme known for its role in the production of various lipids. It was previously shown that DGAT1 knockout in mice caused SG atrophy, which was thought to be caused by an increased level of retinoic acid within the skin, which in turn caused atrophy of the gland. The current project aimed to further investigate the role of the DGAT1 enzyme in murine skin. Based on the results of the previous experiments, HF and SG morphology of spontaneously-cycling DGAT1 knockout mice were assessed. It was found that DGAT1 knockout caused delayed HF morphogenesis, altered HF cycling, increased HF length (P<0.001), more acute HF growth angle (P<0.001), increased SG apoptosis(P<0.001), decreased SG lipid content (P<0.001) and dysfunctional lipid droplet formation. The impact of DGAT1 knockout on HF morphology and cycling suggests that DGAT1 knockout causes alterations in the WNT/ beta-catenin signalling pathway, as these processes are highly controlled by this signalling pathway. In order to investigate the role of the DGAT1 enzyme in human HFs, and to investigate the hypothesis that DGAT1 may directly interact with the WNT/ beta-catenin signalling pathway, HFs were organ-cultured in the presence of a pharmacological DGAT1 inhibitor (AZD7687). It was found, at the transcriptional level, that one of the major canonical pathways affected by DGAT1 inhibition in human HFs was the WNT/ beta-catenin signalling pathway. DGAT1 inhibition was found to cause suppression of the WNT/beta-catenin signalling pathway via a down-regulation of a number of WNT/beta-catenin related genes. Overall, these results show that SG morphology is largely dependent upon HF homeostasis, and suggest that the DGAT1 enzyme may possess a previously unknown role, directly impacting the WNT/ beta-catenin signalling pathway.

No / In mammals, hairs fulfil a number of important functions including thermoregulation, collecting sensory information, protection against environmental stressors, social communication and mimicry [1]. Hairs are produced by the pilosebaceous unit that consists of the hair follicle and associated structures such as sebaceous gland, perifollicular nerve fibres and arrector pili muscle [1, 2]. In humans, hair follicles are distributed throughout the body with exception of the soles, palm and part of the external genitalia and produce two major hair types (terminal and vellus hairs) that show distinct morphology and distribution patterns [3].

This review presents several aspects of the innovative concept of sebaceous immunobiology, which summarizes the numerous activities of the sebaceous gland including its classical physiological and pathophysiological tasks, namely sebum production and the development of seborrhea and acne. Sebaceous lipids, which represent 90% of the skin surface lipids in adolescents and adults, are markedly involved in the skin barrier function and perifollicular and dermal innate immune processes, leading to inflammatory skin diseases. Innovative experimental techniques using stem cell and sebocyte models have clarified the roles of distinct stem cells in sebaceous gland physiology and sebocyte function control mechanisms. The sebaceous gland represents an integral part of the pilosebaceous unit and its status is connected to hair follicle morphogenesis. Interestingly, professional inflammatory cells contribute to sebocyte differentiation and homeostasis, whereas the regulation of sebaceous gland function by immune cells is antigen-independent. Inflammation is involved in the very earliest differentiation changes of the pilosebaceous unit in acne. Sebocytes behave as potent immune regulators, integrating into the innate immune responses of the skin. Expressing inflammatory mediators, sebocytes also contribute to the polarization of cutaneous T cells towards the Th17 phenotype. In addition, the immune response of the perifollicular infiltrate depends on factors produced by the sebaceous glands, mostly sebaceous lipids. Human sebocytes in vitro express functional pattern recognition receptors, which are likely to interact with bacteria in acne pathogenesis. Sex steroids, peroxisome proliferator-activated receptor ligands, neuropeptides, endocannabinoids and a selective apoptotic process contribute to a complex regulation of sebocyte-induced immunological reaction in numerous acquired and congenital skin diseases, including hair diseases and atopic dermatitis.

Thesis (M.Sc. (Pharmacy)) - Rhodes University, 2008