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No / The nervous system communicates with peripheral tissues through nerve fibres and the systemic release of hypothalamic and pituitary neurohormones. Communication between the nervous system and the largest human organ, skin, has traditionally received little attention. In particular, the neuro-regulation of sebaceous glands (SGs), a major skin appendage, is rarely considered. Yet, it is clear that the SG is under stringent pituitary control, and forms a fascinating, clinically relevant peripheral target organ in which to study the neuroendocrine and neural regulation of epithelia. Sebum, the major secretory product of the SG, is composed of a complex mixture of lipids resulting from the holocrine secretion of specialised epithelial cells (sebocytes). It is indicative of a role of the neuroendocrine system in SG function that excess circulating levels of growth hormone, thyroxine or prolactin result in increased sebum production (seborrhoea). Conversely, growth hormone deficiency, hypothyroidism, and adrenal insufficiency result in reduced sebum production and dry skin. Furthermore, the androgen sensitivity of SGs appears to be under neuroendocrine control, as hypophysectomy (removal of the pituitary) renders SGs largely insensitive to stimulation by testosterone, which is crucial for maintaining SG homeostasis. However, several neurohormones, such as adrenocorticotropic hormone and α-melanocyte-stimulating hormone, can stimulate sebum production independently of either the testes or the adrenal glands, further underscoring the importance of neuroendocrine control in SG biology. Moreover, sebocytes synthesise several neurohormones and express their receptors, suggestive of the presence of neuro-autocrine mechanisms of sebocyte modulation. Aside from the neuroendocrine system, it is conceivable that secretion of neuropeptides and neurotransmitters from cutaneous nerve endings may also act on sebocytes or their progenitors, given that the skin is richly innervated. However, to date, the neural controls of SG development and function remain poorly investigated and incompletely understood. Botulinum toxin-mediated or facial paresis-associated reduction of human sebum secretion suggests that cutaneous nerve-derived substances modulate lipid and inflammatory cytokine synthesis by sebocytes, possibly implicating the nervous system in acne pathogenesis. Additionally, evidence suggests that cutaneous denervation in mice alters the expression of key regulators of SG homeostasis. In this review, we examine the current evidence regarding neuroendocrine and neurobiological regulation of human SG function in physiology and pathology. We further call attention to this line of research as an instructive model for probing and therapeutically manipulating the mechanistic links between the nervous system and mammalian skin. / Agency for Science, Technology and Research. Grant Numbers: A*STAR Research Attachment Programme (ARAP), IAF‐PP H17/01/a0/004, IAF‐PP H17/01/a0/008; NIHR Manchester Biomedical Research Centre, Inflammatory Hair Disease Programme; University of Manchester; University of Miami

Erythromycin (ERY) is a macrolide antibiotic which is used in the treatment of acne vulgaris.Acne is a common skin condition that occurs when the sebaceous glands and hair shafts become infected by the bacteria Propionibacterium acnes. Acne is a chronic condition that may last for years and the severity of the effects of the disease on patients is often undermined especially in third world countries where more emphasis is placed on other more life-threatening diseases. It may cause considerable physical and emotional distress to sufferers along with the possibility of permanent scarring. Although use of topical ERY formulations is not the first line of treatment it has proven to be effective in treating inflammation of skin and skin structures cause by the responsible bacteria. To-date there are a variety of vehicles which are used in preparing topical ERY formulations namely ointment and gel bases, alcoholic solutions and pledgets. All the gel formulations on the market contain hydroxypropyl cellulose, alcohol and water along with the active ingredient(s). However, some gel formulations contain propylene glycol in addition to these excipients an example being Emgel®. Propylene glycol has been shown to affect the penetration of topically applied drugs through the skin suggesting that it would be highly likely that those formulations which contain propylene glycol may release more ERY into the skin following application. With this in mind, two ERY gel formulations were produced which contained different percentages of propylene glycol. According to the FDA guidelines, pharmacokinetic measurements in blood, plasma and/or urine of topical dermatological drug products are not feasible to document bioequivalence since the active ingredient(s) in topical formulations is/are not intended to be absorbed into the systemic circulation and in addition, concentrations in extracutaneous biological tissues would generally not be measurable. This limits determination of bioavailability and assessment of bioequivalence of such products to pharmacodynamic measurements, clinical trials and dermatopharmacokinetic (DPK) measurements such as tape stripping (TS) and microdialysis (MD).TS is a sampling technique which involves sequential removal of layers of the stratum corneum using strips of adhesive tape. This technique has found increasing use in DPK studies for investigation of drug kinetics in the skin following the application of a topical formulation. The technique has also been used as a diagnostic tool in assessing the quality of the stratum corneum in diseased skin. In the current research study, the tape stripping technique was used to investigate the pharmaceutical/biological availability of topical gel formulations containing ERY. MD is another DPK sampling technique which has been used to determine the amount of a topically applied drug that penetrates through the stratum corneum to reach deeper tissues of the skin. The in vivo sampling technique involves the insertion of microdialysis probes beneath the skin surface in the dermal tissue and allows for real-time sampling of the analyte at its target site. Recently in vitro MD has also been successfully used to assess the pharmaceutical availability of a topical corticosteroid, mometesone furoate, from topical formulations. Based on this work, microdialysis was used to determine the pharmaceutical availability of ERY from gel formulations which were developed for use in this research. The results of the pharmaceutical availability of ERY from in vivo tape stripping studies and the in vitro microdialysis studies were compared to establish correlation between the data. Pharmaceutical equivalence and bioequivalence data obtained from the respective studies on the gel formulations were investigated by statistical analysis of the data generated from both the in vitro and in vivo experiments. In summary the objectives of this research were: 1. To develop and validate a high performance liquid chromatography method suitable to analyse ERY concentrations obtained from in vitro microdialysis studies and in vivo tape stripping studies. 2. To prepare two different ERY gel formulations with different percentage content of propylene glycol. 3. To determine the pharmaceutical availability of ERY from two different gel formulations using in vitro microdialysis. 4. To develop and validate a tape stripping technique which could be used to determine percutaneous penetration and bioequivalence of the gel formulations. 5. To compare in vitro microdialysis and in vivo tape stripping data and attempt to establish a correlation between the two different approaches.

Introdução: Acne é uma dermatose que apresenta o padrão do sebo alterado, tanto quali, quanto quantitativamente. Objetivos: Estudar as possíveis alterações quali e quantitativas dos ácidos graxos encontrados no sebo de portadores de acne vulgar graus II ou III mediante ao uso diário de limeciclina e/ou suplemento oral a base de ácidos linoleico, gamalinolênico e oleico. Métodos: Quarenta e cinco sujeitos de pesquisa masculinos, de 12 a 40 anos de idade, portadores de acne vulgar graus II ou III, submeteram-se a 90 dias de uso de: Grupo A, 300mg/dia de limeciclina; Grupo B, 540mg de ácidos gamalinolênico, 1.200mg linoleico e 510mg oleico/dia; Grupo C: Grupos A+B. A cada 30 dias, eles tinham amostra de sebo da fronte coletada para análise cromatográfica dos ácidos graxos nele presentes. Resultados: Quarenta sujeitos de pesquisa (88,9%) concluíram o estudo, os quais ingeriram todas as doses dos produtos, sem apresentarem eventos adversos em qualquer dos Grupos. O número de comedões, pústulas e cistos reduziu com o tempo (p<0,001, para todos), nos três Grupos. Com relação ao número total de lesões, houve uma maior quantidade de lesões em pacientes do Grupo B, quando comparados aos do Grupo A (p=0,033) e aos do Grupo C (p=0,030). Sete ácidos graxos apresentaram mudanças de seu padrão durante o estudo. De um modo geral, as mudanças que se tornaram mais evidentes foram: 1) a concentração de esqualeno no SB não reduziu em qualquer Grupo de estudo; 2) C12:0, C14:0 e C16:1 tiveram suas respectivas concentrações aumentadas nos três Grupos com o tempo de terapêuticas; 3) há indicativo de aumento de C18:1n9c+C18:1n9t na associação das duas classes terapêuticas estudadas; 4) limeciclina e/ou ingestão de ácido linoleico não aumentaram a participação do ácido linoleico no sebo; 5) ácido -linolênico teve sua concentração aumentada e, depois diminuída com o uso de LM e/ou com sua própria suplementação oral. Conclusões: A administração diária de limeciclina e/ou ácidos gamalinolênico, linoleico e oleico pode alterar o comportamento de alguns dos ácidos graxos presentes no sebo de pacientes portadores de acne vulgar graus II ou III. Os ácidos gamalinolênico, linoleico e oleico, se no uso sistêmico, não são considerados agentes terapêuticos na abordagem da acne; mais estudos precisam ser realizados a fim de se inferir a existência de possível benefício clínico de seu uso isolado e/ou associado na abordagem desta dermatose / Introduction: Acne is a dermatosis that presents an altered sebum pattern, quantitatively and qualitatively. Objectives: To study the possible quantitative and qualitative changes of fatty acids found in the sebum of patients with acne vulgaris grade II or III, through the daily use of lymecycline and/or oral supplementation based on linoleic, gamma-linolenic, and oleic acids. Methods: Fortyfive male research subjects, ages 12 to 40, presenting acne vulgaris grade II or III, were submitted to a 90-day use of: Group 1, 300mg of lymecycline per day; Group 2, 540mg of gamma-linolenic acid, 1,200mg of linoleic acid, and e 510mg of oleic acid per day; Group 3: Groups A+B. Every 30 days, a sample of the sebum of their forehead was collected for chromatographic analysis of the fatty acids contained therein. Results: Forty research subjects (88.9%) concluded the study. They ingested all dosages of the products, without presenting side effects in any of the Groups. The number of comedones, pustules, and cysts reduced with time (p<0.001, for all), in all the 3 Groups. With respect to the total number of lesions, Group B´s patients presented a larger quantity of lesions, as compared to those of Group A (p=0.033) and Group C (p=0.030). Seven fatty acids presented pattern changes during the study. In general, the changes that became more evident were: 1) the squalene concentration in the sebum did not diminish in any Group under study; 2) C12:0, C14:0, and C16:1 had their respective concentrations increased in the 3 Groups over the time of the treatments; 3) there is an indication for increasing of C18:1n9t+C18:1n9c when both of therapies are associated; 4) lymecycline and/or the ingestion of linoleic acid did not increase the participation of linoleic acid in the sebum; and 5) gama-linolenic acid had its concentration increased during the first 60-day and diminished during the last 30-day therapies period using lymecycline and/or with its own oral supplementation. Conclusions: The daily administration of lymecycline and/or gamma-linolenic, linoleic, and oleic acids may alter the behavior of some fatty acids present in the sebum of patients with acne vulgaris grade II or III. Gamma-linolenic, linoleic, and oleic acids, under systemic use, are not considered therapeutic agents in the treatment of acne; more studies need to be carried out in order to infer the existence of a possible clinical benefit of their isolated use and/or association in the treatment of this dermatosis

This doctoral thesis describes unusual skin and soft-tissue tumors, which were the basis of the postgraduate study of Ladislav Hadravský, MD at Medical faculty in Pilsen of Charles University in Prague during 2013 - 2016. It contains documented cases of skin and soft-tissue tumors related to hereditary syndromes, unusual morphology, rare biological behavior, minor causal association with the respective disease, or different phenotypes. These cases were published in journals with the impact factor and in peer-reviewed journals. Regarding skin tumors, the study focused on sebaceous tumors of the skin, which may occur within Muir-Torre syndrome. In the retrospective study of sebaceous skin tumors, two unusual cases were found: the case of aggressive extraocular sebaceous carcinoma on the scalp in a patient with Muir-Torre syndrome and the case of multiple sebaceous skin tumors in a patient with MUTYH-associated polyposis of the colon mimicking Muir-Torre syndrome. As far as soft-tissue tumors are concerned, the study aimed at the morphological comparison of cases of myxoinflammatory fibroblastic sarcoma and pleomorhic hyalinizing angiectatic tumor.

Introdução: Acne é uma dermatose que apresenta o padrão do sebo alterado, tanto quali, quanto quantitativamente. Objetivos: Estudar as possíveis alterações quali e quantitativas dos ácidos graxos encontrados no sebo de portadores de acne vulgar graus II ou III mediante ao uso diário de limeciclina e/ou suplemento oral a base de ácidos linoleico, gamalinolênico e oleico. Métodos: Quarenta e cinco sujeitos de pesquisa masculinos, de 12 a 40 anos de idade, portadores de acne vulgar graus II ou III, submeteram-se a 90 dias de uso de: Grupo A, 300mg/dia de limeciclina; Grupo B, 540mg de ácidos gamalinolênico, 1.200mg linoleico e 510mg oleico/dia; Grupo C: Grupos A+B. A cada 30 dias, eles tinham amostra de sebo da fronte coletada para análise cromatográfica dos ácidos graxos nele presentes. Resultados: Quarenta sujeitos de pesquisa (88,9%) concluíram o estudo, os quais ingeriram todas as doses dos produtos, sem apresentarem eventos adversos em qualquer dos Grupos. O número de comedões, pústulas e cistos reduziu com o tempo (p<0,001, para todos), nos três Grupos. Com relação ao número total de lesões, houve uma maior quantidade de lesões em pacientes do Grupo B, quando comparados aos do Grupo A (p=0,033) e aos do Grupo C (p=0,030). Sete ácidos graxos apresentaram mudanças de seu padrão durante o estudo. De um modo geral, as mudanças que se tornaram mais evidentes foram: 1) a concentração de esqualeno no SB não reduziu em qualquer Grupo de estudo; 2) C12:0, C14:0 e C16:1 tiveram suas respectivas concentrações aumentadas nos três Grupos com o tempo de terapêuticas; 3) há indicativo de aumento de C18:1n9c+C18:1n9t na associação das duas classes terapêuticas estudadas; 4) limeciclina e/ou ingestão de ácido linoleico não aumentaram a participação do ácido linoleico no sebo; 5) ácido -linolênico teve sua concentração aumentada e, depois diminuída com o uso de LM e/ou com sua própria suplementação oral. Conclusões: A administração diária de limeciclina e/ou ácidos gamalinolênico, linoleico e oleico pode alterar o comportamento de alguns dos ácidos graxos presentes no sebo de pacientes portadores de acne vulgar graus II ou III. Os ácidos gamalinolênico, linoleico e oleico, se no uso sistêmico, não são considerados agentes terapêuticos na abordagem da acne; mais estudos precisam ser realizados a fim de se inferir a existência de possível benefício clínico de seu uso isolado e/ou associado na abordagem desta dermatose / Introduction: Acne is a dermatosis that presents an altered sebum pattern, quantitatively and qualitatively. Objectives: To study the possible quantitative and qualitative changes of fatty acids found in the sebum of patients with acne vulgaris grade II or III, through the daily use of lymecycline and/or oral supplementation based on linoleic, gamma-linolenic, and oleic acids. Methods: Fortyfive male research subjects, ages 12 to 40, presenting acne vulgaris grade II or III, were submitted to a 90-day use of: Group 1, 300mg of lymecycline per day; Group 2, 540mg of gamma-linolenic acid, 1,200mg of linoleic acid, and e 510mg of oleic acid per day; Group 3: Groups A+B. Every 30 days, a sample of the sebum of their forehead was collected for chromatographic analysis of the fatty acids contained therein. Results: Forty research subjects (88.9%) concluded the study. They ingested all dosages of the products, without presenting side effects in any of the Groups. The number of comedones, pustules, and cysts reduced with time (p<0.001, for all), in all the 3 Groups. With respect to the total number of lesions, Group B´s patients presented a larger quantity of lesions, as compared to those of Group A (p=0.033) and Group C (p=0.030). Seven fatty acids presented pattern changes during the study. In general, the changes that became more evident were: 1) the squalene concentration in the sebum did not diminish in any Group under study; 2) C12:0, C14:0, and C16:1 had their respective concentrations increased in the 3 Groups over the time of the treatments; 3) there is an indication for increasing of C18:1n9t+C18:1n9c when both of therapies are associated; 4) lymecycline and/or the ingestion of linoleic acid did not increase the participation of linoleic acid in the sebum; and 5) gama-linolenic acid had its concentration increased during the first 60-day and diminished during the last 30-day therapies period using lymecycline and/or with its own oral supplementation. Conclusions: The daily administration of lymecycline and/or gamma-linolenic, linoleic, and oleic acids may alter the behavior of some fatty acids present in the sebum of patients with acne vulgaris grade II or III. Gamma-linolenic, linoleic, and oleic acids, under systemic use, are not considered therapeutic agents in the treatment of acne; more studies need to be carried out in order to infer the existence of a possible clinical benefit of their isolated use and/or association in the treatment of this dermatosis

This doctoral thesis describes unusual skin and soft-tissue tumors, which were the basis of the postgraduate study of Ladislav Hadravský, MD at Medical faculty in Pilsen of Charles University in Prague during 2013 - 2016. It contains documented cases of skin and soft-tissue tumors related to hereditary syndromes, unusual morphology, rare biological behavior, minor causal association with the respective disease, or different phenotypes. These cases were published in journals with the impact factor and in peer-reviewed journals. Regarding skin tumors, the study focused on sebaceous tumors of the skin, which may occur within Muir-Torre syndrome. In the retrospective study of sebaceous skin tumors, two unusual cases were found: the case of aggressive extraocular sebaceous carcinoma on the scalp in a patient with Muir-Torre syndrome and the case of multiple sebaceous skin tumors in a patient with MUTYH-associated polyposis of the colon mimicking Muir-Torre syndrome. As far as soft-tissue tumors are concerned, the study aimed at the morphological comparison of cases of myxoinflammatory fibroblastic sarcoma and pleomorhic hyalinizing angiectatic tumor.