La microscopía confocal de reflectancia in vivo (MCR) es una técnica no invasiva que permite obtener un diagnóstico de forma inmediata y en tiempo real de patología cutánea tumoral con una precisión diagnóstica que se acerca al diagnóstico histológico convencional. La MCR puede permitir un seguimiento clínico de respuesta a tratamientos no invasivos de patología tumoral, como la terapia fotodinámica, sin necesidad de realizar biopsias. El presente trabajo reúne cuatro estudios realizados con el fin de demostrar la utilidad de la técnica de MCR en el estudio y manejo clínico de las neoplasias cutáneas. En el primer estudio se incluyeron de forma prospectiva 154 tumores cutáneos para establecer qué parámetros de microscopía confocal se relacionaban con cada tumor, analizar si estos criterios eran reproducibles y finalmente evaluar la correlación de estos parámetros con la dermatoscopia y la histología convencional. Según los resultados de este primer trabajo, cuatro características observables mediante MCR permitían diferenciar las lesiones melanocíticas (LM) de las no melanocíticas (LNM): patrón epidérmico en empedrado, crecimiento pagetoide, presencia de nidos celulares en la dermis y presencia de papilas dérmicas bien definidas en toda la lesión. Dentro de las LM, la presencia de células redondas en estratos suprabasales y de células nucleadas atípicas en la dermis se asociaban al diagnóstico de melanoma; mientras la presencia de papilas dérmicas con contorno reflectante (anillos basales) así como la observación de células basales típicas, se asociaban a nevus. Basándonos en la reproducibilidad y correlación histológica y dermatoscópica de los criterios de MCR, se desarrolló un algoritmo en dos etapas para el diagnóstico de melanoma consiguiendo una sensibilidad del 86,1% y una especificidad del 95.3% (J Am Acad Dermatol. 2009;61:216-29). En el segundo trabajo, se estudiaron los parámetros de microscopía confocal en melanomas de extensión superficial (MES) en fase de crecimiento vertical y en melanomas nodulares (MNs). Para ello se incluyeron de forma prospectiva 10 MNs, 10 MES con área nodular y 10 MES con área palpable. Se realizó un análisis sistemático y estudio estadístico de las características dermatoscópicas, confocales e histológicas de los 3 grupos de lesiones. Mientras los MNs mostraban patrones de dermatoscopia inespecíficos, los MES exhibían patrones multicomponente y puntuaciones más altas en los algoritmos de dermatoscopia. Por MCR, los MNs tenían poco crecimiento pagetoide y presentan a menudo un patrón normal de la epidermis, a diferencia de los MES que se caracterizaban por un patrón desestructurado de la epidermis y la presencia de abundantes células en estratos suprabasales Tanto en los MNs como en las áreas nodulares de los MES, en la unión dermo-epidérmica no se visualizaban las papilas dérmicas, en su lugar se observa una proliferación de células reflectantes atípicas no agregadas. En la dermis, los MNs exhibían a menudo unos agregados celulares característicos de aspecto cerebriforme, que podían observarse también en las áreas nodulares de algunos MES (Arch Dermatol. 2008;144:1311-20). En un tercer artículo estudiamos las características del carcinoma basocelular pigmentado (CBC) mediante MCR, histología e inmunohistoquímica (S-100, MelanA, HMB-45 y CD1a).Mediante MCR demostramos la presencia de estructuras reflectantes muy características de aspecto dendrítico dentro de los nidos tumorales situados en la dermis de los CBC estudiados, que correspondían por estudio inmunohistoquímico a melanocitos no neoplásicos que poblaban los nidos (Arch Dermatol. 2007;143:883-6). Finalmente, en un cuarto trabajo estudiamos la aplicabilidad de la MCR en el diagnóstico y seguimiento de pacientes con genodermatosis de alto riesgo de desarrollar cáncer cutáneo (síndrome de Gorlin -SG- y Xeroderma pigmentoso -XP-) afectos de CBCs múltiples y tratados con terapia fotodinámica con metil-aminolevulinato (MAL). Se incluyeron 4 pacientes con SG y 2 hermanos con XP. Se trataron lesiones únicas o múltiples en zonas localizadas con 1 a 3 ciclos de TFD-MAL. La exploración con MCR se realizó antes y 3 meses después del tratamiento en las lesiones diana. Se trataron 13 CBCs pigmentados faciales en los pacientes afectos de XP y múltiples lesiones en cara o tronco (hasta 200) en los afectos de SG. Globalmente se obtuvo una remisión clínica completa en un 25- 67% de las lesiones. La respuesta al tratamiento puedo ser correctamente evaluada mediante MCR (J Eur Acad Dermatol Venereol. 2011;25:819-27). En conclusión, la MCR parece ser útil en el diagnóstico diferencial de las lesiones pigmentadas y complementa a la dermatoscopia en el diagnóstico del melanoma. Esta técnica permite caracterizar subtipos de melanoma como el melanoma nodular. También sirve de ayuda en el diagnóstico y caracterización del carcinoma basocelular pigmentado y en su monitorización tras tratamiento con terapias no invasivas como la terapia fotodinámica. / This work brings together four studies to demonstrate the clinical utility of reflectance confocal microscopy (RCM) in the clinical management of cutaneous neoplasms. In the first study we prospectively included 154 skin tumors in order to develop an algorithm for the in vivo diagnosis of skin tumors. We analyzed RCM features on stored images before excision and performed statistical analyses to determine the association of RCM features with tumor types. Four confocal features differentiated melanocytic lesions (ML) from non-melanocytic lesions (NML): cobblestone pattern of epidermal layers, pagetoid spread, mesh appearance of the dermoepidermal junction, and the presence of dermal nests. Within ML, the presence of roundish suprabasal cells and atypical nucleated cells in the dermis was associated with melanoma, and the presence of edged papillae and typical basal cells was associated with nevi. Based on the reproducibility and histological and dermoscopic correlation of MCR criteria, we developed a two-step algorithm for the diagnosis of melanoma, achieving a sensitivity of 86.1% and specificity of 95.3% (J Am Acad Dermatol. 2009; 61: 216-29). In the second work we characterized nodular melanoma (NM) by dermoscopy, RCM and histopathology. We included 10NMs, 10 superficial spreading melanomas (SSMs) with a nodular area, and 10 SSMs with a blue palpable area but not yet nodular. Whereas NMs had predominantly nonspecific global dermoscopic patterns, SSMs exhibited a multicomponent pattern and higher dermoscopic scores. By RCM, distinctive confocal features were observed at all cutaneous levels in NMs compared with SSMs, suggesting different biological behavior. (Arch Dermatol. 2008, 144:1311-20). In the third article we explored the confocal features of pigmented basal cell carcinoma (BCC) and correlated the findings with histology and immunohistochemistry. RCM revealed highly refractive dendritic structures within tumor nests that corresponded to the presence of melanocytes within the tumor. RCM allowed the study of pigmented BCC and the identification of specific criteria. (Arch Dermatol. 2007; 143:883-6). Finally, in the fourth paper we aimed to evaluate the efficacy of methyl-aminolevulinate (MAL) photodynamic therapy (PDT) in basal cell carcinomas (BCCs) from patients with Gorlin syndrome (GS) and Xeroderma pigmentosum (XP), and to determine the utility of RCM in the diagnosis and the evaluation of therapeutic response. We included 4 patients with GS and 2 siblings with XP. Single or multiple lesions in localized areas were treated with 1 to 3 cycles of MAL PDT. RCM was performed before and 3 months after the treatment in target lesions. Overall, we obtained a complete clinical remission in 25 to 67% of the lesions. RCM could identify confocal features for BCC and assess tumor remissions after treatment (J Eur Acad Dermatol Venereol. 2011; 25:819-27).

Chlamydia trachomatis (CT) can cause infertility and is the most common sexually transmitted infection (STI) of bacterial origin in Europe. Surveys in seven countries estimated a population prevalence of 1.4-3.0 % in people 18 to 44 years. Approximately 87% of those diagnosed in Sweden are 15-29 years. Since 1997, with the exception of 2009-2010, despite all efforts, CT has increased steadily in many European countries including Sweden. That made us investigate risk factors associated with catching STIs, especially CT. In Sweden partner notification is mandatory by law when a patient is diagnosed with CT. Centralised partner notification, performed by a few experienced counsellors, and evaluation of the sexual history for at least 12 months back in time, shows superior results compared to other studies. Phone-interviews are a good option in remote areas. “The Västerbotten model” for partner notification fulfils these criteria and our evaluation has functioned as a model for changing recommendations of partner notification in Sweden. Preventing CT by primary prevention such as information and counselling is, however, still of great importance. We investigated whether it was necessary to test for CT in the throat. We found that patients testing positive for pharyngeal CT neither had more symptoms or signs nor a sexual history that differed from others. We therefore believe that we will find most or all of these patients by conventional testing of urine and cervical/vaginal samples. We wanted to further identify risk factors among patients attending a clinic for sexually transmitted infections to enable individualized care depending on risk. None or inconsistent use of condoms with new/temporary partners in combination with having at least one new/temporary partner within the past 6 months could identify persons with risk behaviour and at increased risk of CT (re)infection. Additional information about whether the condom was used during the whole intercourse did not add any risk of infection. A drop-in reception is a good contribution to an opportunistic screening approach. The rate of CT infected is high and the clinic attracts men and individuals ≥25 years old at risk of infection, groups which usually have a reduced test rate. The mean age was 28 years and 58% of the patients were men. The figure of correct condom usage is very low indicating the need for risk reducing counselling also in this grown-population. Among adult STI patients anxiety was common and depression uncommon. Neither was linked to high risk sexual behaviour nor ongoing CT infection. Hazardous alcohol consumption, however, was common and linked to anxiety and high risk sex. We conclude that preventive work can not only focus on STI prevention, but must consider the high frequency of hazardous alcohol consumption, which probably is contributing to sexual risk behaviour.

Nickel allergy is the most prevalent contact allergy and has been discussed as a possible riskfactor for hand eczema. However, hand eczema is one of the most frequently occurring skindiseases and has multifactorial origin. The aim of this thesis was to study the association between nickel allergy and hand eczema in the general population. There are only a fewpopulation-based studies previously published, that include patch testing. In addition, this thesis aimed to evaluate methods to follow the prevalence of nickel allergy.The study cohort consisted of 908 women who had been patch tested for the occurrence of nickel allergy as schoolgirls. Twenty years later, they were invited to participate in a follow-up questionnaire study. The response rate was 81%. In total, 17.6% of respondents reported handeczema after the age of 15 years and there was no statistically significant difference in the occurrence of hand eczema between those who were nickel-positive and those who were nickel negativeas schoolgirls. To further investigate possible links, another study was performed,which included a second questionnaire, a clinical investigation and patch testing. All schoolgirls from the baseline study who were still living in the area as adults were invited to participate and the participation rate was 77%. Patch test showed 30.1% nickel-positive individuals.When all participants were included in the analysis, there was no statistically significant difference between nickel-positive and nickel-negative women regarding occurrence of hand eczema. The most important risk factor for hand eczema was childhood eczema. Adjusted prevalence proportion ratio (PPR) for hand eczema after age 15 in relation to nickel patch testresults was 1.03 (95% CI 0.71--1.50) and in relation to childhood eczema 3.68 (95% CI 2.45--5.54). When women with and without history of childhood eczema were analyzed separately, the hand eczema risk was doubled in nickel-positive women without history of childhood eczema. In conclusion, the risk of hand eczema in nickel-positive women may previously havebeen overestimated. Next, the validity of self-reported nickel allergy was investigated. In the established cohort; two questions regarding nickel allergy were compared with patch test results. The validity of self-reported nickel allergy was low, and the questions regarding nickel allergy overestimated the true prevalence of nickel allergy. The positive predictive values were 59% and 60%. Another method for estimating the prevalence of nickel allergy, namely self-patch testing, was validated in the last study. In total, 191 patients from three different dermatology departments participated. The validity of self-testing for nickel allergy was adequate, with sensitivity 72%and proportion of agreement 86%. / Nickelallergi är vanligt förekommande. Prevalensen i Skandinavien är 15--25% hos kvinnor och cirka 3% hos män. Sambandet mellan nickelallergi och uppkomst av handeksem har tidigare diskuterats och i vissa studier anges att 30--45% av alla individer med nickelallergi får handeksem. Det finns dock endast ett fåtal publicerade studier där personer ur normalbefolkningen har lapptestats för nickel. Handeksem ärvanligt och har ofta flera olika kombinerade orsaker. Det övergripande syftet med avhandlingen var att studera nickelallergins betydelse för uppkomst av handeksem. Detfinns ett intresse av att följa förekomsten av nickelallergi över tid, speciellt sedan det i början av 2000-talet infördes ett EU-direktiv som begränsar nickelinnehåll i klockor,smycken, metallknappar etc. Ytterligare ett syfte med avhandlingen var att utvärderaepidemiologiska metoder för att följa förekomsten av nickelallergi.Den första studien var en uppföljningsstudie av 908 flickor ur normalbefolkningen,vilka i skolåldern lapptestats med nickel. Tjugo år senare skickades en enkät till dessa kvinnor, svarsfrekvensen var hög (81%). Förekomsten av självrapporterat handeksemefter 15 års ålder var 17.6%. Det förelåg ingen signifikant skillnad i förekomst avhandeksem mellan de kvinnor som var nickelallergiska som barn jämfört med dem som inte var nickelallergiska. År 2006 utfördes ytterligare en studie, som inkluderade de kvinnor som fortfarande bodde i Örebro län. Studien omfattade en klinisk undersökning av händerna samt ett lapptest. 30% av kvinnorna var positiva för nickel.Det förelåg ingen signifikant skillnad i förekomst av handeksem mellan de som var positiva för nickel och de som var negativa. Vid separat analys av de kvinnor som angav tidigare barneksem jämfört med dem som aldrig hade haft barneksem visade det sig att risken för handeksem var dubbelt så stor hos nickelallergiker i den gruppen som aldrig hade haft barneksem. Båda studierna visade att barneksem var den största riskfaktorn för att få handeksem som vuxen, med en 3-4 gånger ökad risk. Den tredje studien var en validering av självrapporterad nickelallergi. Överensstämmelsen var låg mellan enkätfrågor gällande nickelallergi och lapptestverifierad nickelallergi. Av dem som själva bedömde sig vara nickelallergiska var endast 59% positiva enligt lapptest. För att följa förekomsten av nickelallergi i befolkningen behövs därför andra metoder. I den fjärde studien utvärderades ett självtest för nickelallergi. 191 patienter från tre olika hudkliniker i Sverige deltog i studien. Validiteten för metoden självtest var tillfredsställande, sensitiviteten var 72%och graden av överensstämmelse var 86%.

Background: According to current guidelines the cost of productivity loss should be considered in pharmacoeconomic analyses. The cost of health-related productivity loss in psoriasis patients is unknown. Objective: To estimate the cost of productivity loss in psoriasis and its association with health-related quality of life and clinical disease severity. Methods: Cross-sectional study, recruitment of adult participants through Internet advertisements. 201 (72.3%) out of 278 eligible participants completed the study. Health-related work productivity loss, quality of life and clinical severity of psoriasis were assessed by standardized instruments. Results: Indirect costs of productivity loss clearly exceed the total direct cost. In contrast to objective clinical disease severity, health-related quality of life (measured by the Dermatology Life Quality Index) is an independent predictor of work productivity. Conclusions: There is good reason to believe that intervention can reduce health-related productivity loss by improving patients’ quality of life. Savings from increased work productivity might offset comparatively high acquisition costs of biological agents. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: Chronic plaque-type psoriasis is a major dermatosis, but a significant question is still unanswered: What defines severity in chronic plaque-type psoriasis? While objective assessments like the Psoriasis Area and Severity Index (PASI) have frequently been used in clinical trials, quality of life (QOL) questionnaires are currently becoming more and more popular. Objective: This article summarizes the most important objective and subjective measurements of severity in psoriasis. For every dermatologist it is critically important to distinguish between severe psoriasis and psoriasis that severely affects QOL. Even if the PASI also has disadvantages, it is the most adequate instrument available to evaluate severity in plaque-type psoriasis. Result: We provide reasons why PASI >12 defines severe, PASI 7–12 moderate and PASI <7 mild chronic plaque-type psoriasis. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The aims of this study were to document the levels of cobalamin, folate, methylmalonic acid (MMA) and total homocysteine (tHcy) in serum and their relations to symptoms, clinical findings, and other factors in order to improve the possibilities of detecting early deficiency of vitamin B12 or folate, and to study the effects of cobalamin and folic acid treatment over a three-year period. The study population consisted of a 20% random sample of persons 70 years or older living in Älvkarleby in mid-Sweden. They were invited to a survey and 224 (88.4%) persons responded. Data were obtained by questionnaire, laboratory investigations and physical examination for the period 1993 – 1999. In a multivariate analysis performed at baseline, serum MMA and tHcy were significantly and independently correlated to age, serum cobalamin, and creatinine levels, and tHcy also to sex and serum folate. Neither serum cobalamin, folate, MMA nor tHcy had any significant correlation to haemoglobin or mean red cell volume. Almost half of the study population had signs of low tissue levels of vitamin B12 or folate. Among those who took multivitamin preparations, the proportion was much lower, 25%. Among traditional symptoms and clinical findings that have been linked to vitamin B12 or folate tissue deficiency, only changes in the tongue mucosa and mouth angle stomatitis were significantly associated with abnormal serum folate and tHcy levels. Traditional symptoms of vitamin deficiency may appear later in the course. 69 persons who had laboratory indications of early or overt tissue deficiency of vitamin B12 or folate and who had no ongoing vitamin treatment were given cobalamin for six months. Those whose MMA or tHcy levels did not normalise were given folic acid in addition to cobalamin. After further treatment for three months, all persons but one had normal levels. The laboratory effect still remained after three years of treatment. There was a tendency towards improvement of vibration sense, especially in the long nerve paths, and improvement of neurological symptoms and oral mucosa findings. Conclusion: A substantial proportion of elderly persons have laboratory signs of incipient tissue deficiency of vitamin B12 and folate. Treatment normalises lab parameters and some symptoms.

Treatment results and clinical characteristics in adult acute lymphoblastic leukaemia (ALL) were evaluated regarding three issues: a new treatment with cytarabine up-front, stem cell transplantation and a comparison between adult and paediatric treatment protocols. All studies were conducted on a national basis. Furthermore, activity of imatinib was investigated by in vitro cytotoxicity assay. The national protocol was evaluated in 153 adult ALL patients. A high complete remission rate, 86%, was achieved with 29% overall survival at 3-years. Favourable outcome was identified in patients &lt; 40 years with precursor B phenotype and continuous complete remission was higher for precursor B compared to T-ALL. Stem cell transplantation was evaluated in 187 patients. No differences in outcome between allogeneic and autologous transplantation were found, with the exception of Philadelphia-positive ALL, in which allogeneic transplantation was preferable. Limited chronic graft-versus-host disease (compared to none) resulted in superior disease free survival. The paediatric NOPHO-92 and the Adult protocols were evaluated for 243 ALL-patients. Superior remission rate and survival were achieved for 10-18 year-olds treated according to the Paediatric protocol compared to both 15-25 and 25-40 year-olds treated according to the Adult protocol. Treatment protocol was a significant prognostic factor for patients aged 15-20 years. Fluorometric Microculture Cytotoxicity Assey was used to analyze 15 tumour cell samples from ALL patients. High concordance was determined between in vitro sensitivity to imatinib and presence of BCR-ABL. Daunorubicin, prednisolone and cytarabine had the greatest benefit from a combination with imatinib. The national adult treatment protocol’s results were consistent with international trials regarding precursor B ALL but may be under performing for T-ALL. Adolescents may benefit from treatment according to the Paediatric protocol. No difference in outcome between allogeneic and autologous stem cell transplantation was determined except for Philadelphia-positive patients, despite the indication of a graft-versus-leukaemia effect.

The aims of the thesis were (i) to investigate the impact of repetitive low-intensity work exposure on proprioception and (ii) to examine effects of muscle stretching (especially sensory effects and effects on muscle nociception) and to relate its application to the prevention, alleviation and/or treatment of work-related neuromuscular disorders. The effects of low-intensity repetitive work on the shoulder proprioception were tested in healthy subjects. The effect of working time on the retention of subjective fatigue and their relation to changes in proprioception, and the immediate effect of stretching on shoulder proprioception were investigated. A new method to test the stretchability of the rectus femoris muscle was investigated for reliability and validity and used to assess the effects of a two-week stretching regimen on range of motion and on subjective stretch sensation. Finally, the interactions between innocuous muscle stretch and nociceptive chemical stimulation on discharge behavior of nociceptive dorsal horn neurons in the feline spinal cord were explored. The main findings were as follows: 1) The repetitive low-intensity work to fatigue diminished the shoulder proprioception; the working time as well as the retention of subjective fatigue were partly related to the extent of changed proprioception. 2) There was no effect of acute muscle stretching on the proprioception. 3) The new method for testing muscle stretchability proved valid and reliable. A two-week stretching regimen increased the tolerance to stretch torque, but the range of motion remained unchanged. 4) Half of the nociceptive dorsal horn neurons that responded to close arterial injections of bradykinin were modulated by muscle stretching applied directly after the injections. Altogether, the results give credence to the hypothesis of an involvement of sensory information distortion due to repetitive low-intensity work exposure in the development of work-related neuromuscular disorders. Increased tolerance to stretch torque may be an important mechanism in explaining improvements following stretch treatment. The spinal interactions between innocuous stretch and nociceptive muscle afferent inputs indicate a possible mechanism involved in stretching-induced pain alleviation.

Orientador: Hélio Amante Miot / Resumo: Fundamentos: Campo de cancerização cutâneo representa uma área com alterações genômicas induzidas pela radiação ultravioleta, cujo sinal de atividade são as queratoses actínicas (QA). Tratamentos que visem sua estabilização podem reduzir a incidência de QA e de tumores cutâneos não melanoma. Estudos em terapia fotodinâmica com metil aminolevulinato (TFD-MAL) no tratamento do campo de cancerização cutâneo mostram redução de até 89% na contagem de QA, já com colchicina tópica, há redução de até 78%. Até o momento, não há estudos comparando colchicina com TFD-MAL. Esse trabalho objetiva avaliar eficácia e segurança de colchicina 0,5% creme versus TFD-MAL no tratamento do campo de cancerização dos antebraços.Casuística e métodos: Ensaio clínico aberto, controlado, randomizado, envolvendo 36 pacientes do ambulatório de Dermatologia da UNESP-Botucatu, com 3-10 QAs em cada antebraço, tratados (cada antebraço) com creme de colchicina 0,5% (2x/dia por 10 dias) ou uma sessão de TFD-MAL; reavaliados após 60 dias. A avaliação clínica foi realizada pela contagem de QAs, seus subtipos clínicos, sua escala de gravidade e escala de fotoenvelhecimento dos antebraços. Avaliação histopatológica foi realizada pelo escore KIN (Keratinocyte Intraepithelial Neoplasia), atrofia epitelial e imunohistoquímica de p53 e Ki67. Todos os pacientes incluídos no estudo e randomizados fizeram parte da população ITT (intention to treat). Os dados do único dropout foram imputados como LOCF (last observed car... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

L’exploration du tissu cutané est aujourd’hui limitée par le peu de méthodes dites quantitatives permettant de décrire objectivement les propriétés mécaniques du tissu cutané. L’élastographie permet une exploration locale d’un milieu et offre la possibilité pour certaines méthodes d’estimer quantitativement le module d’élasticité (module d’Young). Nous avons mis au point une technique d’élastographie ultrasonore impulsionnelle haute fréquence 1D (HF-TE) et haute résolution permettant une description micrométrique des propriétés mécaniques du tissu cutané pour des applications en cosmétique et en dermatologie. / Nowadays, exploration of cutaneous tissue is limited by the few number of available approaches, known as quantitative methods, allowing an objective description of the mechanical properties of skin tissue. Elastography allows a local exploration of a medium and offers the possibility for some strategies to quantitatively estimate the modulus of elasticity (Young’s modulus). A 1-D high-frequency ultrasonic transient elastography method (HF-TE) allowing a micrometric description of the mechanical properties of skin tissue has been designed for cosmetic and dermatological applications. An experimental system of high-frequency transient elastography has been developed : software, hardware and measurement methodology. The HF-TE technique has been validated using simulation and measurements in monolayer and bilayer calibrated phantoms developed in the laboratory. The Young’s modulus values measured in monolayer media were then compared with those measured by two others dynamic techniques.