The use of the twin model to investigate the genetics and epigenetics of skin diseases with genomic, transcriptomic and methylation data.

Twins have always fascinated medical research even before the discovery of DNA and the understanding of the differences between identical and non-identical twins. Dermatology with the benefit of being able to visualize phenotypes was one of the first specialities reporting on the fascinating concordance in identical (MZ) twins in the 1920's. Over the last 20 years, the heritability of skin diseases using twins has been clearly demonstrated, across a wide variety of traits including melanoma, polymorphic light eruption, psoriasis, eczema and acne. Other rarer diseases have also been shown to have a significant genetic basis such as lupus, sarcoidosis and lichen sclerosus. Following evidence of heritability for many skin disease the next step was Genome-Wide Association Studies (GWAS) which are uncovering new genes in large twin cohorts. The twin model is also ideal for the new field of epigenetics, investigating subtle differences in DNA methylation within discordant MZ pairs for a disease, as well as differences in CNVs. Twins are also valuable for examining differences in gene function via RNA expression in twins discordant for a skin trait or disease.

Stress-controlled shear flow alignment of collagen type I hydrogel systems.

Disease research and drug screening platforms require in vitro model systems with cellular cues resembling those of natural tissues. Fibrillar alignment, occurring naturally in extracellular matrices, is one of the crucial attributes in tissue development. Obtaining fiber alignment in 3D, in vitro remains an important challenge due to non-linear material characteristics. Here, we report a cell-compatible, shear stress-based method allowing to obtain 3D homogeneously aligned fibrillar collagen hydrogels. Controlling the shear-stress during gelation results in low strain rates, with negligible effects on the viability of embedded SH-SY5Y cells. Our approach offers reproducibility and tunability through a paradigm shift: The shear-stress initiation moment, being the critical optimization parameter in the process, is related to the modulus of the developing gel, whereas state of the art methods often rely on a predefined time to initiate the alignment procedure. After curing, the induced 3D alignment is maintained after the release of stress, with a linear relation between the total acquired strain and the fiber alignment. This method is generally applicable to 3D fibrillar materials and stress/pressure-controlled setups, making it a valuable addition to the fast-growing field of tissue engineering. STATEMENT OF SIGNIFICANCE: Controlling fiber alignment in vitro 3D hydrogels is crucial for developing physiologically relevant model systems. However, it remains challenging due to the non-linear material characteristics of fibrillar hydrogels, limiting the scalability and repeatability. Our approach tackles these challenges by utilizing a stress-controlled rheometer allowing us to monitor structural changes in situ and determine the optimal moment for applying a shear-stress inducing alignment. By careful parameter control, we infer the relationship between time, induced strain, alignment and biocompatibility. This tunable and reproducible method is both scalable and generally applicable to any fibrillar hydrogel, therefore, we believe it is useful for research investigating the link between matrix anisotropy and cell behavior in 3D systems, organ-on-chip technologies and drug research.

Sentinel lymph node biopsy in melanoma patients.

Appropriate surgical management of regional lymph nodes is critical in patients with cutaneous melanoma. The use of intraoperative lymphatic mapping and sentinel lymph node biopsy (SLNB) has increased significantly in the past decade. SLNB is performed as minimally invasive procedure that provides accurate staging of melanoma patients with no clinically detectable nodal disease. In many melanoma units across the world, it became the standard for detection of occult regional node metastasis in patients with intermediate-thickness primary melanoma. Use of SLNB in patients with thin melanomas is still under evaluation. Although SLNB has been established as staging procedure in melanoma patients, its therapeutic role is still not clear. Large-scale ongoing randomized trials should elucidate whether SLNB with complete lymphadenectomy has a survival benefit in melanoma patients with early lymph node metastases compared to 'watch-and-wait' policy (observation).

The use of polarised polychromatic non-coherent light alone as a therapy for venous leg ulceration.

OBJECTIVE: This study assessed the effectiveness of polarised, polychromatic, non-coherent light therapy in the treatment of venous leg ulcers. Investigators in previous studies have advocated the use of light as an adjunct to other proven therapies or on its own. METHOD: This was a pilot prospective case-series study. We enrolled 25 patients with venous leg ulcers. All were treated with light only. Phototherapy (light therapy) treatments were given once a day over four weeks. RESULTS: All ulcers except one (99%) had a positive value for the change in healing area at the end of the four weeks. The total number of 73 leg ulcers recorded at the beginning of the study was reduced to 51 at the end of the four weeks (p < 0.01). The decrease in wound surface area following the treatment was statistically significant (mean: 57.15%; SD: 31.87%; p < 0.01). CONCLUSION: Polarised, polychromatic light therapy applied as a monotherapy was associated with positive healing rates in patients with venous leg ulcers. It is a simple and non-invasive treatment. However, a well-designed randomised controlled study is needed to confirm the efficacy of this form of phototherapy and to objectively evaluate recommendations for its routine use in clinical practice.

[Disorders affecting the emotional sphere and impulse control in Parkinson's disease]. / Alteraciones de la esfera emocional y el control de los impulsos en la enfermedad de Parkinson.

INTRODUCTION: Parkinson's disease (PD) is associated with mood and behavioral symptoms contributing to morbidity and reduced quality of life of the patients. Most characteristic are depression, anxiety and impulse control disorder. DEVELOPMENT: Identification and treatment of neuropsychiatric symptoms is necessary for an appropriate management of PD. Affective symptoms may be the initial manifestation of PD, are highly prevalent and pathogenically complex. Impulse control disorders are usually not a spontaneous complaint, so asking about these symptoms may be the only way to detect and treat a serious socio-familial problem. Pharmacological treatment of these manifestations is difficult to balance with an adequate control of motor symptoms. Psychological support from early stages and throughout the evolution of PD is fundamental. CONCLUSIONS: Neurologist and other healthcare professionals treating PD patients need to be aware of behavioral and emotional manifestations of the disease. This will lead to an appropriate patient management and better adaptation of the familial and social situation.

An association between cutaneous melanoma and non-Hodgkin's lymphoma: pooled analysis of published data with a review.

BACKGROUND: Several epidemiological studies have suggested an association between cutaneous melanoma and non-Hodgkin's lymphoma. METHODS: We pooled the data from seven cohort studies and calculated the risk of secondary occurrence of cutaneous melanoma after non-Hodgkin's lymphoma, and of non-Hodgkin's lymphoma subsequent to the occurrence of cutaneous melanoma. RESULTS: There were 137 612 patients with primary non-Hodgkin's lymphoma and 109 532 patients with primary cutaneous melanoma. We found a statistically significant increased risk of non-Hodgkin's lymphoma among cutaneous melanoma survivors [standardised incidence ratio (SIR) 2.01, 95% confidence interval (CI) 1.79-2.24] and cutaneous melanoma among non-Hodgkin's lymphoma survivors (SIR 1.41, 95% CI 1.26-1.58). CONCLUSION: Our study confirmed an association between cutaneous melanoma and non-Hodgkin's lymphoma occurring in the same patient indicative of a need to examine further the role of the common risk factors.

Desmoplastic malignant melanoma: a systematic review.

BACKGROUND: Desmoplastic melanoma (DM) is an uncommonly encountered type of malignant melanoma. The clinical appearance of DM can be highly variable and thus, diagnosis of this tumour is difficult and very often may mislead the physician. OBJECTIVES: To make a critical review of the contemporary literature on DM, to pool the data from published studies and to evaluate the clinical and morphological characteristics of this neoplasm. METHODS: All studies or reports on DM including 10 or more participants with reported clinical and histological characteristics of the tumour were included. RESULTS: In the 17 studies that met the inclusion criteria a total of 856 patients with DM was reported. There was a male predilection, with a male/female ratio of almost 2 : 1 (63% of the lesions were diagnosed in males). The head and neck were the most common sites of DM for both sexes (53.2%). The data confirmed that DM usually has an advanced Breslow thickness at the time of presentation. Histopathological diagnosis of DM is sometimes difficult and the absence of pigmentation is probably the major cause for failure to recognize DM histologically. The pooled data from included studies showed that the incidence of nodal metastasis is lower in patients with DM than in patients with other forms of cutaneous melanoma. CONCLUSIONS: Prompt definitive surgical excision is the treatment of choice for DM. Improved knowledge of the clinical behaviour and histological features of DM is important for more effective management of patients with DM.

Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma.

During the past several decades, there has been a substantial increase in the incidence of cutaneous melanoma among all caucasian populations. The number of deaths due to cutaneous malignant melanoma has also increased in most fair-skinned populations throughout the world in the past few decades. Trends in melanoma incidence worldwide are examined. The most recent data on the mortality from cutaneous melanoma are reported. The role of different environmental, genetic and host factors in the aetiology of melanoma is discussed.

Management of regional lymph nodes in patients with malignant melanoma: questionnaire survey of UK current practice.

In 2001, a short postal questionnaire regarding the management of regional lymph nodes in patients with cutaneous malignant melanoma was sent to 69 NHS departments of plastic and reconstructive surgery in the UK. Questionnaires were returned by 53 units, giving a response rate of 76.8%. Of these 53 units, 49 reported that they treat patients with primary malignant melanoma. There was considerable variation in the number of melanoma patients managed by each unit. This survey confirmed that elective lymph-node dissection is not routinely practiced in the UK; observation and therapeutic lymph-node dissection for patients who develop regional metastasis is the preferred pattern of care. The majority of centres in the UK do not use sentinel lymph node mapping: only 15 of the 49 units do so (30.6%). The number of sentinel lymph node biopsies performed in each unit varied significantly. There was considerable variation in the materials used and the process of care for sentinel lymph node biopsy. On the basis of this current practice, we recommend the setting up of a prospective clinical melanoma register to record the surgical treatment of melanoma patients.

Tumour thickness as a predictor of occult lymph node metastases in patients with stage I and II melanoma undergoing sentinel lymph node biopsy.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a minimally invasive procedure used accurately to stage nodal basins at risk of occult metastases. There are no data as yet to show a survival benefit from SLNB and its use remains controversial. If Breslow thickness of the tumour correlates well with positive SLNB, it could be used to select patients for SLNB. METHODS: A quantitative systematic review of published studies on SLNB in patients with melanoma available by September 2001 was performed. RESULTS: Twelve studies containing 4218 patients with stage I and II melanoma were identified; 17.8 (95 per cent confidence interval 16.7 to 19.0) per cent of patients had nodal micrometastases detected by SLNB. The incidence of micrometastasis in sentinel nodes correlated directly with Breslow tumour thickness; it was 1.0 per cent for lesions of less than or equal to 0.75 mm, 8.3 per cent for 0.76-1.50 mm, 22.7 per cent for 1.51-4.0 mm and 35.5 per cent for more than 4.0 mm. CONCLUSION: The Breslow thickness of primary melanoma predicts the presence of a sentinel node metastasis. The published data are not sufficient to demonstrate a correlation between other known prognostic indicators and a positive SLNB.

Differential antibody isotype reactivity to specific antigens in human lymphatic filariasis: gp15/400 preferentially induces immunoglobulin E (IgE), IgG4, and IgG2.

Lymphatic filarial infection in humans is associated with a strong skewing of the immune response towards the TH2 arm, with prominent interleukin 4-producing cells and elevated levels of immunoglobulin G4 (IgG4) and IgE antibodies in peripheral blood. To determine how such a generalized TH2 imbalance governs responses to individual parasite antigens, the profiles of isotypes of antibodies to two recombinant proteins of Brugia spp. were studied. One molecule was the C-terminal portion of the filarial heat shock protein 70 (Bpa-26), representative of a cytoplasmic protein, and the second antigen was a single unit of the tandem repeats of a Brugia polypeptide (BpL-4), a secreted product which is prominently exposed to the immune system. Serum samples from 146 individuals resident in areas in which brugian filariasis is endemic were used, and it was found that whereas the levels of IgG1 and IgG3 responses to both Bpa-26 and BpL-4 were high, IgG4 and IgE antibodies to only BpL-4, not to Bpa-26, were prominent. Thus, an antigen which is chronically exposed to the immune system elicited a TH2-dependent isotype switch, as manifested by increased IgG4 and IgE responses. Moreover, IgG4 and IgE responses to BpL-4 showed a strong negative association, suggesting that mediators other than interleukin 4 must be responsible for such differential regulation of these two isotypes. When the data were analyzed as a function of clinical status, a striking association between elevated levels of IgG3 antibodies to Bpa-26 and manifestation of chronic obstructive disease was found; elephantiasis patients showed significantly higher levels of IgG3 antibodies to Bpa-26 than microfilaremics and asymptomatic amicrofilaremics. This indicates that an imbalance of isotypes of antibodies to particular filarial antigens might play a role in the pathogenesis of chronic disease.