Current Non-viral siRNA Delivery Systems as a Promising Treatment of Skin Diseases.

BACKGROUND: Gene therapy is a new approach to discover and treat many diseases. It has attracted considerable attention from researchers in the last decades. The gene therapy through RNA interference has been considered one of the most recent and revolutionary approaches used in individualized therapy. In the last years, we have witnessed the rapid development in the field of the gene silencing and knockdown by topical siRNA. Its application in gene therapy has become an attractive alternative for drug development. METHODS: This article will address topical delivery of siRNA as a promising treatment for skin disorders. An update on the advances in siRNA-based nanocarriers as a powerful therapeutic strategy for several skin diseases will be discussed giving emphasis on in vitro evaluations. RESULTS: Through the in-depth review of the literature on the use of siRNAs for skin diseases we realize how widespread this use is. We have also realized that nanoparticles as non-viral vectors are increasingly being explored. Skin diseases where the use of siRNA has been explored most are skin cancer (melanoma and nonmelanoma), psoriasis, vitiligo, dermatitis and leprosy. But we also report here other diseases where the use of siRNA has been growing as acne, alopecia areata, cutaneous leishmaniasis, mycoses, herpes, epidermolysis bullosa and oculocutaneous albinism. Also highlighted, the first clinical trial of siRNA for cutaneous diseases, aimed at Pathyounychia Congenita. CONCLUSION: The treatment of skin diseases based on topical delivery of siRNA, which act by inhibiting the expression of target transcripts, offers many potential therapeutic advantages for suppressing genes into the skin.

Basic genetics for dermatologists.

During the past few decades, advances in the field of molecular genetics have enriched us in understanding the pathogenesis of diseases, their identification, and appropriate therapeutic interventions. In the last 20 years, genetic basis of more than 350 monogenic skin diseases have been elucidated and is counting. The widespread use of molecular genetics as a tool in diagnosis is not practiced routinely due to genetic heterogenicity, limited access and low sensitivity. In this review, we have presented the very basics of genetics so as to enable dermatologists to have working understanding of medical genetics.

Genome-wide association study of skin complex diseases.

Complex diseases are caused by both genetic and environmental factors. Over decades, scientists endeavored to uncover the genetic myth of complex diseases by linkage and association studies. Since 2005, the genome-wide association study (GWAS) has been proved to be the most powerful and efficient study design thus far in identifying genetic variants that are associated with complex diseases. More than 230 complex diseases and traits have been investigated by this approach. In dermatology, 10 skin complex diseases have been investigated, a wealth of common susceptibility variants conferring risk for skin complex diseases have been discovered. These findings point to genes and/or loci involved in biological systems worth further investigating by using other methodologies. Certainly, as our understanding of the genetic etiology of skin complex diseases continues to mature, important opportunities will emerge for developing more effective diagnostic and clinical management tools for these diseases.

Ectodermal dysplasia-skin fragility syndrome.

Ectodermal dysplasia-skin fragility (EDSF) syndrome is a rare and first described inherited disorder of desmosomes. It occurs due to loss-of-function mutations in PKP1 gene resulting in poorly formed desmosomes and loss of desmosomal and epidermal integrity. We report a case of a 2-year-old Indian male child who presented with palmoplantar hyperkeratosis with fissuring, short, sparse, and easily pluckable scalp hair, nail dystrophy, and multiple erosions over the skin. Skin biopsy showed epidermal hyperplasia with widening of intercellular spaces. His developmental milestones were delayed but intelligence was normal. Echocardiography, X-ray chest, and electrocardiogram were normal. Very few cases of this syndrome have been reported in the literature. We consider this as the first case report from India.

Molecular diagnostics in genodermatoses - simplified.

The field of genetics in dermatology has progressed at an astonishing rate. Most of the known single gene disorders have at least been mapped to a particular chromosomal region and the causative genes have been identified and studied in many of them. However, most research work in genetics relating to genodermatoses has been confined to the western population. Very few reports, if any, have been published from Indian studies. A first step may be to develop a registry to link most of these cases providing a full description of the clinical phenotype. We would next need to attempt genetic analysis of these conditions thereby detecting any novel mutations in known and unknown genes different from the western population. This would help in designing indigenous assays appropriate to the Indian population. The review describes various techniques used in a molecular biology/ genetics laboratory with special focus on polymerase chain reaction (PCR), gene sequencing, genotyping and DNA micro arrays. Gene identification strategies have also been described with appropriate examples in dermatology.

Screening, early detection, and trends for melanoma: current status (2000-2006) and future directions

In the past 5 years, there have been notable strides toward the earlier recognition and discovery of melanoma, including new technologies to complement and augment the clinical examination and new insights to help clinicians recognize early melanoma. However, incidence and mortality rates throughout most of the developed world have risen over the past 25 years, while education and screening, potentially the best means for reducing the disease, continue to be severely underutilized. Much progress needs to be made to reach middle-aged and older men and persons of lower socioeconomic status who suffer a disproportionate burden of death from melanoma. Worldwide melanoma control must also be a priority, and comprehensive educational and screening programs should be directed to Northern Ireland and a number of Eastern European nations, whose 5-year survival rates range between 53% and 60%, mirroring those of the United States and Australia more than 40 years ago. LEARNING OBJECTIVE: After completing this learning activity, participants should be aware of the most recent melanoma epidemiologic data, both in the United States and internationally; worldwide early detection and screening programs; clinical strategies to recognize and improve the detection of early melanoma; the latest technologies for early detection of melanoma; and public and professional education programs designed to enhance early detection.

Cutaneous signs of child abuse

Maltreatment of children is a major public health crisis, and it is estimated that each year more than 3 million children are victims of abuse. Safeguarding the welfare of children is a priority, and it is the moral and ethical responsibility of healthcare professionals to detect cases of abuse and intervene appropriately to prevent further harm. Clinicians are often challenged to differentiate signs of child abuse from skin conditions that mimic maltreatment. Because cutaneous injury represents the most recognizable and common form of abuse, dermatologists are often called upon to help distinguish signs of intentional injury from skin conditions that mimic maltreatment. However, few resources specific to dermatologic signs of abuse exist to aid in diagnosis. A review of the literature will provide an educational resource to assist dermatologists and other clinicians in differentiating cutaneous signs of child abuse, including physical and sexual abuse, from mimickers of inflicted injury. LEARNING OBJECTIVE: After completing this learning activity, participants should be able to distinguish signs of intentional injury from skin conditions that mimic maltreatment and understand the clinician's role in the diagnosis and reporting of cases of suspected child abuse.

Involvement of C4 allotypes in the pathogenesis of human diseases.

The complement system is an important humoral defense mechanism that plays a relevant role against microbial agents, inflammatory response control, and immunocomplex clearance. Classical complement pathway activation is antibody-dependent. The C4 component participates in the initial step of activation, and C4 expression is determined by 2 pairs of allotypes: C4A and C4B. Deficiencies in C4 allotypes have been associated with several diseases. The aim of the present review is evaluate the reported data in the literature regarding specific C4A and C4B deficiencies and characterize their clinical relevance. We searched the MEDLINE and LILACS databases. Papers referring to total C4 deficiency without allotype evaluation and case reports of primary C4 deficiency were not included. Deficiencies in C4 allotypes have been associated with Mycobacterium leprae infection, erythema nodosum, systemic sclerosis with anti-topoisomerase I antibodies, intermediate congenital adrenal hyperplasia with DR5 genotype, diabetes mellitus type 1 with DR3,4 genotype, and diabetes mellitus with antibodies against islet cells. C4 allotype deficiency is also related to C4B deficiency and autoimmune-associated diseases, such as systemic lupus erythematosus, or diseases with an autoimmune component, such as autism. Some reports associate C4A with thyroiditis after delivery as well as limited and systemic sclerosis without anti-topoisomerase I antibodies. However, the studies with C4A and C4B have been concentrated in isolated populations, and some of the studies could not be reproduced by other authors.

Involvement of C4 allotypes in the pathogenesis of human diseases

O sistema complemento constitui um importante sistema de defesa humoral, exercendo papel relevante na resposta contra agentes microbianos, no controle da resposta inflamatória e na depuração de imunocomplexos. A ativação da via clássica é dependente da formação do complexo antígeno-anticorpo. O componente C4 do complemento participa da etapa inicial de ativação desta via e a sua expressão é determinada por dois alótipos : C4A e C4B. A deficiência dos alótipos de C4 tem sido relacionada a várias doenças. O objetivo do presente estudo foi avaliar os dados de literatura que descrevem as deficiências específicas de C4A e C4B com a finalidade de caracterizar seu significado clínico. Foi realizada uma ampla revisão bibliográfica através do MEDLINE e LILACS, avaliando-se os dados de literatura. Excluiu-se estudos com a avaliação de C4 total sem a análise dos alótipos e relatos de caso isolados de deficiência total de C4. Verificou-se que a deficiência dos alótipos de C4 está relacionada com algumas doenças: hanseníase, esclerose sistêmica com anticorpos anti-topoisomerase I, hiperplasia adrenal congênita intermediária com genótipo DR5, diabetes mellitus tipo 1 com genótipo DR3,4 e diabetes mellitus tipo 1 com anticorpos anti-células das ilhotas. Também foram observadas algumas associações entre C4B e doenças auto-imunes como lupus eritematoso sistêmico, ou que se supõe terem um componente autoûimune como o autismo. Estudos demonstraram associações do C4A com tireoidite pós-parto, esclerose limitada e esclerose sistêmica sem anticorpos anti-topoisomerase I. Porém, os estudos dos alótipos de C4 se concentraram em populações isoladas e alguns destes não conseguiram ser reproduzidos por outros autores.

Comparison of the T cell patterns in leprous and cutaneous sarcoid granulomas. Presence of Valpha24-invariant natural killer T cells in T-cell-reactive leprosy together with a highly biased T cell receptor Valpha repertoire.

The T-cell-reactive (eg, tuberculoid and reversal) forms of leprosy represent a well-defined granulomatous reaction pattern against an invading pathogen. The immune response in cutaneous sarcoidosis is a granulomatous condition that pathologically is very similar to T-cell reactive leprosy. However, it lacks a defined causative agent. In view of the role of NKT cells in murine granulomas induced by mycobacterial cell walls, we have searched for the presence of NKT cells in the cutaneous lesions of both leprosy and sarcoidosis. These cells were present in T-cell-reactive leprosy but were undetectable in cutaneous sarcoidosis. We have also studied the TCR Valpha repertoire in the two diseases. In addition to Valpha24(+) NKT cells, all patients with T-cell-reactive leprosy showed a very restricted T-cell-reactive Valpha repertoire with a strong bias toward the use of the Valpha6 and Valpha14 segments. Valpha6 and Valpha14(+) T cells were polyclonal in terms of CDR3 length and Jalpha usage. In contrast, most sarcoidosis patients showed a diverse usage of Valpha chains associated with clonal or oligoclonal expansions reminiscent of antigen-driven activation of conventional T cells. Thus the origin and perpetuation of the two kinds of granulomatous lesions appear to depend on altogether distinct T-cell recruiting mechanisms.

Gamma delta T-cell receptor-positive cells in human skin. I. Incidence and V-region gene expression in granulomatous skin lesions.

BACKGROUND: There have been many reports that gamma delta T-cell receptor (TCR)+ cells respond to mycobacterial antigens in vitro, but there is little available information on human gamma delta TCR+ cells in clinical conditions. OBJECTIVE: Our purpose was to investigate the distribution and involvement of human gamma delta TCR+ cells in granulomatous skin lesions. METHODS: The incidence and V-region gene expression of human gamma delta TCR+ cells was examined in granulomatous skin diseases, including cutaneous tuberculosis and leprosy, by immunohistochemical procedures. RESULTS: gamma delta TCR+ cells in the dermis were increased in most patients with borderline lepromatous leprosy, and they were less frequently found in lepromatous leprosy and erythema nodosum leprosum. Other granulomatous skin lesions, including sarcoidosis, contained only a few gamma delta TCR+ cells. The gamma delta TCR+ cells that were found to be increased in this study were mostly delta TCS1-, BB3+, Ti gamma A+ (V delta 1-, V delta 2+, V gamma 9+). CONCLUSION: The gamma delta TCR+ cells in human granulomatous skin lesions may respond to some mycobacterial antigens, but they do not appear to be directly involved in granuloma formation.