Eleonora Ruocco

Beneficial Long-Term Effects of Combined Oral/Topical Antioxidant Treatment with the Carotenoids Lutein and Zeaxanthin on Human Skin: A Double-Blind, Placebo-Controlled Study

Background: The skin is exposed to numerous environmental assaults that can lead to premature aging. Of these agents, perhaps none is more ubiquitous than the ultraviolet (UV) wavelengths of sunlight. The primary immediate defense against environmental skin damage is the antioxidant capacity of the skin. However, this defense system can be compromised by moderate exposure to UV light. Therefore, bolstering the antioxidant defense system of the skin is a potentially important strategy for reducing environmentally induced skin damage. Aim of the Study: This clinical trial was designed to study the efficacy of lutein and zeaxanthin, two potentially important antioxidants found naturally in the skin, upon five skin physiology parameters (surface lipids, hydration, photoprotective activity, skin elasticity and skin lipid peroxidation – malondialdehyde) of human subjects. These xanthophyllic carotenoids were administered either orally, topically, or in combination (both oral and topical routes). Results: The results obtained indicate that the combined oral and topical administration of lutein and zeaxanthin provides the highest degree of antioxidant protection. However, oral and topical administration of these antioxidants individually also provides significant activity in the skin. In addition, oral administration of lutein may provide better protection than that afforded by topical application of this antioxidant when measured by changes in lipid peroxidation and photoprotective activity in the skin following UV light irradiation.

The immunocompromised district: a unifying concept for lymphoedematous, herpes-infected and otherwise damaged sites.

Systemic immunodeficiency is known to facilitate the onset of opportunistic infections, tumours and immune disorders in any district of the body. There are clinical events, such as chronic lymphoedema, herpetic infections, vaccinations and heterogeneous physical injuries which can selectively damage and immunologically mark the cutaneous district they act upon. After the causing event has disappeared, the affected district may appear clinically normal, but its immune behaviour is often compromised forever. An immunocompromised district becomes a site which is particularly susceptible to subsequent outbreaks of opportunistic infections, tumours and immune disorders confined to the district itself.

Three-point checklist of dermoscopy

Background: Dermoscopy used by experts has been demonstrated to improve the diagnostic accuracy for melanoma. However, little is known about the diagnostic validity of dermoscopy when used by nonexperts. Objective: To evaluate the diagnostic performance of nonexperts using a new 3-point checklist based on a simplified dermoscopic pattern analysis. Methods: Clinical and dermoscopic images of 231 clinically equivocal and histopathologically proven pigmented skin lesions were examined by 6 nonexperts and 1 expert in dermoscopy. For each lesion the nonexperts assessed 3 dermoscopic criteria (asymmetry, atypical network and blue-white structures) constituting the 3-point method. In addition, all examiners made an overall diagnosis by using standard pattern analysis of dermoscopy. Results: Asymmetry, atypical network and blue-white structures were shown to be reproducible dermoscopic criteria, with a kappa value ranging from 0.52 to 0.55. When making the overall diagnosis, the expert had 89.6% sensitivity for malignant lesions (tested on 68 melanomas and 9 pigmented basal cell carcinomas), compared to 69.7% sensitivity achieved by the nonexperts. Remarkably, the sensitivity of the nonexperts using the 3-point checklist reached 96.3%. The specificity of the expert using overall diagnosis was 94.2% compared to 82.8 and 32.8% achieved by the nonexperts using overall diagnosis and 3-point checklist, respectively. Conclusion: The 3-point checklist is a valid and reproducible dermoscopic algorithm with high sensitivity for the diagnosis of melanoma in the hands of non-experts. Thus it may be applied as a screening procedure for the early detection of melanoma.

Bullous pemphigoid: Etiology, pathogenesis, and inducing factors: Facts and controversies

The term pemphigoids includes a group of autoimmune bullous diseases characterized by subepidermal blistering. Bullous pemphigoid (BP) is not only the most common disorder within the pemphigoid group, but also represents the most frequent autoimmune blistering disease in general. The onset and course of BP depend on a variable interaction between predisposing and inducing factors. HLA genes are the most significant genetic predisposition factor to autoimmunity mechanisms. Many studies show an association between HLA-DQβ1*0301 and distinct clinical pemphigoid variants. Imbalance between autoreactive T helper (Th) and T regulatory cells, toll-like receptor activation, and Th17/IL-17 pathway are the three possible autoimmunity triggers underlying BP. The pathomechanism of BP hinges on an autoantibody response toward structural components of the hemidesmosome (BP180 and BP230). The binding of autoantibodies leads to complement activation, recruitment of inflammatory cells, and release of proteolytic enzymes. The inflammatory cascade also may be directly triggered by activation of Th17 cells with no intervention of autoantibodies. The intervention of inducing factors in BP can be identified in no more than 15% of patients. Facilitating factors in genetically predisposed individuals are various (drug intake, physical agents, and viral infections). Drugs may act as triggers by either modifying the immune response or altering the antigenic properties of the epidermal basement membrane. Cases of induction of BP by physical agents (eg, radiation therapy, ultraviolet radiation, thermal or electrical burns, surgical procedures, transplants) are rare, but well-documented events. A contributing role in inducing BP has been suggested for infections, in particular human herpes virus (HHV) infections (cytomegalovirus, Epstein-Barr virus, and HHV-6), but also hepatitis B and C viruses, Helicobacter pylori, and Toxoplasma gondii. Unlike pemphigus, no dietary triggers have been suspected of being involved in the induction of BP. In all patients who have a diagnosis of BP, an environmental agent as a potential cause should always be considered, because the prompt discontinuation of it might result in rapid improvement or even cure of the disease.

Detection of herpesvirus DNA in peripheral blood mononuclear cells and skin lesions of patients with pemphigus by polymerase chain reaction

Pemphigus is an autoimmune disease where both endogenous (genetic) and exogenous (environmental) factors play a part. Viral infections, in particular herpesvirus infections, have been identified as a possible triggering factor for pemphigus. In this study, using the polymerase chain reaction, we studied peripheral blood mononuclear cells (PBMC) and skin biopsies from patients with pemphigus, and in some of these were able to demonstrate the presence of DNA sequences of herpes simplex virus 1/2 (50% in PBMC and 71% in skin biopsies), Epstein–Barr virus (15% in PBMC and 5% in skin biopsies) and human herpesvirus 6 (20% in PBMC only). However, the inability to detect herpesvirus DNA consistently in these cases suggests that viral infection may only be an occasional factor triggering the outbreak or exacerbation of the disease. The possible role of interferons and interleukins in the pathogenesis of virus‐induced pemphigus is discussed.

Kaposi's sarcoma: aetiopathogenesis, histology and clinical features

Kaposis sarcoma (KS) represents today one of the most common skin cancers in transplanted Mediterranean subjects and, since the epidemic of human immunodeficiency virus/acquired immune deficiency syndrome, in young unmarried single men. The disease has been associated with the recent identified human herpesvirus (HHV)‐8 or KS herpesvirus and its incidence in the general population shows a north to south gradient that parallels the HHV‐8 increasing prevalence from Nordic countries to sub‐Saharan regions. The identification of the aetiopathogenetic mechanisms (viral agents and immunodeficiency) involved in the pathogenesis of KS, are relevant for identifying susceptible subjects (HHV‐8 seropositive subjects), monitoring the immune levels in iatrogenic immune suppressed patients, and developing new therapeutic approaches based on antiviral and immune modulators.

Possible role of Malassezia furfur in psoriasis: modulation of TGF‐β1, integrin, and HSP70 expression in human keratinocytes and in the skin of psoriasis‐affected patients

Background:  Psoriasis is a disease characterized by an abnormal pattern of keratinocyte growth and differentiation. Malassezia furfur forms part of the normal human skin flora. It may also be involved in the pathogenesis of psoriasis. To define the role of M. furfur in the pathogenesis of psoriasis, we investigated how M. furfur regulates molecules involved in cell migration and proliferation. The experiments were performed using human keratinocytes and skin biopsies from M. furfur‐positive and ‐negative psoriasis‐affected patients. In addition, we examined the signal transduction mechanisms involved.

Pemphigus: Associations and management guidelines: Facts and controversies

Pemphigus, a prototypical organ-specific human autoimmune disease, may be associated with other immunity-related disorders, viral infections, and different types of tumors. Coexistence with immune diseases is fairly frequent and, for some of them (eg, myasthenia gravis, Basedows disease, rheumatoid arthritis, or lupus erythematosus), common pathogenic mechanisms can be considered. The association with viral infections (mainly herpesvirus infections) raises the question of whether the virus triggers the outbreak of the disease or simply complicates its clinical course. Neoplastic proliferations coexisting with pemphigus have a different histogenesis and the pathogenic link may vary according to the associated tumor (thymoma, lymphoma, carcinoma, or sarcoma). A subset of pemphigus-neoplasia association is represented by Anhalts paraneoplastic pemphigus, with peculiar clinical, histologic, and immunologic features characterizing it. Coexistence of pemphigus with Kaposis sarcoma, albeit not frequent, offers an intriguing speculative interest. The cornerstone of management in pemphigus is the combination of systemic corticosteroids and immunosuppressants. The conventional treatment used in most cases is based on oral administration of deflazacort and azathioprine. In selected cases, mycophenolate mofetil is preferred to azathioprine. Severe forms of pemphigus require intravenous pulse therapy with dexamethasone (or methylprednisolone) and cyclophosphamide. In the recent years, the use of high-dose intravenous immunoglobulin therapy has gained several consents. Rituximab, a monoclonal anti-CD 20 antibody, which affects both the humoral and cell-mediated responses, has proved to give a good clinical response, often paralleled by decrease of pathogenic autoantibodies. The combination with intravenous immunoglobulin offers the double advantage of better clinical results and a reduced incidence of infection. Interventional treatments, such as plasmapheresis and extracorporeal immunoadsorption, are aimed at patients with life-threatening forms of pemphigus and high levels of circulating autoantibodies, a circumstance where the medical therapy alone risks failing. Second-line treatments include gold salts (which we do not favor because of the acantholytic potential inherent in thiol structure) and the association of oral tetracyclines with nicotinamide, which is rather safe. Local treatments, supplementary to the systemic therapy, are aimed at preventing infections and stimulating reepithelialization of eroded areas. Innovative topical treatments are epidermal growth factor, nicotinamide gel, pimecrolimus, and a proteomics-derived desmoglein peptide. Pemphigus patients should be warned against over-indulging in unnecessary drug intake, prolonged exposure to ultraviolet rays, intense emotional stress, and too spiced or too hot foods. Cigarette smoking is not contraindicated in pemphigus patients because of the nicotine anti-acantholytic properties.

Kaposi’s sarcoma: Etiology and pathogenesis, inducing factors, causal associations, and treatments: Facts and controversies

Abstract Kaposis sarcoma (KS), an angioproliferative disorder, has a viral etiology and a multifactorial pathogenesis hinged on an immune dysfunction. The disease is multifocal, with a course ranging from indolent, with only skin manifestations to fulminant, with extensive visceral involvement. In the current view, all forms of KS have a common etiology in human herpesvirus (HHV)-8 infection, and the differences among them are due to the involvement of various cofactors. In fact, HHV-8 infection can be considered a necessary but not sufficient condition for the development of KS, because further factors (genetic, immunologic, and environmental) are required. The role of cofactors can be attributed to their ability to interact with HHV-8, to affect the immune system, or to act as vasoactive agents. In this contribution, a survey of the current state of knowledge on many and various factors involved in KS pathogenesis is carried out, in particular by highlighting the facts and controversies about the role of some drugs (quinine analogues and angiotensin-converting enzyme inhibitors) in the onset of the disease. Based on these assessments, it is possible to hypothesize that the role of cofactors in KS pathogenesis can move toward an effect either favoring or inhibiting the onset of the disease, depending on the presence of other agents modulating the pathogenesis itself, such as genetic predisposition, environmental factors, drug intake, or lymph flow disorders. It is possible that the same agents may act as either stimulating or inhibiting cofactors according to the patient’s genetic background and variable interactions. Treatment guidelines for each form of KS are outlined, because a unique standard therapy for all of them cannot be considered due to KS heterogeneity. In most cases, therapeutic options, both local and systemic, should be tailored to the patient’s peculiar clinical conditions.

Malassezia furfur invasiveness in a keratinocyte cell line (HaCat): effects on cytoskeleton and on adhesion molecule and cytokine expression

Abstract The lipophilic yeast Malassezia furfur is a member of the cutaneous microbiota, also associated with several chronic diseases such as pityriasis versicolor, folliculitis, seborrhoeic dermatitis, and some forms of atopic dermatitis, psoriasis and confluent and reticulate papillomatosis. In this study we determined the immunomodulatory and invasive capacity of M. furfur in a human keratinocyte cell culture, HaCat. At a yeast cell to HaCat ratio of 30 : 1, M. furfur penetration was only 30% with poor phagolysosome fusion and with cytoskeleton modification. Transglutaminase I gene expression was also inhibited, supporting the hypothesis that M. furfur causes an initial break in the barrier function of the epidermis. Moreover, we demonstrated that M. furfur modulates proinflammatory and immunomodulatory cytokine synthesis by downregulating IL-1α and by inhibiting IL-6 and TNF-α and by upregulating IL-10 and TGF-β1. The suppressed inflammatory response induced by M. furfur may play a role in chronic disease.