Ljiljana Medenica

Systemic retinoids in chemoprevention of non-melanoma skin cancer.

Background: The incidence of non-melanoma skin cancer is increasing worldwide. Systemic retinoids are useful for the chemoprophylaxis of non-melanoma skin cancers. Retinoids have pleiotropic effects, but their exact cancer chemopreventive mechanism is still not clear. Objective: The aim of this study was to review published literature evaluating the use of oral retinoids in the chemoprevention of non-melanoma skin cancers. Methods: The study reviewed all relevant papers found through a search of the electronic databases MEDLINE (from 1966 to January 2008) and Embase (from 1974 to January 2008). Results/conclusion: General and specific indications for retinoid chemoprophylaxis are defined. The pharmacokinetics and dose regimens of the two most commonly used oral retinoids (isotretinoin and acitretin) in the chemoprevention of non-melanoma skin cancers are presented. The use of oral retinoids is associated with adverse effects, which are discussed in detail. The future of retinoid cancer chemoprevention depends on the development and research of novel retinoids with improved bioavailability and minimized toxicity.

Antioxidative capacity of C60 (buckminsterfullerene) and newly synthesized fulleropyrrolidine derivatives encapsulated in liposomes

C60 (buckminsterfullerene or fullerene C60) has been recognized an efficient free‐radical scavenger. Owing to its high antioxidative capacity, C60 and its derivatives have a great potential for application in biological systems where prevention of oxidative cell damage is desirable. However, poor solubility of native C60 in water represents a major drawback for its use in biological systems. In order to increase the efficiency of delivery of fullerenes to target tissues it is of great interest to enhance their water solubility by developing hydrophilic organoderivatives of C60 with retained antioxidative properties, and/or by encapsulating fullerenes in biocompatible liposomes. In the present study, using EPR spin‐trapping and spin‐labelling techniques, we investigated the antioxidative capacity of C60 and newly synthesized fulleropyrrolidine derivatives Q‐C60 [N‐methyl‐(2‐quinolyl)fulleropyrrolidine60] and I‐C60 [N‐methyl‐(2‐indolyl)fulleropyrrolidine60] encapsulated in multilamellar phospholipid liposomes. The capacity for removal of •OH (hydroxyl radical) and O2•− (superoxide radical) and for the prevention of lipid peroxidation should be stressed as the most relevant biological antioxidative parameters. When these parameters for novel organofullerenes were compared with the the performance of C60, Q‐C60 and I‐C60 showed similar, or even better, antioxidative characteristics. However, further research is required to establish the toxicity of these derivatives and their antioxidant efficacy in vivo.

Novel and Recurrent FERMT1 Gene Mutations in Kindler Syndrome

Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.

Bullous Pemphigoid Induced by Penicillamine in a Patient with Wilson Disease

We report a 47-year-old man with Wilson disease who developed bullous lesions on the trunk and extremities after 20 years of penicillamine treatment. The histologic and immunofluorescence findings were diagnostic of bullous pemphigoid. When penicillamine was replaced by zinc sulfate, the patient’s bullous skin lesions improved rapidly. However, after 2 months of zinc sulfate treatment, the patient’s skin condition remained improved but his neurologic disease became worse and penicillamine was reinstituted. Bullous lesions recurred within 1 week and the diagnosis of penicillamine-induced bullous pemphigoid was confirmed. This is the first report of penicillamine-induced bullous pemphigoid in a patient with Wilson disease.

Prospective studies on the routine use of a novel multivariant enzyme-linked immunosorbent assay for the diagnosis of autoimmune bullous diseases

Background: Serologic diagnosis of autoimmune blistering disease (AIBD) usually follows a sophisticated multistep algorithm. Objective: We sought validation of a multivariant enzyme‐linked immunosorbent assay (ELISA) in the routine diagnosis of AIBD. Methods: The multivariant ELISA comprising 6 recombinant immunodominant forms of major AIBD target antigens, ie, desmoglein 1, desmoglein 3, envoplakin, BP180, BP230, and type VII collagen was applied in: (1) a cohort of well‐characterized AIBD (n = 173) and control sera (n = 130), (2) a prospective multicenter study with 204 sera from patients with newly diagnosed AIBD with positive direct immunofluorescence microscopy, and (3) a prospective monocenter study with 292 consecutive sera from patients with clinical suspicion of AIBD in comparison with the conventional multistep diagnostic algorithm. Results: Concordant results in the multivariant ELISA compared with direct immunofluorescence microscopy were seen in 94% of patients with pemphigus and 71% of patients with pemphigoid (Cohen &kgr; value, 0.95 and 0.66) and with the conventional multistep diagnostic approach in 91% of patients with pemphigus and 88% of patients with bullous pemphigoid and 93% of autoantibody‐negative sera (Cohen &kgr;, 0.95, 0.84, and 0.78). Limitations: IgA autoantibodies and less common target antigens were not analyzed. Conclusions: The multivariant ELISA is a practical, highly standardized, and widely available novel diagnostic tool for the routine diagnosis of AIBD.

Dexamethasone-cyclophosphamide pulse therapy in pemphigus: a review of 72 cases.

AbstractBackground: Autoimmune pemphigus is a group of severe blistering diseases. Although corticosteroids have dramatically altered the prognosis of pemphigus, morbidity and mortality resulting from the adverse effects of systemic corticosteroids remain high. Dexamethasone-cyclophosphamide pulse (DCP) therapy was introduced to diminish the adverse effects of prolonged conventional daily dose regimens. Objective: To report our experience with the use of the DCP regimen in patients with autoimmune pemphigus. Methods: In the period 1998–2002, 72 patients with various forms of autoimmune pemphigus treated with DCP therapy were included, of whom 36 patients were previously treated with conventional corticosteroid therapy, and 36 were newly diagnosed patients. Results: Of the 72 patients, 43 completed treatment, while 13 patients did not respond adequately to the treatment and continued with the conventional daily regimen, nine patients were lost to follow-up, and seven patients died. Two of these deaths were probably a consequence of DCP therapy. Conclusion: DCP regimen is a beneficial treatment for patients with pemphigus, sparing the adverse effects of conventional regimens.

Stevens–Johnson syndrome and toxic epidermal necrolysis: a 20‐year single‐center experience

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life‐threatening diseases that are most frequently caused by drugs.

Pemphigus vulgaris and pemphigus foliaceus determined by CD86 and CTLA4 polymorphisms

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are rare autoimmune blistering diseases with presumed T-cell-dependent pathology. Activation of naïve T cells is dependent on antigen recognition, subsequent signaling through the T-cell receptor complex (signal 1), and various other interactions of T cells with antigen presenting cells that may be collectively designated as signal 2, which is unconditionally required for T-cell activation both in response to infection and to autoantigens. Among the best described interactions contributing to signal 2 are those mediated by B7 family molecules, such as CD80 and CD86 with their ligands; CD28, providing activation signals; and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), conferring inhibition. Single nucleotide polymorphisms (SNPs) within genes encoding those molecules may alter the signaling process. It is not known whether functional genetic polymorphisms within genes encoding the aforementioned proteins may increase risk for developing PV and PF and, if so, whether they might serve as biomarkers for susceptibility to these diseases. To address those questions, we examined functional single nucleotide polymorphisms within CD86 (rs1129055) and CTLA4 (rs733618 and rs5742909) genes in 61 pemphigus patients and 486 healthy controls. We found statistically significant differences in allele and genotype frequencies between PV patients and controls for rs1129055, as well as for rs5742909 among PV and PF patients. Namely, the rs1129055 A allele was significantly more common in PV patients compared with controls (35.4% versus 25.7%, respectively; P = .040), whereas the rs5742909 T allele was significantly more common in PF compared with PV patients (19.2% versus 5.2%, respectively; P = .035). The frequency of the rs5742909 T allele did not, however, differ significantly in PF or in PV compared with controls (10.5%; P = .187 and P = .100, respectively). We report a novel association of SNPs within CD86 and CTLA4 genes with pemphigus. The CD86 rs1129055 A allele appears to confer susceptibility to PV but not to PF.

TNF, IL12B, and IFNG Gene Polymorphisms in Serbian Patients with Psoriasis

Background Psoriasis is a common chronic inflammatory skin disease with a strong genetic basis. Cytokines such as tumor necrosis factor alpha (TNF-α), interleukins (ILs) such are IL-12 and IL-23, and interferon gamma (IFN-γ) are released from various inflammatory and resident cells, and have been implicated in the initiation/maintenance of inflammation. Certain alleles of the aforementioned cytokines may be associated with disease susceptibility/severity. Objective To investigate the association of three common functional gene polymorphisms, namely TNF -308 G/A (rs1800629), IL12B (encoding the p40 subunit of IL-12/23) +1188 A/C (rs3212227), and IFNG +874 T/A (rs2430561) with psoriasis development and severity in Serbian patients. Methods We genotyped 130 patients with psoriasis (26 of whom also had psoriatic arthritis) and 259 controls; rs1800629 and rs3212227, and rs2430561, by real-time PCR assay. Results The TNF GG genotype was detected at a higher frequency in patients with psoriasis compared to control subjects (OR, 1.420; 95% CI, 0.870~2.403) without statistical significance (p=0.191). Lack of the TNF G allele was associated with lower psoriasis severity (p=0.007). The IL12B AC genotype was underrepresented in the patients with psoriatic arthritis compared to healthy subjects (OR, 0.308; 95% CI, 0.090~1.057; p=0.049). The distribution of the rs2430561 allele and genotype frequencies was similar between patients with psoriasis and controls. Conclusion Our study demonstrates an effect of the rs1800629 on psoriasis severity, and a marginal impact of the rs3212227 on susceptibility to psoriatic arthritis. Collectively, our results obtained in a Serbian cohort expand current knowledge regarding individual predisposition to psoriatic disease.

Laugier-Hunziker syndrome - Case report

Laugier-Hunziker syndrome is a rare, acquired disorder characterized by lenticular hyperpigmentation of the oral mucosa and longitudinal melanonychia. We present the case of a 63-year-old female with progressive, asymptomatic hyperpigmentation of buccal mucosa and a 7-year history of hyperpigmentation in several fingernails. Laugier-Hunziker syndrome was diagnosed based on the clinical features presented, dermoscopic findings and exclusion of underlying systemic diseases. Laugier-Hunziker syndrome is regarded as a diagnosis of exclusion. By identifying Laugier-Hunziker syndrome, other, more severe syndromes associated with hyperpigmentations can be excluded, namely Addison’s disease and Peutz-Jeghers syndrome.