Afatinib-induced toxic epidermal necrolysis: A case report with a literature review.

We present a 70-year-old female patient diagnosed with epidermal growth factor receptor-mutated metastatic non-small cell lung cancer (T4N2M1a), who developed afatinib-induced toxic epidermal necrolysis (TEN). We have also performed a PubMed/Medline literature review to detect other possible cases of TEN/Stevens-Johnson syndrome associated with afatinib treatment and found only 5 other cases reported. To our best knowledge, this is the first case of afatinib-induced TEN successfully treated with cyclosporine.

Dermatologist-like explainable AI enhances trust and confidence in diagnosing melanoma.

Artificial intelligence (AI) systems have been shown to help dermatologists diagnose melanoma more accurately, however they lack transparency, hindering user acceptance. Explainable AI (XAI) methods can help to increase transparency, yet often lack precise, domain-specific explanations. Moreover, the impact of XAI methods on dermatologists' decisions has not yet been evaluated. Building upon previous research, we introduce an XAI system that provides precise and domain-specific explanations alongside its differential diagnoses of melanomas and nevi. Through a three-phase study, we assess its impact on dermatologists' diagnostic accuracy, diagnostic confidence, and trust in the XAI-support. Our results show strong alignment between XAI and dermatologist explanations. We also show that dermatologists' confidence in their diagnoses, and their trust in the support system significantly increase with XAI compared to conventional AI. This study highlights dermatologists' willingness to adopt such XAI systems, promoting future use in the clinic.

Fusion partners of NTRK3 affect subcellular localization of the fusion kinase and cytomorphology of melanocytes.

A subset of Spitz tumors harbor fusions of NTRK3 with ETV6, MYO5A, and MYH9. We evaluated a series of 22 melanocytic tumors in which an NTRK3 fusion was identified as part of the diagnostic workup. Tumors in which NTRK3 was fused to ETV6 occurred in younger patients were predominantly composed of epithelioid melanocytes and were classified by their histopathologic features as Spitz tumors. In contrast, those in which NTRK3 was fused to MYO5A were predominantly composed of spindled melanocytes arrayed in fascicles with neuroid features such as pseudo-Verocay bodies. To further investigate the effects of the fusion kinases ETV6-NTRK3 and MYO5A-NTRK3 in melanocytes, we expressed them in immortalized melanocytes and determined their subcellular localization by immunofluorescence. ETV6-NTRK3 was localized to the nucleus and diffusely within the cytoplasm and caused melanocytes to adopt an epithelioid cytomorphology. In contrast, MYO5A-NTRK3, appeared excluded from the nucleus of melanocytes, was localized to dendrites, and resulted in a highly dendritic cytomorphology. Our findings indicate that ETV6-NTRK3 and MYO5A-NTRK3 have distinct subcellular localizations and effects on cellular morphology.

Indoor salt water baths followed by artificial ultraviolet B light for chronic plaque psoriasis.

BACKGROUND: Chronic plaque psoriasis is an immune-mediated, chronic, inflammatory skin disease, which can impair quality of life and social interaction. Disease severity can be classified by the psoriasis area and severity index (PASI) score ranging from 0 to 72 points. Indoor artificial salt bath with or without artificial ultraviolet B (UVB) light is used to treat psoriasis, simulating sea bathing and sunlight exposure; however, the evidence base needs clear evaluation. OBJECTIVES: To assess the effects of indoor (artificial) salt water baths followed by exposure to artificial UVB for treating chronic plaque psoriasis in adults. SEARCH METHODS: We searched the following databases up to June 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trial registers, and checked the reference lists of included studies, recent reviews, and relevant papers for further references to relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of salt bath indoors followed by exposure to artificial UVB in adults who have been diagnosed with chronic plaque type psoriasis. We included studies reporting between-participant data and within-participant data. We evaluated two different comparisons: 1) salt bath + UVB versus other treatment without UVB; eligible comparators were exposure to psoralen bath, psoralen bath + artificial ultraviolet A UVA) light, topical treatment, systemic treatment, or placebo, and 2) salt bath + UVB versus other treatment + UVB or UVB only; eligible comparators were exposure to bath containing other compositions or concentrations + UVB or UVB only. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence. The primary efficacy outcome was PASI-75, to detect people with a 75% or more reduction in PASI score from baseline. The primary adverse outcome was treatment-related adverse events requiring withdrawal. For the dichotomous variables PASI-75 and treatment-related adverse events requiring withdrawal, we estimated the proportion of events among the assessed participants. The secondary outcomes were health-related quality of life using the Dermatology Life Quality Index, (DLQI) pruritus severity measured using a visual analogue scale, time to relapse, and secondary malignancies. MAIN RESULTS: We included eight RCTs: six reported between-participant data (2035 participants; 1908 analysed), and two reported within-participant data (70 participants, 68 analysed; 140 limbs; 136 analysed). One study reported data for the comparison salt bath with UVB versus other treatment without UVB; and eight studies reported data for salt bath with UVB versus other treatment with UVB or UVB only. Of these eight studies, only five reported any of our pre-specified outcomes and assessed the comparison of salt bath with UVB versus UVB only. The one included trial that assessed salt bath plus UVB versus other treatment without UVB (psoralen bath + UVA) did not report any of our primary outcomes. The mean age of the participants ranged from 41 to 50 years of age in 75% of the studies. None of the included studies reported on the predefined secondary outcomes of this review. We judged seven of the eight studies as at high risk of bias in at least one domain, most commonly performance bias. Total trial duration ranged between at least two months and up to 13 months. In five studies, the median participant PASI score at baseline ranged from 15 to 18 and was balanced between treatment arms. Three studies did not report PASI score. Most studies were conducted in Germany; all were set in Europe. Half of the studies were multi-centred (set in spa centres or outpatient clinics); half were set in a single centre in either an unspecified settings, a psoriasis daycare centre, or a spa centre. Commercial spa or salt companies sponsored three of eight studies, health insurance companies funded another, the association of dermatologists funded another, and three did not report on funding. When comparing salt bath plus UVB versus UVB only, two between-participant studies found that salt bath plus UVB may improve psoriasis when measured using PASI 75 (achieving a 75% or more reduction in PASI score from baseline) (risk ratio (RR) 1.71, 95% confidence interval (CI) 1.24 to 2.35; 278 participants; low-certainty evidence). Assessment was conducted at the end of treatment, which was equivalent to six to eight weeks after start of treatment. The two trials which contributed data for the primary efficacy outcome were conducted by the same group, and did not blind outcome assessors. The German Spas Association funded one of the trials and the funding source was not stated for the other trial. Two other between-participant studies found salt bath plus UVB may make little to no difference to outcome treatment-related adverse events requiring withdrawal compared with UVB only (RR 0.96, 95% CI 0.35 to 2.64; 404 participants; low-certainty evidence). One of the studies reported adverse events, but did not specify the type of events; the other study reported skin irritation. One within-participant study found similar results, with one participant reporting severe itch immediately after Dead Sea salt soak in the salt bath and UVB group and two instances of inadequate response to phototherapy and conversion to psoralen bath + UVA reported in the UVB only group (low-certainty evidence). AUTHORS' CONCLUSIONS: Salt bath with artificial ultraviolet B (UVB) light may improve psoriasis in people with chronic plaque psoriasis compared with UVB light treatment alone, and there may be no difference in the occurrence of treatment-related adverse events requiring withdrawal. Both results are based on data from a limited number of studies, which provided low-certainty evidence, so we cannot draw any clear conclusions. The reporting of our pre-specified outcomes was either non-existent or limited, with a maximum of two studies reporting a given outcome. The same group conducted the two trials which contributed data for the primary efficacy outcome, and the German Spas Association funded one of these trials. We recommend further RCTs that assess PASI-75, with detailed reporting of the outcome and time point, as well as treatment-related adverse events. Risk of bias was an issue; future studies should ensure blinding of outcome assessors and full reporting.

Smell and taste in titanium and nickel allergic sensitization in orthodontic patients.

OBJECTIVE: To assess the prevalence of allergic sensitization to titanium and nickel in orthodontic patients and to evaluate alterations of smell and taste. SUBJECTS AND METHODS: A total of 250 subjects were invited to participate, 245 accepted. The age range was 11-45 years, 68% were females and 52% adolescents. An epicutaneous patch test was performed. Of the positive subjects in the patch test, 26 participated in the taste and smell testing and were matched by age and sex with 26 negative subjects. RESULTS: The prevalence of hypersensitivity to titanium and/or nickel in orthodontic patients was 15.5%. Taste and smell were more impaired in sensitized subjects (P ≤ .025), taste was more affected than smell and the tastes most affected were sour and bitter tastes, while the sweet taste was least impaired. CONCLUSION: The allergic sensitization to titanium is more uncommon than to nickel, with altered smell and taste related to those hypersensitivities.

Spitz melanoma is a distinct subset of spitzoid melanoma.

Melanomas that have histopathologic features that overlap with those of Spitz nevus are referred to as spitzoid melanomas. However, the diagnostic concept is used inconsistently and genomic analyses suggest it is a heterogeneous category. Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations, such as kinase fusions or HRAS mutations. It is unclear what fraction of "spitzoid melanomas" defined solely by their histopathologic features belong to the category of Spitz melanoma or to other melanoma subtypes. We assembled a cohort of 25 spitzoid melanomas diagnosed at a single institution over an 8-year period and performed high-coverage DNA sequencing of 480 cancer related genes. Transcriptome wide RNA sequencing was performed for select cases. Only nine cases (36%) had genetic alterations characteristic of Spitz melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8. The remaining cases were divided into those with an MAPK activating mutation and those without an MAPK activating mutation. Both Spitz melanoma and spitzoid melanomas in which an MAPK-activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid melanomas with non-Spitz MAPK-activating mutations. The MAPK-activating mutations identified affected non-V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1, and KIT, while BRAF V600 mutations, the most common mutations in melanomas of the WHO low-CSD category, were entirely absent. While the "spitzoid melanomas" comprising our cohort were enriched for bona fide Spitz melanomas, the majority of melanomas fell outside of the genetically defined category of Spitz melanomas, indicating that histomorphology is an unreliable predictor of Spitz lineage.

Early laser intervention to reduce scar formation in wound healing by primary intention: A systematic review.

BACKGROUND: Hypertrophic scars frequently follow primary closure of surgical wounds. Laser application at or shortly after suture may be associated with a reduction in scar formation, although the respective study results vary. AIM: The objective was to evaluate the efficacy of early laser applied within the first six months after surgery to reduce scar formation compared to no treatment. METHODS: We searched the databases MEDLINE and CENTRAL on 14 January 2019 and included randomized controlled trials (RCTs). Primary outcome was the Vancouver Scar Scale (VSS). Measure of treatment effect was the mean difference from baseline. RESULTS: Seventeen relevant RCTs randomized 430 scars (413 assessed) and compared laser versus no treatment. Fourteen studies applied a split-scar and three applied a simple parallel design. Three studies with a split-scar design favored the laser group on VSS, and one study had indifferent findings. Considerable heterogeneity I2 = 86% did not justify a meta-analysis. The remaining 13 studies did not report appropriate data. CONCLUSION: On the basis of the currently available evidence, we are uncertain whether early laser can reduce scar formation, and more high-quality research is needed for a definitive conclusion.

Interventions for pityriasis rosea.

BACKGROUND: Pityriasis rosea is a scaly, itchy rash that mainly affects young adults and lasts for 2 to 12 weeks. The effects of many available treatments are uncertain. This is an update of a Cochrane Review first published in 2007. OBJECTIVES: To assess the effects of interventions for the management of pityriasis rosea in any individual diagnosed by a medical practitioner. SEARCH METHODS: We updated our searches of the following databases to October 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We searched five trials registers. We also checked the reference lists of included and excluded studies, contacted trial authors, scanned the abstracts from major dermatology conference proceedings, and searched the CAB Abstracts database. We searched PubMed for adverse effects to November 2018. SELECTION CRITERIA: Randomised controlled trials of interventions in pityriasis rosea. Treatment could be given in a single therapy or in combination. Eligible comparators were no treatment, placebo, vehicle only, another active compound, or placebo radiation treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane. Our key outcomes were good or excellent rash improvement within two weeks, rated separately by the participant and medical practitioner; serious adverse events; resolution of itch within two weeks (participant-rated); reduction in itch score within two weeks (participant-rated); and minor participant-reported adverse events not requiring withdrawal of the treatment. MAIN RESULTS: We included 14 trials (761 participants). In general, risk of selection bias was unclear or low, but risk of performance bias and reporting bias was high for 21% of the studies. Participant age ranged from 2 to 60 years, and sex ratio was similar. Disease severity was measured by various severity indices, which the included studies did not categorise. Six studies were conducted in India, three in Iran, two in the Philippines, and one each in Pakistan, the USA, and China. The included studies were conducted in dermatology departments and a paediatric clinic. Study duration ranged from 5 to 26 months. Three studies were funded by drug manufacturers; most studies did not report their funding source. The included studies assessed macrolide antibiotics, an antiviral agent, phototherapy, steroids and antihistamine, and Chinese medicine. None of the studies measured participant-rated good or excellent rash improvement. All reported outcomes were assessed within two weeks of treatment, except for adverse effects, which were measured throughout treatment. There is probably no difference between oral clarithromycin and placebo in itch resolution (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.47 to 1.52; 1 study, 28 participants) or rash improvement (medical practitioner-rated) (RR 1.13, 95% CI 0.89 to 1.44; 1 study, 60 participants). For this comparison, there were no serious adverse events (1 study, 60 participants); minor adverse events and reduction in itch score were not measured; and all evidence was of moderate quality. When compared with placebo, erythromycin may lead to increased rash improvement (medical practitioner-rated) (RR 4.02, 95% CI 0.28 to 56.61; 2 studies, 86 participants, low-quality evidence); however, the 95% CI indicates that the result may also be compatible with a benefit of placebo, and there may be little or no difference between treatments. Itch resolution was not measured, but one study measured reduction in itch score, which is probably larger with erythromycin (MD 3.95, 95% CI 3.37 to 4.53; 34 participants, moderate-quality evidence). In the same single, small trial, none of the participants had a serious adverse event, and there was no clear difference between groups in minor adverse events, which included gastrointestinal upset (RR 2.00, CI 0.20 to 20.04; moderate-quality evidence). Two trials compared oral azithromycin to placebo or vitamins. There is probably no difference between groups in itch resolution (RR 0.83, 95% CI 0.28 to 2.48) or reduction in itch score (MD 0.04, 95% CI -0.35 to 0.43) (both outcomes based on one study; 70 participants, moderate-quality evidence). Low-quality evidence from two studies indicates there may be no difference between groups in rash improvement (medical practitioner-rated) (RR 1.02, 95% CI 0.52 to 2.00; 119 participants). In these same two studies, no serious adverse events were reported, and there was no clear difference between groups in minor adverse events, specifically mild abdominal pain (RR 5.82, 95% CI 0.72 to 47.10; moderate-quality evidence). Acyclovir was compared to placebo, vitamins, or no treatment in three trials (all moderate-quality evidence). Based on one trial (21 participants), itch resolution is probably higher with placebo than with acyclovir (RR 0.34, 95% CI 0.12 to 0.94); reduction in itch score was not measured. However, there is probably a significant difference between groups in rash improvement (medical practitioner-rated) in favour of acyclovir versus all comparators (RR 2.45, 95% CI 1.33 to 4.53; 3 studies, 141 participants). Based on the same three studies, there were no serious adverse events in either group, and there was probably no difference between groups in minor adverse events (only one participant in the placebo group experienced abdominal pain and diarrhoea). One trial compared acyclovir added to standard care (calamine lotion and oral cetirizine) versus standard care alone (24 participants). The addition of acyclovir may lead to increased itch resolution (RR 4.50, 95% CI 1.22 to 16.62) and reduction in itch score (MD 1.26, 95% CI 0.74 to 1.78) compared to standard care alone. Rash improvement (medical practitioner-rated) was not measured. The trial reported no serious adverse events in either group, and there may be no difference between groups in minor adverse events, such as headache (RR 7.00, 95% CI 0.40 to 122.44) (all results based on low-quality evidence). AUTHORS' CONCLUSIONS: When compared with placebo or no treatment, oral acyclovir probably leads to increased good or excellent, medical practitioner-rated rash improvement. However, evidence for the effect of acyclovir on itch was inconclusive. We found low- to moderate-quality evidence that erythromycin probably reduces itch more than placebo. Small study sizes, heterogeneity, and bias in blinding and selective reporting limited our conclusions. Further research is needed to investigate different dose regimens of acyclovir and the effect of antivirals on pityriasis rosea.

Tumor Necrosis Factor Antagonists in the Treatment of Pyoderma Gangrenosum, Acne, and Suppurative Hidradenitis (PASH) Syndrome.

The clinical triad of pyoderma gangrenosum (PG), acne and suppurative hidradenitis (HS) has been described under the acronym PASH syndrome and is considered to represent a distinct entity in the group of autoinflammatory diseases. It is a fairly new, only recently recognized disorder with a limited number of reported cases and without defined treatment recommendations. We aimed to summarize currently available data on the use of tumor necrosis factor (TNF) antagonists in the management of PASH syndrome and report on our own experience with the use of adalimumab in a patient presenting with this specific constellation of clinical signs and symptoms. Among the 11 cases identified in the literature, infliximab and adalimumab were the most commonly used agents, both exhibiting favorable effects in the majority of, but not all, patients. This was particularly evident in terms of relatively rapid remission of PG whereas HS lesions seemed to be more resistant to treatment. In our patient, adalimumab monotherapy resulted in a remarkable and sustained remission, although significant improvement of HS lesions was observed only from week 16 of therapy onwards. In summary, TNF antagonists are a promising treatment for PASH; however, conclusions regarding the choice of a specific agent, optimal dosing or use in combination with other treatment modalities cannot yet be drawn.

Cytotoxic T lymphocytes as a potential brake of keratinocyte proliferation in psoriasis.

Psoriasis is a chronic papulosquamous skin disease, histologically characterized by epidermal hyperproliferation and dermal infiltration of inflammatory cells. The majority of T lymphocytes infiltrating dermis are CD4+ T lymphocytes secreting type 1 and type 17 cytokines. These cytokines are responsible for triggering keratinocyte proliferation as well as chemokine secretion and subsequent migration of other inflammatory cells in the skin. Contrarily, lymphocytes that accumulate in epidermis are mainly CD8+ T lymphocytes. According to the recent findings, these cells can also secrete type 1 and type 17 cytokines. However, it is demonstrated so far that epidermal CD8+ T lymphocytes contain higher amounts of cytolytic molecules, such as perforin, granzyme B and granulysin whose role in psoriasis pathogenesis is still unknown. Therefore, in this article we hypothesize the active involvement of cell mediated cytotoxicity in killing the proliferating keratinocytes as a mechanism of potential self-defense and possible brake in psoriatic plaque formation, maintaining skin homeostasis.

Negative and positive life experiences in patients with psoriatic arthritis.

Recent data suggest that childhood and adulthood stressors may play a significant role in the development of an autoimmune disease. The present study explores the relationship between psoriatic arthritis (PsA) and positive and negative life events during childhood and adulthood in psoriatic patients. Forty-five patients with psoriatic arthritis and 101 controls (patients with skin conditions considered to be "non-psychosomatic") were enrolled in the study. All participants completed a specific questionnaire measuring traumatic life experiences [Traumatic Antecedents Questionnaire (TAQ)]. The TAQ assesses positive personal experiences (competence and safety) and negative personal experiences (neglect, separation, secrets, emotional, physical and sexual abuse, trauma witnessing, other traumas and exposure to alcohol/drugs) from early childhood to adulthood. The patients with psoriatic arthritis exhibited lower mean scores of total positive experiences during late childhood (latency) as compared to the control group. Negative experiences during four developmental periods appeared more frequently in patients with psoriatic arthritis than in the controls. The most frequently reported negative experiences were neglect, emotional abuse, physical abuse, sexual abuse, alcohol/drug abuse and other traumas. The present findings add evidence to the relationship between retrospectively reported childhood experiences and psoriatic arthritis. Furthermore, a high amount of reported emotional and physical abuse occurs in patients with psoriatic arthritis during latency and adolescence.

Expression of TWEAK in normal human skin, dermatitis and epidermal neoplasms: association with proliferation and differentiation of keratinocytes.

BACKGROUND: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of various inflammatory pathologies and cancer. We aimed to investigate its expression in normal human skin, inflammatory skin diseases and epidermal neoplasms. METHODS: Immunohistochemistry for TWEAK was performed in samples of healthy skin, plaque psoriasis, lichen planus, prurigo nodularis, discoid lupus erythematosus, lichen sclerosus, seborrheic keratosis, common warts, actinic keratosis, Bowen's disease, keratoacanthoma and basal and squamous cell carcinoma. Double immunofluorescence was used to investigate co-localization of TWEAK with cytokeratin-10 and proliferating cell nuclear antigen (PCNA). RESULTS: TWEAK was robustly expressed in the epidermis of healthy skin and decreased in inflammatory conditions, both in the context of epidermal hyperplasia and atrophy. Decreased TWEAK immunoreactivity was regularly observed in common warts, actinic keratosis and Bowen's disease, particularly in areas of marked proliferation as evidenced by PCNA-positive nuclei. In squamous cell carcinoma, expression of TWEAK ranged from strong to completely absent, and it mostly corresponded with the expression of cytokeratin-10. TWEAK was absent in keratoacanthoma and basal cell carcinoma. CONCLUSIONS: TWEAK is a constitutively expressed epidermal protein whose downregulation might be an early indicator of disturbed differentiation or pathologic proliferation of keratinocytes that accompany inflammatory and neoplastic skin diseases.

Increased expression of TRAIL and its death receptors DR4 and DR5 in plaque psoriasis.

TNF-related apoptosis-inducing ligand (TRAIL) is recognized as an important regulator of immune responses during infections and various autoimmune-mediated pathologies. Its role in inflammatory dermatoses is largely unknown. We aimed to investigate the expression of TRAIL and its receptors DR4 and DR5 in psoriasis vulgaris. Immunohistochemistry for TRAIL, DR4 and DR5 was performed on samples of lesional (n = 10) and non-lesional (n = 10) skin of patients with plaque psoriasis and skin of healthy volunteers (n = 10). Expression of TRAIL and its receptors was further examined by means of double immunofluorescence staining and co-localization with CD4, CD8, CD11c, CD68, CD16 and CD56 markers. Immunohistochemical staining for TRAIL was significantly enhanced in psoriatic lesional as well as non-lesional epidermis compared to the epidermis of healthy skin. Lesional epidermis also showed increased immunoreactivity for DR5. In addition, expression of TRAIL and both of its receptors was significantly increased in the dermis of lesional skin. As evidenced by double immunofluorescence, TRAIL was readily expressed by most of the examined cells of the inflammatory infiltrate in psoriatic lesions. In contrast, the expression of DR4 was found mostly among CD4+ and CD8+ cells but was only nuclear, while DR5 showed cytoplasmic staining in rare CD16+, CD56+ and CD68+ cells. According to abundant in situ presence of TRAIL and its receptors in lesional psoriatic skin, it seems that this cytokine participates in the complex interplay between keratinocytes and cells of the dermal infiltrate and thus contributes to the inflammatory cycle in psoriasis vulgaris.

[The role of perforin mediated cell cytotoxicity in psoriasis]. / Uloga stanicne citotoksicnosti posredovane perforinom u psorijazi.

Psoriasis is a common chronic inflammatory skin disease characterized by hyperproliferation and incomplete differentiation of epidermal keratinocytes as well as by inflammatory infiltrate of T-lymphocytes in dermis and epidermis. Psoriasis is nowadays also recognized as a T cell mediated disease resulting from aberrant activation of both innate and adaptive immunity. The main effector cells in mediating psoriatic phenotype are helper CD4+ T cells and cytotoxic CD8+ T cells. Both, CD4+ and CD8+ T cells, mediate apoptosis via the release of cell granules, perforin and granzymes or by binding of ligands to their death receptors on target cells. The role of cell cytotoxicity mechanisms, particularly those mediated by perforin, in psoriasis is as yet unclear. Perforin is a pore forming molecule, located within the cytoplasm of cytotoxic T cells and natural killer cells, which enables entry of granzymes and other apoptotic molecules into the target cell in order to mediate programmed cell death. The importance of perforin-mediated cytotoxicity has been demonstrated in several autoimmune diseases and in some inflammatory skin diseases. Recent studies claimed its role in the immunopathogenesis of psoriasis as well. Accumulation of perforin-positive cells in psoriatic epidermis close to damaged keratinocytes suggests that T lymphocytes induce damage to keratinocytes by releasing cytolytic molecules. On the other hand, apoptotic keratinocytes might trigger an injury response program causing regenerative hyperplasia of epidermal keratinocytes, a hallmark of psoriasis. Progress in understanding of effector part of cell cytotoxicity in psoriatic plaque might in future enable more specific treatment of psoriatic patients by blocking selectively each of proposed cytolytic mechanisms and molecules as potential new therapeutic targets.

The role of CD4 and CD8 lymphocytes and macrophages in psoriasis vulgaris.

Current knowledge of the immunopathogenesis of psoriasis vulgaris is based on the crucial role of CD4 and CD8 lymphocytes. Also, the connection of activated lymphocytes with macrophages, especially dendritic cells and plasmacytoid dendritic cells, is considered to be significant. In the present study, the expression of CD4+ lymphocytes as well as CD8+ lymphocytes (P < 0.001) and macrophages (P < 0.001) was found to be significantly increased in lesional skin epidermis and dermis in psoriasis vulgaris patients as compared with healthy skin. These findings suggested a cascade or chain reaction with cells and cytokines playing an important role to be involved in the immunopathogenesis of psoriasis vulgaris.

Treatment of severe psoriasis with infliximab: report of two cases.

Infliximab is an anti-tumor necrosis factor-monoclonal antibody shown to be effective in the treatment of moderate-to-severe psoriasis and psoriatic arthritis. We report on the first two patients in Croatia in which the efficacy of infliximab therapy was monitored and evaluated primarily on the basis of cutaneous manifestations of psoriasis. Both patients had severe, treatment-resistant chronic plaque psoriasis and psoriatic arthritis and were on methotrexate therapy before the initiation and throughout the course of infliximab treatment. Infliximab was administered intravenously at a dose of 4 or 5 mg/kg at week 0, 2, 6 and every 8 weeks thereafter. Disease severity was measured before each infusion by means of Psoriasis Area and Severity Index (PASI) score. A remarkable clinical response was achieved in both patients with a 50% or greater improvement in baseline PASI at week 2 after therapy initiation and a 90% or greater improvement at week 6 in one patient and at week 14 in the other. Both patients also reported a significant decline in their arthritis symptoms shortly after the introduction of infliximab. The concomitant use of infliximab and methotrexate in these two patients resulted in rapid and sustained remission of psoriasis with no major adverse effects detected.

Effects of the hyperbaric oxygen treatment on the Na+,K+ -ATPase and superoxide dismutase activities in the optic nerves of global cerebral ischemia-exposed rats.

The effects of hyperbaric oxygen (HBO) treatment on the Na+,K+ -ATPase and superoxide dismutase (SOD) activities were examined in the optic nerves of the rats exposed to global cerebral ischemia. Animals were exposed to global cerebral ischemia of 20-min duration and were either sacrificed or exposed to the first HBO treatment immediately, 0.5, 1, 2, 6, 24, 48, 72 or 168 h after ischemic procedure (for Na+,K+ -ATPase activities measurement) or 2, 24, 48 or 168 h after ischemia (for SOD activities measurement). HBO procedure was repeated for 7 consecutive days. It was found that global cerebral ischemia induced a statistically significant decrease in the Na+,K+ -ATPase activity of the optic nerves, starting from 0.5 to 168 h of reperfusion. Maximal enzymatic inhibition was registered 24 h after the ischemic damage. The decline in the Na+,K+ -ATPase activity was prevented in the animals exposed to HBO treatment within the first 6 h of reperfusion. The results of the presented experiments demonstrated also a statistically significant increase in the SOD activity after 24, 48 and 168 h of reperfusion in the optic nerves of non-HBO-treated ischemic animals as well as in the ischemic animals treated with HBO. Our results indicate that global cerebral ischemia induced a significant alterations in the Na+,K+ -ATPase and SOD activities in the optic nerves during different periods of reperfusion. HBO treatment, started within the first 6 h of reperfusion, prevented ischemia-induced changes in the Na+,K+ -ATPase activity, while the level of the SOD activity in the ischemic animals was not changed after HBO administration.