Quality of life and psychological disturbances in adults with atopic dermatitis in the Czech Republic.

Atopic dermatitis (AD) leads to severe psychosocial disturbances that are quite frequently underestimated. We evaluate the quality of life (QoL) of adult patients with AD and their family members using DLQI, B-IPQ, FDLQI questionnaires, observe psychopathological features with CAQ II questionnaire and evaluate correlations between QoL, psychological disturbances and objective/subjective parameters of disease severity. A reduction in QoL has been proven by all questionnaires with statistically significant relationships between all of them. The QoL of the patient (DLQI, B-IPQ) was found to be correlated to FDLQI. We also confirmed statistically significant relationships between DLQI, FDLQI, B-IPQ and objective severity of AD, as evaluated by SCORAD, in DLQI and FDLQI also by TEWL, in B-IPQ also by IgE. All the QoL questionnaires have statistically significant relationship to subjective symptoms (pruritus and sleep disturbance). Interestingly, no significant relationship between QoL and age and extent of eczema in visible localizations was found. CAQ II revealed high numbers of psychological disturbances - the most often paranoia, hypochondria, suicidal depression, anxiety and depression - and high prevalence of suicidal thoughts (10.9%). Although AD is not life-threatening, its negative impact on the QoL of adult patients and their family members/partners can be further influenced by pathological personality traits of the patients.

Genetic predisposition for chronic venous insufficiency in several genes for matrix metalloproteinases (MMP-2, MMP-9, MMP-12) and their inhibitor TIMP-2.

OBJECTIVE: The project was scheduled as a case-control study to investigate the correlation between MMP-2 (rs243864), MMP-9 (3918242), MMP-12 (rs7123600) and TIMP-2 (rs8176329) polymorphisms and chronic venous disease (CVD) risk. The genotype and phenotype research envisages the testing of possible associations between MMP and TIMP-2 genotypes and phenotypes of CVD. MATERIAL AND METHODS: 150 patients with CVD and 227 controls were enrolled into the study. The MMPs and TIMP-2 genotypes were identified by the PCR method and restriction analysis according to standard protocols. RESULTS: The G allele of MMP-2 -790 T/G was 1.85 times more frequent in men with CVD than in the control group (P = 0.008). The T allele of MMP-9 -1562 C/T was observed 2.571 times more frequently in patients with CVD than in the control individuals (both in men and women) with clinically significant specificity (P = 0.0000009). The G allele of MMP-12 rs7123600 was determined 2.082 times more frequently in female patients with CVD than in the control group with clinically significant specificity (P = 0.02). No significant result in TIMP-2 rs8176329 polymorphism in the case-control study was observed. CVD women with G allele in MMP-2 -790 T/G in the genotype-phenotype study are seen to develop ulceration 2.539 times more frequently (P = 0.003). The G allele of MMP-12 rs7123600 was detected 3.167 times more frequently in CVD women with ulceration compared with CVD women without ulceration (P = 0.007). In CVD men in C6 stage, the incidence of AG genotype in rs7123600 MMP-12 polymorphism was found to be 4.675 times higher compared to CVD women with C6 staging (P = 0.005). The AG genotype in TIMP 2 rs8176329 polymorphism was found to be associated with higher risk of tumour (P = 0.01). CONCLUSION: Studying these polymorphisms can contribute to better identification of patients at higher risk of developing CVD, while providing the most appropriate prevention and treatment strategies for limiting the progression and complications of CVD.

[A Case of Delayed Dia-gnosis of Acral Lentiginous Melanoma]. / Prípad pozdne dia-gnostikovaného akrolentiginózního melanomu.

BACKGROUND: Melanoma is a malignant skin disease. The tumor development is caused by an uncontrollable proliferation of melanocytes. The most common occurrence is on the skin, but melanoma may also develop on the mucous membrane, meninges, and eyes. Some melanomas develop from melanocytic nevus. Acral lentiginous melanoma occurs on palms, feet, fingers and under nails, and is the most common type of melanoma for phototype VI. The most important factor for successful treatment of malignant melanoma is an early detection, excision of the primary tumor and histological staging. Surgical treatment of an early-stage melanoma is a key to successful therapy; however, many patients (mostly men) do not seek medical attention before it istoo late. CASE REPORT: This case study presents a 59-year-old patient, who suffers from white coat syndrome and whose finger was amputated for alleged gangrene. Subsequently, brownish black nodules appeared across his arm. Histological examination proved metastases of malignant melanoma. It was only at this phase, when the patient admitted a nevus at the tip of his amputated finger, from which ulceration and gangrene gradually emerged. CONCLUSION: This case demonstrates a combination of multiple unfavorable factors, which led to delayed diagnosis and therapy.

[Squamous cell carcinoma in localized scleroderma]. / Spinocelulárny karcinóm v lozisku cirkumskriptnej sklerodermie.

We present a case of a young 26-year-old woman, who has been suffering from localised scleroderma (morphea) for 15 years. Recently, a lesion on the dorsum of her right foot ulcerated. Based on a CT scan and X-ray a diagnosis of ulcerative osteomyellitis was established. The patient was treated with a combination of antibiotics. Subsequent histological examinations showed granulomatous tissue and chronic inflammatory changes on top of pseudoepiteliomatous hyperplasia. The patients status was deteriorating, which resulted in a limb amputation under the knee. Three months later, there was a metastasis of squamous cell carcinoma found in the patients inguinal lymph node. In spite of combined therapy (surgery, radioterapy and systemic chemotherapy), new metastases occurred and the patient succumbed to the disease several months afterwards. The case was concluded as a squamous cell carcinoma camouflaged by osteomyelitis. Malignant turn of localised sclerodema is very rare. It usually occurs on the lower extremities of patients with a long course of the disease and is associated with pansclerotic or generalised variants of morphea.

[Diffuse plane normolipemic xanthomatosis and necrobiotic xanthogranuloma associated with monoclonal gammopathy--determining the disease stage with PET-CT and treatment experience. Two case studies and literature review]. / Difuzní plosná normolipemická xantomatóza a nekrobiotický xantogranulom, asociované s monoklonální gamapatií--prínos PET-CT pro stanovení rozsahu nemoci a zkusenosti s lécbou. Popis dvou prípadu a prehled literatury.

UNLABELLED: Monoclonal gammopathy may manifest itself through a range of skin disorders, including plane normolipemic xanthoma and necrobiotic xanthogranuloma. The present paper describes two patients with these cutaneous symptoms. The first has extensive areas of skin affected by flat xanthomas, monoclonal gammopathy with > 10% infiltration of bone marrow with clonal plasmocytes and, according to PET-CT, unclear lymphadenopathy in the retroperitoneal area. The size of this lymphadenopathy (histologically no malignant infiltration and no confirmed infectious aetiology) has not changed significantly over a 4-year follow-up. Repeated PET-CT scans showed decrease in SUV value in this infiltration from 7.5 to 3.8. Four cycles of treatment with a combination of bortezomib, cyclophosphamide and dexamethasone brought neither reduction in monoclonal immunoglobulin nor change to skin morphology. We believe that the abdominal lymphadenopathy is associated with xanthomatosis but have been unable to confirm this unequivocally. The second patient is being followed up for more than 10 years, originally for MGUS, later for asymptomatic multiple myeloma. Last year, painful subcutaneous and cutaneous infiltrates, isolated on an upper limb and more frequent on lower limb, started to occur. These infiltrates are palpable. PET-CT imaging provided an excellent depiction of these infiltrates, showing no pathology on the head, chest and abdomen and no osteolytic foci on the skeleton. CT imaging showed clearly numerous infiltrates in the skin and subcutaneous tissue of lower limbs, particularly both shanks, reaching up to 2 cm in depth. The largest infiltrate, measuring 3.5 by 2 by 10 cm, was identified in the distal dorsal part of the right shank. PET imaging of lower limbs showed distinctly pathological accumulation in all infiltrates described above; the accumulation of glucose in the lower part of the right shank reached 10.0 SUV. CT images of lower limbs showed increased density saturated hypodermis even in the areas where there is no increased accumulation of 18 fluoroglucose. Following 40 Gy irradiation, the size of infiltrate in the radiated area decreased and their soreness ceased. CONCLUSION: PET-CT imaging offered information on extra-cutaneous signs of plane normolipemic xanthomas and provided excellent depiction of the areas of the skin and hypodermis affected by necrobiotic xanthogranuloma. Chemotherapy with cyclophosphamide, bortezomib and dexamethasone brought no reduction in monoclonal immunoglobulin concentration, and no reduction in plane normolipemic xanthomas. Radiotherapy targeted at large foci of xanthogranulomas led to partial regression and ceased infiltrate soreness.

[Skin adverse effects of amiodarone]. / Nezádoucí úcinky amiodaronu na kuzi.

BACKGROUND: Amiodarone has belonged to frequently used antiarrhythmic in the treatment of supraventricular and ventricular tachyarrhytmias since the sixties of the twentieth century. Amiodarone is a chemically iodinated benzofuran derivative with mono-N-desethylamiodarone as its major metabolite. OBJECTIVE: This review is focused on numerous adverse reactions. The incidence of amiodarone induced side-effects ranges from 16-98% of patients receiving amiodarone and it appears to be dose related. CASE REPORTS: We describe three cases of hyperpigmentation after using amiodarone in elder men. CONCLUSION: Skin side effects are common, they usually occur as photosensitivity, more rarely as a slate-grey discoloration of the skin. Amiodarone induced slate-grey pigmentation is commonly observed in unprotected light exposed skin. Its incidence ranges from 2-57%. Hyperpigmentation is due to accumulation of amiodarone and its metabolites in the skin.

[IgA pemphigus accompanying multiple myeloma has disappeared following the treatment with bortezomib (Velcade), cyclophosphamide and dexamethasone. Case study and literature review]. / IgA pemfigus provázející mnohocetný myelom vymizel pri lécbe bortezomibem (Velcade), cyklofosfamidem a dexametazonem. Popis prípadu a prehled literatury.

IgA pemphigus, resembling subcorneal pustulous dermatosis, represents a rare complication of IgA type monoclonal gammopathy. The patient dates the onset of initial symptoms of vesicular-bullous disease to 1990. She was first examined at our clinic in 2001 with the following conclusion "type IgA monoclonal gammopathy of unknown significance". The first immunosuppressive treatment of vesicular-bullous disorder was administered in 2003 (dexamethasone 20 mg on days 1-4 and 15-18 in monthly cycles + daily cyclophosphamide 50 mg). Cyclophosphamide was administered for 6 months in total and dexamethasone for further 3 months. During the treatment, intensity of the skin disorder ameliorated and monoclonal IgA levels decreased to non-detectable levels. Nevertheless, skin symptoms recurred immediately after dexamethasone treatment in its original intensity was terminated, even though the concentration of monoclonal immunoglobulin IgA remained below the sensitivity of quantitative detection for further 6 months (positive immunofixation only). Six rituximab 600 mg infusions were administered in a weekly interval after stopping cyclophosphamide and dexamethasone to prevent early recurrence of skin symptoms but this treatment was without any lasting effect. Transformation into multiple myeloma was identified in 2007. First line treatment (cyclophosphamide, adriamycin and dexamethasone - CAD) remained without any haematological or dermatological treatment response. Second line treatment (thalidomide, cyclophosphamide and dexamethasone - CTD) brought about significant deterioration of skin symptoms up to the clinical picture of erythrodermia. Third line treatment (bortezomib 1.3 mg/sqm i.v. on days 1,4, 8 and 15, cyclophosphamide 50 mg daily and dexamethasone 20 mg on days 1-4 and 15-18 in 28-day cycles - VCD) resulted in rapid decline in monoclonal immunoglobulin IgA concentrations immediately following the first cycle and to negative immunofixation after 5 cycles. In total, six VCD cycles were administered. The patient has had no skin symptoms from the third cycle of this treatment and complete skin and haematological remission has been maintained for 12 months after completion of bortezomib-containing treatment. Combined treatment containing bortezomib has proven useful in the treatment of IgA pemphigus accompanying monoclonal gammopathy of uncertain significance transformed into multiple myeloma.

[Langerhans cell histiocytosis in adult patients--a disease with many faces. Experience of a centre and an overview of the disease symptoms]. / Histiocytóza z Langerhansových bunek u osob dospelého veku--nemoc s mnoha tváremi. Zkusenosti jednoho pracoviste a prehled projevu nemoci.

Over a period of 18 years, 17 patients with proven Langerhans cell histiocytosis (LCH) were treated at the Haematological Clinic in Brno. In 13 of them, the disease was diagnosed at adult age, and 4 patients were referred to the centre with LCH diagnosed at early child age. One of these 4 patients suffered from repeated recurrences of the disease at adult age and was diagnosed with progressive neurodegenerative damage of the CNS at the age of 25 which in its terminal phase resulted in the patient's immobility, loss of sphincter control, incapacity to communicate and death at the age of 32. LCH was diagnosed at adult age in 13 patients. The form with primary bone involvement was detected in 8 out of 13 patients (62%). Only 2 of 13 patients (15%) had multiple bone lesions upon diagnosis, the remaining 6 patients (46%) had only one lesion at the time of diagnosis. Repeated recurrence of bone involvement was only recorded in 3 out of 13 patients (23%). The combination of recurrent bone involvement and the development of lung affection (dyspnoea, irritating cough, nodularities and cysts in HRCT images) were documented in 2 out of 13 patients (15%). One of the patients diagnosed with LCH at the age of37 had repeated recurrence of bone involvement, which was also treated by 2 cycles of high-dose chemotherapy and autologous transplantation. He died of bronchopneumonia due to the affection of the lungs by LCH at 48 years of age. Primary extraoseal (extamedular) involvement was diagnosed in 5 out of 13 patients (38%) (mandibular gum infiltration, single cervical node infiltration, hand skin infiltration, infiltration of the perineal region and infiltration of the hypophysial infundibular and primary lung form of LCH). In the 1st case, excision was the solution applied to the infiltration of the lingual side ofthe gums, without further recurrence. In the 2nd case, the infiltrated region of skin over the metacarpophalangeal joint was irradiated and the infiltration disappeared. In the 3rd case, the first sign ofthe disease was diabetes insipidus in a 34-year-old man, and an infiltrate in the anal region similar to condylomata acuminata. The diagnosis was confirmed 2 years after the development of diabetes insipidus from perianal infiltrates. After treatment with leustatin in 4 cycles (10 mg a day for 5 consecutive days), control MR showed that the infiltration in the hypophysial infundibular had disappeared, while the finding in the perianal region only regressed by 50% after therapy with leustatin, the reason for subsequent application of radiotherapy (20 Gy). The finding in the perianal region is normal one year after therapy, but substitution therapy with adiuretin is still necessary. The 4th patient was a case of LCH with primary pulmonary involvement diagnosed on the basis of HRCT and lavage with an immunohistochemical proof (expression of CD1 and of protein S-100) of a high number of Langerhans cells. The occurrence of LCH at adult age is rare and the disease may affect the skeleton as well as other organs. Therefore each new osteolytic lesion should be submitted for histological exam, as well as each pathologic formation, because diagnosing the disease without a microscopic and immunohistochemical exams is not possible. In the case of occurrence of diabetes insipidus at adult age, LCH should be considered as one of the possible underlying diseases. LCH pulmonary involvement should be considered in patients with an interstitial pulmonary process and the examinations should be focused accordingly (thoracoscopy with sampling for histological exams or bronchoalveolar lavage) plus the indispensable immunohistochemical examination.

[Systemic and paraneoplastic manifestations of malignant diseases]. / Systémové a paraneoplastické projevy maligních onemocnení.

Timely diagnosis of malignant diseases largely depends on attention being given to early symptoms and on timely start of an extensive diagnostic process. Only this way can a tumour be diagnosed in its initial stage, and better effect of therapy can be achieved. The following overview provides a list of systemic (paraneoplastic - distant) manifestations of a tumour, and of symptoms related to local tumour expansion. The objective of the overview is to draw attention to all early symptoms of malignant diseases in patients, and to contribute to timely diagnosis and treatment.

[Association of polymorphic variants in endothelin-1 (EDN1) genes with the therapy of patients with cutaneous T-cell lymphomas]. / Asociace variant polymorfismu v genu pro endotelin-1 (EDN1) s terapií u pacientu s kozními T lymfomy.

BACKGROUND: The cutaneous T-cell lymphomas (CTCL) are diseases characterised by cutaneous infiltrates of malignant, clonally expanded T-cells. Because individual genetic determination of angiogenetic and antioxidant properties of blood vessels could take part in responsibility to phototherapy in CTCL patients, the association of two frequent polymorphisms in endothelin-1 gene with phototherapy was tested. METHODS AND RESULTS: 77 patients with CTCL, diagnosed and treated at the First Dermatological Clinic of St. Ann's Faculty Hospital Bmo (46 men and 31 women, median age 62, range 28-82 years) were included in the study. Diagnosis of CTCL according to the clinical picture was verified histologically. The genotype distributions and allelic frequencies between CTCL with phototherapy and those without phototherapy were compared. The 4A4A variant of -3A/-4A EDN1 is more frequent in patients treated with phototherapy (8/30 vs. 1/38, OR=10.13; P=0.01). The GA and AA genotypes of G8002A EDN1 polymorphism are more frequent in CTCL patients treated with phototherapy compared to those without it (15/23 vs. 7/32, OR=2.98; P=0.03). CONCLUSIONS: Some polymorphic variants in EDN1 genes, a homozygote -4A-4A in -3A/-4A EDN1 and genotypes GA and GG in G8002A EDN1) seem to carry an advantage for phototherapy effectiveness in patients with CTCL.

Association of variants in angiotensin-converting enzyme and endothelin-1 genes with phototherapy in cutaneous T-cell lymphoma.

BACKGROUND: The cutaneous T-cell lymphoma (CTCL) is a disease characterised by cutaneous infiltrates of malignant, clonally expanded T-cells. Because individual genetic determination of angiogenetic and antioxidant properties of blood vessels could be partly responsible for phototherapy in CTCL patients, three polymorphisms in angiotensin converting enzyme and endothelin-1 genes were determined. METHODS: 77 patients with CTCL, diagnosed and treated at the First Dermatological Clinic of St. Ann's Faculty Hospital Brno (46 men and 31 women, median age 62, range 26-80 years) were compared to a control non-CTCL group of the similar age and gender distribution (n=203: 137 men and 66 women, median age 54, range 27-86 years) with negative family history of severe skin diseases and without signs of malignancy. Diagnosis of CTCL was verified according to the clinical picture and histologically. The genotype distributions and allelic frequencies between CTCL with phototherapy and those without phototherapy were compared. RESULTS: Significant differences were found in genotype distributions of I/D ACE polymorphism between CTCL patients treated with phototherapy and those treated without it. Heterozygote ID was more frequent in the group treated with phototherapy (25/13 vs. 12/27, OR=4.33, 95% confidential interval 1.67-11.24, P=0.02. The 4A4A variant of -3A/-4A EDN1 is more frequent in patients treated with phototherapy (8/30 vs. 1/38, OR=10.13, 95% confidential interval 1.20-85.55, P=0.01). The GA and AA genotypes of G8002A EDN1 polymorphism are more frequent in CTCL patients treated with phototherapy compared to those without it (15/23 vs. 7/32, OR=2.98, 95% confidential interval 1.05-8.48, P=0.03). DISCUSSION: Some polymorphic variants in ACE and EDN1 genes (a heterozygote ID in I/D ACE, a homozygote -4A-4A in -3A /-4A EDN1 and genotypes GA and GG in G8002A EDN1) seem to carry an advantage for phototherapy effectiveness in patients with CTCL.

Genotype association of C(-735)T polymorphism in matrix metalloproteinase 2 gene with G(8002)A endothelin 1 gene with plaque psoriasis.

BACKGROUND: Excessive angiogenesis is one of the characteristic features of psoriasis. OBJECTIVE: To determine the possible genetic background of neo-angiogenesis in plaque psoriasis, frequent polymorphisms in matrix metalloproteinase 2 (MMP-2) and endothelin 1 (ET-1) genes were studied. METHODS: The case group (n = 119) included patients with plaque psoriasis, aged 44 +/- 15 years. The age of onset of psoriasis was 27 +/- 11 years. The control group (n = 184) consisted of healthy subjects without any individual history of psoriasis, aged 37 +/- 15 years. C(-735)T MMP-2 and G(8002)A ET-1 polymorphisms were determined by PCR reaction with subsequent restriction analyses. RESULTS: A significant difference in genotype distribution of C(-735)T MMP-2 between psoriatic and control patients was found (p(corr) = 0.008). Two associated genotypes (CCGG and CTGG) of the two polymorphisms were significantly less frequent in psoriatic patients (p(corr) = 0.03 and p(corr) = 0.008, respectively). CONCLUSION: The results seem to reflect a different susceptibility of MMP-2 as well as of some associated MMP-2 and ET-1 genotypes to psoriasis.

Gene polymorphisms (G82S, 1704G/T, 2184A/G and 2245G/A) of the receptor of advanced glycation end products (RAGE) in plaque psoriasis.

Having in mind the relationships among oxidative stress, psoriasis and common disorders, the association between polymorphisms in the gene encoding the receptor for advanced glycation end products (RAGE) and plaque psoriasis, including patients with a personal history of diabetes mellitus, cardiovascular disorders, cancer and allergy, was investigated. The allele frequencies and genotype distribution combinations of the four polymorphisms in the RAGE gene (6p21.3, G82S, 1704G/T, 2184A/G and 2245A/G) were compared in a case-control study of 272 subjects (130 patients with plaque psoriasis and 142 healthy control subjects of comparable age and sex distribution). The polymerase chain reaction with subsequent restriction analysis was used for detection of genotype variants. There was a significantly higher frequency of the 2184G allele of the 2184A/G RAGE polymorphism in psoriatic patients than in the control subjects (odds ratio 2.18, 95% CI 1.32-3.59, P=0.001). The 2184G allele occurred more often in psoriatic patients with a negative history of cardiovascular diseases (odds ratio 2.38, 95% CI 1.35-4.18, P=0.001, Pcorr=0.004), in those with a negative history of diabetes mellitus (odds ratio 2.05, 95% CI 0.1.22-3.45, P=0.004, Pcorr=0.012) and in those with a negative history of cancer (odds ratio 1.97, 95% CI 1.17-3.31, P=0.007, Pcorr=0.014) compared with the corresponding control subjects. We conclude that the 2184G allele of the RAGE gene is a significant risk factor for plaque psoriasis. The risk is associated with the non-presence of some common, especially cardiovascular, diseases in psoriatic patients.

Polymorphisms in inflammation genes (angiotensinogen, TAP1 and TNF-beta) in psoriasis.

This study focused on the association between plaque psoriasis and polymorphisms of several inflammation genes. Included in the study were 142 Caucasian (Czech) patients with plaque psoriasis and 141 healthy subjects. The genotypes of the polymorphisms in angiotensinogen [M235T ATG, A(-6)G ATG], in transporters associated with antigen processing TAP1 (TAP1*0101, TAP*02011 and TAP1*0301) and in lymphotoxin alpha (TNFbeta) (NcoI in intron 1) were detected by polymerase chain reaction-based methods and restriction enzyme analysis. An increase in B1 (less frequent) allele of NcoI TNFbeta polymorphism was found in psoriatic patients compared to healthy individuals (odds ratio = 1.6, 95% confidence interval 1.13-2.26, P = 0.006). A positive family history of psoriasis was associated with a higher B1 allele frequency in NcoI TNFbeta (P = 0.011). Hardy-Weinberg disequilibrium was found in TAP1 polymorphism A-->G at nucleotide 1207 in psoriatic patients. A case-control difference was found in the allelic concurrence of M235T and A(-6)G ATG polymorphisms. The most frequent population genotypes MMGG, MTAG and TTAA were observed in 92% of patients vs 74% of control subjects (odds ratio 0.29, 95% confidence interval 0.14-0.60, P = 0.0003). A positive history of tonsillitis and/or tonsillectomy was associated with a higher T allele frequency of the M235T ATG polymorphism (P = 0.037) as well as with a higher G allele frequency of the A(-6)G ATG polymorphism (P = 0.022). Polymorphisms in proinflammatory angiotensinogen and TNFbeta genes were associated with plaque psoriasis, a positive family history of psoriasis and with frequent tonsillitis in childhood.

[Objective assessment of the effect of sodium lauryl sulfate on the surface of the skin in childhood]. / Beitrag zur Objektivierung des Einflusses von Natriumlaurylsulfat auf die Hautoberfläche im Kindesalter.

The influence of sodium lauryl sulfate on physiological properties of the skin surface in children was assessed by continuous measuring of electric conductivity in the course of iontophoresis with physiological solution. The results achieved have shown that even very low concentrations of sodium lauryl sulfate (0.1% water solution) provoke changes of physiological properties in the skin surface. A concentration of 0.5% has been established to be the limit concentration of sodium lauryl sulfate which can evidently injure the barrier functions. The degree of changes in electric conductivity was not dependent on the intensity of the skin irritation.