Hypoxic Gene Signature of Primary and Metastatic Melanoma Cell Lines: Focusing on HIF-1ß and NDRG-1

Background: Hypoxia is an important microenvironmental factor significantly affecting tumor proliferation and progression. The importance of hypoxia is, however, not well known in oncogenesis of malignant melanoma. Aims: To evaluate the difference of hypoxic gene expression signatures in primary melanoma cell lines and metastatic melanoma cell lines and to find the expression changes of hypoxia-related genes in primary melanoma cell lines at experimental hypoxic conditions. Study Design: Cell study. Methods: The mRNA expression levels of hypoxia-related genes in primary melanoma cell lines and metastatic melanoma cell lines and at experimental hypoxic conditions in primary melanoma cell lines were evaluated by using real-time polymerase chain reaction. Depending on the experimental data, we focused on two genes/proteins, the hypoxia-inducible factor-1 beta and the N-myc downstream regulated gene-1. The expression levels of the two proteins were investigated by immunohistochemistry methods in 16 primary and metastatic melanomas, 10 intradermal nevi, and a commercial tissue array comprised of 208 cores including 192 primary and metastatic malignant melanomas. Results: The real-time polymerase chain reaction study showed that hypoxic gene expression signature was different between metastatic melanoma cell lines and primary melanoma cell lines. Hypoxic experimental conditions significantly affected the hypoxic gene expression signature. In immunohistochemical study, N-myc downstream regulated gene-1 expression was found to be lower in primary cutaneous melanoma compared to in intradermal nevi (p=0.001). In contrast, the cytoplasmic expression of hypoxia-inducible factor-1 beta was higher in primary cutaneous melanoma than in intradermal nevi (p=0.001). We also detected medium/strong significant correlations between the two proteins studied in the study groups. Conclusion: Hypoxic response consists of closely related proteins in more complex pathways. These findings will shed light on hypoxic processes in melanoma and unlock a Pandora's box for development of new therapeutic strategies.

PCR investigation of Panton-Valentine leukocidin, enterotoxin, exfoliative toxin, and agr genes in Staphylococcus aureus strains isolated from psoriasis patients.

BACKGROUND/AIM: Staphylococcus aureus colonization is a determiner of disease activation in psoriasis patients. Here we evaluate the presence of genes encoding Panton-Valentine leukocidin (PVL), enterotoxins, TSST-1, exfoliative toxins, and the accessory gene regulatory locus by polymerase chain reaction (PCR) in S. aureus isolates obtained from healthy and diseased skin regions and anterior nares of psoriasis patients and healthy controls. MATERIALS AND METHODS: The presence of PVL and toxin genes was investigated, and agr typing was performed by PCR. RESULTS: Eighteen of the isolated strains carried the sei, 1 carried the seb-sec, and 1 carried the seg enterotoxin gene. Eight of the strains carrying enterotoxin genes were isolated from nasal swabs, 6 from diseased skin swabs, and 4 from healthy skin swabs. None of the strains isolated from the control group carried the agr locus. On the other hand, 11 of the S. aureus strains isolated from the patients carried type 1, 7 carried type 1 + 3, 4 carried type 2, 4 carried type 3, and 1 carried type 1 + 2 agr loci. CONCLUSION: Enterotoxin production and the carried accessory gene regulatory locus may be important in the aggravation of psoriasis.

Clear cell sarcoma.

Malignant melanoma (MM) of soft tissue, also called clear cell sarcoma (CCS) of tendons and aponeuroses, derives from the neural crest. CCS is similar morphologically to MM but has no precursor skin lesion, and instead, has a characteristic chromosomal translocation. Prognosis is related to the tumor size. Early recognition and initial radical surgery is the key to a favorable outcome. The tumor has to be differentiated from other benign and malignant lesions of the soft tissues, such as fibrosarcoma. The demonstration of melanin and a positive immunohistochemical reaction for S-100 protein and HMB-45 can assist in the differential diagnosis. We report the case of a 58-year-old woman with CCS arising from the soft tissue of her little finger.

Tangier disease in a Turkish family.

In this report we describe the upper gastrointestinal tractus involvement in a rare genetic disease of lipid metabolism. A 12-year-old boy presented with sore throat and fever. On physical examination, orange-yellow tonsils and adenoid tissue were noted. Mild hepatosplenomegaly was present. Lipid profile was compatible with Tangier disease (TD). Endoscopy of the upper gastrointestinal tract showed white-yellowish fatty deposits on the gastric mucosa. Microscopically, biopsy specimens contained numerous histiocytes with a foamy cytoplasm packed in the lamina propria of the gastric mucosa and at the crypt basement of the duodenum. His sister, 8 years old, was also diagnosed with TD based on abnormal lipid profile and orange-yellow tonsils. TD is a rare familial disorder of lipid metabolism, characterized by deposition of cholesteryl esters, probably involving the entirety of the gastrointestinal tract from the mouth to the anus.

Markers of endothelial dysfunction and evaluation of vascular reactivity tests in Behçet disease.

We assessed endothelial dysfunction (ED) in patients with Behcet disease (BD; n=40) and healthy controls (n=20). Serum lipid, homocysteine, asymmetric dimethylarginine (ADMA) and high-sensitivity C-reactive protein (hsCRP) levels, erythrocyte sedimentation rates (ESRs), and ultrasonographic flow-mediated dilatation (FMD) were measured. Mean hsCRP, ESR, homocysteine, and ADMA were significantly higher in the BD group (P<.001 for all). Patients with active BD had higher serum levels of hsCRP, homocysteine, and ESR compared with those in remission (P<.001, P<.001, and P=.005, respectively). Flow-mediated dilatation was significantly lower in patients with BD than in controls (P=.001). Flow-mediated dilatation correlated negatively with BD duration and serum ADMA levels (P<.001, r=-.745 and P<.001, r=-.682); a positive correlation was seen between serum ADMA levels and BD duration (P<.001, r=.552). Only stepwise multivariate regression analysis revealed BD duration to have a significant effect on FMD. Flow-mediated dilatation, in conjunction with markers of inflammation, may evaluate ED in patients with BD.

Retinal nerve fiber layer thickness in vitiligo patients.

BACKGROUND: This study was designed to investigate the effect of vitiligo on the retinal nerve fiber layer (RNFL) thickness. MATERIALS AND METHODS: This prospective study was conducted in the Department of Ophthalmology at Kirikkale University during 2010 and 2011. Sixty eight eyes of 34 vitiligo patients were included in the study. Eighty four eyes were served as control. RNFL thickness was measured by scanning laser polarimetry (Nerve Fiber Analyzer, GDx VCC: 5.3.3; Laser Diagnostic Technologies, San Diego, CA, USA). RESULTS: The mean duration of vitiligo was found to be 9.8 ± 2.3 years. The mean average RNFL thickness outside the disc margin was significantly lower in the right eyes of vitiligo group in comparison to the controls (P = 0.02). The mean average thickness of RNFL beneath the measuring ellipse in the superior sector of both eyes were significantly lower than the controls (P = 0.004, P = 0.008, respectively). The topographical distributions of RNFL thickness in superior, inferior, nasal and temporal quadrants were similar for two groups. CONCLUSION: RNFL thickness seems to be unaffected in vitiligo patients.

Sneddon's syndrome presenting with neuropathic pain.

A 55-year-old man was admitted to us with a sense of numbness, tingling, and burning in his feet and headache, characterized as a feeling of pressure all around his head, for 1 year and aggravated in the past 3 months. The patient's neurologic examination was normal and he had no other known diseases except for hypertension according to his medical history. During the examination, we recognized purplish lesions on the patient's body. His kidney, liver, and thyroid function test results and vitamin B12 levels were all normal. His hematocrit level was 41.8%, platelet value was 234,000 (150,000-500,000); and sedimentation rate was 9 mm/h (0-20). Electromyography was performed and results were found to be normal. The patient was diagnosed as having small fiber neuropathy. Dermatologic examination revealed reddish blue mottling of the skin with fishnet reticular pattern on his back, on the front side of the body, and on both arms and legs, and the lesions were classified as livedo racemosa (Figure 1). Brain magnetic resonance imaging (MRI) showed subcortical hyperintense ischemic-gliotic signal changes on T2-FLAIR in the deep white matter of bilateral frontoparietal vertex, centrum semiovale, and corona radiata (Figure 2). FLAIR sequence axial MRI of the brain of our patient showed subcortical hyperintense lesions in both cerebral hemispheres. His cardiac examination was normal and minimal aortic regurgitation was seen on echocardiography. His cognitive assessment Minimental Test Score was 22, and Montreal Cognitive Assessment score was 18. Laboratory values for inflammatory markers and autoimmune antibodies including syphilis serology, lupus anticoagulants, and anticardiolipin antibodies were negative. Factor V Leiden mutation was not detected in the patient. The patient was diagnosed with Sneddon's syndrome with the above signs and symptoms and small fiber neuropathy. Clopidogrel 75 mg and gabapentin 1200 mg was started once a day and blood pressure regulation was achieved.

Topical ophthalmic cyclosporine in the treatment of toxic epidermal necrolysis.

Aim. To describe a case of toxic epidermal necrolysis (TEN) with ocular involvement treated with topical ophthalmic cyclosporine. Case Presentation. A 20-year-old woman developed TEN following administration of carbamazepine that was prescribed for epilepsy. Ophthalmic examination revealed bilateral pseudomembranous conjunctivitis. She was hospitalized in the intensive care unit and treated with intravenous corticosteroid and immunoglobulin. Topical cyclosporine was used in combination with topical corticosteroids for ocular surface disease. Following two months of ocular treatment, she recovered without any severe ocular complication. Ocular examination at the four-month followup showed a 2 mm of symblepharon in the lower fornix as the sole pathologic finding. Conclusion. Topical ophthalmic cyclosporine may contribute to decrease the ophthalmic complications of TEN and should be considered in the acute stage of the disease.

Assessment of ovarian stromal artery Doppler characteristics and serum hormone levels in patients with Behçet disease.

PURPOSE: The aim of the study was to examine serum hormone levels, ovarian volume, stromal artery Doppler parameters of patients with Behçet disease (BD) to assess whether there are vascular changes in the gonads of these patients. MATERIALS AND METHODS: Twenty patients with BD and 31 healthy controls aged between 18-45 years were examined in the early follicular phase of the menstrual cycle (day 2-3) with transvaginal ultrasound to evaluate ovarian volume and ovarian stromal artery Doppler parameters. On the same day, blood was drawn for determining serum hormone levels. RESULTS: Patients with BD and the controls were comparable with regard to age and body mass index at study inclusion. Although comparison of the ovarian stromal artery Doppler velocimetric parameters did not show significant differences, resistivity, pulsatility indexes and systolic/diastolic ratio were higher, while peak systolic and end diastolic velocities were lower, in BD patients compared to controls. The mean ovarian volume of patients with BD was smaller than the controls but this difference did not reach statistical significance. There were no statistically significant differences between serum hormone levels of either group. We did not find any correlations between hormone levels and mean ovarian stromal artery Doppler parameters of patients with BD. CONCLUSION: Ovarian stromal artery Doppler parameters of patients with BD did not show any significant differences compared to healthy controls. Therefore, we conclude that ovarian stromal artery is not involved in patients with BD as assessed by transvaginal Doppler ultrasound and serum hormone levels do not differ from the levels of healthy controls.

A case of brucellosis presenting with widespread maculopapular rash.

Human brucellosis is a multisystemic infectious disease with a broad spectrum of clinical manifestations. Severe complications involving musculoskeletal, nervous, genitourinary, and cardiovascular systems may be encountered during the course of the disease; however, cutaneous complications have been reported rarely. We report a patient with brucellosis in whom the main presenting clinical feature was a maculopapular rash and fever. He was initially diagnosed as brucellosis based on the standard tube agglutination test and blood culture positivity. Histopathologic examination of these maculopapular lesions showed perivascular and periadnexal inflammation with loose granuloma formation including giant cells. We emphasize that brucellosis is an infectious disease that should always be kept in mind in the differential diagnosis of a patient with rash and fever, especially in endemic areas.

Diffuse plane xanthomatosis in a patient with Budd-Chiari syndrome and monoclonal gammopathy.

Diffuse plane xanthomas are characterized by the presence of yellowish plaques on the eyelids, neck, upper trunk, buttocks, and flexural folds. Histology shows foamy histiocytes in the dermis. Approximately half of the cases are associated with lymphoproliferative disorders. Budd-Chiari syndrome is an uncommon condition induced by thrombotic or nonthrombotic obstruction of hepatic venous outflow. We present a case of diffuse plane xanthoma in a 62-year-old man who developed normolipemic plane xanthomas coinciding with Budd-Chiari syndrome and monoclonal gammopathy. We review the English-language literature regarding the rare association of xanthomas and Budd-Chiari syndrome.

The effect of Behçet's disease on sexual function and psychiatric status of premenopausal women.

INTRODUCTION: Little is known about the relationship between Behçet's disease (BD) and female sexual dysfunction (FSD). AIMS: The aims were to evaluate the prevalence of FSD in premenopausal BD patients and to compare hormonal and psychiatric conditions to healthy subjects. METHODS: A total of 71 married women with BD and 63 healthy married women between 18 and 44 years old were enrolled into the study. After evaluating detailed history and physical examination, serum steroid hormone levels were measured. Presence of genital ulcerations in physical examination and any medical treatment were recorded in patients. All subjects were asked to complete the Female Sexual Function Index (FSFI) for sexual status and Beck Depression Inventory (BDI) for psychiatric assessment. MAIN OUTCOMES MEASURES: FSFI and BDI scores and serum sex steroid hormone levels were measured in women with BD and healthy controls. RESULTS: The mean BDI score of patients was significantly greater than that for controls (P = 0.001), and there was a statistically significant difference between BDI scores (Pearson chi2 = 19.109, P = 0.001). FSD was found in 34 patients with BD (47.9%) and in 11 controls (17.5%). A statistically significant difference was found between the two groups (Pearson chi2 = 13.855, P = 0.001). While the most common sexual problem in the patients with BD was diminished arousal (n = 49, 69.0%), diminished desire was found in 32 patients (45.1%) and lubrication problems in 36 patients (50.7%). There was a statistically significant negative correlation between BDI and FSFI score in BD patients. On the contrary, there was no relationship between FSFI and presence of genital ulcerations. CONCLUSION: FSD is more common in BD patients than in healthy subjects. We conclude that depressive mood according to the BDI scale correlates with the sexual status of BD patients, and this may be because of the depressive effect of BD as a chronic disease.

Absence of estrogen and progesterone receptors around the affected vessels of angioma serpiginosum: case report.

Angioma serpiginosum is a disorder of dilated superficial dermal capillaries. The disease is considered by some authors to be a consequence of increasing levels of estrogens. We present a case of angioma serpiginosum in a 46-year-old White woman. The lesions consisting of red-purple puncta were grouped as vaguely annular and angular patches with serpiginous borders, located on the right side of the neck, the right side of the abdomen, and on the left arm. Histopathologic examination revealed clusters of dilated capillaries in the dermal papillae, without endothelial proliferation. Periodic acid-Schiff (PAS) stain-positive deposits were noted around the affected blood vessels. However, immunohistochemical analysis revealed the absence of estrogen and progesterone receptors within the involved blood vessels. Hormonal assays were also normal. Our observations suggest that a hormonal stimulus probably plays no role in the pathogenesis of angioma serpiginosum. The significance of PAS-positive deposits as a diagnostic marker for angioma serpiginosum needs further confirmation.

Executive dysfunctions and depression in Behçet's disease without explicit neurological involvement.

This study aims to assess the executive functions and depression status in patients with Behçet's disease without explicit neurological involvement and to evaluate cognitive functions in this group of patients independent of accompanying depression. In the present study, 30 patients with Behçet's disease in the non-active phase of their illness and 30 healthy volunteers were included. In the evaluation of depression levels, Beck Depression Inventory was employed. The executive functions of the patients were evaluated by Wisconsin Card Sorting Test (WCST) and Stroop Test (ST). Beck Depression Inventory scores measured in the Behçet's disease group, in which no clinically serious depression was observed, were higher than the control group. Then, it was observed that the scores of neuropsychological tests of the Behçet's disease group were found to be significantly lower, especially in WCST, while significant relations were revealed between Beck Depression Inventory scores and WCST, ST scores. The authors' findings suggest that there may be factors other than depression causing executive impairment in patients with Behçet's disease without explicit neurological symptoms. Executive dysfunctions may occur in association with mild depressive states due to chronic disease stress or silent and/or future neurological involvement of Behçet's disease, especially in the frontal lobes.

Bilateral upper eyelid edema in Melkersson-Rosenthal syndrome.

Melkersson-Rosenthal syndrome is an uncommon disorder characterized by a triad of facial nerve palsy, orofacial edema, and fissured tongue. A 42-year-old woman with Melkersson-Rosenthal syndrome presented with painless, nonpitting, bilateral asymmetric upper eyelid edema. The left eyelid was a bit larger than the right eyelid. CT and MRI demonstrated periorbital soft tissue thickening compatible with the microscopic findings of infiltration of lymphocytes, edema, and cystic dilatation of lymphatic vessels. After treatment by systemic doxycycline and corticosteroid, she showed some improvement of the eyelid edema. Isolated bilateral eyelids swelling may be observed in Melkersson-Rosenthal syndrome. In the case of unexplained nonpitting eyelid edema, biopsy should be performed.

Peripheral neuropathy in Behçet's disease.

Behçet's disease (BD) is a multisystem disorder. Since its first description, the involvement of many organ-systems has been studied. However, the involvement of the peripheric nervous system has not been well documented yet. Twenty-six patients involved in the study were without prominent complaints of neuropathic symptoms. They were surveyed through the outpatient clinic of the department of dermatology. Each patient filled out a total neuropathy score (TNS) questionnaire after their neurologic exam. A neurology specialist conducted the electrophysiological study. Our results were noteworthy because this complication was present without significant complaint. We hypothesized that the nerve dysfunction or peripheral neuropathy of BD is an axonal type of distal polyneuropathy and predominantly involves the lower extremities. We did not find a predominant motor or sensory nerve involvement. This complication is mentioned and reported rarely in BD.

Focal acral hyperkeratosis: a rare cutaneous disorder within the spectrum of Costa acrokeratoelastoidosis.

Acrokeratoelastoidosis and focal acral hyperkeratosis share similar clinical features and identical histologic epidermal alterations. These disorders are distinguished solely on the basis of the absence of elastorrhexis in the latter. We present a case of focal acral hyperkeratosis in a 9-year-old girl. The lesions consisted of translucent polygonal papules clustered on the thenar regions of the palms and over the metacarpophalangeal and interphalangeal joints. Histopathologic examination revealed orthohyperkeratosis within focal clavus-like depressions of the epidermis and prominent hypergranulosis. There was no evidence of alterations in elastic tissue. The clinicopathologic distinction between focal acral hyperkeratosis and acrokeratoelastoidosis is blurred. There is enough evidence to consider the former as a histologic variant of Costa acrokeratoelastoidosis syndrome, and a better nomenclature for this disorder would be "acrokeratoelastoidosis without elastorrhexis."