Thirty Mouse Strain Survey of Voluntary Physical Activity and Energy Expenditure: Influence of Strain, Sex and Day-Night Variation.

We measured indirect calorimetry and activity parameters, VO2 and VCO2 to extract respiratory exchange ratio (RER) and energy expenditure in both sexes of 30 inbred mouse strains of 6 genetic families at 9-13 weeks during one photophase and the subsequent scotophase. We observed a continuous distribution of all traits. While males had higher body weights than females, we observed no sex difference for food and water intake. All strains drank and fed more during the night even if they displayed no day-night difference in activity traits. Several strains showed absent or weak day-night variation in one or more activity traits and these included FVB and 129X1, males of 129S1, SWR, NZW, and SM, and females of SJL. In general females showed higher rearing and ambulatory activity with 6 and 9 strains, respectively, showing a sex difference. Fine motor movements, like grooming, showed less sex differences. RER underlied a strong day-night difference and no sex effect. Only FVB females and males of the RIIIS and SM strain had no day-night variation. Energy expenditure underlies a large day-night variation which was absent in SWR and in FVB females and RIIIS males. In general, female bodies had a tendency to higher energy expenditure values, which became a significant difference in C3H, MAMy, SM, DBA1, and BUB. Our data illustrate the diversity of these traits in male and female inbred mice and provide a resource in the selection of strains for future studies.

Increased Activity and Apoptosis of Eosinophils in Blister Fluids, Skin and Peripheral Blood of Patients with Bullous Pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease that is more common in elderly individuals. The aim of this study was to determine the functional activity of eosinophils in patients with BP compared with healthy donors. Blood, skin and blister-derived eosinophils were strongly activated in patients with BP, seen by increased surface expression of CD69 compared with controls. CD11b was also increased in BP blood eosinophils, which may explain the striking accumulation of eosinophils in BP (1×106 per ml blister fluid). Furthermore, CCL26 was expressed by activated eosinophils in BP skin and in blister fluid. BP eosinophils also released IL-6, IL-8 and IL-1α in BP blister fluids. Apoptosis in cultivated BP eosinophils was increased and accompanied by enhanced surface externalization of CD95. Caspase 3 positive eosinophils in lesional BP skin and blister fluid also showed the initiation of apoptosis. These results reveal novel pathophysiological aspects of BP, with a strong activation pattern and increased apoptosis of eosinophils in the peripheral blood, skin and blister fluids.

Evaluation of visual outcomes and patient satisfaction after implantation of a diffractive trifocal intraocular lens.

PURPOSE: To evaluate clinical outcomes after the implantation of a diffractive trifocal intraocular lens (IOL). SETTING: Nine European ophthalmology centers. DESIGN: Prospective noncomparative interventional multicenter study. METHODS: The trifocal diffractive AT LISA tri 839MP IOL was implanted in eyes with bilateral cataract. Monocular and binocular visual performance was assessed as was the level of perceived photic phenomena, patient satisfaction, and spectacle dependence 1 month and 3 months postoperatively. RESULTS: The IOL was implanted in 208 eyes of 104 patients. The mean binocular uncorrected distance visual acuity improved from 0.44 logMAR ± 0.30 (SD) to 0.02 ± 0.10 logMAR and 0.03 ± 0.09 logMAR at 1 month and 3 months, respectively (P < .01). The mean binocular uncorrected intermediate visual acuity (80 cm) improved from 0.51 ± 0.30 logMAR to 0.09 ± 0.13 logMAR and 0.10 ± 0.15 logMAR at 1 month and 3 months, respectively (P < .01). The mean binocular uncorrected near visual acuity improved from 0.67 ± 0.31 logMAR to 0.16 ± 0.14 logMAR and 0.15 ± 0.14 logMAR, respectively (P < .01). Among the more frequently perceived photic phenomena were halos; however, approximately 75% of patients were not bothered by them. More than 90% of patients were satisfied with the outcome. Spectacle independence at all distances was higher than 90%. CONCLUSION: This IOL provided excellent visual outcomes and high refractive predictability at all distances, including intermediate, leading to high levels of patient satisfaction and spectacle independence. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

A mild form of dermatomyositis as a prodromal sign of lung adenocarcinoma: a case report.

BACKGROUND: Dermatomyositis is an idiopathic connective tissue disease characterized by specific cutaneous findings and inflammatory lesions in the muscle biopsy. An association between dermatomyositis and malignancy, including breast, ovarian, lung and colon cancer was recognized many years ago, with an incidence of malignancy in approximately 20 % of cases. Dermatomyositis is hypothesized to be an autoimmune reaction against factors or hormones secreted by the tumor; however, the exact autoimmune mechanism of the disease pathogenesis remains unknown. CASE PRESENTATION: Here we report a case of a woman with dermatomyositis who was diagnosed with lung adenocarcinoma in the setting of weight loss, progressive fatigue and muscle weakness. A 43-year-old Caucasian woman was referred to our hospital by her physician for suspected contact dermatitis since she described mild itching sensations in her arms and legs as her major symptom. A physical examination revealed erythematous papular lesions over her metacarpophalangeal and proximal interphalangeal joints together with a periungual involvement with redness, hyperkeratosis and capillary telangiectasia along the distal nailfolds on her hands. She was unaware of these features and they did not seem to bother her. A thorough examination of her medical history, however, revealed more symptoms. Pain and weakness in the muscles of her proximal extremities and neck flexor muscles led to difficulty in raising her arms and climbing stairs. At the same time she experienced swallowing difficulties and reported an uncharacteristic weight loss of 10 kg in the last 3 months. The results of laboratory tests showed increased values of serum creatine kinase and myoglobin. An electromyogram, a skin biopsy and a muscle biopsy confirmed the diagnosis of dermatomyositis. A computed tomography of her thorax showed a nodular mass in the upper lobe of her right lung. A histological examination of the lung biopsy showed an adenocarcinoma of moderate differentiation. She was diagnosed with paraneoplastic dermatomyositis as the first sign of a lung adenocarcinoma. CONCLUSIONS: Our case report highlights the importance of a thorough search for underlying malignancy in patients with dermatomyositis even if dermatomyositis has a mild appearance or a discrete skin manifestation.

Non-melanoma skin cancer is reduced after switch of immunosuppression to mTOR-inhibitors in organ transplant recipients.

BACKGROUND: Organ transplant recipients are prone to the development of non-melanoma skin cancer. Organ transplant recipients often develop multiple non-melanoma skin cancers and the tumors show an aggressive growth pattern, therefore surgical therapy can be difficult. Switch of the immunosuppressive regimen to mTOR-inhibitors such as everolimus or sirolimus can have an antitumor effect. PATIENTS AND METHODS: In a monocentric retrospective study we evaluated organ transplant recipients who presented with non-melanoma skin cancer in the years 2008-2010. Experience with patients who were switched to an mTOR-inhibitor due to non-melanoma skin cancer are reported in detail, and recent clinical studies are reviewed. RESULTS: 60 organ transplant recipients with non-melanoma skin cancer were evaluated. Due to the development of multiple non-melanoma skin cancer within a few years, the immunosuppressive regimen was switched to everolimus in 7 patients and to sirolimus in 5 patients. Eight patients were evaluable for the effect of mTOR-inhibitors on the development of non-melanoma skin cancer; 4 patients had to discontinue the medication with mTOR-inhibitors early due to various side effects. In the year before the switch to mTOR-inhibitors, 8 patients developed 16 squamous cell carcinomas, 3 Basal cell carcinomas and 22 cases of Bowen's disease. All tumors were histologically confirmed. In the year after switch of immunosuppression, the rate of squamous cell carcinomas (n = 2) and Bowen's disease (n = 3), but not of basal cell carcinomas (n = 2) was significantly reduced. Moreover, 5 prospective randomized trials recently have demonstrated a reduced number of non-melanoma skin cancers in organ transplant recipients after switch of the immunosuppressive regimen to mTOR-inhibitors. CONCLUSION: Switch of the immunosuppressive regimen to mTOR-inhibitors should be considered for organ transplant recipients suffering from multiple non-melanoma skin cancers.

Is there a therapeutic benefit of complete lymph node dissection in melanoma patients with low tumor burden in the sentinel node?

In the case of a positive sentinel lymph node (SLN), melanoma patients are recommended to proceed to complete lymph node dissection (CLND). However, CLND for SLN-positive patients - especially with minimal tumor burden in SLN - is becoming more controversial. We analyzed the clinical course of 305 SLN-positive patients with a mean follow-up of 51.1 months by Kaplan-Meier analyses. Overall, 58/305 (17%) patients did not undergo CLND. These were compared with a matched selection of 58 comparable patients who underwent CLND. Moreover, 106/305 patients with minimal tumor burden in SLN (<0.1 mm diameter of the largest tumor deposit) were analyzed separately. Of these 106 patients, 34 did not undergo CLND, whereas 72/106 patients were treated by CLND. In the matched groups, the CLND group and the non-CLND group did not differ significantly with respect to clinical characteristics, characteristics of the primary melanoma, and histopathological parameters of SLN. There were no differences in recurrence-free survival (P=0.765) and overall survival (P=0.844). The total number of regional lymph node metastases and time to regional lymph node metastases were not significantly higher for non-CLND patients. The subgroup of patients with minimal tumor burden in SLN also did not benefit significantly from CLND. In our analyses from a single German center, we could not find any evidence for a therapeutic survival benefit for CLND after positive SLN. However, future prospective randomized trials should confirm these data.

Lower prevalence of lymphatic metastasis and poorer survival of the sentinel node-negative patients limit the prognostic value of sentinel node biopsy for head or neck melanomas.

Head or neck location of primary cutaneous melanomas has been described as an adverse prognostic factor, but this has to be reassessed after the introduction of sentinel lymph node (SLN) excision (SLNE). Descriptive statistics, Kaplan-Meier estimates and Cox proportional hazard models were used to study retrospectively a population of 2302 consecutive melanoma patients from three German melanoma centres undergoing SLNE. Approximately 10% of the patients (N=237) had a primary melanoma located at the head or neck (HNM). In both the SLN-positive and SLN-negative subpopulation, patients with HNM were significantly older, more frequently men and had thicker primaries compared with patients with tumours in other locations. The proportion of positive SLNs was lower in HNM compared with other locations of the primary (20 vs. 26%, P=0.048). The false-negative rate was higher in HNM (17.5 vs. 8.4%, P=0.05). In patients with HNM, the SLN status was a significant factor for recurrence-free survival but not for overall survival. SLN-negative HNM patients had a significantly worse overall survival than the SLN negatives with primaries at other sites, whereas the prognosis of the SLN-positive patients was similar in both groups. The prevalence of lymph node metastases after SLNE is lower in patients with HNM compared with other melanoma locations. As a result, the prognostic information provided by the SLN for HNM seems less important. Decision making for SLNE in HNM should be carefully balanced considering the potential morbidity of the procedure.

Dynamic changes in nevi of a patient with melanoma treated with vemurafenib: importance of sequential dermoscopy.

BACKGROUND Therapy with vemurafenib, an inhibitor of mutated BRAF, yields a response rate of approximately 50% in patients with metastatic melanoma harboring a BRAF V600E mutation. As an adverse effect of vemurafenib, proliferative disorders of keratinocytes, including squamous cell carcinoma, have been described. Low concentration of vemurafenib as present in the epidermis were found to activate wild-type RAF, which, in combination with a preexisting RAS mutation, can promote keratinocyte proliferation. While activating BRAF mutations occur in approximately 50% of melanomas, they are even more frequently observed in melanocytic nevi. OBSERVATION We present the case of a patient with dynamic changes of melanocytic nevi well documented by sequential digital dermoscopy during vemurafenib therapy. A variety of dermoscopic changes were observed. First, nevi involuted, and all of these originally showed a centrally elevated papillomatous and predominant globular pattern. Second, preexisting nevi increased in size, and pigmentation that rendered them atypical. Such lesions were flat and showed a predominant reticular pattern at baseline. Third, multiple new nevi occurred. One example of each of the latter 2 categories was excised and showed wild-type BRAF. CONCLUSION Our findings of changing nevi in a patient treated with vemurafenib highlight the need for sequential skin examinations, including dermoscopy.

microRNA-21 is upregulated in malignant melanoma and influences apoptosis of melanocytic cells.

Overexpression of microRNA-21 (miR-21) has been observed in various cancer types, but little is known about the role of miR-21 in melanoma. In this study, we demonstrate that levels of miR-21 are significantly increased in primary melanoma tissues as compared to benign nevi and in human melanoma cell lines as compared to melanocytic cell preparations. We show that downregulation of miR-21 in melanoma cell lines with high endogenous miR-21 expression induced apoptosis, whereas proliferation was not significantly altered. Upregulation of miR-21 in melanocytes resulted in increased proliferation and decreased apoptosis. However, in the MEWO melanoma cells with low endogenous miR-21 expression, upregulation of miR-21 had no functional effects. These findings indicate a potential pathogenetic role of miR-21 upregulation in a subgroup of melanomas.

Contact allergy to dental materials.

The oral mucosa is constantly exposed to a large number of potentially irritating and sensitizing dental materials. Dental materials used for fillings and fixed or removable replacements must have a good biocompatibility. Metals including palladium are used in alloys for the production of the core of crowns, onto which porcelain is bonded for the generation of an artificial tooth to which the patient can develop an allergic contact dermatitis. The clinical manifestations of contact allergy to dental materials are not uniform. Objective symptoms of a contact allergy include a stomatitis and lichenoid reactions. However, patients may present with more subjective affections of the oral mucosa including burning, pain and dryness which need to be differentiated from a real contact allergic reaction. In this article we focus on the management of contact allergy to dental materials.

Cutaneous side effects of new antitumor drugs: clinical features and management.

BACKGROUND: Many new antitumor drugs have been approved in recent years. Their side-effect profiles are distinct from those of older drugs, and their adverse effects are sometimes highly specific, particularly with respect to the skin. METHODS: This article is based on articles retrieved by a selective search in Medline and the database of the American Society of Clinical Oncology (ASCO), as well as on the authors' personal experience. RESULTS: Cutaneous adverse effects are among the more common adverse effects of new antitumor drugs: they occur in up to 34% of patients receiving multikinase inhibitors, up to 90% of those receiving selective tyrosine kinase inhibitors (such as EGFR or mutant BRAF inhibitors), and up to 68% of those receiving immunotherapeutic agents (such as CTLA4 inhibitors). These adverse effects can be correlated with therapeutic benefit, but they can also be treatment-limiting because of their severity or visibility. CONCLUSION: The recognition and proper management of cutaneous adverse effects is an important part of treatment with new antitumor drugs.

Modulation of basophil activity: a novel function of the neuropeptide α-melanocyte-stimulating hormone.

BACKGROUND: Little is known about the effect of neuropeptides on basophils, which are important effector cells in immune and allergic responses. OBJECTIVE: This study aimed at revealing the role of α-melanocyte-stimulating hormone (α-MSH) on basophil function. METHODS: Expression of melanocortin receptors and proopiomelanocortin (POMC) was analyzed by means of RT-PCR, Western immunoblotting, fluorescence-activated cell sorting, and double-immunofluorescence analysis. Signal transduction studies included cyclic AMP and Ca(2+) mobilization assays. Basophil activity was assessed based on CD63 surface expression and cytokine release. RESULTS: MC-1R expression was detectable in basophils isolated from human peripheral blood, as well as in basophils within nasal tissue. In isolated basophils from human blood, truncated POMC transcripts were present, but there was no POMC protein. Treatment of basophils with α-MSH increased intracellular Ca(2+) but not cyclic AMP levels. α-MSH at physiologic doses potently suppressed basophil activation induced by N-formyl-methionyl-leucyl-phenylalanine, phorbol 12-myristate 13-acetate, or grass pollen allergen in whole blood of healthy or allergic subjects, respectively. The effect of α-MSH on basophil activation was MC-1R mediated (as shown by blockade with a peptide analogue of agouti-signaling protein) and imitated by adrenocorticotropic hormone but not elicited by the tripeptides KPV and KdPT, both of which lack the central pharmacophore of α-MSH. Moreover, α-MSH at physiologic doses significantly suppressed secretion of 3 proallergic cytokines, IL-4, IL-6, and IL-13, in basophils stimulated with anti-IgE, N-formyl-methionyl-leucyl-phenylalanine, or phorbol 12-myristate 13-acetate. CONCLUSION: Our findings highlight a novel functional activity of α-MSH, which acts as a natural antiallergic basophil-response modifier. These findings might point to novel therapeutic strategies in treating allergic diseases.

The impact of oral vitamin A derivatives on lipid metabolism - What recommendations can be derived for dealing with this issue in the daily dermatological practice?

Retinoids and vitamin A derivatives have been widely used topically and systemically in the treatment of hyper- and parakeratotic skin diseases, genodermatoses, severe acne, autoimmune diseases (i. e. lupus erythematosus) or cutaneous T-cell lymphoma for more than 30 years. In addition to the desired proliferation-inhibiting, differentiation-inducing and antiinflammatory or sebo-suppressive effects, vitamin A derivatives also affect lipid metabolism. This is shown primarily by an increase of transaminases, triglycerides or cholesterol levels which vary in intensity from patient to patient. The degree of impact on the different parameters of lipid metabolism depends on the nature of the vitamin A derivative on the one hand due to different receptor specific binding interactions (RAR/RXR), while on the other hand posttranslational processes also play a major role. This review paper gives a brief, concise overview of the vitamin A derivatives and possible effects on lipid metabolism that can be expected. Additionally it contains a recommendation for secure handling of abnormal laboratory values before, during and after oral therapy with vitamin A derivatives. The aim of this article is to provide practical help and confidence in dealing with vitamin A derivatives in daily clinical practice. The publication was created in cooperation with the Deutsche Dermatologische Gesellschaft (DDG) and Deutsche Gesellschaft zur Bekämpfung von Fettstoffwechselstörungen und ihren Folgeerkrankungen (DGFF [Lipid-Liga] e. V.).