Xenon isotopes in 67P/Churyumov-Gerasimenko show that comets contributed to Earth's atmosphere.

The origin of cometary matter and the potential contribution of comets to inner-planet atmospheres are long-standing problems. During a series of dedicated low-altitude orbits, the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis (ROSINA) on the Rosetta spacecraft analyzed the isotopes of xenon in the coma of comet 67P/Churyumov-Gerasimenko. The xenon isotopic composition shows deficits in heavy xenon isotopes and matches that of a primordial atmospheric component. The present-day Earth atmosphere contains 22 ± 5% cometary xenon, in addition to chondritic (or solar) xenon.

Abundant molecular oxygen in the coma of comet 67P/Churyumov-Gerasimenko.

The composition of the neutral gas comas of most comets is dominated by H2O, CO and CO2, typically comprising as much as 95 per cent of the total gas density. In addition, cometary comas have been found to contain a rich array of other molecules, including sulfuric compounds and complex hydrocarbons. Molecular oxygen (O2), however, despite its detection on other icy bodies such as the moons of Jupiter and Saturn, has remained undetected in cometary comas. Here we report in situ measurement of O2 in the coma of comet 67P/Churyumov-Gerasimenko, with local abundances ranging from one per cent to ten per cent relative to H2O and with a mean value of 3.80 ± 0.85 per cent. Our observations indicate that the O2/H2O ratio is isotropic in the coma and does not change systematically with heliocentric distance. This suggests that primordial O2 was incorporated into the nucleus during the comet's formation, which is unexpected given the low upper limits from remote sensing observations. Current Solar System formation models do not predict conditions that would allow this to occur.

Comparison of user-friendliness and treatment cost of Loceryl® vs. Ciclopoli®--a patient's perspective.

Topical monotherapy is a valid therapeutic approach in onychomycosis. Due to its lengthy course and its non-reimbursed product status, cost and compliance are important issues and non-pharmacological properties such as over-the-counter price and ease of use should be considered when deciding which product to recommend. We investigated surrogate parameters for patient-friendliness and treatment cost in Germany in a questionnaire-based prospective, comparative, intra-individual, open-label trial of the two common topical antifungal nail lacquers Loceryl(®) (amorolfine 5%) and Ciclopoli(®) (ciclopirox 8%) in eight patients with clinically diagnosed onychomycosis. The 2.5 ml bottle of Loceryl(®) covered a treatment period of 308 days, resulting in treatment costs of €0.10 per day in comparison to the 3.3 ml bottle of Ciclopoli(®), covering 127 days at €0.21 per day, given once-daily application for Ciclopoli(®) and once-weekly application for Loceryl(®) in accordance with regulatory approval. Six out of eight patients favoured the Loceryl(®) treatment regimen. Furthermore, four out of eight patients found Loceryl(®) easier to apply, whereas three preferred Ciclopoli(®). In total, seven out of eight stated a clear preference for Loceryl(®) over Ciclopoli(®). Loceryl(®) therapy is less expensive and less time-consuming. The therapeutic period that can be covered is longer and more patients stated a clear preference for Loceryl(®) in comparison to Ciclopoli(®). The differences are statistically significant, underlining probable clinical relevance.

Safety and efficacy of adapalene 0.1% / benzoyl peroxide 2.5% in the long-term treatment of predominantly moderate acne with or without concomitant medication - results from the non-interventional cohort study ELANG.

BACKGROUND: Acne is a chronic inflammatory disease requiring long-term treatment. The fixed-dose combination adapalene 0.1%/benzoyl peroxide 2.5% (adapalene-BPO) is indicated for the once-daily topical treatment of Acne vulgaris when comedones, papules and pustules are present. OBJECTIVE: The main objectives of this non-interventional study were to assess long-term efficacy and safety of adapalene-BPO in moderate to severe acne with and without concomitant medication. METHODS: Patients with moderate to severe acne received adapalene-BPO alone or in combination with concomitant medication over a course of 9 months. The primary efficacy endpoint was changes in acne severity according to the Leeds Revised Acne Grading System; secondary endpoints included treatment success assessed by the patient and safety. RESULTS: In total, 5131 patients were eligible for efficacy and 5141 for safety evaluation. The majority of patients (78.8%) received adapalene-BPO alone. About 21.2% received adapalene-BPO in combination with another agent, mostly topical antibiotics (8.8%) or systemic antibiotics (8.7%). Mean (±SD) acne severity improved from 5.6 ± 1.5 at baseline to 3.3 ± 1.9 at month 3, and further to 1.9 ± 1.9 at month 9 (both P < 0.0001). The degree of improvement correlated significantly with the severity at baseline. After 3 and 9 months of treatment, the facial skin was cleared completely (no more visible acne lesions) in 420 (8.2%) and 1326 patients (25.8%), respectively. A therapeutic effect was noted by the patients after a median time of 3 weeks (range: from 1 day to 12 weeks). No serious adverse events were reported. Facial skin irritations, mostly mild to moderate, occurred in 49.5% of patients and led to discontinuation in only 1.7% of cases. CONCLUSION: In consistence with previous clinical findings, the use of adapalene-BPO in daily practice routine is safe and effective in the long-term management of patients with moderate to severe acne.

Effect of adapalene 0.1%/benzoyl peroxide 2.5% topical gel on quality of life and treatment adherence during long-term application in patients with predominantly moderate acne with or without concomitant medication - additional results from the non-interventional cohort study ELANG.

BACKGROUND: In addition to physical long-lasting effects such as permanent scarring and disfigurement, acne has acute and long-term psychosocial effects that affect the individual's quality of life. As with other chronic diseases, treatment success is often compromised by poor adherence. OBJECTIVE: Two main objectives of this non-interventional study were to assess the long-term effect of the fixed-dose combination adapalene 0.1%/benzoyl peroxide 2.5% (adapalene-BPO gel) on quality of life and treatment adherence. METHODS: Patients with moderate to severe facial acne receiving adapalene-BPO alone or in combination with other drugs were enrolled in this non-interventional study. Data were documented at baseline and after 3 and 9 months of adapalene-BPO treatment. The secondary outcomes reported here include quality of life determined by the Cardiff Acne Disability Index (CADI), treatment adherence assessed by the ECOB (Elaboration d'un outil d'evaluation de l'observance des traitements medicamenteux) questionnaire, and patient satisfaction. RESULTS: In total, 5131 patients were included in the efficacy evaluation. After 9 months, mean (±SD) quality of life (CADI) improved significantly from 5.9 ± 3.0 to 2.4 ± 2.7 (P < 0.0001). Patients with more severe acne at baseline tended to achieve a greater improvement in quality of life. Long-term adherence was found to be good in 83.9% of patients. Adherence had a significant effect on efficacy and quality of life (P < 0.0001 respectively). The vast majority of patients (92.1%) reported subjective improvement at the interim analysis. Accordingly, most patients (84.8%) were satisfied or very satisfied with adapalene-BPO by the end of the observation period. CONCLUSION: The clinical improvement of the disease led to an increase in quality of life among acne patients. The treatment success may be a motivation factor for patients to stay adherent over the long-term treatment course, indicating the qualification of adapalene-BPO topical gel as an appropriate medication also in the long-term usage.

Molecular nitrogen in comet 67P/Churyumov-Gerasimenko indicates a low formation temperature.

Molecular nitrogen (N2) is thought to have been the most abundant form of nitrogen in the protosolar nebula. It is the main N-bearing molecule in the atmospheres of Pluto and Triton and probably the main nitrogen reservoir from which the giant planets formed. Yet in comets, often considered the most primitive bodies in the solar system, N2 has not been detected. Here we report the direct in situ measurement of N2 in the Jupiter family comet 67P/Churyumov-Gerasimenko, made by the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis mass spectrometer aboard the Rosetta spacecraft. A N2/CO ratio of (5.70 ± 0.66) × 10(-3) (2σ standard deviation of the sampled mean) corresponds to depletion by a factor of ~25.4 ± 8.9 as compared to the protosolar value. This depletion suggests that cometary grains formed at low-temperature conditions below ~30 kelvin.

Cometary science. Time variability and heterogeneity in the coma of 67P/Churyumov-Gerasimenko.

Comets contain the best-preserved material from the beginning of our planetary system. Their nuclei and comae composition reveal clues about physical and chemical conditions during the early solar system when comets formed. ROSINA (Rosetta Orbiter Spectrometer for Ion and Neutral Analysis) onboard the Rosetta spacecraft has measured the coma composition of comet 67P/Churyumov-Gerasimenko with well-sampled time resolution per rotation. Measurements were made over many comet rotation periods and a wide range of latitudes. These measurements show large fluctuations in composition in a heterogeneous coma that has diurnal and possibly seasonal variations in the major outgassing species: water, carbon monoxide, and carbon dioxide. These results indicate a complex coma-nucleus relationship where seasonal variations may be driven by temperature differences just below the comet surface.

Cometary science. 67P/Churyumov-Gerasimenko, a Jupiter family comet with a high D/H ratio.

The provenance of water and organic compounds on Earth and other terrestrial planets has been discussed for a long time without reaching a consensus. One of the best means to distinguish between different scenarios is by determining the deuterium-to-hydrogen (D/H) ratios in the reservoirs for comets and Earth's oceans. Here, we report the direct in situ measurement of the D/H ratio in the Jupiter family comet 67P/Churyumov-Gerasimenko by the ROSINA mass spectrometer aboard the European Space Agency's Rosetta spacecraft, which is found to be (5.3 ± 0.7) × 10(-4)­that is, approximately three times the terrestrial value. Previous cometary measurements and our new finding suggest a wide range of D/H ratios in the water within Jupiter family objects and preclude the idea that this reservoir is solely composed of Earth ocean-like water.

Optimization of mass spectrometers using the adaptive particle swarm algorithm.

Optimization of mass spectrometers using the adaptive particle swarm algorithm (APSA) is described along with implementations for ion optical simulations and various time-of-flight (TOF) instruments. The need for in situ self optimization is addressed through discussion of the reflectron TOF mass spectrometer (RTOF) on the European Space Agency mission Rosetta. In addition, a tool for optimization of laboratory mass spectrometers is presented and tested on two different instruments. After the application of APSA optimization, a substantial increase in performance for mass spectrometers that have manually been tuned for several weeks or months is demonstrated.

Different physicochemical properties of antimycotic agents are relevant for penetration into and through human nails.

This article reports the characterization of the physicochemical properties of two important antifungal topical drugs, amorolfine and ciclopirox. Furthermore, the release of the drugs from commercial lacquer formulations for treatment of onychomycosis was studied using the online FTIR-ATR technique. Based on the physicochemical background of these two drugs and their release from commercial lacquer formulations for treatment of onychomycosis, the suitability of these drugs for optimized local antifungal therapy to human nails is discussed. Amorolfine appears to be more suitable for drug delivery to human nails because it penetrates into the nails via the hydrophilic pathway. Furthermore amorolfine penetrates very well into fungal cells, due to the pH value of the nail, as well as the pKa value of this antimycotic agent and the lipophilic properties of its base form.

Sublimation of antimycotic agents as proved by various analytical methods.

Qualitative and quantitative results demonstrate that the pure substances amorolfine base, amorolfine hydrochloride, two selected morpholine derivatives and terbinafine hydrochloride are clearly able to sublimate. As amorolfine hydrochloride is also capable to sublimate from galencial forms laquer and cream in this experimental setup, a clinical relevance of sublimation phenomenon at least for topical treatment of onychomycosis has to be considered. This phenomenon could be one reason for advantageous clinical and mycological cure rates of amorolfine nail laquer to comparable topical products reported in the literature.

Agar sublimation test for the in vitro determination of the antifungal activity of morpholine derivatives.

We studied the in vitro antifungal activities of a wide range of antimycotic agents, including amorolfine, terbinafine, naftifine, five morpholine derivatives, ciclopiroxolamine, bifonazole, clotrimazole, ketoconazole, itraconazole, fluconazole, voriconazole, flucytosine, amphotericin B, nystatin, and caspofungin, against Candida albicans and Trichophyton rubrum by conventional agar diffusion tests and by a novel sublimation method. For the sublimation method, 6 mm filter paper disks were soaked with defined amounts of antimycotic drugs, air dried, placed in the center of the lids of 9 cm Petri dishes, and incubated upside down with inoculated agar plates 10 mm above the disks. The conventional disk diffusion tests produced inhibition zones as previously described. The disk sublimation tests produced large inhibition zones with amorolfine, five amorolfine derivatives, and terbinafine, but with none of the other antifungal agents. Possible therapeutic advantages of agents, which are able to overcome air cavities in mycotic lesions, e.g. in onychomycosis, are discussed.

[Disseminated melanoma cells in blood and bone marrow. Significance and detection by potential tumor markers]. / Disseminierte Melanomzellen in Blut und Knochenmark. Bedeutung und Nachweis durch potenzielle Tumormarker.

As the majority of primary malignant melanomas can be cured by surgical excision, the prognosis of melanomas is dependent on whether tumor cells have disseminated orare capable of doing so at the time of surgery. A prospective and valid detection of this minimal residual disease is not currently possible. The most important known so-called markers of melanoma disease, tyrosinase, S100 and MIA, all are more likely to be present in patients with more advanced disease. A valid prognostic effect has only been shown for S100 in patients with already identified metastatic disease. Further prospective studies are required to determine the potential gain of information by routine determination of these markers in melanoma patients.

[Therapy of metastatic malignant uveal melanoma]. / Therapie des metastasierten malignen Uveamelanoms.

The uvea is the most common site for extra-cutaneous melanoma and uveal melanoma is the most frequent primary intraocular tumour in adults. Because its different location, biology, histology, genetic features and prognosis in comparison to cutaneous melanoma, this tumour is considered as a distinct entity in the group of malignant melanoma. While primary uveal melanoma is usually treated by ophthalmologic oncologists, metastatic diseases is often managed by dermatologic oncologists. Hematogenous spread predominantly involves the liver and is often restricted to this organ for a long period. Metastatic uveal melanoma is usually resistant to chemotherapeutic regimens established for the therapy of cutaneous melanoma. Newer therapeutic modalities, such as local intra-arterial chemotherapy into the hepatic artery, perhaps combined with embolisation of feeder blood vessels of liver metastases, improves the prognosis of metastatic uveal melanoma. Currently the nitrosourea derivate fotemustine is the drug of choice in the local hepatic and systemic treatment and seems to be superior to other chemotherapeutic agents. Following the characterisation of primary uveal melanoma, we summarize the results of different treatment protocols for metastatic disease and give an overview of new strategies.

Prognosis of metastatic melanoma: no correlation of tyrosinase mRNA in bone marrow and survival time.

Recent publications suggest that tyrosinase mRNA in blood as well as in bone marrow is detectable only in a subgroup of patients with metastatic melanoma. This would imply that tyrosinase mRNA is of limited value as a tumor marker. We addressed the question of whether patients with metastatic melanoma and RT-PCR-detectable tyrosinase mRNA in blood or bone marrow have a different prognosis than tyrosinase mRNA-negative patients. Twenty melanoma patients with widespread clinical metastases were enrolled; the survival time after first diagnosis of visceral metastases was correlated to tyrosinase mRNA presence in blood and bone marrow samples. The time of survival of eight patients with metastatic melanoma and detectable tyrosinase mRNA in either blood or bone marrow was not different from the prognosis of 12 patients without detectable tyrosinase mRNA in either blood or bone marrow. Detection of tyrosinase mRNA in blood or bone marrow samples of melanoma patients with advanced disease seems to have no substantial relevance for survival time and outcome of disease. In this constellation, detection of tyrosinase mRNA by RT-PCR is not a valid tumor marker. Nevertheless, tyrosinase positivity in bone marrow in earlier tumor stages might indicate increased risk for the development of distant metastases. This should be addressed in further studies.

Transient complete remission of metastasized Merkel cell carcinoma by high-dose polychemotherapy and autologous peripheral blood stem cell transplantation.

Merkel cell carcinoma (MCC) is a rare cutaneous tumour with neuroendocrine differentiation. Metastasis occurs preferentially to regional lymph nodes but distant and multiple visceral metastases may occur. Chemotherapy has been performed with a variety of protocols based largely on agents active in small-cell lung cancer. Owing to the rarity of MCC, there is no standard protocol for the treatment of metastatic disease. We report a 59-year-old patient with systemic metastatic MCC. After diagnosis of distant metastases, first-line polychemotherapy (cisplatin 80 mg m(-2), doxorubicin 50 mg m(-2), etoposide 300 mg m(-2) and bleomycin 30 mg) was administered four times at 3-weekly intervals and resulted in partial remission of metastases. Subsequently, high-dose chemotherapy according to the PEI regimen (ifosfamide 12 g m(-2), carboplatin 900 mg m(-2) and etoposide 1500 mg m(-2)) was applied, followed by autologous blood stem cell transplantation (ABSCT). This protocol resulted in a complete remission that lasted for 6 months. This is the first report on a complete remission of metastatic MCC after high-dose polychemotherapy and ABSCT. High-dose chemotherapy might be a therapeutic option in chemosensitive metastatic MCC, and further evaluation is warranted.

Interleukin-6 and its surrogate C-reactive protein are useful serum markers for monitoring metastasized malignant melanoma.

Malignant melanoma cells are known to secrete interleukin-6, and elevated interleukin-6 serum levels were reported to correlate with shorter median survival rates. We, therefore, investigated serum values of interleukin-6 and its surrogate C-reactive protein for the ability to discriminate progressive from non-progressive metastatic melanoma disease. Just prior to re-staging examinations, interleukin-6, C-reactive protein and the conventional parameter lactate dehydrogenase were determined in 74 patients with stage IV malignant melanoma according to the criteria of the American Joint Committee on Cancer. We found all tested serum parameters to be significantly elevated in progressive disease. Calculating sensitivities and specificities by logistic regression analysis, the highest sensitivities, according to the established thresholds, were found for interleukin-6 and C-reactive protein with 86% and 76%, respectively. Lactate dehydrogenase had the highest specificity with 94%. Calculating Somers' D rank correlation and the area under the "Receiver Operating Characteristic" curve, all three parameters showed high ability to driscriminate progressive from non-progressive disease. By multiple logistic regression, lactate dehydrogenase was identified to be the most statistically significant marker for progressive disease. We conclude that, comparable to lactate dehydrogenase, interleukin-6 and its surrogate C-reactive protein are useful serum markers for monitoring metastatic malignant melanoma.

S100-Beta, melanoma-inhibiting activity, and lactate dehydrogenase discriminate progressive from nonprogressive American Joint Committee on Cancer stage IV melanoma.

PURPOSE: Monitoring advanced malignant melanoma, serum levels of S100-beta (S100beta) and melanoma-inhibiting activity (MIA) were assessed for the ability to discriminate progressive from nonprogressive disease. S100beta and MIA were supposed to be superior to conventional variables, such as lactate dehydrogenase (LDH) level. PATIENTS AND METHODS: Seventy-one patients with stage IV malignant melanoma according to the criteria of the American Joint Committee on Cancer (AJCC) were included in the study. Results of restaging examinations were used as an independent reference standard for diagnosing progressive disease, and S100beta, MIA, LDH level, and erythrocyte sedimentation rate (ESR) were determined in venous blood just before restaging. Sensitivities and specificities of the parameters were calculated by logistic regression analysis. Discrimination ability was assessed by Somers' D(xy) rank correlation and the area under the receiver-operating characteristic curve (ROC-AUC). RESULTS: All tested serum parameters were significantly elevated in patients with progressive disease. The highest sensitivities according to the established thresholds were found for S100beta and MIA (91% and 88%, respectively). LDH had the highest specificity (92%). ESR was dropped from the analysis because of low specificity. In calculating Somers' D(xy) and ROC-AUC values, S100beta, MIA, and LDH showed high discrimination ability. By multiple logistic regression, LDH was identified to be the only statistically significant marker for progressive disease. S100beta and MIA did not provide additional significant information because of their high correlation with LDH with respect to clinical outcome. CONCLUSION: Elevated serum levels of S100beta, MIA, and LDH indicate current disease progression in AJCC stage IV melanoma. LDH was the most relevant overall parameter.

[Pathogenesis of malignant melanoma. Molecular biology aspect]. / Pathogenese des malignen Melanoms. Molekularbiologische Aspekte.

The incidence of melanoma, the most aggressive tumor of the skin, is increasing worldwide. The genetic mechanisms responsible for the initiation and progression of melanoma are poorly understood. Mutations of p16 (CDKN2), p53, ras, neurofibromatosis type I gene (NF-1), bcl2 and the retinoblastoma gene have been described, but none are common. Suggesting heterogeneous mechanisms of carcinogenesis. Both familial inheritance of potential tumor suppressor genes, e.g. p16, and differences in DNA-repair capacity contribute to the individual risk for melanoma. The most important carcinogen for melanoma seems to be u.v. exposition whose mutagenic effects can be demonstrated by molecular analysis of detected point mutations in relevant genes. The u.v.-induced DNA damage generates mutations which are capable of activating proto-oncogenes or inactivating tumor suppressor genes, demonstrating the molecular link between u.v. exposition, DNA damage, mutations and tumor initiation and/or progression. A stage-dependent model of melanoma carcinogenesis analogous to colorectal cancer remains to be established, despite the existence of morphologically and histopathologically well defined melanoma precursor lesions in the skin.

The human herpesvirus-type 8 is not involved in malignant melanoma.

Malignant melanomas were supposed to harbour the human herpesvirus-type 8 (HHV-8) genome, as melanoma cells were reported to express interleukin-6 and a homologue of interleukin-6 was found in the HHV-8 genome. We therefore investigated 33 primary malignant melanomas by polymerase chain reaction, but could not find this tumorigenic gamma-herpesvirus in any tumour.