A novel therapeutic option in Cogan diseases? TNF-α blockers

Cogan's syndrome is characterized by non-infectious, interstitial keratitis combined with a vestibulo-auditory deficit. Despite therapy with corticosteroids in combination with immunosuppressive agents, relapses occurred in two subjects and the clinical course suggested a progression of the disease. Treatment with anti-TNF-α was started leading to a rapid and sustained clinical remission for over 2 respectively 3year

Soliton and black hole solutions of su(N) Einstein-Yang-Mills theory in anti-de Sitter space

We present new soliton and hairy black hole solutions of su(N) Einstein-Yang-Mills theory in asymptotically anti-de Sitter space. These solutions are described by N+1 independent parameters, and have N-1 gauge field degrees of freedom. We examine the space of solutions in detail for su(3) and su(4) solitons and black holes. If the magnitude of the cosmological constant is sufficiently large, we find solutions where all the gauge field functions have no zeros. These solutions are of particular interest because we anticipate that at least some of them will be linearly stable.Comment: 15 pages, 20 figures, minor changes, accepted for publication in Physical Review

Potentially Diagnostic Electron Paramagnetic Resonance Spectra Elucidate the Underlying Mechanism of Mitochondrial Dysfunction in the Deoxyguanosine Kinase Deficient Rat Model of a Genetic Mitochondrial DNA Depletion Syndrome

A novel rat model for a well-characterized human mitochondrial disease, mitochondrial DNA depletion syndrome with associated deoxyguanosine kinase (DGUOK) deficiency, is described. The rat model recapitulates the pathologic and biochemical signatures of the human disease. The application of electron paramagnetic (spin) resonance (EPR) spectroscopy to the identification and characterization of respiratory chain abnormalities in the mitochondria from freshly frozen tissue of the mitochondrial disease model rat is introduced. EPR is shown to be a sensitive technique for detecting mitochondrial functional abnormalities in situ and, here, is particularly useful in characterizing the redox state changes and oxidative stress that can result from depressed expression and/or diminished specific activity of the distinct respiratory chain complexes. As EPR requires no sample preparation or non-physiological reagents, it provides information on the status of the mitochondrion as it was in the functioning state. On its own, this information is of use in identifying respiratory chain dysfunction; in conjunction with other techniques, the information from EPR shows how the respiratory chain is affected at the molecular level by the dysfunction. It is proposed that EPR has a role in mechanistic pathophysiological studies of mitochondrial disease and could be used to study the impact of new treatment modalities or as an additional diagnostic tool

Interactive effects of vertical mixing, nutrients and ultraviolet radiation: In situ photosynthetic responses of phytoplankton from high mountain lakes of Southern Europe.

Global change, together with human activities, has resulted in increasing amounts of organic material (includ-ing nutrients) that water bodies receive. This input further attenuates the penetration of solar radiation, leading to the view that opaque lakes are more “protected” from solar ul-traviolet radiation (UVR) than clear ones. Vertical mixing, however, complicates this view as cells are exposed to fluc-tuating radiation regimes, for which the effects have, in gen-eral, been neglected. Furthermore, the combined impacts of mixing, together with those of UVR and nutrient inputs are virtually unknown. In this study, we carried out complex in situ experiments in three high mountain lakes of Spain (Lake Enol in the National Park Picos de Europa, Asturias, and lakes Las Yeguas and La Caldera in the National Park Sierra Nevada, Granada), used as model ecosystems to evaluate the joint impact of these climate change variables. The main goal of this study was to address the question of how short-term pulses of nutrient inputs, together with vertical mixing and increased UVR fluxes modify the photosynthetic responses of phytoplankton. The experimentation consisted in all pos-sible combinations of the following treatments: (a) solar radi-ation: UVR + PAR (280–700 nm) versus PAR (photosynthet-ically active radiation) alone (400–700 nm); (b) nutrient ad-dition (phosphorus (P) and nitrogen (N)): ambient versus ad-dition (P to reach to a final concentration of 30 µg P L−1, and N to reach N:P molar ratio of 31); and (c) mixing: mixed (one rotation from surface to 3 m depth (speed of 1 m 4 min−1, to-tal of 10 cycles)) versus static. Our findings suggest that un-der ambient nutrient conditions there is a synergistic effect between vertical mixing and UVR, increasing phytoplank-ton photosynthetic inhibition and excretion of organic carbon (EOC) from opaque lakes as compared to algae that received constant mean irradiance within the epilimnion. The opposite occurs in clear lakes where antagonistic effects were deter-mined, with mixing partially counteracting the negative ef-fects of UVR. Nutrient input, mimicking atmospheric pulses from Saharan dust, reversed this effect and clear lakes be-came more inhibited during mixing, while opaque lakes ben-efited from the fluctuating irradiance regime. These climate change related scenarios of nutrient input and increased mix-ing, would not only affect photosynthesis and production in lakes, but might also further influence the microbial loop and trophic interactions via enhanced EOC under fluctuat-ing UVR exposure.Fil: Helbling, Eduardo Walter. Fundación Playa Unión. Estación de Fotobiología Playa Unión; Argentina;Fil: Carrillo, P.. Universidad de Granada. Instituto Universitario de Investigación del Agua; España;Fil: Medina Sanchez, J. M.. Universidad de Granada. Facultad de Ciencias. Departamento de Ecología; España;Fil: Durán, C.. Universidad de Granada. Instituto Universitario de Investigación del Agua; España;Fil: Herrera, G.. Universidad de Granada. Instituto Universitario de Investigación del Agua; España;Fil: Villar Argaiz, M.. Universidad de Granada. Facultad de Ciencias. Departamento de Ecología; España;Fil: Villafañe, Virginia Estela. Fundación Playa Unión. Estación de Fotobiología Playa Unión; Argentina

Direct and indirect effects of vertical mixing, nutrients and ultraviolet radiation on the bacterioplankton metabolism in high-mountain lakes from southern Europe

As a consequence of global change, modifications in the interaction among abiotic stressors on aquatic ecosystems have been predicted. Among other factors, UVR transparency, nutrient inputs and shallower epilimnetic layers could alter the trophic links in the microbial food web. Currently, there are some evidences of higher sensitiveness of aquatic microbial organisms to UVR in opaque lakes. Our aim was to assess the interactive direct and indirect effects of UVR (through the excretion of organic carbon – EOC – by algae), mixing regime and nutrient input on bacterial metabolism. We performed in situ short-term experiments under the following treatments: full sunlight (UVR + PAR, >280 nm) vs. UVR exclusion (PAR only, >400 nm); ambient vs. nutrient addition (phosphorus (P; 30 μg PL−1) and nitrogen (N; up to final N : P molar ratio of 31)); and static vs. mixed regime. The experiments were conducted in three high-mountain lakes of Spain: Enol [LE], Las Yeguas [LY] and La Caldera [LC] which had contrasting UVR transparency characteristics (opaque (LE) vs. clear lakes (LY and LC)). Under ambient nutrient conditions and static regimes, UVR exerted a stimulatory effect on heterotrophic bacterial production (HBP) in the opaque lake but not in the clear ones. Under UVR, vertical mixing and nutrient addition HBP values were lower than under the static and ambient nutrient conditions, and the stimulatory effect that UVR exerted on HBP in the opaque lake disappeared. By contrast, vertical mixing and nutrient addition increased HBP values in the clear lakes, highlighting for a photoinhibitory effect of UVR on HBP. Mixed regime and nutrient addition resulted in negative effects of UVR on HBP more in the opaque than in the clear lakes. Moreover, in the opaque lake, bacterial respiration (BR) increased and EOC did not support the bacterial carbon demand (BCD). In contrast, bacterial metabolic costs did not increase in the clear lakes and the increased nutrient availability even led to higher HBP. Consequently, EOC satisfied BCD in the clear lakes, particularly in the clearest one [LC]. Our results suggest that the higher vulnerability of bacteria to the damaging effects of UVR may be particularly accentuated in the opaque lakes and further recognizes the relevance of light exposure history and biotic interactions on bacterioplankton metabolism when coping with fluctuating radiation and nutrient inputs.Fil: Durán, C.. Universidad de Granada; EspañaFil: Medina Sánchez, J. M.. Universidad de Granada; EspañaFil: Herrera, G.. Universidad de Granada; EspañaFil: Villar Argaiz , M.. Universidad de Granada; EspañaFil: Villafañe, Virginia Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico; ArgentinaFil: Helbling, Eduardo Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico; ArgentinaFil: Carrillo, P.. Universidad de Granada; Españ

Interdisciplinary evidence-based recommendations for the follow-up of testicular cancer patients: a joint effort

Detailed recommendations for the treatment of testicular cancer exist and due to the stringent application of the standard therapies, most patients can nowadays be cured. Moreover in the treatment of early stage disease, active surveillance is now a cornerstone of treatment. Hence there is a clear need for recommendations regarding the long term follow-up of these young patients. These have to be safe, feasible and the intensity of procedures have to reflect the known risk of recurrence. Different proposals have been published but they differ widely especially in terms of frequency and modality of imaging. In the last few years, new evidence has become available regarding the relapse pattern of different disease stages of testicular cancer, the use of imaging in follow-up and the risks of excessive radiation due to imaging, in particular with CT scans. In this article, an interdisciplinary, multinational working group has reviewed the evidence and based on this has formulated practical recommendations for the follow-up of patients with testicular cancer

Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK

Background: To determine the activity and tolerability of adding cetuximab to the oxaliplatin and capecitabine (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC). Patients and methods: In a multicenter two-arm phase II trial, patients were randomized to receive oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1-14 every 3 weeks alone or in combination with standard dose cetuximab. Treatment was limited to a maximum of six cycles. Results: Seventy-four patients with good performance status entered the trial. Objective partial response rates after external review and radiological confirmation were 14% and 41% in the XELOX and in the XELOX + Cetuximab arm, respectively. Stable disease has been observed in 62% and 35% of the patients, with 76% disease control in both arms. Cetuximab led to skin rash in 65% of the patients. The median overall survival was 16.5 months for arm A and 20.5 months for arm B. The median time to progression was 5.8 months for arm A and 7.2 months for arm B. Conclusion: Differences in response rates between the treatment arms indicate that cetuximab may improve outcome with XELOX. The correct place of the cetuximab, oxaliplatin and fluoropyrimidine combinations in first-line treatment of MCC has to be assessed in phase III trial

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07

Background We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). Patients and methods Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Results Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). Conclusions The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicit

In search of the authentic nation: landscape and national identity in Canada and Switzerland

While the study of nationalism and national identity has flourished in the last decade, little attention has been devoted to the conditions under which natural environments acquire significance in definitions of nationhood. This article examines the identity-forming role of landscape depictions in two polyethnic nation-states: Canada and Switzerland. Two types of geographical national identity are identified. The first – what we call the ‘nationalisation of nature’– portrays zarticular landscapes as expressions of national authenticity. The second pattern – what we refer to as the ‘naturalisation of the nation’– rests upon a notion of geographical determinism that depicts specific landscapes as forces capable of determining national identity. The authors offer two reasons why the second pattern came to prevail in the cases under consideration: (1) the affinity between wild landscape and the Romantic ideal of pure, rugged nature, and (2) a divergence between the nationalist ideal of ethnic homogeneity and the polyethnic composition of the two societies under consideration