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Background and aims Infantile hemangiomas can be successfully treated by both systemic propranolol and neodymium:YAG (Nd:YAG)-dye laser combination therapy. In this retrospective study, the efficacy and safety of sequential and parallel therapy of complicated hemangiomas treated with both methods were evaluated. Patients and methods 30 children with 48 complicated hemangiomas were treated with propranolol and Nd:YAG-dye laser combination therapy. Using photo comparison, the percentage remission rate was evaluated by three investigators on a four-step scale (I: 0-25 %, II: 26-50 %, III: 51-75 % and IV: 76-100 %). Results Eleven children received propranolol and laser therapy in parallel (A), twelve children received laser therapy after propranolol (B) and seven children received propranolol after laser therapy (C). Due to emigration abroad, one child was lost to follow-up. A strong improvement (IV) was observed in 23/29 (79.3 %) of all treated children (A: 90.9 %, B 75 %, C 66.7 %). The mean duration of propranolol therapy in all children was 8.6 months (A: 8.9 months, B: 8.2 months, C: 8.9 months). On average, 2.33 laser treatments were performed per hemangioma (A: 1.95, B: 3.2, C: 1.91). Serious side effects caused by propranolol and laser therapy were not observed. Conclusions Propranolol and Nd:YAG-dye laser combination therapy can be used sequentially or in parallel safely and effectively. They complement each other in a meaningful manner.

Zusammenfassung CTLA-4 und PD-1 sind mogliche Angriffspunkte fur eine Tumor-bedingte Herunterregulation lymphozytarer Immunantworten. Immuncheckpoint-modulierende monoklonale Antikorper wirken gegenteilig und induzieren eine Immunantwort gegen diverse Tumoren. CTLA-4- und PD1-Antikorper modulieren die Interaktion von Tumor, Antigen-prasentierenden Zellen und T-Lymphozyten. Die Therapie mit dem CTLA-4-Antikorper Ipilimumab und den PD1-Antikorpern Nivolumab und Pembrolizumab konnte in klinischen Studien einen Vorteil fur das Gesamtuberleben der Patienten zeigen, so dass nach einer Zulassung fur Ipilimumab im Jahr 2011 dann im Sommer 2015 die Zulassung der beiden PD1-Antikorper erfolgte. Eine derartig induzierte und verstarkte Immunantwort bringt unweigerlich in analoger Wirkung Autoimmunphanomene mit sich. Die Kenntnis dieses Nebenwirkungsspektrums ist fur Prophylaxe und Management durch den behandelnden Arzt unerlasslich. Als schwere Nebenwirkung ist mit einer Kolitis zu rechnen, welche sich schon fruh in ausgepragten und anhaltenden Diarrhoen bemerkbar macht. Daneben sind auch andere immunvermittelte Erkrankungen wie die Dermatitis, die Hypophysitis, die Thyreoiditis, die Hepatitis, Iridozyklitis und weitere, eher seltenere Autoimmunphanomene beschrieben worden. Durch eine fruhzeitige Diagnosestellung und Therapieeinleitung konnen Risiken und Folgeschaden fur Patienten reduziert werden. Diese Ubersichtsarbeit beschreibt die Wirkung einer Immun-Checkpoint-Blockade beim metastasierten Melanom und stellt detailliert das Nebenwirkungsspektrum und -management dieser Therapeutika dar.

European settlement has led to increased loads of fine suspended sediment (SS) entering the River Murray, Australia's largest, and arguably, most important river. The River Murray's anthropogenic sediment history can be divided into four periods with varying source areas, sediment loads, and seasonal patterns. The Aboriginal period (before 1840) was characterized by clear water at summer low-flows in the River Murray and its southern tributaries, with more sediment coming from the northern catchment than the southern, and the Darling River being turbid at all flows. There is little evidence that Aboriginal burning resulted in any measurable increase in SS. SS loads peaked in the 1870s and 1880s (the gold and gully period, 1850–1930) as valley floors were incised by gullies (mostly in northern tributaries), and gold sluicing flushed huge amounts of sludge into southern tributaries. Sedimentation in wetlands and on floodplains increased by 2–10 times in this period, and the biota in wetlands switched from clear water to turbid water communities. In the hiatus period (1930–1960) sediment supply from gullies and gold mining waned and low flow SS concentrations returned to low levels. Dam construction through the 1960s and 1970s (the regulation period, 1960 on) disconnected the River Murray from catchment derived sediment. Despite this, SS levels increased again: now largely derived from instream sources including bank erosion from long duration summer irrigation flows, the spread of bottom-feeding carp (Cyprinus carpio), and wave erosion from boats. Erosion switched from winter to summer dominated. Significant investment in securing water for the environment in the Murray-Darling Basin could be complemented by addressing in-channel sediment sources in the River Murray itself to reduce turbidity. Overall, European era SS concentrations remain relatively low with small sediment delivery to the ocean (0.1 Mt per annum), despite high catchment erosion rates. This is due to poor sediment delivery efficiency through the low-gradient landscape.

Aim: Riparian ecosystems are regarded as vulnerable to the effects of climate change. Because of their reliance on passive dispersal to migrate from areas where conditions have become unfavourable, plants are particularly susceptible. On dryland river floodplains, the species diversity of herbaceous annuals is often high while that of structurally dominant woody perennials is low. We examined gene flow genetic structure and dispersal in Acacia stenophylla, a small perennial tree widely distributed throughout river systems of inland Australia. The role of the river corridor in shaping patterns of gene flow and genetic structure is also investigated. Location: Murray-Darling Basin, south eastern Australia. Methods: A total of 127 individuals, from 12 subpopulations located on seven rivers were genotyped at 13 microsatellite loci. Several population and landscape genetic tools were applied to the microsatellite data to evaluate spatial patterns of gene flow and genetic structure and make inferences regarding possible modes of dispersal. Results: High gene flow and weak genetic structure was identified for the 12 subpopulations of A. stenophylla sampled, a surprising result given large distances between subpopulations. Pairwise genetic distance between subpopulations was low to moderate and could largely be explained (R2 = 0.68) by two variables: distance along the river and the proportion of no flow days. structure analysis revealed two genetic clusters. Subpopulations located on the Darling and Lower Balonne rivers were dominated by cluster one while subpopulations from the Warrego and Paroo rivers showed largely mixed ancestry with individuals descending from both clusters one and two. Main Conclusions: These results indicate that the river corridor facilitates extensive gene flow between subpopulations of A. stenophylla in this system. Hydrochory appears to be the dominant process; however, upstream movements of propagules most probably via animal movement are sufficient to negate effects expected under unidirectional dispersal.

Author contributions: MWS and MCT contributed equally to all aspects of this research and manuscript preparation. Key Points 1. The physical character of different functional process zones (FPZs)-r...

Resilience is a well‐used term in many disciplines, but inconsistently or little applied in river geomorphology and river science. Recent developments in ecosystem ecology conceptualize resilience as comprising system resistance to, and recovery from disturbance. The objectives of this paper are to consider how the concept of resilience in this bivariate form applies to river geomorphology and provide a framework for bridging the disciplines of ecology and geomorphology within the setting of river management, using principles of resilience. River geomorphology sets the physical template upon which lotic processes act, thus, understanding the resilience of this template is critical. The importance of consistency in defining the principles of resilience thinking within the context of river science and management is important especially when promoting ecosystem resilience as a river management goal. The application of resilience thinking with respect to river habitat is provided through a series of examples from Australian and New Zealand river systems. AIM: How is the concept of resilience applied to river geomorphology, and what does a geomorphologically resilient river look like?

The magnitude of hydropower developments in emerging regions threatens the sustainability of their riverine landscapes. Fragmentation of river networks by multiple barriers and the imposition of new hydrological regimes influences the ability of these river ecosystems to absorb and adapt to these developments and other stressors. Direct transfer of paradigms built from a restricted geographical base to a global context is fraught with issues because of regional differences in eco‐hydro‐geomorphology, biological communities, and nonlinear interactions between the two. In this manuscript, some impacts of hydropower development on Chilean riverine ecosystems are presented. To understand the context of hydropower, we provide the political context of energy development in Chile. Interactions between hydropower generation and Chilean river ecosystems with special reference to native Chilean fish fauna are outlined. Three case studies are presented that considers: (a) habitat alteration downstream of the Rucue Dam, (b) the effects of daily hydropeaking in the Biobio River, and (c) mitigation strategies to reduce habitat alteration upstream of the San Pedro Dam. These case studies illustrate the expanding scientific knowledge on Chilean riverine landscapes. Finally, new measures to reduce ecosystem impacts of hydropower development on native Chilean fish communities are outlined. Although specific scientific information is available, developing regional ecohydrological models and improving knowledge of ecosystem and sustainability science is required. The scientific approach on which solutions are sought to address present and future river ecosystem problems in Chile are inherently interdisciplinary nature.

Background We investigated 2 cases of deceptively bland cutaneous angiosarcoma (AS), which showed a uniform clinical presentation with a rapidly growing tumor on the nose. It remains unclear whether this was a primary cutaneous manifestation or a metastasis. Both tumors initially presented a high histologic overlap with a benign vascular tumor. The diagnosis was primarily based on the rapidly progressing clinical course and on the results of the staging procedures. Methods Immunohistochemical stains were performed for cytokeratin (AE1/AE3 and MNF116), CD31, ERG, CD34 (HPCA1/my10), D2-40/podoplanin, LYVE-1, Ki67, PHH3, αSMA (1A4), MYC, FOS-B, CAMTA-1, TFE-3, WT1, nestin, VEGFR-2(KDR), VEGFR-3(FLT4), HHV8. MYC amplification was also investigated by fluorescence in situ hybridization. Results The tumor cells were negative for MYC and revealed no D2-40/podoplanin expression. SMA-positive pericytes formed rims around the vessel. The proliferative activity (Ki-67) was elevated, in one case only in a later stage. Discussion Cutaneous ASs can be rather bland and may easily be mistaken for benign vascular tumors. Both cases presented a uniform clinical picture, which implied a malignant vascular tumor. In contrast, the cytomorphology of the endothelial cells and the immunohistochemical profile were not suspicious. We worked out subtle histological criteria, which should allow an early detection of such tumors.

Despite much research and investment into understanding and managing nutrients across agricultural landscapes, nutrient runoff to freshwater ecosystems is still a major concern. We argue there is currently a disconnect between the management of watershed surfaces (agricultural landscape) and river networks (riverine landscape). These landscapes are commonly managed separately, but there is limited cohesiveness between agricultural landscape-focused research and river science, despite similar end goals. Interdisciplinary research into stream networks that drain agricultural landscapes is expanding but is fraught with problems. Conceptual frameworks are useful tools to order phenomena, reveal patterns and processes, and in interdisciplinary river science, enable the joining of multiple areas of understanding into a single conceptual-empirical structure. We present a framework for the interdisciplinary study and management of agricultural and riverine landscapes. The framework includes components of an ecosystems approach to the study of catchment-stream networks, resilience thinking, and strategic adaptive management. Application of the framework is illustrated through a study of the Fox Basin in Wisconsin, USA. To fully realize the goal of nutrient reduction in the basin, we suggest that greater emphasis is needed on where best management practices (BMPs) are used within the spatial context of the combined watershed-stream network system, including BMPs within the river channel. Targeted placement of BMPs throughout the riverine landscape would increase the overall buffering capacity of the system to nutrient runoff and thus its resilience to current and future disturbances.

Biocomplexity is an emergent property of ecosystems that captures the interplay of structures and processes at multiple scales. These interactions can establish a dynamic habitat template that serves as a filter to define ecological organization across landscapes. Studies of biocomplexity in floodplain rivers typically focus on hydrological variability or geomorphic heterogeneity separately, with their interactions being an output rather than the direct focus of investigations. This study examines the interaction of hydrological variability and geomorphic heterogeneity across 25 off‐channel habitats (OCHs) of the Upper Mississippi River, USA. Questions posed were as follows: What are the interactive effects of hydrological variability and geomorphic heterogeneity shaping the physical habitat template of OCHs? and How does the organization of the physical habitat template influence fish community composition within OCHs? Three distinct OCH groups emerged from this study: where hydrological variability defined Group 1 (Lake group); Group 2 was organized via geomorphic heterogeneity (Backwater group); and a combination of hydrological and geomorphological variables defined Group 3 (Slackwater group). Thus, the differential interaction of hydrology and geomorphology defined the dynamic physical habitat template of OCHs in this riverine landscape. No significant difference between the association matrices of the hydrogeomorphic template and fish community composition for the 25 OCH sites was recorded. A priori grouping of fish into the three OCH groups revealed marked differences in fish community composition. A subset of hydrogeomorphic variables that defined the physical character of the OCHs acted as an environmental filter for the fish community composition of the three OCH groups. A conceptual model explaining hydrogeomorphic–ecological interactions across the OCHs of this floodplain river system is provided.

Watersheds are spatially explicit landscape units that contain a range of interacting physical, ecological and social attributes. They are social–ecological systems that provide a range of ecosystem services valued by the society. Their ability to provide these services depends, in part, on the degree to which they are impaired by human-related activity. An array of indicators is used by natural resource managers, both private and government, to assess watersheds and their sub-components. Often these assessments are performed in comparison with a reference condition. However, assessments can be hampered because natural settings of many systems differ from those sites used to characterize reference conditions. Additionally, given the ubiquity of human-related alterations across landscapes (e.g. atmospheric deposition of anthropogenically derived nitrogen), truly unaltered conditions for most, if not all, watersheds cannot be described. Definitions of ‘integrity’ have been developed for river ecosystems, but mainly at the reach or site scale and usually for particular species, such as fish or macroinvertebrates. These scales are inappropriate for defining integrity at the watershed scale. In addition, current assessments of endpoints do not indicate the source of impairment. Our definition of watershed ‘integrity’ is the capacity of a watershed to support and maintain the full range of ecological processes and functions essential to the sustainability of biodiversity and of the watershed resources and services provided to society. To operationalize this definition as an assessment tool, we identify key functions of unimpaired watersheds. This approach can then be used to model and map watershed integrity by incorporating risk factors (human-related alterations or stressors) that have been explicitly shown to interfere with and degrade key functions in watersheds. An advantage of this approach is that the index can be readily deconstructed to identify factors influencing index scores, thereby directly supporting the strategic adaptive management of individual components that contribute to watershed integrity. Moreover, the approach can be iteratively applied and improved as new data and information become available. © 2015 The Authors. River Research and Applications published by John Wiley & Sons Ltd.

Zusammenfassung Hintergrund und Zielsetzung Botulinumtoxin Typ A ist eine wirksame, gut vertragliche, wenn auch temporare Therapieoption gegen primare axillare Hyperhidrose. Uber den Einfluss von wiederholten Injektionen auf die Wirkdauer ist jedoch wenig bekannt. Patienten und Methoden 139 Patienten mit primarer axillarer Hyperhidrose wurden 50 Botulinumtoxin-Einheiten je Axilla injiziert. Die Wirkdauer wurde bei 101 Patienten, die mindestens 3 Behandlungen erhalten hatten, nach der ersten, zweiten, und letzten Behandlung untersucht. Ergebnisse Die Wirkung hielt im Durchschnitt nach der ersten, zweiten, und letzten Injektion jeweils 4,0 Monate, 4,5 Monate, und 5,0 Monate an. Insgesamt war die Wirkdauer nach der letzten Injektion signifikant langer als nach der ersten Injektion (p = 0,0055, Wilcoxon-Vorzeichen-Rang-Test). Ebenso gab es deutliche Unterschiede zwischen der ersten und der zweiten Injektion (p = 0,0302), sowie zwischen der zweiten und der letzten Injektion (p = 0,0381). Bei 25,7 % der Patienten blieb die Wirkdauer uber die gesamte Behandlungszeit unverandert. Schlussfolgerungen Wiederholte Botulinumtoxin-Behandlungen fuhrten zu einer signifikant verlangerten Wirkdauer bei axillarer Hyperhidrose. Wahrend sich die durchschnittliche Wirkdauer mit jeder Behandlung weiter erhohte, gab es dennoch erhebliche interindividuelle Unterschiede.

Summary Background and objectives Botulinum toxin type A is an effective, well-tolerated, albeit temporary treatment for primary axillary hyperhidrosis. However, little is known about the influence of repetitive injections on the duration of efficacy. Patients and methods 139 patients with primary axillary hyperhidrosis were injected with 50 units of botulinum toxin per axilla. In 101 patients, who received at least three treatments, the duration of efficacy after the first, second, and last treatment was evaluated. Results The median duration of efficacy was 4.0 months, 4.5 months, and 5.0 months after the first, second, and last injection, respectively. Overall, the duration of efficacy was significantly longer after the last injection compared to the duration of efficacy after the first injection (p = 0.0055, Wilcoxon matched-pairs signed-rank test). Likewise, the difference between the first and second injection (p = 0.0302) as well as the difference between the second and the last injection (p = 0.0381) were significant. In 25.7 % of patients, the duration of efficacy remained unchanged over the entire treatment period. Conclusions Repetitive botulinum toxin treatments led to a significantly increased duration of efficacy in axillary hyperhidrosis. While the average duration of efficacy continued to increase with each treatment, there were considerable interindividual differences.

Spatial and temporal variability in flooding plays a significant role in the productivity of semi-arid floodplain ecosystems. Floodplains may be perceived as boom–bust systems, but this model does not account for transitions that may occur between wet and dry floodplain states. This study used the concept of adaptive cycles to examine how floodplain vegetation productivity changes in response to wetting and drying. Floodplain vegetation productivity was tracked through a wet and dry state using the normalized difference vegetation index (NDVI). Floodplain inundation revealed complex vegetation productivity responses to resource availability. There was low NDVI in the dry phase, whereas vegetation vigour increased and decreased through the wetting, wet and drying phases. There was a marked difference in NDVI class area, number of transitions, direction of transitions, probability of transitions and NDVI class diversity between the dry phase and the combined wetting, wet and drying phases of floodplain inundation. The distribution of transition probabilities was platykurtic in the dry phase and bimodal during the wetting, wet and drying phases. Overall, anti-clockwise hysteresis was the dominant direction of hysteresis. All vegetation productivity measures demonstrated a switch in direction during the wet phase. The hysteresis observed in this study indicates the cyclic nature of vegetation response to floodplain inundation through dry, wetting, wet and drying phases. We propose that vegetation productivity response follows an adaptive cycle and that this is an appropriate model for understanding the complexity of semi-arid floodplain vegetation response to wetting and drying. Copyright © 2015 John Wiley & Sons, Ltd.

Zusammenfassung Hintergrund Infantile Hamangiome (IH) konnen zu schwerwiegenden Komplikationen wie Obstruktion, Ulzeration oder Herzinsuffizienz fhren. Daher ist bei bestimmten Problemlokalisationen oder bei ausbleibender Regression eine rechtzeitige und suffiziente Therapie notwendig. Da systemische Therapien wie der β-Blocker Propranolol oder orale Kortikosteroide in seltenen Fallen ernstzunehmende Nebenwirkungen haben konnen, sind gut wirksame und vertragliche Lokaltherapien als Erganzung oder Alternative wnschenswert. Patienten und Methodik Im Rahmen einer interdisziplinaren retrospektiven Studie wurden 38 Kinder mit insgesamt 77 IH mit dem gepulsten Farbstofflaser (PDL) (595 nm) und Nd:YAG-Laser (1 064 nm) behandelt. Der Therapieerfolg und die Nebenwirkungen wurden sowohl anhand objektiver Parameter wie sonographisch bestimmter Tiefenausdehnung als auch subjektiv von den Eltern der Kinder bewertet. Ergebnisse Alle 77 behandelten IH sprachen auf die Therapie an, wobei 52,8% nach Therapieabschluss abgeheilt waren und 47,2% nur noch eine minimale Restgrofle aufwiesen. Der Behandlungserfolg wurde von den Eltern in 92,6% als sehr gut oder gut bewertet. Als Hauptnebenwirkung trat in 45,9% eine transiente Blasenbildung auf. Schlussfolgerungen Die Kombinationsbehandlung mit PDL und Nd:YAG-Laser ist eine wirksame und nebenwirkungsarme lokale Therapie gegen IH.

Summary Background Infantile hemangiomas (IH) can cause severe complications such as obstruction, ulceration or heart failure. Therefore, in certain difficult-to-treat areas, or when there is no sign of involution, early and effective therapy is required. In rare instances, systemic treatments, like the beta-blocker propranolol and oral corticosteroids, can cause serious side effects. Effective and well-tolerated local treatment options are thus desirable as additive or alternative methods. Patients and Methods In this retrospective interdisciplinary study, 38 children with 77 IH were treated with pulsed dye laser (PDL) (595 nm) and Nd:YAG laser (1,064 nm). The treatment success and side effects were evaluated according to objective and subjective parameters, including hemangioma thickness measured by ultrasound and the parents’ evaluation of treatment. Results All 77 treated IH responded to the therapy, of which 52.8 % healed after the end of treatment and 47.2 % had only minimum residual components. The success of treatment was assessed by the parents in 92.6 % as very good or good. Transient blistering occurred as the main side effect in 45.9 %. Conclusions Combination therapy with PDL and Nd:YAG laser represents an effective local method for IH with minimal side effects.

UV-induced skin cancers comprise a major problem in organ transplant recipients (OTRs). Cyclosporin A, a calcineurin inhibitor, is used as a standard immunosuppressant and clearly increases the skin cancer risk. Azathioprine does not appear to result in such an increase in skin cancer risk, and mTOR inhibitors are associated with an even lesser skin cancer risk. The underlying molecular mechanisms of these clinically important differences among immunosuppressants are still unclear and may relate to other than immunological effects. Insights may be gained by the multistep skin cancer theory and xeroderma pigmentosum, where defective nucleotide excision repair (NER) results in a cellular mutator phenotype and cutaneous carcinogenesis. This viewpoint assay summarizes current knowledge about the influence of the most commonly used immunosuppressive drugs in OTRs on DNA repair. Calcineurin inhibition results in a 200-fold increased skin cancer risk compared with the normal population and inhibits NER. The skin cancer risk under azathioprine is threefold less compared with calcineurin inhibitors, which may relate to inhibition of only the last step of NER, i.e. gap filling. mTOR inhibitors do not reduce NER in the global genome and can inhibit the growth of already initiated tumors, which may account for the markedly reduced skin cancer risk compared with calcineurin inhibitors. We conclude that OTRs may benefit from treatment regimens other than calcineurin inhibitors and speculate that a targeted modulation of calcineurin-dependent signalling may prevent UV-induced tumor formation by enhancing NER not only in OTRs but also in the general population, at least in part.

Cyclosporin A (CsA) inhibits nucleotide excision repair (NER) in human cells, a process that contributes to the skin cancer proneness in organ transplant patients. We investigated the mechanisms of CsA-induced NER reduction by assessing all xeroderma pigmentosum (XP) genes (XPA-XPG). Western blot analyses revealed that XPA and XPG protein expression was reduced in normal human GM00637 fibroblasts exposed to 0.1 and 0.5 lm CsA. Interestingly, the CsA treatment reduced XPG, but not XPA, mRNA expression. Calcineurin knockdown in GM00637 fibroblasts using RNAi led to similar results suggesting that calcineurin-dependent signalling is involved in XPA and XPG protein regulation. CsA-induced reduction in NER could be complemented by the overexpression of either XPA or XPG protein. Likewise, XPA-deficient fibroblasts with stable overexpression of XPA (XP2OS-pCAH19WS) did not show the inhibitory effect of CsA on NER. In contrast, XPC-deficient fibroblasts overexpressing XPC showed CsA-reduced NER. Our data indicate that the CsA-induced inhibition of NER is a result of downregulation of XPA and XPG protein in a calcineurin- dependent manner.

Deciphering patterns and inferring processes in multicausal floodplain river ecosystems is a challenge in river science. The effects of larger-scale top-down constraints and smaller-scale bottom-up influences on the spatial patterns of nutrient concentrations across multiple inset-floodplain surfaces was studied in a large dryland floodplain river (Barwon-Darling River, south-east Australia). The distribution of sediment-associated carbon, nitrogen, and phosphorus was primarily related with significant differences in the textural character of the different floodplain surfaces. Elevation of the different floodplain surfaces above the active channel was a secondary influence on the distribution of carbon and phosphorus. Combined, these factors produce a spatial patch mosaic of sediment associated carbon, nitrogen, and phosphorous across these floodplain surfaces.

Unlike other immunosuppressive drugs including everolimus, cyclosporin A causes a dramatic increase of UV-induced skin cancer, a feature that is reminiscent of xeroderma pigmentosum (XP), where defective nucleotide excision repair (NER) of UV-induced DNA damage results in cutaneous carcinogenesis. The molecular basis of the clinically important differential activities of cyclosporin A and everolimus is still unclear. We measured post-UV cell survival of cyclosporin A- and everolimus-treated human fibroblasts and lymphoblasts using a cell proliferation assay (MTT). The cellular NER capacity was assessed by host cell reactivation. Using an ELISA and specific antibodies, cyclobutane pyrimidine and pyrimidine-6,4-pyrimidone photoproduct removal from the cellular genome was measured. The effect of calcineurin on NER was investigated using a calcineurin A expression vector and specific RNAi. Cyclosporin A led to a dose dependent decrease in post-UV cell survival, inhibited NER and blocked photoproduct removal. In contrast, none of these effects where seen in everolimus-treated cells. Overexpression of calcineurin A resulted in increased NER and complemented the Cyclosporin A-induced reduction of NER. Downregulation of calcineurin using RNAi inhibited NER comparable to cyclosporin A-treatment. We conclude that cyclosporin A, but not everolimus, leads to an increased skin cancer risk via a calcineurin signalling-dependent impairment of NER.

Hydrological connectivity is an important driver of ecosystem structure in floodplain rivers; however, little is known of how hydrological connectivity affects the structure and functioning of food webs in these systems. This study examines aquatic food web structure in 10 floodplain lakes on a dryland river floodplain in eastern Australia across a connectivity gradient. Results for fishes suggest that benthic carbon sources are more important in high connectivity billabongs than in low connectivity billabongs and that pelagic sources are more important in low connectivity billabongs than in high connectivity billabongs. Fishes in less connected billabongs were also found to feed at higher trophic levels than in more connected billabongs. We hypothesize that in high connectivity billabongs, where suitable benthic primary sources are abundant, common fish species such as carp and bony bream feed as detritivores or herbivores; while in low connectivity billabongs, where benthic sources are less abundant, the same species feed as planktivores, insectivores or piscivores. This dietary difference may also be promoted by greater predation efficiency in less structurally complex low connectivity billabongs. The feeding behaviour of these fish species subsequently influences the trophic positions of fishes higher in the food chain and ultimately the total food chain lengths that high and low connectivity billabongs support. The results of this study highlight the importance of hydrological connectivity to the structure of food webs in these systems and the potential for them to be affected by water resource development. Copyright © 2011 John Wiley & Sons, Ltd.

Hydrological regime, physical habitat structure and water chemistry are interacting drivers of fish assemblage structure in floodplain rivers throughout the world. In rivers with altered flow regimes, understanding fish assemblage responses to flow and physico-chemical conditions is important in setting priorities for environmental flow allocations and other river management strategies. To this end we examined fish assemblage patterns across a simple gradient of flow regulation in the upper Murray-Darling Basin, Australia. We found clear separation of three fish assemblage groups that were spatially differentiated in November 2002, at the end of the winter dry season. Fish assemblage patterns were concordant with differences in water chemistry, but not with the geomorphological attributes of channel and floodplain waterholes. After the summer-flow period, when all in-channel river sites received flow, some floodplain sites were lost to drying and one increased in volume, fish assemblages were less clearly differentiated. The fish assemblages of river sites did not increase in richness or abundance in response to channel flow and the associated potential for increased fish recruitment and movement associated with flow connectivity. Instead, the more regulated river's fish assemblages appeared to be under stress, most likely from historical flow regulation. These findings have clear implications for the management of hydrological regimes and the provision of environmental flows in regulated rivers of the upper Murray-Darling Basin.

Summary Background: The value of the status of the sentinel lymph node (SLN) in patients with thick melanomas (Breslow thickness ≥ 4 mm) is controversial. Patients and Methods: Using Kaplan-Meier estimates and Cox regression models, we studied 152 patients with primary melanomas ≥ 4 mm thickness who underwent sentinel lymph node excision (SLNE) at the university hospitals of Hannover and Gottingen, Germany, between 1998 and 2006. Results: The median tumor thickness was 5.2 (4–18) mm; 58.5% of primary melanomas were ulcerated. Micrometastasis to a SLN was found in 48.7%. The patients with positive SLNs were significantly younger than those with negative SLN (p = 0.01). Of the complete lymph node dissections, 32% contained positive non-SLN. The estimated 5 year recurrence-free survival was 42.5 ± 5% (± standard error) (26.3 ± 6.6% after positive SLNE, 58.7 ± 7.1% after negative SLNE). The 5 year overall survival rate was 53.2 ± 5.4% (37.5 ± 8.1% after positive SLNE, 67.6 ± 6.7% after negative SLNE). By multivariate analysis, the SLN was a highly significant predictor for overall survival (p = 0.007, relative risk 2.3, 95%, confidence interval 1.2–4.2). The overall survival was significantly associated with penetration of nodal metastases into the SLN > 0.3 mm (p = 0.001). Other parameters such as tumor thickness, ulceration, age and sex were not significant. In the subgroup of patients with negative SLN, neither tumor thickness nor ulceration was significant. Conclusions: The status of the SLN represents the most important prognostic parameter in patients with thick melanomas, whereas other parameters such as tumor thickness and ulceration loose their prognostic value.

1. Management of whole rivers and river catchments requires a comprehensive set of information about river condition and use, both existing and historical, and the links between them at regional, state or national scales. This paper outlines a new approach to the assessment of river condition, using a small team was able to assess 210 000 km of rivers across more than 3 million km(2) of Australia in little more than a year. 2. The approach was driven by a hierarchical model of river function, which assumed that broad-scale catchment characteristics affect local hydrology, habitat features, water quality and, ultimately, aquatic biota. The model provided the basis for selecting important ecologically relevant features that indices should represent. For each reach of each river we derived a biological index and an environmental index based on measures quantifying catchment and hydrological condition, and habitat and water quality condition. Data came from existing state and national databases, satellite images, site measurements and process models. 3. All indices were calculated as deviation from a reference condition, were range-standardised and were divided into equivalent bands of condition. Amalgamation of index components and of sub-indices was determined by consideration of their ecological effects; for example, general degradation might be additive, but toxic effects of one component would override all others. 4. Several internal and external validation methods were employed, with the all-important validation of the final assessments undertaken by comparison with a similar index based on locally measured data. 5. The environmental assessment classified 14% of reaches as largely unmodified, 67% as moderately modified and 19% as substantially modified by human impacts. The biological assessment based on site assessments and modelled data using invertebrates indicated that 70% of reaches were equivalent to reference condition and that 30% were significantly impaired. Catchment disturbance, elevated sediment and nutrient loads, and habitat degradation all contributed to these results. These impacts have all occurred during the last 200 years (post-European settlement). 6. Partly as a result of the assessments of this study the Australian Government has begun to adopt a more environmentally sustainable approach to broad-scale water management.

Australian dryland rivers are acknowledged as being among the most variable and unpredictable in the world in terms of their flow regimes. Although renowned for their spectacular floods over vast and complex floodplains, rivers exist for much of the time as discrete waterholes, which are important refugia for aquatic biota. Recent work has shown that waterholes are filled by surface flows and there is little evidence of groundwater contributions. The permanence of these refugia is largely determined by waterhole morphology and evaporative loss, and some waterholes can clearly persist for 2 years or more without surface flow connection. As a consequence, the spatial distribution of refugia for aquatic biota is determined not only by the physical template but also by the duration of dry spells and the timing of flow events. Flow variability also has a major influence on aquatic production in these systems and ultimately influences food availability for fish and other consumers. During dry spells, aquatic food webs in waterholes are largely supported by algal production in the shallow littoral zone. At the other extreme, during floods, the boom of aquatic production on floodplains provides an immense food resource. However, there are many occasions when in-channel flows (flow pulses) result in periods where neither of these sources of production is likely to be available. Although such flow pulses are essential for the physical persistence and connectivity of waterholes, we propose that they may lead to food limitation and stress for populations of fish and other consumers. Water resource development in dryland rivers often leads to an increase in the frequency and duration of flow pulses, due to reduced floods and elevated base flows. This increase in the ‘bits in between’ natural boom or bust conditions may help to explain the observed decline in ecosystem health in dryland river systems with significant water resource development. Copyright © 2006 John Wiley & Sons, Ltd.