Deciphering microRNA code in pain and inflammation: lessons from bladder pain syndrome

MicroRNAs (miRNAs), a novel class of molecules regulating gene expression, have been hailed as modulators of many biological processes and disease states. Recent studies demonstrated an important role of miRNAs in the processes of inflammation and cancer, however, there are little data implicating miRNAs in peripheral pain. Bladder pain syndrome/interstitial cystitis (BPS/IC) is a clinical syndrome of pelvic pain and urinary urgency/frequency in the absence of a specific cause. BPS is a chronic inflammatory condition that might share some of the pathogenetic mechanisms with its common co-morbidities inflammatory bowel disease (IBD), asthma and autoimmune diseases. Using miRNA profiling in BPS and the information about validated miRNA targets, we delineated the signaling pathways activated in this and other inflammatory pain disorders. This review projects the miRNA profiling and functional data originating from the research in bladder cancer and immune-mediated diseases on the BPS-specific miRNAs with the aim to gain new insight into the pathogenesis of this enigmatic disorder, and highlighting the common regulatory mechanisms of pain and inflammation.

Solute transport in crystalline rocks at Äspö — II: Blind predictions, inverse modelling and lessons learnt from test STT1

Based on the results from detailed structural and petrological characterisation and on up-scaled laboratory values for sorption and diffusion, blind predictions were made for the STT1 dipole tracer test performed in the Swedish A¨ spo¨ Hard Rock Laboratory. The tracers used were nonsorbing, such as uranine and tritiated water, weakly sorbing 22Na+, 85Sr2 +, 47Ca2 +and more strongly sorbing 86Rb+, 133Ba2 +, 137Cs+. Our model consists of two parts: (1) a flow part based on a 2D-streamtube formalism accounting for the natural background flow field and with an underlying homogeneous and isotropic transmissivity field and (2) a transport part in terms of the dual porosity medium approach which is linked to the flow part by the flow porosity. The calibration of the model was done using the data from one single uranine breakthrough (PDT3). The study clearly showed that matrix diffusion into a highly porous material, fault gouge, had to be included in our model evidenced by the characteristic shape of the breakthrough curve and in line with geological observations. After the disclosure of the measurements, it turned out that, in spite of the simplicity of our model, the prediction for the nonsorbing and weakly sorbing tracers was fairly good. The blind prediction for the more strongly sorbing tracers was in general less accurate. The reason for the good predictions is deemed to be the result of the choice of a model structure strongly based on geological observation. The breakthrough curves were inversely modelled to determine in situ values for the transport parameters and to draw consequences on the model structure applied. For good fits, only one additional fracture family in contact with cataclasite had to be taken into account, but no new transport mechanisms had to be invoked. The in situ values for the effective diffusion coefficient for fault gouge are a factor of 2–15 larger than the laboratory data. For cataclasite, both data sets have values comparable to laboratory data. The extracted Kd values for the weakly sorbing tracers are larger than Swedish laboratory data by a factor of 25–60, but agree within a factor of 3–5 for the more strongly sorbing nuclides. The reason for the inconsistency concerning Kds is the use of fresh granite in the laboratory studies, whereas tracers in the field experiments interact only with fracture fault gouge and to a lesser extent with cataclasite both being mineralogically very different (e.g. clay-bearing) from the intact wall rock.

Nuclear power plants and childhood leukaemia: lessons from the past and future directions

In the 1980s, leukaemia clusters were discovered around nuclear fuel reprocessing plants in Sellafield and Dounreay in the United Kingdom. This raised public concern about the risk of childhood leukaemia near nuclear power plants (NPPs). Since then, the topic has been well-studied, but methodological limitations make results difficult to interpret. Our review aims to: (1.) summarise current evidence on the relationship between NPPs and risk of childhood leukaemia, with a focus on the Swiss CANUPIS (Childhood cancer and nuclear power plants in Switzerland) study; (2.) discuss the limitations of previous research; and (3.) suggest directions for future research. There are various reasons that previous studies produced inconclusive results. These include: inadequate study designs and limited statistical power due to the low prevalence of exposure (living near a NPP) and outcome (leukaemia); lack of accurate exposure estimates; limited knowledge of the aetiology of childhood leukaemia, particularly of vulnerable time windows and latent periods; use of residential location at time of diagnosis only and lack of data on address histories; and inability to adjust for potential confounders. We conclude that risk of childhood leukaemia around NPPs should continue to be monitored and that study designs should be improved and standardised. Data should be pooled internationally to increase the statistical power. More research needs to be done on other putative risk factors for childhood cancer such as low-dose ionizing radiation, exposure to certain chemicals and exposure to infections. Studies should be designed to allow examining multiple exposures.

A Normative Theory of Forgetting: Lessons from the Fruit Fly

Recent experiments revealed that the fruit fly Drosophila melanogaster has a dedicated mechanism for forgetting: blocking the G-protein Rac leads to slower and activating Rac to faster forgetting. This active form of forgetting lacks a satisfactory functional explanation. We investigated optimal decision making for an agent adapting to a stochastic environment where a stimulus may switch between being indicative of reward or punishment. Like Drosophila, an optimal agent shows forgetting with a rate that is linked to the time scale of changes in the environment. Moreover, to reduce the odds of missing future reward, an optimal agent may trade the risk of immediate pain for information gain and thus forget faster after aversive conditioning. A simple neuronal network reproduces these features. Our theory shows that forgetting in Drosophila appears as an optimal adaptive behavior in a changing environment. This is in line with the view that forgetting is adaptive rather than a consequence of limitations of the memory system.

Projecting a relevant "next": Instruction sequences in driving lessons

Car interaction and the organisation of multi-activity in cars have become a fertile topic of research within CA and EM (Laurier 2005, Haddington & Keisanen 2009). While previous research has focused exclusively on everyday car rides, in this paper we will analyse a specific kind of car interaction, namely driving lessons. In addition to"driving" and"talking", as the two main parallel activities in everyday car rides (Mondada in press), in driving lessons a central activity is"instructing", that we understand to be a collaborative accomplishment (Sanchez Svensson et al. 2009). Drawing on a corpus of 7 video-recorded driving lessons, we will analyse the sequential organisation of"instruction sequences", i.e. of those actions that are initiated by the driving instructor with a turn projecting the next relevant action to be executed by the learner. Learners carry out next actions in two different ways: a) as"single" actions (e.g. using the indicator); b) as a complex series of overlapping or parallel actions. We will show that"single" actions occur as responses to instructions concerning the learner's command of the car, while complex actions occur when the instructors formulate direction indications. The aims of our analyses are twofold. Firstly, we will analyse how instruction sequences are fitted to the emerging contingencies of the car ride (movement in space, changing environment): we will show that a) the turn format of the instruction initiation displays the degree of"urgency" of the requested action; b) learners have the possibility to start the relevant"next" before the instruction initiation comes to completion. Secondly, we will focus on those"seconds" that the driving instructor treats as problematic by initiating a repair sequence (e.g. an improper use of the indicator). Our research contributes to the discussion about the multimodal resources that participants can employ to fulfil a projected action. In addition, it offers insights in a hitherto scarcely investigated topic, namely the organisation of instructions and the ecology of apprenticeship. References HADDINGTON, P. & KEISANEN, T. (2009) Location, mobility and the body as resources in selecting a route. Journal of Pragmatics 41 (10), 1938-1961. LAURIER, Eric (2005): Searching for a parking space. Intellectica 41-42/2-3: 101-116. MONDADA, Lorenza (in press). Talking and driving: multi-activity in the car. Semiotica. SANCHEZ SVENSSON, M. et al. (2009) "Embedding instruction in practice: contingency and collaboration during surgical training", Sociology of Health & Illness, 31/6: 889-906.

Shared Rule in Federal Political Systems: Conceptual Lessons from Subnational Switzerland

This article reconceptualizes shared rule and uses novel data to measure it, thus addressing two shortcomings of federal literature. First, while most studies focus on self-rule, one question that is largely neglected is how lower-level governments can influence politics at a higher level in the absence of “second” chambers. The answer is through shared rule. A second shortcoming is that even when addressing this question, scholars concentrate on constitutional-administrative aspects of vertical intergovernmentalism, neglecting more informal, “political” dynamics. Comparing the twenty-six Swiss cantons allows drawing two lessons for federal studies: That shared rule is multifaceted and complex, and that to study informal territorial actors as well as direct political processes is indispensable to understand how power is actually distributed in federal political systems.

Lessons learned from the International Renal Cell Carcinoma-Venous Thrombus Consortium (IRCC-VTC)

Renal cell carcinoma (RCC) extension into the renal vein or the inferior vena cava occurs in 4%-10% of all kidney cancer cases. This entity shows a wide range of different clinical and surgical scenarios, making natural history and oncological outcomes variable and poorly characterized. Infrequency and variability make it necessary to share the experience from different institutions to properly analyze surgical outcomes in this setting. The International Renal Cell Carcinoma-Venous Tumor Thrombus Consortium was created to answer the questions generated by competing results from different retrospective studies in RCC with venous extension on current controversial topics. The aim of this article is to summarize the experience gained from the analysis of the world's largest cohort of patients in this unique setting to date.