Carcinoma-associated fibroblasts stimulate tumor progression of initiated human epithelium

The present study demonstrates that fibroblasts associated with carcinomas stimulate tumor progression of initiated nontumorigenic epithelial cells both in an in vivo tissue recombination system and in an in vitro coculture system. Human prostatic carcinoma-associated fibroblasts grown with initiated human prostatic epithelial cells dramatically stimulated growth and altered histology of the epithelial population. This effect was not detected when normal prostatic fibroblasts were grown with the initiated epithelial cells under the same experimental conditions. In contrast, carcinoma-associated fibroblasts did not affect growth of normal human prostatic epithelial cells under identical conditions. From these data, we conclude that in this human prostate cancer model, carcinoma-associated fibroblasts stimulate progression of tumorigenesis. Thus, carcinoma-associated fibroblasts can direct tumor progression of an initiated prostate epithelial cell

Is the water footprint an appropriate tool for forestry and forest products: The Fennoscandian case

The water footprint by the Water Footprint Network (WF) is an ambitious tool for measuring human appropriation and promoting sustainable use of fresh water. Using recent case studies and examples from water-abundant Fennoscandia, we consider whether it is an appropriate tool for evaluating the water use of forestry and forest-based products. We show that aggregating catchment level water consumption over a product life cycle does not consider fresh water as a renewable resource and is inconsistent with the principles of the hydrologic cycle. Currently, the WF assumes that all evapotranspiration (ET) from forests is a human appropriation of water although ET from managed forests in Fennoscandia is indistinguishable from that of unmanaged forests. We suggest that ET should not be included in the water footprint of rain-fed forestry and forest-based products. Tools for sustainable water management should always contextualize water use and water impacts with local water availability and environmental sensitivity

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Facing others’ misfortune: Personal distress mediates the association between maladaptive emotion regulation and social avoidance

Previous research has linked the use of certain emotion regulation strategies to the vicarious experience of personal distress (PD) and empathic concern (EC). However, it has not been tested yet whether (1) vicarious PD is positively associated with maladaptive emotion regulation strategies, (2) vicarious EC is positively associated with adaptive emotion regulation strategies and whether (3) PD and EC mediate the link between emotion regulation and reports of approach/avoidance in response to a person in distress. To that aim, we assessed people’s reports of PD (i.e., anxious, troubled, and upset) and EC (i.e., concerned, sympathetic, and soft-hearted) in response to a video depicting a person in a threatening situation (n = 78). Afterwards, we assessed participants’ reports of avoidance and approach in regards to the character and their disposition to use maladaptive and adaptive emotion regulation strategies. Results showed that PD as well as EC were positively related to maladaptive strategies and negatively related to adaptive strategies, and that the association between maladaptive regulation strategies (i.e., rumination) and the willingness to avoid the person in distress was mediated by greater reports of PD. This study thus expands previous evidence on the relationship between maladaptive regulation strategies and affective empathy and provides novel insights about the main role that personal distress played in the association between maladaptive strategies and social avoidance

A critical review of smaller state diplomacy

In The Peloponnesian War, Thucydides (1972: 402) highlights the effects of the general, overall weakness of smaller states vis-à-vis larger, more powerful ones in a key passage, where the Athenians remind the Melians that: “… since you know as well as we do that, as the world goes, right is only in question between equals in power. Meanwhile, the strong do what they can and the weak suffer what they must.” Concerns about the vulnerability of small, weak, isolated states have echoed throughout history: from Thucydides, through the review by Machiavelli (1985) of the risks of inviting great powers to intervene in domestic affairs, through 20th century US-led contemporary political science (Vital, 1971; Handel, 1990) and Commonwealth led scholarship (Commonwealth Secretariat, 1985). In the context of 20th century ‘Balkanization’, the small state could also prove unstable, even hostile and uncooperative, a situation tempting enough to invite the intrusion of more powerful neighbours: a combination, according to Brzezinski (1997: 123-124) of a power vacuum and a corollary power suction2: in the outcome, if the small state is ‘absorbed’, it would be its fault, and its destiny, in the grand scheme of things. In an excellent review of small states in the context of the global politics of development, Payne (2004: 623, 634) concludes that “vulnerabilities rather than opportunities are the most striking consequence of smallness”. It has been recently claimed that, since they cannot defend or represent themselves adequately, small states “lack real independence, which makes them suboptimal participants in the international system” (Hagalin, 2005: 1). There is however, a less notable and acknowledged but more extraordinary strand of argumentation that considers ‘the power of powerlessness’, and the ability of small states to exploit their smaller size in a variety of ways in order to achieve their intended, even if unlikely, policy outcomes. The pursuance of smaller state goals becomes paradoxically acceptable and achievable precisely because such smaller states do not have the power to leverage disputants or pursue their own agenda. A case in point concerns the smallest state of all, the Vatican, whose powers are both unique and ambiguous, but certainly not insignificant (The Economist, 2007). Smaller states have “punched above their weight” (e.g. Edis, 1991); and, intermittently, political scientists confront their “amazing intractability” (e.g. Suhrke, 1973: 508). Henry Kissinger (1982: 172) referred to this stance, with obvious contempt, as “the tyranny of the weak”3. This paper seeks a safe passage through these two, equally reductionist, propositions. It deliberately focuses first on a comparative case analysis of two, distinct ‘small state-big state’ contests drawn from the 1970s, seeking to infer and tease out the conditions that enable smaller ‘Lilliputian’ states (whether often or rarely) to beat their respective Goliaths. The discussion is then taken forward to examine whether similar tactics can work in relation to contemporary concerns with environmental vulnerability, with a focus on two other, small island states. Before that, the semiotics of ‘the small state’ need to be explored, since they are suggestive of the perceptions and expectations that are harboured by decision makers at home and abroad and which tend towards the self-fulfilling prophecy.peer-reviewe

Comparing Dutch Case management care models for people with dementia and their caregivers: The design of the COMPAS study

<p>Abstract</p> <p>Background</p> <p>Dementia care in the Netherlands is shifting from fragmented, ad hoc care to more coordinated and personalised care. Case management contributes to this shift. The linkage model and a combination of intensive case management and joint agency care models were selected based on their emerging prominence in the Netherlands. It is unclear if these different forms of case management are more effective than usual care in improving or preserving the functioning and well-being at the patient and caregiver level and at the societal cost. The objective of this article is to describe the design of a study comparing these two case management care models against usual care. Clinical and cost outcomes are investigated while care processes and the facilitators and barriers for implementation of these models are considered.</p> <p>Design</p> <p>Mixed methods include a prospective, observational, controlled, cohort study among persons with dementia and their primary informal caregiver in regions of the Netherlands with and without case management including a qualitative process evaluation. Inclusion criteria for the cohort study are: community-dwelling individuals with a dementia diagnosis who are not terminally-ill or anticipate admission to a nursing home within 6 months and with an informal caregiver who speaks fluent Dutch. Person with dementia-informal caregiver dyads are followed for two years. The primary outcome measure is the Neuropsychiatric Inventory for the people with dementia and the General Health Questionnaire for their caregivers. Secondary outcomes include: quality of life and needs assessment in both persons with dementia and caregivers, activity of daily living, competence of care, and number of crises. Costs are measured from a societal perspective using cost diaries. Process indicators measure the quality of care from the participant’s perspective. The qualitative study uses purposive sampling methods to ensure a wide variation of respondents. Semi-structured interviews with stakeholders based on the theoretical model of adaptive implementation are planned.</p> <p>Discussion</p> <p>This study provides relevant insights into care processes, description of two case management models along with clinical and economic data from persons with dementia and caregivers to clarify important differences in two case management care models compared to usual care.</p

The immunology and genetics of resistance of sheep to Teladorsagia circumcincta

Teladorsagia circumcincta is one of the most economically important gastrointestinal nematode parasites of sheep in cool temperate regions, to which sheep show genetically-varying resistance to infection. This is a very common parasite and viable sheep production requires the extensive use of anthelmintic drugs. However, the emergence of drug-resistant parasites has stimulated the search for alternative control strategies to curb production losses. Lambs become infected soon after weaning and begin to control parasite burden within 8-10 weeks of continual infection. This control is an acquired characteristic mediated by the development of parasite-specific antibodies. This paper describes the immunology associated with resistance and susceptibility, focussing on differential T cell activation that regulates the production of specific effector mechanisms. It continues by summarizing the methods used to identify genes that could be exploited as molecular markers of selection for resistance. In particular it focusses on the link between understanding the molecular immunology of infection and the identification of candidate genes for selection

Sleep-Deprivation Regulates α-2 Adrenergic Responses of Rat Hypocretin/Orexin Neurons

We recently demonstrated, in rat brain slices, that the usual excitation by noradrenaline (NA) of hypocretin/orexin (hcrt/orx) neurons was changed to an inhibition following sleep deprivation (SD). Here we describe that in control condition (CC), i.e. following 2 hours of natural sleep in the morning, the α2-adrenergic receptor (α2-AR) agonist, clonidine, had no effect on hcrt/orx neurons, whereas following 2 hours of SD (SDC), it hyperpolarized the neurons by activating G-protein-gated inwardly rectifying potassium (GIRK) channels. Since concentrations of clonidine up to a thousand times (100 µM) higher than those effective in SDC (100 nM), were completely ineffective in CC, a change in the availability of G-proteins is unlikely to explain the difference between the two conditions. To test whether the absence of effect of clonidine in CC could be due to a down-regulation of GIRK channels, we applied baclofen, a GABAB agonist known to also activate GIRK channels, and found that it hyperpolarized hcrt/orx neurons in that condition. Moreover, baclofen occluded the response to clonidine in SDC, indicating that absence of effect of clonidine in CC could not be attributed to down-regulation of GIRK channels. We finally tested whether α2-ARs were still available at the membrane in CC and found that clonidine could reduce calcium currents, indicating that α2-ARs associated with calcium channels remain available in that condition. Taken together, these results suggest that a pool of α2-ARs associated with GIRK channels is normally down-regulated (or desensitized) in hcrt/orx neurons to only become available for their inhibition following sleep deprivation

Predictive factors for new onset or progression of knee osteoarthritis one year after trauma: MRI follow-up in general practice

Objective: To prospectively evaluate prognostic factors for new onset or progression of degenerative change on follow-up MRI one year after knee trauma and the association with clinical outcome. Methods: Within a prospective observational cohort study in general practice, we studied a subgroup of 117 patients with acute knee trauma (mean age 41 years, 43% women). Degenerative change was scored on MRI at baseline and after one year follow-up. Multivariate logistic regression analysis was performed to evaluate prognostic factors for new onset or progressive degenerative change on follow-up MRI. Association between new or progressive degeneration and clinical outcome after one year was assessed. Results: On follow-up MRI 15% of patients with pre-existing knee osteoarthritis showed progression and 26% of patients demonstrated new degenerative change. The only statistically significant prognostic variable in the multivariate analysis was bone marrow oedema on initial MRI (OR 5.29 (95% CI 1.64-17.1), p∈=∈0.005). A significant association between new or progressive degenerative change and clinical outcome was found (p∈=∈0.003). Conclusion: Bone marrow oedema on MRI for acute knee injury is strongly predictive of new onset or progression of degenerative change of the femorotibial joint on follow-up MRI one year after trauma, which is reflected in clinical outcome