Explaining differences in environmental governance patterns between Canada, Italy and the United States.

The objective of the paper is to formulate a hypothesis that can help explain the different patterns of environmental governance in three countries: Canada and the United States (both federal states) and Italy (a decentralized unitary state). To that effect, we will make use of what is a robust theory of the assignment of powers in federal and decentralized unitary states on the role of competition as a driving force in shaping these assignments. The differing patterns of environmental governance we wish to explain are that most environmental policies are enacted and implemented by the national government in the United States, by provincial governments in Canada, and by both national and regional governments in Italy.

The concept of mechanism from a realist approach: a scoping review to facilitate its operationalization in public health program evaluation

International audienceBackground: Public health interventions are complex by nature, and their evaluation requires unpacking their intervention logic and their interactions with open social systems. By focusing on the interrelationships between context, mechanism, and outcome, Pawson and Tilley's realist approach appears a promising innovation for public health-related evaluation works. However, and as expected of any methodological innovation, this approach is being constructed gradually by answering the multiple challenges to its operationalization that fall in its path. One of these challenges, users of this approach agree on, is the necessity of clarifying its key concept of mechanism.Method: We first collected the definitions of mechanism from published works of Pawson and colleagues. Secondly, a scoping review was conducted to identify the ones quoted by users of the realist approach for evaluating public health interventions (1997–2012). We then appraised the clarity and precision of this concept against the three dimensions defined by Daigneault and Jacobs " term, sense and referent. "Results: Of the 2344 documents identified in the scoping review, 49 documents were included. Term: Users of the realist approach use adjectives qualifying the term mechanism that were not specifically endorsed by Pawson and colleagues. Sense: None of the attributes stated by Pawson and colleagues has been listed in all of the documents analyzed, and some contributions clarified its attributes. Referent: The concept of mechanism within a realist approach can be ascribed to theory-based evaluation, complex social interventions, and critical realism.Conclusion: This review led us to reconsider the concept of mechanism within the realist approach by confronting the theoretical stance of its proponents to the practical one of its users. This resulted in a clearer, more precise definition of the concept of mechanism which may in turn trigger further improvements in the way the realist approach is applied in evaluative practice in public health and potentially beyond. A mechanism is hidden but real, is an element of reasoning and reactions of agents in regard to the resources available in a given context to bring about changes through the implementation of an intervention, and evolves within an open space-time and social system of relationships

Association of Basal Hyperglucagonemia with Impaired Glucagon Counterregulation in Type 1 Diabetes

Glucagon counterregulation (GCR) protects against hypoglycemia, but is impaired in type 1 diabetes (T1DM). A model-based analysis of in vivo animal data predicts that the GCR defects are linked to basal hyperglucagonemia. To test this hypothesis we studied the relationship between basal glucagon (BasG) and the GCR response to hypoglycemia in 29 hyperinsulinemic clamps in T1DM patients. Glucose levels were stabilized in euglycemia and then steadily lowered to 50 mg/dL. Glucagon was measured before induction of hypoglycemia and at 10 min intervals after glucose reached levels below 70 mg/dL. GCR was assessed by CumG, the cumulative glucagon levels above basal; MaxG, the maximum glucagon response; and RIG, the relative increase in glucagon over basal. Analysis of the results was performed with our mathematical model of GCR. The model describes interactions between islet peptides and glucose, reproduces the normal GCR axis and its impairment in diabetes. It was used to identify a control mechanism consistent with the observed link between BasG and GCR. Analysis of the clinical data showed that higher BasG was associated with lower GCR response. In particular, CumG and RIG correlated negatively with BasG (r = −0.46, p = 0.012 and r = −0.74, p < 0.0001 respectively) and MaxG increased linearly with BasG at a rate less than unity (p < 0.001). Consistent with these results was a model of GCR in which the secretion of glucagon has two components. The first is under (auto) feedback control and drives a pulsatile GCR and the second is feedback independent (basal secretion) and its increase suppresses the GCR. Our simulations showed that this model explains the observed relationships between BasG and GCR during a three-fold simulated increase in BasG. Our findings support the hypothesis that basal hyperglucagonemia contributes to the GCR impairment in T1DM and show that the predictive power of our GCR animal model applies to human pathophysiology in T1DM

Complement dependent cytotoxicity activity of therapeutic antibody fragments is acquired by immunogenic glycan coupling

Abstract Oligosaccharides are implicated in the development of the immune response notably in complement activation. Anti-tumoural immunotherapy by monoclonal antibodies (mAbs) offers some advantages to chemotherapy including cell targeting but some of them are inefficient to generate cytotoxicity dependent complement (CDC) known to be important in the antibody\u2019s efficacy. The aim of this study is to give a CDC activity of mAb by linkage of a complement activating oligosaccharide to this antibody via a hetero-bifunctional linker allowing control of the conjugation reaction. We worked on non Hodgkin Burkitt\u2019s lymphoma as cancer source, Fab fragments of rituximab devoid of complement activity as mAb and the trisaccharide Gal\u3b1(1\u21923)Gal\u3b2(1\u21924)GlcNAc as immunogenic glycan. The bioconjugate Fab-Gal was characterized by biochemical methods and we demonstrated that the \u3b1-Gal epitope was recognized by seric immunoglobulins. After checking the recognition capacity of the Fab- Gal conjugate for the CD20 epitope, in vitro assays were performed to evaluate the activation of the complement cascade by the Fab-Gal conjugate. The effect of this bioconjugate was confirmed by the evaluation of the proliferation response of Burkitt\u2019s cell line. The relative facility realization of this strategy represents new approaches to increase activities of mAbs

Precision Determination of the Neutron Spin Structure Function g1n

We report on a precision measurement of the neutron spin structure function $g^n_1$ using deep inelastic scattering of polarized electrons by polarized ^3He. For the kinematic range 0.014<x<0.7 and 1 (GeV/c)^2< Q^2< 17 (GeV/c)^2, we obtain $\int^{0.7}_{0.014} g^n_1(x)dx = -0.036 \pm 0.004 (stat) \pm 0.005 (syst)$ at an average $Q^2=5 (GeV/c)^2$. We find relatively large negative values for $g^n_1$ at low $x$. The results call into question the usual Regge theory method for extrapolating to x=0 to find the full neutron integral $\int^1_0 g^n_1(x)dx$, needed for testing quark-parton model and QCD sum rules.Comment: 5 pages, 3 figures To be published in Phys. Rev. Let

Measurement of the Proton and Deuteron Spin Structure Function g_1 in the Resonance Region

We have measured the proton and deuteron spin structure functions g_1^p and g_1^d in the region of the nucleon resonances for W^2 < 5 GeV^2 and $Q^2\simeq 0.5$ and $Q^2\simeq 1.2$ GeV^2 by inelastically scattering 9.7 GeV polarized electrons off polarized $^{15}NH_3$ and $^{15}ND_3$ targets. We observe significant structure in g_1^p in the resonance region. We have used the present results, together with the deep-inelastic data at higher W^2, to extract $\Gamma(Q^2)\equiv\int_0^1 g_1(x,Q^2) dx$. This is the first information on the low-Q^2 evolution of Gamma toward the Gerasimov-Drell-Hearn limit at Q^2 = 0.Comment: 7 pages, 2 figure

TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex

•TNF deficiency alters the spatial organization of neurogenic zones.•TNF deficiency decreases WNT signaling-related proteins.•TNF deficiency alters neuronal and microglial numbers.•Long-term use of non-selective TNF inhibitors impairs learning and memory.•Long-term use of the soluble TNF selective inhibitor XPro1595 does not affect neurogenesis, learning and memory. Although tumor necrosis factor (TNF) inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF−/−) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF−/− mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult WT and TNF−/− mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment