The Appellate Body Approach to the Applicability of Article XX GATT In the Light of China - Raw Materials: A Missed Opportunity?

This article attempts to analyse and investigate the implications of the approach to the applicability of Article XX GATT adopted in the recent China – Raw Materials. Using the decision on the non-availability of Article XX defences for violations of China’s WTO-plus commitments on export duties as a backdrop, it scrutinizes the more general, ‘systemic’ approach to the applicability of Article XX exceptions developed by theWTO dispute settlement bodies, and sheds light on the implications of such approach with respect to the relationship between GATT 1994 andWTO obligations arising from different instruments of theWTOAgreement, such as new members’ accession protocols. It also suggests that an exception to this general approach could be envisaged when the fundamental environmental goals protected under Article XX b) and g) are at stake.

Successful Careers in Football – Findings of a Person-Oriented Study

A successful career in football is the result of the appropriate interaction between different aspects of an individual’s life, since the various areas and phases of one’s life depend on each other. An endogenous causal relationship exists throughout a person’s entire history (Mayer, 1990). In particular, their family, work and sports career must be tuned to each other. The transition from the initial stages of education (compulsory schooling) to vocational training, which coincides with the beginning of the selection for the national youth teams, is a particularly critical phase (Wylleman, Theeboom, & Lavallee, 2004). In order to do justice to the overall life situation of a young sports talent during this transition phase, we have adopted a holistic perspective and follow Bergman, Magnusson and El-Khouri (2003) in using a person-oriented and systemic approach. In doing so, our main focus lies on the person-environment system. This overall system is made up of various subsystems, consisting of several operating factors which interact with one another. The different levels to which these operating factors are expressed lead to observable patterns, which can be summarised in the form of types. Particularly promising types can therefore be identified and the developmental process can be described. Former players on the Swiss U16 to U21 national football teams, born between 1981 and 1987 (n=159), were interviewed concerning their careers, and the operating factors school/vocational training, family support and sports environment were examined. With the help of the LICUR method (Linking of Clusters after removal of Residue) (Bergman et al., 2003), developmental types were identified which were promising in terms of achieving top performance in adulthood. A range of developmental types and anti-types emerge for the transition from the under-15 phase to the over-16 phase. One particularly promising type is observed in the over-16 phase, for which the operating factors education, family support and participation in national U16 to U18 teams have slightly above-average scores, with scores that are well above average in the sports environment.

High-dose intravenous immunoglobulins: A promising therapeutic approach for idiopathic systemic capillary leak syndrome

The systemic capillary leak syndrome (SCLS), also known as Clarkson’s disease, is a life-threatening disorder of unknown cause. It is characterised by recurrent acute episodes of hypotension, weight gain and generalised oedema with haemoconcentration and hypoproteinaemia caused by paroxysmal capillary hyperpermeability with a shift of plasma fluid from the intravascular to the interstitial space. We report the case of a 40-year-old woman with chronic SCLS treated with high-dose intravenous immunoglobulins, after a prophylactic therapy with theophylline and terbutaline was poorly tolerated and failed to decrease the frequency and severity of the attacks sufficiently.

Systemic therapy of atopic dermatitis in children and adults

Systemic therapy is required in patients with severe atopic dermatitis (AD) refractory to adequate topical therapy. The aim of a systemic therapy is the rapid and efficient improvement of skin symptoms and pruritus in acute exacerbation and/or the long-term control of severe chronic disease. A number of immunosuppressive and immunomodulating substances are available that may efficiently reduce skin inflammation and thus lead to a relief of symptoms including pruritus. The excellent effects of cyclosporine as short-term as well as maintenance therapy have been documented in several studies in children and adults. Furthermore, other immunosuppressive substances such as azathioprine, mycophenolate mofetil and methotrexate are effective in patients with moderate to severe AD. Intravenous immunoglobulins and γ-interferon exert immunomodulatory effects and thus may improve severe AD. Biological agents are a new approach in AD therapy since they may specifically target cells, cytokines or mediators involved in the pathogenesis of AD.

Current state of evidence on 'off-label' therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland--a consensus report

Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence.

Combined approach to hepatocellular carcinoma: a new treatment concept for nonresectable disease

Depending on tumor burden, hepatic function and patients' performance status, hepatocellular carcinoma is treated by surgery, local procedures, systemic therapy or palliation. The majority of patients are diagnosed at a stage where local therapy is the treatment of choice. Recently, the multikinase inhibitor sorafenib was found to improve the survival of patients with advanced hepatocellular carcinoma and conserved liver function. In this manuscript, we summarize the experimental evidence supporting the combination of a systemic targeted therapy with a local therapy. We also discuss the pros and cons of different schedules of combining such treatments. We conclude that there is enough of a theoretical argument to design clinical trials testing this strategy.

Minimising pain in farm animals: the 3S approach - 'Suppress, Substitute, Soothe'

Recently, the French National Institute for Agricultural Research appointed an expert committee to review the issue of pain in food-producing farm animals. To minimise pain, the authors developed a '3S' approach accounting for 'Suppress, Substitute and Soothe' by analogy with the '3Rs' approach of 'Reduction, Refinement and Replacement' applied in the context of animal experimentation. Thus, when addressing the matter of pain, the following steps and solutions could be assessed, in the light of their feasibility (technical constraints, logistics and regulations), acceptability (societal and financial aspects) and availability. The first solution is to suppress any source of pain that brings no obvious advantage to the animals or the producers, as well as sources of pain for which potential benefits are largely exceeded by the negative effects. For instance, tail docking of cattle has recently been eliminated. Genetic selection on the basis of resistance criteria (as e.g. for lameness in cattle and poultry) or reduction of undesirable traits (e.g. boar taint in pigs) may also reduce painful conditions or procedures. The second solution is to substitute a technique causing pain by another less-painful method. For example, if dehorning cattle is unavoidable, it is preferable to perform it at a very young age, cauterising the horn bud. Animal management and constraint systems should be designed to reduce the risk for injury and bruising. Lastly, in situations where pain is known to be present, because of animal management procedures such as dehorning or castration, or because of pathology, for example lameness, systemic or local pharmacological treatments should be used to soothe pain. These treatments should take into account the duration of pain, which, in the case of some management procedures or diseases, may persist for longer periods. The administration of pain medication may require the intervention of veterinarians, but exemptions exist where breeders are allowed to use local anaesthesia (e.g. castration and dehorning in Switzerland). Extension of such exemptions, national or European legislation on pain management, or the introduction of animal welfare codes by retailers into their meat products may help further developments. In addition, veterinarians and farmers should be given the necessary tools and information to take into account animal pain in their management decisions.

Re-thinking resuscitation: leaving blood pressure cosmetics behind and moving forward to permissive hypotension and a tissue perfusion-based approach

Definitions of shock and resuscitation endpoints traditionally focus on blood pressures and cardiac output. This carries a high risk of overemphasizing systemic hemodynamics at the cost of tissue perfusion. In line with novel shock definitions and evidence of the lack of a correlation between macro- and microcirculation in shock, we recommend that macrocirculatory resuscitation endpoints, particularly arterial and central venous pressure as well as cardiac output, be reconsidered. In this viewpoint article, we propose a three-step approach of resuscitation endpoints in shock of all origins. This approach targets only a minimum individual and context-sensitive mean arterial blood pressure (for example, 45 to 50 mm Hg) to preserve heart and brain perfusion. Further resuscitation is exclusively guided by endpoints of tissue perfusion irrespectively of the presence of arterial hypotension ('permissive hypotension'). Finally, optimization of individual tissue (for example, renal) perfusion is targeted. Prospective clinical studies are necessary to confirm the postulated benefits of targeting these resuscitation endpoints.

Combined systemic and local morpholino treatment rescues the phenotype of the SMA Delta 7 mouse model

Spinal muscular atrophy (SMA) is a childhood fatal motor neuron disease caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, currently without effective treatment. One possible therapeutic approach is the use of antisense oligonucleotides (ASOs) to redirect the splicing of a paralogous gene, SMN2, to increase the production of functional SMN protein. A range of ASOs with different chemical properties is suitable for these applications, including a morpholino (MO) variant, which has a particularly excellent safety, and efficacy profile. We used a 25- nt MO oligomer sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D(-10-34)) with superior efficacy to previously described sequences also in transgenic SMA Δ7 mice. The combined local and systemic administration of MO (bare or conjugated to octa-guanidine) is necessary to increase full-length SMN expression, leading to robust neuropathological features improvement and survival rescue. Additionally, several snRNA levels that are dysregulated in SMA mice could be restored by MO treatment. These results demonstrate that MO therapy is efficacious and can result in phenotypic rescue. These data provide important insights for the development of therapeutic strategies in SMA patients.

Effect of Combined Systemic and Local Morpholino Treatment on the Spinal Muscular Atrophy Δ7 Mouse Model Phenotype

BACKGROUND: Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile. OBJECTIVE: We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region. METHODS: We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features. RESULTS: We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment. CONCLUSION: These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients.

Arterial blood pressure targets in septic shock: is it time to move to an individualized approach?

Xu and colleagues evaluated the impact of increasing mean arterial blood pressure levels through norepinephrine administration on systemic hemodynamics, tissue perfusion, and sublingual microcirculation of septic shock patients with chronic hypertension. The authors concluded that, although increasing arterial blood pressure improved sublingual microcirculation parameters, no concomitant improvement in systemic tissue perfusion indicators was found. Here, we discuss why resuscitation targets may need to be individualized, taking into account the patient's baseline condition, and present directions for future research in this field.