Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias.

Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFβ-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFβ signaling were consistent features in GD and AD fibroblasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFβ signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.

Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

PURPOSE This prospective multicenter phase III study compared the efficacy and safety of a triple combination (bortezomib-thalidomide-dexamethasone [VTD]) versus a dual combination (thalidomide-dexamethasone [TD]) in patients with multiple myeloma (MM) progressing or relapsing after autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS Overall, 269 patients were randomly assigned to receive bortezomib (1.3 mg/m(2) intravenous bolus) or no bortezomib for 1 year, in combination with thalidomide (200 mg per day orally) and dexamethasone (40 mg orally once a day on 4 days once every 3 weeks). Bortezomib was administered on days 1, 4, 8, and 11 with a 10-day rest period (day 12 to day 21) for eight cycles (6 months), and then on days 1, 8, 15, and 22 with a 20-day rest period (day 23 to day 42) for four cycles (6 months). Results Median time to progression (primary end point) was significantly longer with VTD than TD (19.5 v 13.8 months; hazard ratio, 0.59; 95% CI, 0.44 to 0.80; P = .001), the complete response plus near-complete response rate was higher (45% v 25%; P = .001), and the median duration of response was longer (17.2 v 13.4 months; P = .03). The 24-month survival rate was in favor of VTD (71% v 65%; P = .093). Grade 3 peripheral neuropathy was more frequent with VTD (29% v 12%; P = .001) as were the rates of grades 3 and 4 infection and thrombocytopenia. CONCLUSION VTD was more effective than TD in the treatment of patients with MM with progressive or relapsing disease post-ASCT but was associated with a higher incidence of grade 3 neurotoxicity.

Distal and proximal influences on the use of business and moral frames in responsible decisions

We empirically contribute to the debate on business education in building on a decision frame perspective of decision making in corporate responsibility settings. Business schools have been accused to teach amoral theories, leading their students to behave less morally and engendering corporate responsibility scandals. Research has also pointed toward self-selection: business students would differ from non-business students before entering business school. We examine the role of socioeconomic status, core self-evaluations in this regard. Further, we investigate the belief in a free market as a distal influence triggering a business frame, and moral intensity as a proximal influence triggering a moral frame on responsible decision making by business and non-business students. Cross-sectional data obtained from 566 students on two decision making scenarios mostly supported our hypotheses. Socioeconomic status but not core self-evaluations explain the belief in a free market, and had indirect effects on the likelihood to make a less responsible decision. Importantly, the relationship between business studies and the belief in a free market remained significant after accounting for these variables. Our study thus contributes to the socialization and self-selection arguments. We discuss theoretical and practical implications for research on decision frames and for business education, respectively.

Internationalization dynamics in the Swiss Corporate Tax Reform III

Over the last years, in a context of international tax competition, international and regional institutions such as the G20, the OECD, and the European Union are redefining what is acceptable in terms of corporate fiscal policy. Certain Swiss preferential tax treatments are considered by the above-mentioned institutions as harmful tax practices. As a consequence, the Swiss government has planned a third corporate tax reform (CTR III). The objective of this reform is to ensure international acceptability of the corporate tax system without prejudicing local public finances and Swiss corporate tax attractiveness. Therefore, we can posit that the CTR III is an internationalized object influenced by both regulation trends and tax competition framework. The main purpose of this paper is to provide elements of answer on how the currently discussed CTR III is influenced by the international environment, by focusing on its content as well as the reactions and positions of local stakeholders. With the help of internationalization literature, two distinct internationalization processes have been identified through the propositions of compliance measures with internationally-defined standards and competitiveness-enhancing measures. With regard to the configuration of local actors, the degree of conflict seems to be rather high. The current content of the reform is supported by the business community and right-wing parties and rejected by the unions and the Socialist Party.

Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.

This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access.

How Party Linkages Shape Austerity Politics: Clientelism and Fiscal Adjustment in Greece and Portugal during the Eurozone Crisis

Drawing on an analysis of austerity reforms in Greece and Portugal during the sovereign debt crisis from 2009 onwards, we show how the nature of the linkages between parties and citizens shapes party strategies of fiscal retrenchment. We argue that parties which rely to a greater extent on the selective distribution of state resources to mobilize electoral support (clientelistic linkages) are more reluctant to agree to fiscal retrenchment because their own electoral survival depends on their ability to control state budgets to reward clients. In Greece, where parties relied extensively on these clientelistic linkages, austerity reforms have been characterized by recurring conflicts and disagreements between the main parties, as well as a fundamental transformation of the party system. By contrast, in Portugal, where parties relied less on clientelistic strategies, austerity reforms have been more consensual because fiscal retrenchment challenged to a lesser extent the electoral base of the mainstream parties.

Transparency and trust in government (2007-2014): a comparative study

In a 2000 report entitled "Trust in government. Ethics measures in OECD countries," OECD Secretary-General Donald J. Johnston emphasized the fact that public ethics are considered as a keystone of good governance. Moreover, public ethics are a prerequisite to public trust, which is in turn vital not only to any public service, but also to any society in general. At the same time, transparency reforms have flourished over the last few years and have several times been designed as a response to public distrust. Therefore, ethics, transparency and trust are closely linked together in a supposed virtuous circle where transparency works as a factor of better public ethics and leads to more trust in government on the citizens' side. This article explores the links between transparency and levels of trust in 10 countries between 2007 and 2014, using open data indexes and access to information requests as proxies for transparency. A national ranking of transparency, based on requests submitted by citizens to the administration and open data indexes, is then proposed. Key findings show that there is no sharp decline of trust in government in all countries considered in this article, and that transparency and trust in government are not systematically positively associated. Therefore, this article challenges the common assumption, mostly found in the normative literature, about a positive interrelation between the two, where trust in government is conceived as a beneficial effect of administrative transparency.