Angiotensin II blockade and aortic-root dilation in Marfan's syndrome

Background: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor (beta) (TGF-(beta)) that can be mitigated by treatment with TGF-(beta) antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. Methods: We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. Results: The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. Conclusions: In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial

Managing (Sales)People towards Performance: HR Strategy, Leadership & Teamwork

Managing people towards performance is one of the most critical priorities for managers in practice. This dissertation focuses on this important issue and explores how HR Strategy, Leaders, and Teams, impact performance. It addresses respectively how HR as a system of coherent attributes, multiple dimensions of transformational leadership, and team reflexivity can enhance the performance of (sales)people in organizations. Based on a series of field-studies, the present dissertation demonstrates a number of novel insights. First, it reveals that internal coherence of HR strategy has a positive effect on organizational performance. Second, it demonstrates that both a leader’s level of transformational leadership, as well as a team’s level of reflexivity can be functional, but also dysfunctional for job performance of people in organizations. These results are important for managers, as they represent evidence-based insights, some of which are counter-intuitive, on how they can effectively manage people towards performance. For researchers, the findings contribute to a deeper understanding of the HR-performance relationship

Drivers of Sales Performance: A Contemporary Meta-Analysis

It has been twenty-five years since the publication of a comprehensive review of the full spectrum of sales-performance drivers. This study takes stock of the contemporary field and synthesizes empirical evidence from the period 1982–2008. The authors revise the classification scheme for sales performance determinants devised by Walker, Churchill, and Ford (1977) and estimate both the predictive validity of its sub-categories and the impact of a range of moderators on determinant-sales performance relationships. Based on multivariate causal model analysis, the results make two major observations: (1) Five sub-categories demonstrate significant relationships with sales performance: selling-related knowledge (β=.28), degree of adaptiveness (β=.27), role ambiguity (β=-.25), cognitive aptitude (β=.23) and work engagement (β=.23). (2) These sub-categories are moderated by measurement method, research context, and sales-type variables. The authors identify managerial implications of the results and offer suggestions for further research, including the conjecture that as the world is moving toward a knowledge-intensive economy, salespeople could be functioning as knowledge-brokers. The results seem to back this supposition and indicate how it might inspire future research in the field of personal selling

When Intelligence is (Dys)Functional for Achieving Sales Performance

Using two different samples of salespeople, the authors investigate how a combination of general mental ability (GMA) and specific skills and capabilities (social competence and thinking styles) allows salespeople to reach their sales goals. The study finds evidence for an interaction between GMA and social competence. If combined with high social competence, high GMA leads to highest sales performance; if combined with low social competence, high GMA leads to lowest sales performance. In addition, interaction effects between GMA and a judicial thinking style were found. Salespeople high on GMA have the most potential for attaining high levels of sales performance when combined with specific skills; when lacking these skills they may become the firm’s worst performers

Absence of cardiovascular manifestations in a haploinsufficient TGFBR1 mouse model

Loeys-Dietz syndrome (LDS) is an autosomal dominant arterial aneurysm disease belonging to the spectrum of transforming growth factor beta (TGF beta)-associated vasculopathies. In its most typical form it is characterized by the presence of hypertelorism, bifid uvula/cleft palate and aortic aneurysm and/or arterial tortuosity. LDS is caused by heterozygous loss of function mutations in the genes encoding TGF beta receptor 1 and 2 (TGFBR1 and -2), which lead to a paradoxical increase in TGF beta signaling. To address this apparent paradox and to gain more insight into the pathophysiology of aneurysmal disease, we characterized a new Tgfbr1 mouse model carrying a p.Y378* nonsense mutation. Study of the natural history in this model showed that homozygous mutant mice die during embryonic development due to defective vascularization. Heterozygous mutant mice aged 6 and 12 months were morphologically and (immuno) histochemically indistinguishable from wild-type mice. We show that the mutant allele is degraded by nonsense mediated mRNA decay, expected to result in haploinsufficiency of the mutant allele. Since this haploinsufficiency model does not result in cardiovascular malformations, it does not allow further study of the process of aneurysm formation. In addition to providing a comprehensive method for cardiovascular phenotyping in mice, the results of this study confirm that haploinsuffciency is not the underlying genetic mechanism in human LDS

Self-Assembly of Polymer-Modified FePt Magnetic Nanoparticles and Block Copolymers

The fabrication of nanocomposites containing magnetic nanoparticles is gaining interest as a model for application in small electronic devices. The self-assembly of block copolymers (BCPs) makes these materials ideal for use as a soft matrix to support the structural ordering of the nanoparticles. In this work, a high-molecular-weight polystyrene-b-poly(methyl methacrylate) block copolymer (PS-b-PMMA) was synthesized through anionic polymerization. The influence of the addition of different ratios of PMMA-coated FePt nanoparticles (NPs) on the self-assembled morphology was investigated using transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS). The self-assembly of the NPs inside the PMMA phase at low particle concentrations was analyzed statistically, and the negative effect of higher particle ratios on the lamellar BCP morphology became visible. The placement of the NPs inside the PMMA phase was also compared to theoretical descriptions. The magnetic addressability of the FePt nanoparticles inside the nanocomposite films was finally analyzed using bimodal magnetic force microscopy and proved the magnetic nature of the nanoparticles inside the microphase-separated BCP films

Self-Assembly of Polymer-Modified FePt Magnetic Nanoparticles and Block Copolymers

The fabrication of nanocomposites containing magnetic nanoparticles is gaining interest as a model for application in small electronic devices. The self-assembly of block copolymers (BCPs) makes these materials ideal for use as a soft matrix to support the structural ordering of the nanoparticles. In this work, a high-molecular-weight polystyrene-b-poly(methyl methacrylate) block copolymer (PSb-PMMA) was synthesized through anionic polymerization. The influence of the addition of different ratios of PMMA-coated FePt nanoparticles (NPs) on the self-assembled morphology was investigated using transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS). The selfassembly of the NPs inside the PMMA phase at low particle concentrations was analyzed statistically, and the negative effect of higher particle ratios on the lamellar BCP morphology became visible. The placement of the NPs inside the PMMA phase was also compared to theoretical descriptions. The magnetic addressability of the FePt nanoparticles inside the nanocomposite films was finally analyzed using bimodal magnetic force microscopy and proved the magnetic nature of the nanoparticles inside the microphase-separated BCP films

Predictors of Bicuspid Aortic Valve-Associated Aortopathy in Childhood: A Report From the MIBAVA Consortium

BACKGROUND: Bicuspid aortic valve (BAV) is the most prevalent congenital heart defect affecting 1% to 2% of the population. It is associated with ascending aorta dilatation. Valve morphology, aortic stenosis (AS), and aortic insufficiency (AI) have been proposed as potential risk factors; however, evaluating their role is difficult, as these factors are inherently related. The aim of this study was to determine whether BAV morphology and dysfunction are independent determinants for ascending aorta dilatation in pediatric patients. METHODS: A multicenter, retrospective, cross-sectional study of pediatric BAV patients followed since 2004 was performed. Imaging data were assessed for BAV morphology, severity of AS and AI, history of coarctation, and aortic dimensions. Associations were determined using multivariable regression analysis. A subset of patients undergoing aortic interventions (balloon dilation or Ross) were assessed longitudinally. RESULTS: Data were obtained from 2122 patients (68% male; median age 10.2 years). Fifty percent of patients had ascending aorta dilatation. Right and noncoronary cusp fusion, increasing AS and AI, and older age were independently associated with ascending aorta dilatation. A history of coarctation was associated with less ascending aorta dilatation. In patients with neither AS nor AI, 37% had ascending aorta dilatation (4% severe). No complications related to aortic dilatation occurred in this cohort. Aortic CONCLUSIONS: In this large pediatric cohort of patients with BAV, valve morphology, AS, and AI are independently associated with ascending aorta dilatation, suggesting that hemodynamic factors influence aortopathy. However, even in BAVs with no AS or AI, there is significant ascending aorta dilatation independent of valve morphology. Interventions that led to changes in degree of AI and AS did not seem to influence change in aortic dimensions. The current BAV cohort can be used as a reference group for expected changes in aortic dimensions during childhood

Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD

BACKGROUND: Thoracic aortic aneurysm / dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGFβ) signaling (TGFβ receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK). METHODS AND RESULTS: In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGFβ signaling pathway. CONCLUSIONS: MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGFβ signaling