Ventricular tachycardia in a Brugada syndrome patient caused by a novel deletion in SCN5A

The aim of the present study was to identify the molecular mechanism behind ventricular tachycardia in a patient with Brugada syndrome. Arrhythmias in patients with Brugada syndrome often occur during sleep. However, a 28-year-old man with no previously documented arrhythmia or syncope who experienced shortness of breath and chest pain during agitation is described. An electrocardiogram revealed monomorphic ventricular tachycardia; after he was converted to nodal rhythm, he spontaneously went into sinus rhythm, and showed classic Brugada changes with coved ST elevation in leads V(1) to V(2). Mutation analysis of SCN5A revealed a novel mutation, 3480 deletion T frame shift mutation, resulting in premature truncation of the protein. Heterologous expression of this truncated protein in human embryonic kidney 293 cells showed a markedly reduced protein expression level. By performing whole-cell patch clamp experiments using human embryonic kidney 293 cells transfected with the mutated SCN5A, no current could be recorded. Hence, the results suggest that the patient suffered from haploinsufficiency of Na(v)1.5, and that this mutation was the cause of his Brugada syndrome.

Motivational profiles of sport event volunteers.

Aim of the study Due to the valuable contribution made by volunteers to sporting events, a better understanding of volunteers’ motivation is imperative for event managers in order to develop effective volunteer re-cruitment and retention strategies. The adoption of working conditions and task domains to the mo-tives and needs of volunteers is one of the key challenges in volunteer management. Conversely, an ignorance of the motives and needs of volunteers could negatively affect their performance and attitude, which will have negative consequences for the execution of events (Strigas & Jackson, 2003). In general, the motives of volunteers are located on a continuum between selflessness (e.g. helping others), and self-interest (e.g. pursuing one’s own interests). Furthermore, it should take into account that volunteers may be motivated by more than one need or goal, and therefore, configure different bundles of motives, resulting in heterogeneous types of motives for voluntary engagement (Dolnicar & Randle, 2007). Despite the extensive number of studies on the motives of sport event volunteers, only few studies focus on the analysis of individual motive profiles concerning volun-teering. Accordingly, we will take a closer look at the following questions: To what extent do volun-teers at sporting events differ in the motives of their engagement, and how can the volunteers be ade-quately classified? Theoretical Background According to the functional approach, relevant subjective motives are related to the outcomes and consequences that volunteering is supposed to lead to and to produce. This means, individuals’ mo-tives determine which incentives are anticipated in return for volunteering (e.g. increase in social contacts), and are important for engaging in volunteering, e.g. the choice between different oppor-tunities for voluntary activity, or different tasks (Stukas et al., 2009). Additionally, inter-individual differences of motive structures as well as matching motives in the reflections of voluntary activities will be considered by using a person-oriented approach. In the person-oriented approach, it is not the specific variables that are made the entities of investigation, but rather persons with a certain combination of characteristic features (Bergmann et al., 2003). Person-orientation in the field of sports event volunteers, it is therefore essential to implement an orientation towards people as a unit of analysis. Accordingly, individual motive profiles become the object of investigation. The individ-ual motive profiles permit a glimpse of intra-individual differences in the evaluation of different motive areas, and thus represent the real subjective perspective. Hence, a person will compare the importance of individual motives for his behaviour primarily in relation to other motives (e.g. social contacts are more important to me than material incentives), and make fewer comparisons with the assessments of other people. Methodology, research design and data analysis The motives of sports event volunteers were analysed in the context of the European Athletics Championships 2014 in Zürich. After data cleaning, the study sample contained a total of 1,169 volunteers, surveyed by an online questionnaire. The VMS-ISA scale developed by Bang and Chel-ladurai (2009) was used and replicated successfully by a confirmatory factor analysis. Accordingly, all seven factors of the scale were included in the subsequent cluster analysis to determine typical motive profiles of volunteers. Before proceeding with the cluster analysis, an intra-individual stand-ardization procedure (according to Spiel, 1998) was applied to take advantage of the intra-individual relationships between the motives of the volunteers. Intra-individual standardization means that every value of each motive dimension was related to the average individual level of ex-pectations. In the final step, motive profiles were determined using a hierarchic cluster analysis based on Ward’s method with squared Euclidean distances. Results, discussion and implications The results reveal that motivational processes differ among sports event volunteers, and that volunteers sometimes combine contradictory bundles of motives. In our study, four different volunteer motive profiles were identified and described by their positive levels on the individual motive dimension: the community supporters, the material incentive seekers, the social networkers, and the career and personal growth pursuers. To describe the four identified motive profiles in more detail and to externally validate them, the clusters were analysed in relation to socio-economic, sport-related, and voluntary work characteristics. This motive-based typology of sports event volunteers can provide valuable guidance for event managers in order to create distinctive and designable working conditions and tasks at sporting events that should, in relation to a person-oriented approach, be tailored to a wide range of individ-ual prerequisites. Furthermore, specific recruitment procedures and appropriate communication measures can be defined in order to approach certain groups of potential volunteers more effectively. References Bang, H., & Chelladurai, P. (2009). Development and validation of the volunteer motivations scale for international sporting events (VMS-ISE). International Journal Sport Management and Market-ing, 6, 332-350. Bergmann, L. R., Magnusson, D., & El-Khouri, B. M. (2003). Studying individual development in an interindividual context. Mahwah, NJ: Erlbaum. Dolnicar, S., & Randle, M. (2007). What motivates which volunteers? Psychographic heterogeneity among volunteers in Australia. Voluntas, 18, 135-155. Spiel, C. (1998). Four methodological approaches to the study of stability and change in develop-ment. Methods of Psychological Research Online, 3, 8-22. Stukas, A. A., Worth, K. A., Clary, E. G., & Snyder, M. (2009). The matching of motivations to affordances in the volunteer environment: an index for assessing the impact of multiple matches on volunteer outcomes. Nonprofit and Voluntary Sector Quarterly, 38, 5-28.

The role of the interplay between polymer architecture and bacterial surface properties on the microbial adhesion to polyoxazoline-based ultrathin films

Surface platforms were engineered from poly(L-lysine)-graft-poly(2-methyl-2-oxazoline) (PLL-g-PMOXA) copolymers to study the mechanisms involved in the non-specific adhesion of Escherichia coli (E. coli) bacteria. Copolymers with three different grafting densities (PMOXA chains/Lysine residue of 0.09, 0.33 and 0.56) were synthesized and assembled on niobia (Nb O ) surfaces. PLL-modified and bare niobia surfaces served as controls. To evaluate the impact of fimbriae expression on the bacterial adhesion, the surfaces were exposed to genetically engineered E. coli strains either lacking, or constitutively expressing type 1 fimbriae. The bacterial adhesion was strongly influenced by the presence of bacterial fimbriae. Non-fimbriated bacteria behaved like hard, charged particles whose adhesion was dependent on surface charge and ionic strength of the media. In contrast, bacteria expressing type 1 fimbriae adhered to the substrates independent of surface charge and ionic strength, and adhesion was mediated by non-specific van der Waals and hydrophobic interactions of the proteins at the fimbrial tip. Adsorbed polymer mass, average surface density of the PMOXA chains, and thickness of the copolymer films were quantified by optical waveguide lightmode spectroscopy (OWLS) and variable-angle spectroscopic ellipsometry (VASE), whereas the lateral homogeneity was probed by time-of-flight secondary ion mass spectrometry (ToF-SIMS). Streaming current measurements provided information on the charge formation of the polymer-coated and the bare niobia surfaces. The adhesion of both bacterial strains could be efficiently inhibited by the copolymer film only with a grafting density of 0.33 characterized by the highest PMOXA chain surface density and a surface potential close to zero.

Evaluation of chemically modified SLA implants (modSLA) biofunctionalized with integrin (RGD)- and heparin (KRSR)-binding peptides

Enhancing osseointegration through surface immobilization of multiple short peptide sequences that mimic extracellular matrix (ECM) proteins, such as arginine-glycine-aspartic acid (RGD) and lysine-arginine-serine-arginine (KRSR), has not yet been extensively explored. Additionally, the effect of biofunctionalizing chemically modified sandblasted and acid-etched surfaces (modSLA) is unknown. The present study evaluated modSLA implant surfaces modified with RGD and KRSR for potentially enhanced effects on bone apposition and interfacial shear strength during early stages of bone regeneration. Two sets of experimental implants were placed in the maxillae of eight miniature pigs, known for their rapid wound healing kinetics: bone chamber implants creating two circular bone defects for histomorphometric analysis on one side and standard thread configuration implants for removal torque testing on the other side. Three different biofunctionalized modSLA surfaces using poly-L-lysine-graft-poly(ethylene glycol) (PLL-g-PEG) as a carrier minimizing nonspecific protein adsorption [(i) 20 pmol cm⁻² KRSR alone (KRSR); or in combination with RGD in two different concentrations; (ii) 0.05 pmol cm⁻² RGD (KRSR/RGD-1); (iii) 1.26 pmol cm⁻² RGD (KRSR/RGD-2)] were compared with (iv) control modSLA. Animals were sacrificed at 2 weeks. Removal torque values (701.48-780.28 N mm), bone-to-implant contact (BIC) (35.22%-41.49%), and new bone fill (28.58%-30.62%) demonstrated no significant differences among treatments. It may be concluded that biofunctionalizing modSLA surfaces with KRSR and RGD derivatives of PLL-g-PEG polymer does not increase BIC, bone fill, or interfacial shear strength.

Polymer stent coating for prevention of neointimal hyperplasia

AIMS: Restenosis has been the principal limitation of bare metal stents. Based upon the presumption that platelet and inflammatory cell recruitment initiate neointimal proliferation, we explored a novel polymer coating that reduces cell-stent interactions. The purpose of the present study was to investigate the effect of poly(L-lysine)-graft-poly(ethyleneglycol) (PLL-g-PEG) adsorbed to stent surfaces to reduce neointimal hyperplasia in the porcine restenosis model. METHODS AND RESULTS: Seven animals were instrumented each with 2 stainless steel stents (15 mm length, 2.5-3.5 mm diameter), randomly implanted in 1 major epicardial coronary artery. One stent was dip-coated with PLL-g-PEG, whereas the other stent served as the uncoated control stent. All animals were sacrificed after 6 weeks for histological examination. Neointimal hyperplasia was significantly less (-51%) in the PLL-g-PEG-coated stents (1.15 +/- 0.59 mm2) than in the uncoated control stents (2.33 +/- 1.01 mm2; p < 0.001). Conversely, lumen size was larger in the PLL-g-PEG-coated stents (2.91 +/- 1.17 mm2) than in the uncoated stents (2.04 +/- 0.64 mm2; p < 0.001). High magnification histomorphologic examination revealed no signs of inflammation or thrombus formation in either stent group. CONCLUSIONS: Polymeric steric stabilization of stents with PLL-g-PEG significantly reduces neointimal hyperplasia in the porcine restenosis model. Reduction of cell-stent interactions mediated by PLL-g-PEG appear to improve biocompatibility of stainless steel stents without evidence of adverse inflammatory or prothrombotic effects.

Enhanced bone apposition around biofunctionalized sandblasted and acid-etched titanium implant surfaces. A histomorphometric study in miniature pigs

Microrough titanium (Ti) surfaces of dental implants have demonstrated more rapid and greater bone apposition when compared with machined Ti surfaces. However, further enhancement of osteoblastic activity and bone apposition by bio-functionalizing the implant surface with a monomolecular adsorbed layer of a co-polymer - i.e., poly(L-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) and its derivatives (PLL-g-PEG/PEG-peptide) - has never been investigated. The aim of the present study was to examine early bone apposition to a modified sandblasted and acid-etched (SLA) surface coated with an Arg-Gly-Asp (RGD)-peptide-modified polymer (PLL-g-PEG/PEG-RGD) in the maxillae of miniature pigs, and to compare it with the standard SLA surface. Test and control implants had the same microrough topography (SLA), but differed in their surface chemistry (polymer coatings). The following surfaces were examined histomorphometrically: (i) control - SLA without coating; (ii) (PLL-g-PEG); (iii) (PLL-g-PEG/PEG-RDG) (RDG, Arg-Asp-Gly); and (iv) (PLL-g-PEG/PEG-RGD). At 2 weeks, RGD-coated implants demonstrated significantly higher percentages of bone-to-implant contact as compared with controls (61.68% vs. 43.62%; P < 0.001). It can be concluded that the (PLL-g-PEG/PEG-RGD) coatings may promote enhanced bone apposition during the early stages of bone regeneration.

Short telomeres and high telomerase activity in T-cell prolymphocytic leukemia

To test the role of telomere biology in T-cell prolymphocytic leukemia (T-PLL), a rare aggressive disease characterized by the expansion of a T-cell clone derived from immuno-competent post-thymic T-lymphocytes, we analyzed telomere length and telomerase activity in subsets of peripheral blood leukocytes from 11 newly diagnosed or relapsed patients with sporadic T-PLL. Telomere length values of the leukemic T cells (mean+/-s.d.: 1.53+/-0.65 kb) were all below the 1st percentile of telomere length values observed in T cells from healthy age-matched controls whereas telomere length of normal T- and B cells fell between the 1st and 99th percentile of the normal distribution. Leukemic T cells exhibited high levels of telomerase and were sensitive to the telomerase inhibitor BIBR1532 at doses that showed no effect on normal, unstimulated T cells. Targeting the short telomeres and telomerase activity in T-PLL seems an attractive strategy for the future treatment of this devastating disease.

Expression of TCL1 in hematologic disorders

OBJECTIVE: TCL1, MTCP1 and TCL1b are three members of a new family of oncogenes that are expressed in T cell leukemias of ataxia telangiectasia patients (T-PLL, T-CLL). TCL1 is located at 14q32.1 and activated by juxtaposition to the alpha/delta-locus at 14q11 or beta-locus at 7q35 of the T cell receptor during the reciprocal translocations t(14;14)(q11;q32), t(7;14)(q35;q32), or inversion inv(14)(q11;q32). TCL1 encodes a predominantly cytoplasmic protein of 114 aa (14 kD) of unknown function. Recent studies suggest that TCL1 promotes cell survival rather than stimulating cell proliferation, as previously proposed. METHODS: In an attempt to clarify the contexts in which TCL1 is expressed, we investigated TCL1 expression in 114 lymphoma and leukemia patients by Northern blot, RT-PCR and immunohistochemistry. RESULTS: TCL1 expression is restricted to lymphoid cells, and is found in neoplastic (T and B cell neoplasms, and Hodgkin's disease) and nonneoplastic proliferations (reactive lesions). Out of 114 cases, 18 neoplasms of myeloid and 4 cases of epithelial origin were TCL1-negative. In lesions of the lymphoid system, both low- and high-grade lymphomas were found to express TCL1. CONCLUSIONS: We propose that TCL1 expression especially in high-grade B cell non-Hodgkin's lymphomas might interfere with B cell differentiation and promote the transition from low- to high-grade lymphoma.

A Gly98Val mutation in the N-Myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy.

The first cases of early-onset progressive polyneuropathy appeared in the Alaskan Malamute population in Norway in the late 1970s. Affected dogs were of both sexes and were ambulatory paraparetic, progressing to non-ambulatory tetraparesis. On neurologic examination, affected dogs displayed predominantly laryngeal paresis, decreased postural reactions, decreased spinal reflexes and muscle atrophy. The disease was considered eradicated through breeding programmes but recently new cases have occurred in the Nordic countries and the USA. The N-myc downstream-regulated gene (NDRG1) is implicated in neuropathies with comparable symptoms or clinical signs both in humans and in Greyhound dogs. This gene was therefore considered a candidate gene for the polyneuropathy in Alaskan Malamutes. The coding sequence of the NDRG1 gene derived from one healthy and one affected Alaskan Malamute revealed a non-synonymous G>T mutation in exon 4 in the affected dog that causes a Gly98Val amino acid substitution. This substitution was categorized to be "probably damaging" to the protein function by PolyPhen2 (score: 1.000). Subsequently, 102 Alaskan Malamutes from the Nordic countries and the USA known to be either affected (n = 22), obligate carriers (n = 7) or healthy (n = 73) were genotyped for the SNP using TaqMan. All affected dogs had the T/T genotype, the obligate carriers had the G/T genotype and the healthy dogs had the G/G genotype except for 13 who had the G/T genotype. A protein alignment showed that residue 98 is conserved in mammals and also that the entire NDRG1 protein is highly conserved (94.7%) in mammals. We conclude that the G>T substitution is most likely the mutation that causes polyneuropathy in Alaskan Malamutes. Our characterization of a novel candidate causative mutation for polyneuropathy offers a new canine model that can provide further insight into pathobiology and therapy of human polyneuropathy. Furthermore, selection against this mutation can now be used to eliminate the disease in Alaskan Malamutes.