A human ALDH1A2 gene variant is associated with increased newborn kidney size and serum retinoic acid

Nephron number varies widely between 0.3 and 1.3 million per kidney in humans. During fetal life, the rate of nephrogenesis is influenced by local retinoic acid (RA) level such that even moderate maternal vitamin A deficiency limits the final nephron number in rodents. Inactivation of genes in the RA pathway causes renal agenesis in mice; however, the impact of retinoids on human kidney development is unknown. To resolve this, we tested for associations between variants of genes involved in RA metabolism (ALDH1A2, CYP26A1, and CYP26B1) and kidney size among normal newborns. Homozygosity for a common (1 in 5) variant, rs7169289(G), within an Sp1 transcription factor motif of the ALDH1A2 gene, showed a significant 22% increase in newborn kidney volume when adjusted for body surface area. Infants bearing this allele had higher umbilical cord blood RA levels compared to those with homozygous wild-type ALDH1A2 rs7169289(A) alleles. Furthermore, the effect of the rs7169289(G) variant was evident in subgroups with or without a previously reported hypomorphic RET 1476(A) proto-oncogene allele that is critical in determining final nephron number. As maternal vitamin A deficiency is widespread in developing countries and may compromise availability of retinol for fetal RA synthesis, our study suggests that the ALDH1A2 rs7169289(G) variant might be protective for such individuals

Safety and efficacy of botox injection in alleviating post-operative pain and improving quality of life in lower extremity limb lengthening and deformity correction

<p>Abstract</p> <p>Background</p> <p>Distraction osteogenesis is the standard treatment for the management of lower limb length discrepancy of more than 3 cm and bone loss secondary to congenital anomalies, trauma or infection. This technique consists of an osteotomy of the bone to be lengthened, application of an external fixator, followed by gradual and controlled distraction of the bone ends. Although limb lengthening using the Ilizarov distraction osteogenesis principle yields excellent results in most cases, the technique has numerous problems and is not well tolerated by many children. The objective of the current study is to determine if Botulinum Toxin A (BTX-A), which is known to possess both analgesic and paralytic actions, can be used to alleviate post-operative pain and improve the functional outcome of children undergoing distraction osteogenesis.</p> <p>Methods/Design</p> <p>The study design consists of a multi centre, randomized, double-blinded, placebo-controlled trial. Patients between ages 5–21 years requiring limb lengthening or deformity correction using distraction will be recruited from 6 different sites (Shriners Hospital for Children in Montreal, Honolulu, Philadelphia and Portland as well as DuPont Hospital for Children in Wilmington, Delaware and Hospital for Sick Children in Toronto, Ont). Approximately 150 subjects will be recruited over 2 years and will be randomized to either receive 10 units per Kg of BTX-A or normal saline (control group) intraoperatively following the surgery. Functional outcome effects will be assessed using pain scores, medication dosages, range of motion, flexibility, strength, mobility function and quality of life of the patient. IRB approval was obtained from all sites and adverse reactions will be monitored vigorously and reported to IRB, FDA and Health Canada.</p> <p>Discussion</p> <p>BTX-A injection has been widely used world wide with no major side effects reported. However, to the best of our knowledge, this is the first time BTX-A is being used under the context of limb lengthening and deformity correction.</p> <p>Trial Registration</p> <p>NCT00412035</p

Immunoseq: the identification of functionally relevant variants through targeted capture and sequencing of active regulatory regions in human immune cells

$\textbf{BACKGROUND}$: The observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits. In order to efficiently make a comprehensive assessment of the impact of non-coding genetic variation in immune related diseases we emulated the whole-exome sequencing paradigm and developed a custom capture panel for the known DNase I hypersensitive site (DHS) in immune cells - "Immunoseq". $\textbf{RESULTS}$: We performed Immunoseq in 30 healthy individuals where we had existing transcriptome data from T cells. We identified a large number of novel non-coding variants in these samples. Relying on allele specific expression measurements, we also showed that our selected capture regions are enriched for functional variants that have an impact on differential allelic gene expression. The results from a replication set with 180 samples confirmed our observations. $\textbf{CONCLUSIONS}$: We show that Immunoseq is a powerful approach to detect novel rare variants in regulatory regions. We also demonstrate that these novel variants have a potential functional role in immune cells.This work was supported by grants from the Canadian Institute of Health Research (CIHR), the UK Medical Research Council (G1100125), the Swedish Research Council (DO283001) and Knut and Alice Wallenberg Foundation (KAW). We also acknowledge the use of subjects from the Cambridge BioResource and the support of the Cambridge NIHR Biomedical Research Centre. AM was supported by the Fond de Recherche Santé Québec Doctoral training award. TP and CL holds a Canada Research Chair

Variation at the NFATC2 Locus Increases the Risk of Thiazolidinedione-Induced Edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Study

Objective: Thiazolidinediones are used to treat type 2 diabetes. Their use has been associated with peripheral edema and congestive heart failure - outcomes that may have a genetic etiology. Research Design and Methods: We genotyped 4,197 participants of the multiethnic DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) trial with a 50k single nucleotide polymorphisms (SNP) array, which captures ∼2000 cardiovascular, inflammatory, and metabolic genes. We tested 32,088 SNPs for an association with edema among Europeans who received rosiglitazone (n = 965). Results: One SNP, rs6123045, in NFATC2 was significantly associated with edema (odds ratio 1.89 [95% CI 1.47-2.42]; P = 5.32 × 10-7, corrected P = 0.017). Homozygous individuals had the highest edema rate (hazard ratio 2.89, P = 4.22 × 10-4) when compared with individuals homozygous for the protective allele, with heterozygous individuals having an intermediate risk. The interaction between the SNP and rosiglitazone for edema was significant (P = 7.68 × 10-3). Six SNPs in NFATC2 were significant in both Europeans and Latin Americans (P &lt; 0.05). Conclusions: Genetic variation at the NFATC2 locus contributes to edema among individuals who receive rosiglitazone

An Extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the <i>HLA-DRB1</i> locus

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n=63), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (&gt;700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis

Regulating Assisted Reproduction in Canada, Switzerland, and the USA: Comparing the Judicialization of Policy-making

This article analyses the extent to which courts shape policies for assisted reproduction. While the USA is considered to be the most litigious country, Canada has observed a growing involvement of the courts from the 1980’s onward, and Switzerland is characterized by a modest degree of judicialization. Based on national patterns, we would expect litigation and court impact to vary across these three countries. As this paper demonstrates, policy-process specific variables such as the structure of policy conflicts, the novelty of regulation, self-regulation by key stakeholders, and the policies in place better explain the variation in the judicialization of policy-making

SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis

<p>Abstract</p> <p>Background</p> <p>We report our experience of selecting tag SNPs in 35 genes involved in iron metabolism in a cohort study seeking to discover genetic modifiers of hereditary hemochromatosis.</p> <p>Methods</p> <p>We combined our own and publicly available resequencing data with HapMap to maximise our coverage to select 384 SNPs in candidate genes suitable for typing on the Illumina platform.</p> <p>Results</p> <p>Validation/design scores above 0.6 were not strongly correlated with SNP performance as estimated by Gentrain score. We contrasted results from two tag SNP selection algorithms, LDselect and Tagger. Varying r²from 0.5 to 1.0 produced a near linear correlation with the number of tag SNPs required. We examined the pattern of linkage disequilibrium of three levels of resequencing coverage for the transferrin gene and found HapMap phase 1 tag SNPs capture 45% of the ≥ 3% MAF SNPs found in SeattleSNPs where there is nearly complete resequencing. Resequencing can reveal adjacent SNPs (within 60 bp) which may affect assay performance. We report the number of SNPs present within the region of six of our larger candidate genes, for different versions of stock genotyping assays.</p> <p>Conclusion</p> <p>A candidate gene approach should seek to maximise coverage, and this can be improved by adding to HapMap data any available sequencing data. Tag SNP software must be fast and flexible to data changes, since tag SNP selection involves iteration as investigators seek to satisfy the competing demands of coverage within and between populations, and typability on the technology platform chosen.</p

Inter-Destination Multimedia Synchronization; Schemes, Use Cases and Standardization

Traditionally, the media consumption model has been a passive and isolated activity. However, the advent of media streaming technologies, interactive social applications, and synchronous communications, as well as the convergence between these three developments, point to an evolution towards dynamic shared media experiences. In this new model, geographically distributed groups of consumers, independently of their location and the nature of their end-devices, can be immersed in a common virtual networked environment in which they can share multimedia services, interact and collaborate in real-time within the context of simultaneous media content consumption. In most of these multimedia services and applications, apart from the well-known intra and inter-stream synchronization techniques that are important inside the consumers playout devices, also the synchronization of the playout processes between several distributed receivers, known as multipoint, group or Inter-destination multimedia synchronization (IDMS), becomes essential. Due to the increasing popularity of social networking, this type of multimedia synchronization has gained in popularity in recent years. Although Social TV is perhaps the most prominent use case in which IDMS is useful, in this paper we present up to 19 use cases for IDMS, each one having its own synchronization requirements. Different approaches used in the (recent) past by researchers to achieve IDMS are described and compared. As further proof of the significance of IDMS nowadays, relevant organizations (such as ETSI TISPAN and IETF AVTCORE Group) efforts on IDMS standardization (in which authors have been and are participating actively), defining architectures and protocols, are summarized.This work has been financed, partially, by Universitat Politecnica de Valencia (UPV), under its R&D Support Program in PAID-05-11-002-331 Project and in PAID-01-10, and by TNO, under its Future Internet Use Research & Innovation Program. The authors also want to thank Kevin Gross for providing some of the use cases included in Sect. 1.2.Montagud, M.; Boronat Segui, F.; Stokking, H.; Van Brandenburg, R. (2012). Inter-Destination Multimedia Synchronization; Schemes, Use Cases and Standardization. Multimedia Systems. 18(6):459-482. https://doi.org/10.1007/s00530-012-0278-9S459482186Kernchen, R., Meissner, S., Moessner, K., Cesar, P., Vaishnavi, I., Boussard, M., Hesselman, C.: Intelligent multimedia presentation in ubiquitous multidevice scenarios. IEEE Multimedia 17(2), 52–63 (2010)Vaishnavi, I., Cesar, P., Bulterman, D., Friedrich, O., Gunkel, S., Geerts, D.: From IPTV to synchronous shared experiences challenges in design: distributed media synchronization. Signal Process Image Commun 26(7), 370–377 (2011)Geerts, D., Vaishnavi, I., Mekuria, R., Van Deventer, O., Cesar, P.: Are we in sync?: synchronization requirements for watching on-line video together, CHI ‘11, New York, USA (2011)Boronat, F., Lloret, J., García, M.: Multimedia group and inter-stream synchronization techniques: a comparative study. Inf. Syst. 34(1), 108–131 (2009)Chen, M.: A low-latency lip-synchronized videoconferencing system. In: SIGCHI Conference on Human Factors in Computing Systems, CHI’03, ACM, pp. 464–471, New York (2003)Ishibashi, Y., Tasaka, S., Ogawa, H.: Media synchronization quality of reactive control schemes. IEICE Trans. Commun. E86-B(10), 3103–3113 (2003)Ademoye, O.A., Ghinea, G.: Synchronization of olfaction-enhanced multimedia. IEEE Trans. Multimedia 11(3), 561–565 (2009)Cesar, P., Bulterman, D.C.A., Jansen, J., Geerts, D., Knoche, H., Seager, W.: Fragment, tag, enrich, and send: enhancing social sharing of video. ACM Trans. Multimedia Comput. Commun. Appl. 5(3), Article 19, 27 pages (2009)Van Deventer, M.O., Stokking, H., Niamut, O.A., Walraven, F.A., Klos, V.B.: Advanced Interactive Television Service Require Synchronization, IWSSIP 2008. Bratislava, June (2008)Premchaiswadi, W., Tungkasthan, A., Jongsawat, N.: Enhancing learning systems by using virtual interactive classrooms and web-based collaborative work. In: Proceedings of the IEEE Education Engineering Conference (EDUCON 2010), pp. 1531–1537. Madrid, Spain (2010)Diot, C., Gautier, L.: A distributed architecture for multiplayer interactive applications on the internet. IEEE Netw 13(4), 6–15 (1999)Mauve, M., Vogel, J., Hilt, V., Effelsberg, W.: Local-lag and timewarp: providing consistency for replicated continuous applications. IEEE Trans. Multimedia 6(1), 45–57 (2004)Hosoya, K., Ishibashi, Y., Sugawara, S., Psannis, K.E.: Group synchronization control considering difference of conversation roles. In: IEEE 13th International Symposium on Consumer Electronics, ISCE ‘09, pp. 948–952 (2009)Roccetti, M., Ferretti, S., Palazzi, C.: The brave new world of multiplayer online games: synchronization issues with smart solution. In: 11th IEEE Symposium on Object Oriented Real-Time Distributed Computing (ISORC), pp. 587–592 (2008)Ott, D.E., Mayer-Patel, K.: An open architecture for transport-level protocol coordination in distributed multimedia applications. ACM Trans. Multimedia Comput. Commun. Appl. 3(3), 17 (2007)Boronat, F., Montagud, M., Guerri, J.C.: Multimedia group synchronization approach for one-way cluster-to-cluster applications. In: IEEE 34th Conference on Local Computer Networks, LCN 2009, pp. 177–184, Zürich (2009)Boronat, F., Montagud, M., Vidal, V.: Smooth control of adaptive media playout to acquire IDMS in cluster-based applications. In: IEEE LCN 2011, pp. 617–625, Bonn (2011)Huang, Z., Wu, W., Nahrstedt, K., Rivas, R., Arefin, A.: SyncCast: synchronized dissemination in multi-site interactive 3D tele-immersion. In: Proceedings of MMSys, USA (2011)Kim, S.-J., Kuester, F., Kim, K.: A global timestamp-based approach for enhanced data consistency and fairness in collaborative virtual environments. ACM/Springer Multimedia Syst. J. 10(3), 220–229 (2005)Schooler, E.: Distributed music: a foray into networked performance. In: International Network Music Festival, Santa Monica, CA (1993)Miyashita, Y., Ishibashi, Y., Fukushima, N., Sugawara, S., Psannis K.E.: QoE assessment of group synchronization in networked chorus with voice and video. In: Proceedings of IEEE TENCON’11, pp. 393–397 (2011)Hesselman, C., Abbadessa, D., Van Der Beek, W., et al.: Sharing enriched multimedia experiences across heterogeneous network infrastructures. IEEE Commun. Mag. 48(6), 54–65 (2010)Montpetit, M., Klym, N., Mirlacher, T.: The future of IPTV—Connected, mobile, personal and social. Multimedia Tools Appl J 53(3), 519–532 (2011)Cesar, P., Bulterman, D.C.A., Jansen, J.: Leveraging the user impact: an architecture for secondary screens usage in an interactive television environment. ACM/Springer Multimedia Syst. 15(3), 127–142 (2009)Lukosch, S.: Transparent latecomer support for synchronous groupware. In: Proceedings of 9th International Workshop on Groupware (CRIWG), Grenoble, France, pp. 26–41 (2003)Steinmetz, R.: Human perception of jitter and media synchronization. IEEE J. Sel. Areas Commun. 14(1), 61–72 (1996)Stokking, H., Van Deventer, M.O., Niamut, O.A., Walraven, F.A., Mekuria, R.N.: IPTV inter-destination synchronization: a network-based approach, ICIN’2010, Berlin (2010)Mekuria, R.N.: Inter-destination media synchronization for TV broadcasts, Master Thesis, Faculty of Electrical Engineering, Mathematics and Computer Science, Department of Network architecture and Services, Delft University of Technology (2011)Pitt Ian, CS2511: Usability engineering lecture notes, localisation of sound sources. http://web.archive.org/web/20100410235208/http:/www.cs.ucc.ie/~ianp/CS2511/HAP.htmlNielsen, J.: Response times: the three important limits. http://www.useit.com/papers/responsetime.html (1994)ITU-T Rec G. 1010: End-User Multimedia QoS Categories. International Telecommunication Union, Geneva (2001)Biersack, E., Geyer, W.: Synchronized delivery and playout of distributed stored multimedia streams. ACM/Springer Multimedia Syst 7(1), 70–90 (1999)Xie, Y., Liu, C., Lee, M.J., Saadawi, T.N.: Adaptive multimedia synchronization in a teleconference system. ACM/Springer Multimedia Syst. 7(4), 326–337 (1999)Laoutaris, N., Stavrakakis, I.: Intrastream synchronization for continuous media streams: a survey of playout schedulers. IEEE Netw. Mag. 16(3), 30–40 (2002)Ishibashi, Y., Tsuji, A., Tasaka, S.: A group synchronization mechanism for stored media in multicast communications. In: Proceedings of the INFOCOM ‘97, Washington (1997)Ishibashi, Y., Tasaka, S.: A group synchronization mechanism for live media in multicast communications. IEEE GLOBECOM’97, pp. 746–752 (1997)Boronat, F., Guerri, J.C., Lloret, J.: An RTP/RTCP based approach for multimedia group and inter-stream synchronization. Multimedia Tools Appl. J. 40(2), 285–319 (2008)Ishibashi, I., Tasaka, S.: A distributed control scheme for group synchronization in multicast communications. In: Proceedings of International Symposium Communications, Kaohsiung, Taiwan, pp. 317–323 (1999)Lu, Y., Fallica, B., Kuipers, F.A., Kooij, R.E., Van Mieghem, P.: Assessing the quality of experience of SopCast. Int. J. Internet Protoc. Technol 4(1), 11–19 (2009)Shamma, D.A., Bastea-Forte, M., Joubert, N., Liu, Y.: Enhancing online personal connections through synchronized sharing of online video, ACM CHI’08 Extended Abstracts, Florence (2008)Ishibashi, Y., Tasaka, S.: A distributed control scheme for causality and media synchronization in networked multimedia games. In: Proceedings of 11th International Conference on Computer Communications and Networks, pp. 144–149, Miami, USA (2002)Ishibashi, Y., Tomaru, K., Tasaka, S., Inazumi, K.: Group synchronization in networked virtual environments. In: Proceedings of the 38th IEEE International Conference on Communications, pp. 885–890, Alaska, USA (2003)Tasaka, S., Ishibashi, Y., Hayashi, M.: Inter–destination synchronization quality in an integrated wired and wireless network with handover. IEEE GLOBECOM 2, 1560–1565 (2002)Kurokawa, Y., Ishibashi, Y., Asano, T.: Group synchronization control in a remote haptic drawing system. In: Proceedings of IEEE International Conference on Multimedia and Expo, pp. 572–575, Beijing, China (2007)Hashimoto, T., Ishibashi, Y.: Group Synchronization Control over Haptic Media in a Networked Real-Time Game with Collaborative Work, Netgames’06, Singapore (2006)Nunome, T., Tasaka, S.: Inter-destination synchronization quality in a multicast mobile ad hoc network. In: Proceedings of IEEE 16th International Symposium on Personal, Indoor and Mobile Radio Communications, pp. 1366–1370, Berlin, Germany (2005)Brandenburg, R., van Stokking, H., Van Deventer, M.O., Boronat, F., Montagud, M., Gross, K.: RTCP for inter-destination media synchronization, draft-brandenburg-avtcore-rtcp-for-idms-03.txt. In: IETF Audio/Video Transport Core Maintenance Working Group, Internet Draft, March 9 (2012)ETSI TS 181 016 V3.3.1 (2009-07) Telecommunications and Internet converged Services and Protocols for Advanced Networking (TISPAN); Service Layer Requirements to integrate NGN Services and IPTVETSI TS 182 027 V3.5.1 (2011-03) Telecommunications and Internet converged Services and Protocols for Advanced Networking (TISPAN); IPTV Architecture; IPTV functions supported by the IMS subsystemETSI TS 183 063 V3.5.2 (2011-03) Telecommunications and Internet converged Services and Protocols for Advanced Networking (TISPAN); IMS-based IPTV stage 3 specificationBrandenburg van, R., et al.: RTCP XR Block Type for inter-destination media synchronization, draft-brandenburg-avt-rtcp-for-idms-00.txt. In: IETF Audio/Video Transport Working Group, Internet Draft, Sept 24, 2010Williams, A., et al.: RTP Clock Source Signalling, draft-williams-avtcore-clksrc-00. In: IETF Audio/Video Transport Working Group, Internet Draft, February 28, 201