Evolution of vitellogenin genes: comparative analysis of the nucleotide sequences downstream of the transcription initiation site of four Xenopus laevis and one chicken gene.

Electron microscopic analysis of heteroduplexes between the most distantly related Xenopus vitellogenin genes (A genes X B genes) has revealed the distribution of homologous regions that have been preferentially conserved after the duplication events that gave rise to the multigene family in Xenopus laevis. DNA sequence analysis was limited to the region downstream of the transcription initiation site of the Xenopus genes A1, B1 and B2 and a comparison with the Xenopus A2 and the major chicken vitellogenin gene is presented. Within the coding regions of the first three exons, nucleotide substitutions resulting in amino acid changes accumulate at a rate similar to that observed in globin genes. This suggests that the duplication event which led to the formation of the A and B ancestral genes in Xenopus laevis occurred about 150 million years ago. Homologous exons of the A1-A2 and B1-B2 gene pairs, which formed about 30 million years ago, show a quite similar sequence divergence. In contrast, A1-A2 homologous introns seem to have evolved much faster than their B1-B2 counterparts.

Smoking and Public Health: A Review of Reviews of Interventions to Increase Smoking Cessation, Reduce Smoking Initiation and Prevent Further Uptake of Smoking - Evidence Briefing

This evidence briefing collates review-level evidence of interventions including those targeted at pregnant women and evidence for tackling health inequalities in smoking.

Smoking and Public Health: A Review of Reviews of Interventions to Increase Smoking Cessation, Reduce Smoking Initiation and Prevent Further Uptake of Smoking - Summary

The briefing identifies gaps in primary and review-level research and makes a number of recommendations, including further measures to address health inequalities.

Project Initiation Document Phase One: Scoping Exercise within special schools

This Project Initiation Document outlines the purpose and plan of Phase One of the Review of AHP Support for Children with Statements of Special Educational Needs in Special Schools and Mainstream Education.

Project Initiation Document Phase Two: Scoping Exercise within mainstream schools

This Project Initiation Document outlines the purpose and plan of Phase Two of the Review of AHP Support for Children with Statements of Special Educational Needs in Special Schools and Mainstream Education.

Role of ALK gene and mutations in initiation and progression of neuroblastoma

Introduction Le neuroblastome (NB) est la tumeur maligne solide extra-crânienne la plus fréquente chez l'enfant. Sa présentation clinique est très hétérogène, allant d'une tumeur localisée à une atteinte métastatique sévère. Malgré des traitements agressifs, environ 55% des NB de hauts risques sont actuellement résistants aux thérapies. L'espoir réside dans le développement de traitements ciblant les mécanismes moléculaires responsables du développement et de la progression du NB. Le gène Anaplastic Lymphoma Kinase (ALK) codant pour un récepteur tyrosine kinase a été particulièrement étudié ces dernières années car il est muté, amplifié ou surexprimé dans une majorité des NBs. Le but de ce projet était d'investiguer le rôle de ALK-wt, ainsi que de ces deux plus fréquentes mutations, ALK- F1174L et ALK-R1245Q, dans l'oncogenèse du NB. Le NB étant originaire des cellules de la crête neurale, nous avons analysé le potentiel oncogénique de ces différentes formes de ALK dans des cellules progénitrices de la crête neurale (NCPC). Méthode Des NCPC de souris (JoMal), possédant un c-MycER inductible pour leur maintien en culture in vitro, ont été transduites par un rétrovirus permettant l'expression stable de ALK-wt, ALK-F1174L et ALK-R1245Q. Des tests in vitro ont d'abord été effectués pour tester le système c-MycER, la stabilité de nos cellules transduites, leur phénotype, leur capacité de croissance et leur tumorigénicité. Les cellules transduites ont ensuite été injectées dans des souris immunosupprimées en sous-cutané, puis en orthotopique, c'est-à-dire dans leur glande surrénale, afin de mesurer leur tumorigénicité in vivo. Résultats La transduction et l'expression stable de ALK n'ont pas modifié le phénotype indifférencié des JoMal, ni de manière significative la capacité de croissance des cellules in vitro en absence d'activation de c-MycER. Par contre, lorsque c-MycER est actif, les cellules porteuses des mutations Fl 174L et R1245Q ont montré une meilleure capacité de prolifération et de formation de colonies, par rapport aux JoMal-ALK-wt et aux cellules contrôles en culture 3D dans de la méthylcellulose et dans un test de formation de neurosphères. In vivo, les souris injectées avec les cellules JoMal-ALK- F1174L en sous-cutané ou dans la glande surrénale ont rapidement développé des tumeurs, suivies par le groupe JoMal-ALK-R1245Q et le groupe JoMal-ALK-wt, alors que les groupes de souris contrôles n'ont présenté aucune tumeur. En orthotopique, nous avons obtenu 5/6 tumeurs ALK-F1174L, 7/7 tumeurs ALK-R1245Q et 6/7 tumeurs ALK-wt. Les tumeurs sous-cutanées ne présentaient pas de différences morphologiques et histologiques entre les différents groupes et montraient une histologie compatible avec un NB. Les tumeurs orthotopiques restent encore à analyser. Conclusion Cette étude a permis de démontrer que les mutations activatrices Fl 174L et R1245Q ont des propriétés tumorigéniques in vitro dans des NCPC et in vivo tandis que la forme sauvage de ALK montre une capacité oncogénique uniquement in vivo. Bien que la caractérisation des tumeurs orthotopiques n'a pas encore été effectuée, l'analyse des tumeurs sous-cutanées nous suggère que l'expression de ALK- wt ou muté est suffisante pour induire la formation de NB à partir des cellules progénitrices de la crête neurale. Le gène ALK semble donc jouer un rôle important dans l'oncogénèse du NB, aussi bien par la présence de mutations activatrices que par sa fréquente surexpression.

De novo lipogenesis in adipose tissue is associated with course of morbid obesity after bariatric surgery.

OBJECTIVE De novo lipogenesis is involved in fatty acid biosynthesis and could be involved in the regulation of the triglyceride storage capacity of adipose tissue. However, the association between lipogenic and lipolytic genes and the evolution of morbidly obese subjects after bariatric surgery remains unknown. In this prospective study we analyze the association between the improvement in the morbidly obese patients as a result of bariatric surgery and the basal expression of lipogenic and lipolytic genes. METHODS We study 23 non diabetic morbidly obese patients who were studied before and 7 months after bariatric surgery. Also, we analyze the relative basal mRNA expression levels of lipogenic and lipolytic genes in epiploic visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). RESULTS When the basal acetyl-CoA carboxylase 1 (ACC1), acetyl-CoA synthetase 2 (ACSS2) and ATP citrate lyase (ACL) expression in SAT was below percentile-50, there was a greater decrease in weight (P = 0.006, P = 0.034, P = 0.026), body mass index (P = 0.008, P = 0.033, P = 0.034) and hip circumference (P = 0.033, P = 0.021, P = 0.083) after bariatric surgery. In VAT, when the basal ACSS2 expression was below percentile-50, there was a greater decrease in hip circumference (P = 0.006). After adjusting for confounding variables in logistic regression models, only the morbidly obese patients with SAT or VAT ACSS2 expression ≥ P50 before bariatric surgery had a lower percentage hip circumference loss (

The tumor necrosis factor-related apoptosis-inducing ligand receptors TRAIL-R1 and TRAIL-R2 have distinct cross-linking requirements for initiation of apoptosis and are non-redundant in JNK activation.

Overexpression of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors, TRAIL-R1 and TRAIL-R2, induces apoptosis and activation of NF-kappaB in cultured cells. In this study, we have demonstrated differential signaling capacities by both receptors using either epitope-tagged soluble TRAIL (sTRAIL) or sTRAIL that was cross-linked with a monoclonal antibody. Interestingly, sTRAIL was sufficient for induction of apoptosis only in cell lines that were killed by agonistic TRAIL-R1- and TRAIL-R2-specific IgG preparations. Moreover, in these cell lines interleukin-6 secretion and NF-kappaB activation were induced by cross-linked or non-cross-linked anti-TRAIL, as well as by both receptor-specific IgGs. However, cross-linking of sTRAIL was required for induction of apoptosis in cell lines that only responded to the agonistic anti-TRAIL-R2-IgG. Interestingly, activation of c-Jun N-terminal kinase (JNK) was only observed in response to either cross-linked sTRAIL or anti-TRAIL-R2-IgG even in cell lines where both receptors were capable of signaling apoptosis and NF-kappaB activation. Taken together, our data suggest that TRAIL-R1 responds to either cross-linked or non-cross-linked sTRAIL which signals NF-kappaB activation and apoptosis, whereas TRAIL-R2 signals NF-kappaB activation, apoptosis, and JNK activation only in response to cross-linked TRAIL.

Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency.

Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues. This approach yielded the unexpectedly high rate of 20% mutation identification in our series. Recurrent heteroplasmic mutations included two hitherto unreported (T10158C and T14487C) and three previously reported mutations (T10191C, T12706C and A13514G) in children with Leigh or Leigh-like encephalopathy. The recurrent mutations consistently involved T-->C transitions (p<10(-4)). This study supports the view that an efficient molecular screening should be based on an accurate identification of respiratory chain enzyme deficiency.

Molecular characterization of 39 de novo sSMC: contribution to prognosis and genetic counselling, a prospective study.

Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosomes that cannot be characterized by karyotype. In many prenatal cases of de novo sSMC, the outcome of pregnancy is difficult to predict because the euchromatin content is unclear. This study aimed to determine the presence or absence of euchromatin material of 39 de novo prenatally ascertained sSMC by array-comparative genomic hybridization (array-CGH) or single nucleotide polymorphism (SNP) array. Cases were prospectively ascertained from the study of 65,000 prenatal samples [0.060%; 95% confidence interval (CI), 0.042-0.082]. Array-CGH showed that 22 markers were derived from non-acrocentric markers (56.4%) and 7 from acrocentic markers (18%). The 10 additional cases remained unidentified (25.6%), but 7 of 10 could be further identified using fluorescence in situ hybridization; 69% of de novo sSMC contained euchromatin material, 95.4% of which for non-acrocentric markers. Some sSMC containing euchromatin had a normal phenotype (31% for non-acrocentric and 75% for acrocentric markers). Statistical differences between normal and abnormal phenotypes were shown for the size of the euchromatin material (more or less than 1 Mb, p = 0.0006) and number of genes (more or less than 10, p = 0.0009). This study is the largest to date and shows the utility of array-CGH or SNP array in the detection and characterization of de novo sSMC in a prenatal context.

Freedom Trial First-Year Extension: Results from 4 Years of Denosumab Exposure in Women with Postmenopausal Osteoporosis

Aims: To investigate the long-term efficacy and safety of denosumab (DMAb) for the treatment of postmenopausal women with osteoporosis in an open-label extension to the 3-year FREEDOM study.1Methods: All women who completed the FREEDOM study were eligible to enter a long-term open-label extension (up to 10 years). After providing informed consent, participants received 6-monthly subcutaneous injections of DMAb (60 mg). Here we report data from the first year of followup. For women randomized to DMAb in the FREEDOM study ('long-term group'), this represents up to 48 months of DMAb exposure (eight 6-monthly injections). For those randomized to placebo ('de novo group') the data are from up to 12 months of exposure (two injections). All participants continued to take calcium (1 g) and vitamin D (≥400 IU) supplements daily. Changes in bone mineral density (BMD) and bone turnover markers (BTM) are reported for subjects enrolled in the extension. No formal statistical testing was planned for this interim report. P-values are descriptive.Results: Overall, 4,550 eligible women (70.2%) who completed the FREEDOM study entered the open-label extension study (long-term, n=2,343; de novo, n=2,207). During the first year of the extension, lumbar spine (LS) BMD in the long-term group further increased by 2.0% (12.1% increase vs. FREEDOM baseline at 48 months), and total hip (TH) BMD further increased by 0.8% (6.5% increase at 48 months) (p<0.0001 for both BMD gains during year 4; Fig. 1). During the first year of the extension, LS and TH BMD increased by 5.4% and 3.0%, respectively in the de novo group (both p<0.0001). After DMAb initiation, serum C-telopeptide (CTX) in the de novo group decreased rapidly and similarly to the long-term group (Fig. 2). Reductions in BTMs continue to attenuate at the end of the dosing interval as previously reported. Adverse event (AE) rates were similar (70.4% of women in the longterm group and 67.9% in the de novo group). Serious Aes were also similar (9.8% and 11.2% of women, respectively). During year 4, osteoporotic nonvertebral fractures were reported in 31 women in the long-term group and 51 in the denovo group.Fig. 1. Percentage change in BMD with denosumab for4 years (long-term) or 1 year (de novo)Fig. 2. Percentage change in sCTX over timeConclusions: These interim results suggest that continuation of DMAb treatment through 48 months is associated with further significant increases in spine and hip BMD with sustained reduction of bone turnover. The de-novo treatment group results confirm the first year active treatment findings previously reported1.Acknowledgements: Amgen Inc. sponsored this study. Figure ©2010, American Society for Bone and Mineral Research, used by permission, all rights reserved. Disclosure of Interest: H. Bone Grant/Research Support from: Amgen, Eli Lilly, Merck, Nordic Bioscience, Novartis, Takeda Pharmaceuticals, Consultant/Speaker's bureau/ Advisory activities with: Amgen, Merck, Takeda Pharmaceuticals, Zelos, S. Papapoulos Consultant/Speaker's bureau/ Advisory activities with: Amgen, Merck, Novartis, Lilly, Procter and Gamble, GSK, M.-L. Brandi Grant/Research Support from: MSD, GSK, Nycomed, NPS, Amgen, J. Brown Grant/Research Support from: Abbott, Amgen, Bristol Myers Squibb, Eli Lilly, Pfizer, Roche, Consultant/ Speaker's bureau/Advisory activities with: Abbott, Amgen, Eli Lilly, Novartis, Merck, Warner Chilcott,, R. Chapurlat Grant/Research Support from: Servier, Sanofi-Aventis, Warner-Chilcott, Novartis, Merck, Consultant/Speaker's bureau/Advisory activities with: Servier, Novartis, Amgen, E. Czerwinski: None Declared, N. Daizadeh Employee of: Amgen Inc., Stock ownership or royalties of: Amgen Inc., A. Grauer Employee of: Amgen Inc., Stock ownership or royalties of: Amgen Inc., C. Haller Employee of: Amgen Inc., Stock ownership or royalties of: Amgen Inc., M.-A. Krieg: None Declared, C. Libanati Employee of: Amgen Inc., Stock ownership or royalties of: Amgen Inc., Z. Man Grant/Research Support from: Amgen, D. Mellström: None Declared, S. Radominski Grant/Research Support from: Amgen, Pfizer, Roche, BMS, J.-Y. Reginster Grant/Research Support from: Bristol Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva, Lilly, Novartis, Roche, GlaxoSmithKline, Amgen, Servier, Consultant/Speaker's bureau/ Advisory activities with: Servier, Novartis, Negma, Lilly,Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex, UCB, Merck, Sharpe & Dohme, Rottapharm, IBSA, Genvrier, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Novo-Nordisk, H. Resch: None Declared, J. A. Román Grant/Research Support from: Roche, Pharma, C. Roux Grant/Research Support from: Amgen, MSD, Novartis, Servier, Roche, Consultant/ Speaker's bureau/Advisory activities with: Amgen, MSD, Novartis, Servier, Roche, S. Cummings Grant/ Research Support from: Amgen, Lilly, Consultant/Speaker's bureau/Advisory activities with: Amgen, Lilly, Novartis, Merck

Dividendos e informação assimétrica: análise do novo mercado

Em dezembro de 2000, a Bolsa de Valores de São Paulo (Bovespa) criou uma listagem em que diferenciava as empresas que voluntariamente aceitassem práticas de governança corporativa adicionais àquelas exigidas pela Comissão de Valores Mobiliários (CVM). A finalidade da inovação era estreitar a relação entre as empresas e os seus investidores, diminuindo a assimetria informacional e dando maior segurança ao investidor. O objetivo neste artigo é testar os efeitos gerados por essa iniciativa sobre a informação assimétrica do mercado acionário. Para tanto, foi realizado um estudo de eventos tendo como variável central a política de dividendos. O resultado revela que as companhias que aderiram aos mercados com graus diferenciados de governança apresentam menores graus de informação assimétrica e, desse modo, inseriram-se em um ambiente institucional mais seguro. Em outras palavras, a iniciativa da Bovespa teve êxito ao mitigar o problema da informação assimétrica no mercado acionário brasileiro.

Ensino da disciplina administração em enfermagem: em busca de um novo paradigma

Neste trabalho as autoras apresentam, um relato da experiência sobre o ensino da disciplina Administração em Enfermagem, da Escola de Enfermagem da USP, descrevendo como esta vem sendo inserida no novo currículo do curso de graduação em Enfermagem.