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1.
Bone Marrow Transplant ; 56(1): 175-184, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32665674

RESUMO

New diagnostic criteria and severity grading for sinusoidal obstructive syndrome (SOS) among pediatric and adolescent young adult (AYA) patients have been recently endorsed by international consensus. The extent to which these have been adopted in the US remains unclear. We sought to assess the potential impact via retrospective application of these criteria among patients treated at a large academic center in the United States. This is a single center retrospective study of pediatric-AYA patients who underwent hematopoietic cell transplantation (HCT) between July 2009 and 2019. The incidence of SOS was assessed using historic Baltimore and Seattle diagnostic criteria and compared with more recent guidelines (pEBMT) as proposed by the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation. Among 226 patients, application of the pEBMT diagnostic criteria was associated with a higher incidence (15.9%) and earlier time to diagnosis of SOS (by 2.5-3 days) compared with the modified Seattle (12.3%), and Baltimore (6.6%) criteria, respectively. The pEBMT criteria were sensitive and highly specific. Refractory thrombocytopenia was present in 75% of patients at diagnosis. Approximately 61% of patients with SOS were anicteric at diagnosis, though the majority (94.4%) developed hyperbilirubinemia as SOS progressed over a median time of 4 (1-57) days. Application of pEBMT criteria may have resulted in earlier indication for definitive treatment by 3 days. Timely diagnosis and administration of definitive treatment of SOS has been associated with improved outcomes. Prospective studies may better characterize the risk factors and natural course of SOS using pEBMT criteria.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Adolescente , Criança , Hepatopatia Veno-Oclusiva/diagnóstico , Humanos , Incidência , Estudos Prospectivos , Estudos Retrospectivos , Adulto Jovem
2.
Health Educ Res ; 29(4): 566-82, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24488650

RESUMO

This article discusses how process indicators can complement outcomes as part of a comprehensive explanatory evaluation framework, using the example of skills-based behavioural interventions to prevent sexually transmitted infections and promote sexual health among young people in schools. A systematic review was conducted, yielding 12 eligible outcome evaluations, 9 of which included a process evaluation. There were few statistically significant effects in terms of changes in sexual behaviour outcomes, but statistically significant effects were more common for knowledge and self-efficacy. Synthesis of the findings of the process evaluations identified a range of factors that might explain outcomes, and these were organized into two overarching categories: the implementation of interventions, and student engagement and intervention acceptability. Factors which supported implementation and engagement and acceptability included good quality teacher training, involvement and motivation of key school stakeholders and relevance and appeal to young people. Factors which had a negative impact included teachers' failure to comprehend the theoretical basis for behaviour change, school logistical problems and omission of topics that young people considered important. It is recommended that process indicators such as these be assessed in future evaluations of school-based sexual health behavioural interventions, as part of a logic model.


Assuntos
Avaliação de Processos e Resultados em Cuidados de Saúde , Saúde Reprodutiva , Infecções Sexualmente Transmissíveis/prevenção & controle , Adolescente , Comportamento do Adolescente , Educação em Saúde , Humanos , Comportamento Reprodutivo , Serviços de Saúde Escolar , Adulto Jovem
3.
Health Place ; 24: 242-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24177419

RESUMO

Public-health interventions informed by theory can be more effective but complex interventions often use insufficiently complex theories. We systematically reviewed theories of how school environments influence health. We included 37 reports drawing on 24 theories. Narrative synthesis summarised and categorised theories. We then produced an integrated theory of school environment influences on student health. This integrated theory could inform complex interventions such as health promoting schools programmes. Using systematic reviews to develop theories of change might be useful for other types of 'complex' public-health interventions addressing risks at the individual and community levels.


Assuntos
Proteção da Criança , Meio Ambiente , Modelos Teóricos , Instituições Acadêmicas , Adolescente , Criança , Humanos
4.
J Epidemiol Community Health ; 67(8): 677-81, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23682106

RESUMO

BACKGROUND: Owing to the limited effectiveness of traditional health education curricula in schools, there is increasing interest in interventions aiming to promote young people's health by modifying the school environment. Existing systematic reviews cannot determine whether environmental intervention is effective because they examine interventions combining environmental modifications and traditional health education. This gap is significant because school-environment interventions are complex to implement and may be sidelined in underfunded and attainment-focused school systems without evidence to support such an approach. This systematic review examined the effectiveness of school-environment interventions without health-education components on student health and inequalities. METHODS: This was a systematic review of experimental/quasi-experimental studies of school-environment interventions. Sixteen databases were searched, eliciting 62 329 references which were screened, with included studies quality assessed, data extracted and narratively synthesised. RESULTS: Sixteen reports of 10 studies were included, all from the USA and the UK. Five evaluations of interventions aiming to develop a stronger sense of community and/or improve relationships between staff and students suggested potential benefits particularly regarding violence and aggression. Two trials of interventions enabling students to advocate for changes in school catering and physical activity reported benefits for physical activity but not diet. Three evaluations of improvements to school playgrounds offered weak evidence of effects on physical activity. CONCLUSIONS: School environment interventions show the potential to improve young people's health particularly regarding violence, aggression and physical activity. Further trials are required to provide a stronger and more generalisable evidence base.


Assuntos
Meio Ambiente , Nível de Saúde , Instituições Acadêmicas , Estudantes , Promoção da Saúde , Humanos
5.
Health Technol Assess ; 14(7): 1-206, iii-iv, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20178696

RESUMO

OBJECTIVES: To assess the effectiveness and cost-effectiveness of schools-based skills-building behavioural interventions to encourage young people to adopt and maintain safer sexual behaviour and to prevent them from acquiring sexually transmitted infections (STIs). DATA SOURCES: Electronic bibliographic databases (e.g. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CINAHL, PsycINFO, CCRCT, NHS EED and DARE) were searched for the period 1985 to March 2008. Bibliographies of systematic reviews and related papers were screened and experts contacted to identify additional published and unpublished references. REVIEW METHODS: A systematic review of effectiveness and economic evaluation of cost-effectiveness were carried out. A descriptive map of studies that met inclusion criteria was produced, and keywords were developed and systematically applied to these studies to identify a policy-relevant subset of studies for the systematic review. Outcome data for variables including sexual behaviour were extracted. An economic model was developed to compare the costs and consequences of the behavioural interventions. A Bernoulli statistical model was constructed to describe the probability of STI infection. RESULTS: There were few significant differences between the interventions and comparators in terms of changes in sexual behaviour outcomes, although there were some significant differences for knowledge and some measures of self-efficacy. The studies included in this review conducted relatively short follow-up assessments at a time when many young people were becoming sexually active. It is therefore possible that favourable behaviour change may have occurred, and become more cost-effective, with time, as sexual activity becomes more routine in young people's lives. The quality of the intervention provider influenced whether or not young people found the interventions to be acceptable and engaging; enthusiasm and considerable expertise were important for effective class management and delivery of skills-building activities, and a supportive school culture was also helpful. Recognition of young people's individual needs in relation to sexual health was another important factor. No conclusions could be drawn on the impact of the interventions on sexual health inequalities due to a lack of relevant data on socioeconomic status, gender and ethnicity. The results of the economic evaluation were considered to be illustrative, mainly due to the uncertainty of the effect of intervention on behavioural outcomes. The results were most sensitive to changes in parameter values for the intervention effect, the transmission probability of STIs and the number of sexual partners. The costs of teacher-led and peer-led behavioural interventions, based on the resources estimated from the relevant randomised controlled trials in our systematic review, were 4.30 pounds and 15 pounds per pupil, respectively. Teacher-led interventions were more cost-effective than peer-led interventions due to the less frequent need for training. The incremental cost-effectiveness of the teacher-led and peer-led interventions was 20,223 pounds and 80,782 pounds per quality-adjusted life-year gained, respectively. An analysis of individual parameters revealed that future research funding should focus on assessing the intervention effect for condom use from a school-based intervention. CONCLUSIONS: School-based behavioural interventions for the prevention of STIs in young people can bring about improvements in knowledge and increased self-efficacy, but the interventions did not significantly influence sexual risk-taking behaviour or infection rates. Future investigation should include long-term follow-up to assess the extent to which safer sexual behaviour is adopted and maintained into adulthood, and prospective cohort studies are needed to look at the parameters that describe the transmission of STIs between partners. Funding should focus on the effectiveness of the interventions on influencing behaviour.


Assuntos
Comportamento do Adolescente , Comportamento de Redução do Risco , Infecções Sexualmente Transmissíveis/prevenção & controle , Adolescente , Análise Custo-Benefício , Feminino , Humanos , Masculino , Sexo Seguro , Instituições Acadêmicas , Educação Sexual , Reino Unido , Adulto Jovem
6.
Health Educ Res ; 23(5): 770-90, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17984295

RESUMO

This paper describes how barriers to, and facilitators of, good mental health amongst young people (11-21 years) were elucidated from a systematic review of studies of young people's views and how these barriers and facilitators were compared with effectiveness studies to identify effective and appropriate interventions, promising interventions needing further evaluation and the need for further intervention. All studies were published before 2000. No clear pattern for effectiveness emerged in terms of mental health promotion focus, the type of intervention, intervention provider or young people. Well-evaluated interventions neither always target what we know young people themselves see as important barriers to their mental health (for instance, loss of friends and family, violence and bullying) nor always build on what they see as key facilitators, particularly their preferred coping strategies. In particular, while young people see material and physical resources as major influences on their mental health, few evaluated interventions targeted these. Rigorously evaluated interventions more often addressed priorities not raised by young people themselves and populations at low risk for mental health problems. These innovative review methods can inform intervention development and evaluation in a new way based on the strengths and needs identified by the target population.


Assuntos
Promoção da Saúde/métodos , Transtornos Mentais/prevenção & controle , Saúde Mental , Adaptação Psicológica , Adolescente , Criança , Humanos , Transtornos Mentais/terapia , Autoimagem , Adulto Jovem
7.
Health Educ Res ; 21(6): 806-25, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17041020

RESUMO

A systematic review was conducted to examine the barriers to, and facilitators of, physical activity among young people (11-16 years). The review focused on the wider determinants of health, examining community- and society-level interventions. Four trials and 16 studies of young people's views were included. Evidence for the effectiveness of the interventions was limited, with some suggestions of improvements in knowledge and possible differences according to gender. Young women in particular identified barriers to physical activity associated with certain ways of providing physical education in schools. Young people in general identified a need for increased choice and facilities within the community and emphasized physical activity's social side. Some of the barriers and facilitators identified by young people had been addressed by 'soundly evaluated' effective interventions but significant gaps were identified where no evaluated interventions appear to have been published (e.g. initiatives explicitly addressing gender issues or the combination of sport and other leisure activities), or where there were no soundly evaluated interventions. Rigorous evaluation is required particularly to assess initiatives that address the limited practical and material resources that young people identify as barriers to physical activity.


Assuntos
Comportamento do Adolescente/psicologia , Educação em Saúde/métodos , Educação em Saúde/organização & administração , Atividade Motora , Adolescente , Criança , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Características de Residência
8.
Health Educ Res ; 21(2): 239-57, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16251223

RESUMO

A systematic review was conducted to examine the barriers to, and facilitators of, healthy eating among young people (11-16 years). The review focused on the wider determinants of health, examining community- and society-level interventions. Seven outcome evaluations and eight studies of young people's views were included. The effectiveness of the interventions was mixed, with improvements in knowledge and increases in healthy eating but differences according to gender. Barriers to healthy eating included poor school meal provision and ease of access to, relative cheapness of and personal taste preferences for fast food. Facilitators included support from family, wider availability of healthy foods, desire to look after one's appearance and will-power. Friends and teachers were generally not a common source of information. Some of the barriers and facilitators identified by young people had been addressed by soundly evaluated effective interventions, but significant gaps were identified where no evaluated interventions appear to have been published (e.g. better labelling of food products), or where there were no methodologically sound evaluations. Rigorous evaluation is required particularly to assess the effectiveness of increasing the availability of affordable healthy food in the public and private spaces occupied by young people.


Assuntos
Dieta , Comportamento Alimentar , Adolescente , Criança , Humanos , Motivação , Controles Informais da Sociedade
9.
Phys Rev Lett ; 90(15): 155508, 2003 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-12732051

RESUMO

The recently discovered stable semicrystalline phase in binary ultralong alkanes is studied by small-angle neutron and x-ray scattering. Either the shorter or the longer alkane has (CD2)11CD3 ends. It is confirmed that chains are tilted in the crystal layer and found that ca. seven end carbons of the shorter alkane are amorphous. It is also established that the longer chains protrude from the crystal at both ends and that their end groups are preferentially located in the middle of the amorphous layer, suggesting gradual dissipation of orientational order of the chains exiting the crystal.

10.
Br J Fam Plann ; 25(3): 115-8, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10567063

RESUMO

School based sex education provides an opportunity to prepare young people for their sexual careers. However, research has criticised the education provided in terms of it being too late, using didactic teaching methods and focusing on biological information. The present study aimed to explore young peoples' experiences of, and beliefs about, their school sex education in terms of its timing, format and content, and to examine the relationship between these factors and their intentions to use condoms. Sixteen to 19 year olds (n = 967) from educational institutions within the South Thames region completed a questionnaire about their sex education. The results showed that the median age of first receiving sex education was 11, that the majority of subjects believed that the timing was about right and a third believed it was too late. In terms of format, didactic methods such as facts, videos and leaflets were more commonly reported than interactive methods such as role-play and discussions about relationships, with the subjects reporting a preference for the latter. In terms of content the results suggested that the greatest emphasis was on biological information, with least emphasis being placed on relationship information. However, many subjects indicated that they had received practical advice such as how to use a condom correctly. In addition, the results indicated that although the timing and format of sex education were unrelated to behavioural intentions, a greater emphasis on practical advice was related to a greater intention to use a condom in the future. The results are discussed in terms of the contemporary nature of school based sex education programmes and evidence for changes following recent recommendations.


Assuntos
Atitude Frente a Saúde , Educação Sexual , Adolescente , Adulto , Fatores Etários , Biologia , Comunicação , Preservativos , Inglaterra , Feminino , Humanos , Relações Interpessoais , Masculino , Folhetos , Desempenho de Papéis , Instituições Acadêmicas , Aconselhamento Sexual , Educação Sexual/classificação , Educação Sexual/métodos , Educação Sexual/organização & administração , Comportamento Sexual , Inquéritos e Questionários , Ensino/métodos , Gravação em Vídeo
11.
Br J Fam Plann ; 24(4): 141-4, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10023099

RESUMO

Unwanted pregnancies, sexually transmitted diseases and unprotected sex in young people highlight a need to improve the provision of contraceptive services for this age group. The aim of the present study was to examine young men and women's use of and beliefs about, contraceptive services. A questionnaire was completed by 967 16 to 19 year olds from South Thames concerning their use of and beliefs about, a range of services which provide contraception. The results showed variability in both service use and belie about services which related to the respondent's sexual experience and gender In terms of use, the chemist and the condom machine had been used by the largest number of respondents, with more men using the condom machine and women favouring the GP or family planning clinic. In terms of beliefs, the condom machine was regarded as the easiest and most comfortable to use but the least confidential for all respondents with men reporting higher ratings for ease of use than women and non virgins reporting more positive beliefs for all criteria. The results are discussed in terms of the implications for health education. It is suggested that contraception use in young people could be promoted by embracing rather than challenging this variability. Accordingly, health education interventions would involve providing young people with information about contraception services which was designed to be in line, rather than conflict, with their existing concerns and beliefs. Such an approach would enable them to make informed choices about the kind of contraceptive service which matched their own personal needs.


PIP: Beliefs about and experiences with various types of contraceptive services were investigated in a cross-sectional study of 967 British students 16-19 years of age from South Thames. 55.1% of respondents (67.7% of females and 32.3% of males) had experienced sexual intercourse. 87.2% of sexually active respondents (90.6% of females and 80.2% of males) had used one or more community services--primarily chemists and condom machines--to obtain contraception. Respondents differentiated among sources of contraceptive supplies in terms of their perceived ease of access, comfort of use, and confidentiality. While men preferred condom machines, females were more likely to favor a family planning clinic or a general practitioner's office. The condom machine and the chemist were rated as the easiest services to access. Young people identified the chemist and a general practitioner's office as the sources of contraception with which they were least comfortable. Condom machines and chemists were regarded as the least confidential sources. Students who were virgins were substantially more uncomfortable about the possibility of accessing all possible services than their sexually experienced peers. Recommended is a strategy that encourages young people to make informed choices about a source of contraceptive supplies based on their particular needs and perceptions.


Assuntos
Comportamento do Adolescente , Atitude Frente a Saúde , Serviços de Planejamento Familiar/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Psicologia do Adolescente , Estudantes/psicologia , Adolescente , Adulto , Preservativos , Estudos Transversais , Medicina de Família e Comunidade , Feminino , Humanos , Londres , Masculino , Avaliação das Necessidades , Inquéritos e Questionários
12.
Occup Med (Lond) ; 49(8): 540-8, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10658308

RESUMO

The aim of this study was to identify and critically review evaluations of the effectiveness of health promotion programmes in the workplace. In line with guidelines for 'good practice' within the literature on workplace health promotion, this study aimed to assess the extent to which evaluated interventions considered employees' expressed needs or involved employee-employer partnerships. Overall, 110 outcome evaluations were located. Only a quarter of these reported that interventions were implemented in response to the explicit needs and/or views of the employees and very few involved partnerships. Most of the programmes targeted individual behaviour and supportive organizational change was limited. The majority of the outcome evaluations were not sufficiently rigorous to make a strong case for the effectiveness of workplace health promotion. However, some pointers to success were identified. It was concluded that there seems to be a wide disparity between what counts as 'good practice' within workplace health promotion and what is reported in the evaluation of effectiveness literature. This is not to say that 'good practice' does not exist, but that either such programmes are not rigorously evaluated for their effectiveness and/or that many of the evaluation findings remain outside the public domain.


Assuntos
Promoção da Saúde , Doenças Profissionais/prevenção & controle , Humanos , Relações Interprofissionais , Avaliação das Necessidades , Prognóstico , Avaliação de Programas e Projetos de Saúde , Reino Unido
13.
Percept Mot Skills ; 87(1): 108-10, 1998 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9760634

RESUMO

A brief survey measuring satisfaction with the body, concern for physical appearance, and motivations for selection of clothing was administered to 30 women in a university-sponsored support group for bulimic students and 30 women randomly selected from a college campus. No mean differences were found between the groups on concern for physical appearance when in a social setting, but mean differences were significant on satisfaction with weight, satisfaction with body image, and concern for physical appearance when alone.


Assuntos
Imagem Corporal , Bulimia/diagnóstico , Satisfação Pessoal , Autoimagem , Peso Corporal , Bulimia/psicologia , Vestuário/psicologia , Feminino , Humanos , Motivação , Comportamento Social
14.
Leukemia ; 12(7): 1119-27, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9665199

RESUMO

A new cell line with megakaryoblastic features, designated UoC-M1, was established from the malignant cells of a 68-year-old patient with acute myeloid leukemia. The patient's leukemic cells reacted with alpha-naphthyl acetate esterase and acid phosphatase and expressed CD7, CD24, CD34, CD38, CD45, HLA-DR and CD61. Cytogenetic analysis of the patient's malignant cells (and of the UoC-M1 cells) showed a human, male hypodiploid karyotype with many chromosome rearrangements and marker chromosomes. Spectral karyotyping (SKY) analysis complemented the G-banded karyotyping and clarified several chromosomal translocations and identified the marker chromosomes. Fluorescence in situ hybridization (FISH) and SKY analysis demonstrated that one marker chromosome contained three segments of chromosome 9 interspersed with three segments of chromosome 11, as well as a portion of chromosome 19. FISH analysis with a probe for MLL revealed that the UoC-M1 cells contained four copies of the MLL gene. Southern blot analysis determined that the MLL gene had a germline profile while Northern and Western analyses showed that the MLL mRNAs and protein were of the appropriate sizes. This is the first report of amplification of the MLL gene which may be an additional mechanism of leukemogenesis or disease progression.


Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Megacariócitos/citologia , Proto-Oncogenes , Fatores de Transcrição , Células Tumorais Cultivadas , Idoso , Northern Blotting , Southern Blotting , Western Blotting , Amplificação de Genes , Rearranjo Gênico , Histona-Lisina N-Metiltransferase , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Megacariócitos/fisiologia , Microscopia Eletrônica , Proteína de Leucina Linfoide-Mieloide
15.
J Health Psychol ; 3(3): 429-45, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22021401

RESUMO

The study reported in this article uses discourse analysis to examine the meaning and significance of contraception for young adults and emphasizes the social construction of meaning to better explain what can limit and what can facilitate use of contraception. The study used memory work (Crawford et al., Emotion and Gender: Constructing Meaning from Memories. Sage, 1992) and group discussions to collect accounts of contraception. Analysis of the accounts revealed that constructions of contraception used in the memories all signified sex, which invoked wider gendered discourses surrounding sexuality. Such discourses gave rise to contradictory positionings for the actors within the memories. In contrast, the accounts of contraception from the group discussions were predominantly produced with reference to a health promotion discourse. However, further analysis revealed that the constitution of this discourse was always highly precarious. These findings are discussed in terms of the implications for health promotion efforts.

16.
Genes Chromosomes Cancer ; 20(4): 363-71, 1997 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9408752

RESUMO

The MOLT-16 cell line was established from the leukemic cells of a patient with T-cell acute lymphoblastic leukemia and contains a t(8;14)(q24;q11) resulting in juxtaposition of sequences downstream of the MYC gene on chromosome 8 and the J region of the T-cell receptor alpha chain gene (TCRA) on chromosome 14. The reciprocal translocation involved a complex rearrangement with two chromosome breakpoints within the TCRAJ region on chromosome 14, resulting in inversion of a 1.4 kb DNA fragment between the two breakpoints. The 5' border of the inversion joints with another segment of chromosome 14, whereas the 3' border joins with a region of chromosome 8 located at least 257 kb downstream of MYC. Extensive deletions have occurred on both chromosomes 8 and 14 in conjunction with the translocation. To investigate the possible involvement of the V(D)J recombinase in this translocation, we analyzed the nucleotide sequences surrounding the translocation breakpoints. The breakpoint on chromosome 14 occurs between a segment coding for a TCRAJ sequence and its hepatamer-nonamer signal. Heptamer-nonamer consensus sequences are also identified on chromosome 8 adjacent to the breakpoint. Inserted N and P nucleotides are observed at the breakpoint junctions.


Assuntos
Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 8/genética , DNA Nucleotidiltransferases/genética , Leucemia-Linfoma de Células T do Adulto/genética , Translocação Genética , Sequência de Aminoácidos , Sequência de Bases , Southern Blotting , Inversão Cromossômica , Mapeamento Cromossômico , Clonagem Molecular , Sondas de DNA , DNA de Neoplasias/análise , Deleção de Genes , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T/genética , Humanos , Células Híbridas , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Análise de Sequência de DNA , Células Tumorais Cultivadas , VDJ Recombinases
17.
Proc Natl Acad Sci U S A ; 94(16): 8732-7, 1997 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-9238046

RESUMO

The recurring translocation t(11;16)(q23;p13.3) has been documented only in cases of acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II. We show that the MLL gene is fused to the gene that codes for CBP (CREB-binding protein), the protein that binds specifically to the DNA-binding protein CREB (cAMP response element-binding protein) in this translocation. MLL is fused in-frame to a different exon of CBP in two patients producing chimeric proteins containing the AT-hooks, methyltransferase homology domain, and transcriptional repression domain of MLL fused to the CREB binding domain or to the bromodomain of CBP. Both fusion products retain the histone acetyltransferase domain of CBP and may lead to leukemia by promoting histone acetylation of genomic regions targeted by the MLL AT-hooks, leading to transcriptional deregulation via aberrant chromatin organization. CBP is the first partner gene of MLL containing well defined structural and functional motifs that provide unique insights into the potential mechanisms by which these translocations contribute to leukemogenesis.


Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 16 , Proteínas de Ligação a DNA/genética , Leucemia Mieloide/genética , Proteínas Nucleares/genética , Proto-Oncogenes , Transativadores , Fatores de Transcrição/genética , Translocação Genética , Doença Aguda , Sequência de Aminoácidos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Sequência de Bases , Proteína de Ligação a CREB , Histona-Lisina N-Metiltransferase , Humanos , Leucemia Mieloide/tratamento farmacológico , Dados de Sequência Molecular , Proteína de Leucina Linfoide-Mieloide
18.
Pharm Res ; 14(1): 67-72, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9034223

RESUMO

PURPOSE: All transplanted solid organs experience some degree of ischemia-reperfusion (I-R) injury. This I-R injury can contribute to graft dysfunction which stems in part from the acute phase response and a resultant host of cytokines. Recent evidence suggests that organs remote to the site of I-R injury can be affected by circulating cytokines originating from these I-R injuries. Since many of these acute phase cytokines inhibit hepatic cytochrome P-450 (CYP) enzymes, we chose to investigate whether extrahepatic I-R injuries could influence hepatic oxidative drug metabolism. METHODS: Fifteen dogs were divided into three surgical groups: (I) sham I-R; (II) bilateral normothermic renal I-R; and (III) normothermic intestinal I-R. Antipyrine (AP) was selected as a model substrate and administered intravenously at a dose of 10 mg/kg. AP serum concentrations were determined by HPLC and cytokine activity (IL-1, IL-6, and TNFalpha) was measured via bioassay. Serial AP clearance and serum cytokine concentrations were determined 3 days prior to and at 4 hr, 24 hr, 3 days and 7 days after surgery. Hematology and blood chemistries were monitored throughout the study period. RESULTS: AP clearance was significantly reduced in groups II and III at 4 and 24 hrs post-l-R injury, while AP binding and apparent volume of distribution were unaffected. Peak levels of TNF and IL-6 activity occurred at 1 and 4 hours, respectively. IL-I activity was not detected in any group. AP clearance correlated strongly to circulating levels of IL-6 (r = -0.789, p = 0.0002). CONCLUSIONS: Our findings indicate that extrahepatic I-R injury can affect hepatic oxidative drug metabolism and this effect is mediated in part by circulating cytokines.


Assuntos
Antipirina/farmacocinética , Fígado/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Antipirina/sangue , Cães , Interleucina-1/sangue , Interleucina-6/sangue , Intestinos/irrigação sanguínea , Rim/irrigação sanguínea , Fígado/irrigação sanguínea , Masculino , Oxirredução , Fator de Necrose Tumoral alfa/análise
19.
Curr Top Microbiol Immunol ; 211: 259-68, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8585957

RESUMO

Translocations involving chromosome band 11q23, found in acute lymphoid and myeloid leukemias, disrupt the MLL gene. This gene encodes a putative transcription factor with regions of homology to several other proteins including the zinc fingers and other domains of the Drosophila trithorax gene product, and the "AT-hook" DNA-binding motif of high mobility group proteins. We have previously demonstrated that MLL contains transcriptional activation and repression domains using a GAL4 fusion protein system (21). The repression domain, which is capable of repressing transcription 3-5-fold, is located centromeric to the breakpoint region of MLL. The activation domain, located telomeric to the breakpoint region, activated transcription from a variety of promoters including ones containing only basal promoter elements. The level of activation was very high, ranging from 10-fold to more than 300-fold, depending on the promoter and cell line used for transient transfection. In translocations involving MLL, the protein produced from the der(11) chromosome which contains the critical junction for leukemogenesis includes the AT-hook domain and the repression domain. We assessed the DNA binding capability of the MLL AT-hook domain using bacterially expressed and purified AT-hook protein. In a gel mobility shift assay, the MLL AT-hook domain could bind cruciform DNA, recognizing structure rather than sequence of the target DNA. This binding could be specifically competed with Hoechst 33258 dye and with distamycin. In a nitrocellulose protein-DNA binding assay, the MLL AT-hook domain could bind to AT-rich SARs, but not to non-SAR DNA fragments. The role that the AT-hook binding to DNA may play in vivo is unclear, but it is likely that DNA binding could affect downstream gene regulation. The AT-hook domain retained on the der(11) would potentially recognize a different DNA target than the one normally recognized by the intact MLL protein. Furthermore, loss of an activation domain while retaining a repression domain on the der(11) chromosome could alter the expression of various downstream target genes, suggesting potential mechanisms of action for MLL in leukemia.


Assuntos
Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Proto-Oncogenes , Fatores de Transcrição , Sequência de Aminoácidos , DNA/química , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Histona-Lisina N-Metiltransferase , Humanos , Dados de Sequência Molecular , Proteína de Leucina Linfoide-Mieloide , Matriz Nuclear/metabolismo , Conformação de Ácido Nucleico , Ligação Proteica , Proteínas Recombinantes/metabolismo
20.
AIDS Care ; 7(2): 205-10, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-7619873

RESUMO

The present study examined the beliefs and attitudes which surround condoms and their use. Qualitative data in the form of short essays were collected from 12/13 (n = 148) and 16/17 (n = 63) year olds. The results suggest that condoms are conceptualized in terms of a complex set of factual and evaluative factors such as feelings, responsibility and risk and that younger subjects hold more positive beliefs than the older subjects. The results are discussed in terms of models of preventive behaviour and the role of sex education at an early age.


PIP: Students in a London secondary school completed questionnaires exploring their knowledge about and attitudes toward condom use. The first part of the questionnaire sought respondent information on demographic characteristics and beliefs about condoms, while a qualitative section encouraged participants to write free accounts of their knowledge of and beliefs about condoms and their use, imagining they were talking to a peer who does not know what they are or what they are used for. 87% of the 79 male and 91 female 12/13 year olds who completed the questionnaire completed the free account of their thoughts about condoms. Only 39.8% of the 85 male and 72 female 16/17 year olds who completed the questionnaire, however, also completed the essay section of the questionnaire. The older students were also surveyed about their sexual experience. 87 were virgins, 57 were non-virgins, and 13 gave no response in the section on sex behavior. While participants in both age groups had a good understanding of the factual aspects of condoms in terms of their function, where to buy them, and their use, the younger students were more positive about condoms than were the older students. The younger subjects perceived condoms as more fun and humorous, frequently using metaphors in their essays. This lighter attitude toward condoms could reflect a lack of personal sexual experience among younger students or indicate a change in social attitude which has been incorporated into the belief systems of younger cohorts. Overall, the study found adolescents' attitudes to be complex and dynamic, with individual participants having both positive and negative views about condoms. It is also clear that adolescents as young as 12 years old are not ignorant about sex and already have complex belief systems which should be taken into account when promoting safe sex. The authors note that since the most commonly cited function of condoms was to prevent pregnancy, the ability of condom use to protect against the transmission of HIV and other sexually transmitted diseases needs to stressed in intervention campaigns directed to such target audiences.


Assuntos
Preservativos , Conhecimentos, Atitudes e Prática em Saúde , Psicologia do Adolescente , Adolescente , Criança , Feminino , Humanos , Masculino , Prevenção Primária , Assunção de Riscos , Educação Sexual , Comportamento Sexual , Inquéritos e Questionários
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