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2.
Science ; 369(6510): 1497-1500, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32943524

RESUMO

Binary interactions dominate the evolution of massive stars, but their role is less clear for low- and intermediate-mass stars. The evolution of a spherical wind from an asymptotic giant branch (AGB) star into a nonspherical planetary nebula (PN) could be due to binary interactions. We observed a sample of AGB stars with the Atacama Large Millimeter/submillimeter Array (ALMA) and found that their winds exhibit distinct nonspherical geometries with morphological similarities to planetary nebulae (PNe). We infer that the same physics shapes both AGB winds and PNe; additionally, the morphology and AGB mass-loss rate are correlated. These characteristics can be explained by binary interaction. We propose an evolutionary scenario for AGB morphologies that is consistent with observed phenomena in AGB stars and PNe.

3.
Child Abuse Negl ; 103: 104442, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32163767

RESUMO

BACKGROUND: Children placed under governmental supervision and staying in residential or foster care are more vulnerable to violence than children who live with their own families. One specific group of children staying in reception facilities under governmental supervision comprises unaccompanied refugee children who have fled to a host country without their parents. OBJECTIVE: This qualitative study explores the experiences of unaccompanied children with regard to violence in reception facilities in the Netherlands from the perspective of the children. PARTICIPANTS AND SETTING: 183 unaccompanied children (N = 183) sheltered in a variety of reception facilities in the Netherlands. METHOD: Semi-structured interviews were conducted focusing on several topics related to their perceived quality of life. The transcripts of the interviews were analyzed for experiences with violence occurring inside the reception facilities. The codebook that was used was based on the categorization of maltreatment in the fourth United States National Incidence Study (NIS-4) and the interpretation of violence by the Committee on the Rights of the Child in General Comment No. 13 (GC 13). RESULTS: A large share (66 %) of the unaccompanied children had experienced violence in various reception facilities. Most of the experiences reported had to do with either physical and emotional abuse and neglect or institutional violence. CONCLUSION: The breadth of experiences of violence underlines the responsibility of the Dutch state to invest in the safe reception of unaccompanied children in order to protect their development, while also investing in further research on the prevalence of violence in the reception of unaccompanied children.


Assuntos
Maus-Tratos Infantis , Refugiados , Violência , Adolescente , Maus-Tratos Infantis/etnologia , Maus-Tratos Infantis/estatística & dados numéricos , Família , Feminino , Humanos , Masculino , Países Baixos , Pais , Qualidade de Vida , Refugiados/psicologia , Refugiados/estatística & dados numéricos , Violência/etnologia , Violência/psicologia , Violência/estatística & dados numéricos
4.
Trauma Violence Abuse ; 21(2): 242-260, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-29463187

RESUMO

The systematic review presented in this article aims to reveal what supports and hampers refugee children in telling their, often traumatic, life stories. This is important to ensure that migration decisions are based on reliable information about the children's needs for protection. A systematic review was conducted in academic journals, collecting all available scientific knowledge about the disclosure of life stories by refugee minors in the context of social work, guardianship, foster care, asylum procedures, mental health assessment, and therapeutic settings. The resulting 39 studies were thoroughly reviewed with reference to what factors aided or hampered the refugee children's disclosure of their life stories. The main barriers to disclosure were feelings of mistrust and self-protection from the side of the child and disrespect from the side of the host community. The facilitators for disclosing life stories were a positive and respectful attitude of the interviewer, taking time to build trust, using nonverbal methods, providing agency to the children, and involving trained interpreters. Social workers, mentors, and guardians should have time to build trust and to help a young refugee in revealing the life story before the minor is heard by the migration authorities. The lack of knowledge on how refugee children can be helped to disclose their experiences is a great concern because the decision in the migration procedure is based on the story the child is able to disclose.


Assuntos
Refugiados/psicologia , Autorrevelação , Adolescente , Criança , Pré-Escolar , Feminino , Acessibilidade aos Serviços de Saúde/normas , Humanos , Masculino , Confiança
5.
Child Indic Res ; 12(1): 331-351, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931020

RESUMO

Child-rearing practices and beliefs of what determines a 'good quality' of child-rearing differ across cultural contexts and more than one interpretation can be given to "a child's best interests". This study aims to examine the cultural factors that influence judgements of the quality of children's rearing environment, and the construct validity of the Best Interests of the Child-Questionnaire (BIC-Q) scale when used in the Western Balkans. In our research on migrant children who returned to Kosovo and Albania, the BIC-Q is used to assess the quality of the child-rearing environment from a local cultural perspective on child-rearing. To assess cultural differences in judgements of the child-rearing environment, we measured agreement through Cohen's kappa of BIC-Qs completed from a Western-Balkan and a Western-European perspective on child-rearing. The construct validity of the BIC-Q scale was assessed through a Mokken scale analysis. The findings show that - except for two items - there is substantial agreement between Western-European and Western-Balkan assessors regarding the direction of the judgement, i.e. if the scores on the child-rearing conditions are dichotomized (sufficient/insufficient). The judgements of the 'respect' and 'interest' conditions are sensitive to differences in the cultural or professional perspectives of the assessors. The findings of the Mokken scale analysis demonstrate a strong and reliable scale in the cultural context of the Western Balkans (H = .73; Rho = .97). Knowledge gained from using the BIC-Q to assess the living situation of returned migrant children in their countries of origin and insight into child-rearing standards provides input for the best interests of the child determination.

6.
Int J Law Psychiatry ; 59: 20-30, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29996984

RESUMO

Best Interests of the Child (BIC) assessments provide migration authorities with behavioral information about which interests of the child could be taken into account before a decision is made on the request for a residence permit. This study provides insight into the quality and outcomes of BIC assessments with 16 unaccompanied children (15-18 years) and 11 accompanied children (4-16 years) who have recently arrived in the Netherlands and requested asylum (N = 27). The results suggest that BIC assessments provide relevant information that enables assessors to determine the best interests of recently arrived refugee children. The inter-rater reliability of the BIC-Questionnaire, an instrument that evaluates the child-rearing environment and that is one of the components of the BIC assessment, was fairly good. The children in the sample had experienced a high number of stressful life events and a majority reported trauma related stress symptoms or other emotional problems. The quality of the child-rearing environment in the country of origin had protected their development insufficiently in the past and would not protect their development sufficiently in the future. The results show that in many cases forced return to the country of origin can put children's development at risk.


Assuntos
Proteção da Criança/psicologia , Refugiados/psicologia , Inquéritos e Questionários/normas , Criança , Feminino , Humanos , Acontecimentos que Mudam a Vida , Masculino , Países Baixos , Avaliação de Resultados em Cuidados de Saúde , Psicometria , Reprodutibilidade dos Testes , Meio Social
7.
Prostate Cancer Prostatic Dis ; 20(3): 251-258, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28374743

RESUMO

BACKGROUND: Extracellular vesicles (EVs) are a heterogeneous class of lipid bound particles shed by any cell in the body in physiological and pathological conditions. EVs play critical functions in intercellular communication. EVs can actively travel in intercellular matrices and eventually reach the circulation. They can also be released directly in biological fluids where they appear to be stable. Because the molecular content of EVs reflects the composition of the cell of origin, they have recently emerged as a promising source of biomarkers in a number of diseases. EV analysis is particularly attractive in cancer patients that frequently present with increased numbers of circulating EVs. METHODS: We sought to review the current literature on the molecular profile of prostate cancer-derived EVs in model systems and patient biological fluids in an attempt to draw some practical and universal conclusions on the use of EVs as a tool for liquid biopsy in clinical specimens. RESULTS: We discuss advantages and limitations of EV-based liquid biopsy approaches summarizing salient studies on protein, DNA and RNA. Several candidate biomarkers have been identified so far but these results are difficult to apply to the clinic. However, the field is rapidly moving toward the implementation of novel tools to isolate cancer-specific EVs that are free of benign EVs and extra-vesicular contaminants. This can be achieved by identifying markers that are exquisitely present in tumor cell-derived EVs. An important contribution might also derive from a better understanding of EV types that may play specific functions in tumor progression and that may be a source of cancer-specific markers. CONCLUSIONS: EV analysis holds strong promises for the development of non-invasive biomarkers in patients with prostate cancer. Implementation of modern methods for EV isolation and characterization will enable to interrogate circulating EVs in vivo.


Assuntos
Biomarcadores Tumorais/metabolismo , Vesículas Extracelulares/metabolismo , Neoplasias da Próstata/diagnóstico , Ácidos Nucleicos Livres/sangue , Humanos , Biópsia Líquida , Masculino , Células Neoplásicas Circulantes , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia
8.
Astron Astrophys ; 5972017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-28190887

RESUMO

Yellow hypergiants are rare and represent a fast evolutionary stage of massive evolved stars. That evolutionary phase is characterised by a very intense mass loss, the understanding of which is still very limited. Here we report ALMA Compact Array observations of a 50″-mosaic toward the Fried Egg nebula, around one of the few Galactic yellow hypergiants IRAS 17163-3907. The emission from the 12CO J=2-1 line, H30α recombination line, and continuum is imaged at a resolution of ~8″, revealing the morphology of the molecular environment around the star. The continuum emission is unresolved and peaks at the position of the star. The radio recombination line H30α shows unresolved emission at the star, with an approximately gaussian spectrum centered on a velocity of 21±3 km s-1 with a width of 57±6 km s-1. In contrast, the CO 2-1 emission is complex and decomposes into several components beyond the contamination from interstellar gas in the line of sight. The CO spectrum toward the star is a broad plateau, centered at the systemic velocity of +18 km s-1 and with an expansion velocity of 100±10 km s-1. Assuming isotropic and constant mass-loss, we estimate a mass-loss rate of 8±1.5 ×10-5 M⊙ yr-1. At a radius of 25″ from the star, we detect CO emission associated with the dust ring previously imaged by Herschel. The kinematics of this ring, however, is not consistent with an expanding shell, but show a velocity gradient of vsys ±20 km s-1. In addition, we find a puzzling bright feature radially connecting the star to the CO ring, at a velocity of +40 km s-1 relative to the star. This spur feature may trace a unidirectional ejection event from the star. Our ACA observations reveal the complex morphology around IRAS 17163 and illustrate the breakthroughs that ALMA will bring to the field of massive stellar evolution.

9.
Astron Astrophys ; 6002017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31844330

RESUMO

CONTEXT: Born-again stars offer us a unique possibility of studying the evolution of the circumstellar envelope of evolved stars in human timescales. To present, most of the observations of the circumstellar material in these stars have been limited to study the relatively hot gas and dust. In other evolved stars, the emission from rotational transitions of molecules, such as CO, is commonly used to study the cool component of their circumstellar envelopes. Thus, the detection and study of molecular gas in born-again stars would be of great importance to understand their composition and chemical evolution. In addition, the molecular emission would be an invaluable tool to explore the physical conditions, kinematics and formation of asymmetric structures in the circumstellar envelopes of these evolved stars. However, until now, all attempts to detect molecular emission from the cool material around born-again stars have failed. AIMS: We searched for emission from rotational transitions of molecules in the hydrogen-deficient circumstellar envelopes of born-again stars to explore the chemical composition, kinematics, and physical parameters of the relatively cool gas. METHODS: We carried out observations using the APEX and IRAM 30m telescopes to search for molecular emission toward four well studied born-again stars, V4334 Sgr, V605 Aql, A30 and A78, that are thought to represent an evolutionary sequence. RESULTS: We detected for the first time emission from HCN and H13CN molecules toward V4334 Sgr, and CO emission in V605 Aql. No molecular emission was detected above the noise level toward A30 and A78. The detected lines exhibit broad linewidths ≳150 km s-1, which indicates that the emission comes from gas ejected during the born-again event, rather than from the old planetary nebula. A first estimate of the H12CN/H13CN abundance ratio in the circumstellar environment of V4334 Sgr is ≈3, which is similar to the value of the 12C/13C ratio measured from other observations. We derived a rotational temperature of T rot=13±1 K, and a total column density of N HCN=1.6±0.1×1016 cm-2 for V4334 Sgr. This result sets a lower limit on the amount of hydrogen that was ejected into the wind during the born-again event of this source. For V605 Aql, we obtained a lower limit for the integrated line intensities I 12C/I 13C>4.

10.
Clin Child Fam Psychol Rev ; 19(3): 185-203, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27389604

RESUMO

Decision-making regarding an asylum request of a minor requires decision-makers to determine the best interests of the child when the minor is relatively unknown. This article presents a systematic review of the existing knowledge of the situation of recently arrived refugee children in the host country. This research is based on the General Comment No. 14 of UN Committee on the Rights of the Child. It shows the importance of knowing the type and number of stressful life events a refugee child has experienced before arrival, as well as the duration and severity of these events. The most common mental health problems children face upon arrival in the host country are PTSD, depression and various anxiety disorders. The results identify the relevant elements of the best interests of the child assessment, including implications for procedural safeguards, which should promote a child rights-based decision in the asylum procedure.


Assuntos
Direitos Civis/legislação & jurisprudência , Acontecimentos que Mudam a Vida , Refugiados/legislação & jurisprudência , Refugiados/psicologia , Nações Unidas/legislação & jurisprudência , Criança , Humanos
11.
Sci Rep ; 5: 12635, 2015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-26271202

RESUMO

Current methods for detecting disseminated tumor cells in the skeleton are limited by expense and technical complexity. We describe a simple and inexpensive method to quantify, with single cell sensitivity, human metastatic cancer in the mouse skeleton, concurrently with host gene expression, using TRIzol-based DNA/RNA extraction and Alu sequence qPCR amplification. This approach enables precise quantification of tumor cells and corresponding host gene expression during metastatic colonization in xenograft models.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Perfilação da Expressão Gênica/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Elementos Alu/genética , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Marcadores Genéticos/genética , Guanidinas/química , Camundongos , Camundongos Nus , Fenóis/química , RNA Neoplásico/genética , RNA Neoplásico/isolamento & purificação , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
12.
Int J Law Psychiatry ; 36(2): 129-35, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23410917

RESUMO

The Best Interest of the Child Questionnaire (BIC-Q) is an instrument to measure the quality of the childrearing environment. We used a sample of asylum-seeking children (N=79) in the Netherlands to determine the relationship between the quality of the childrearing environment and the child's internalizing behavioural problems. In decisions as to whether asylum-seeking children may remain in the Netherlands or must return to their country of origin, those in favour of the child's positive development are in line with the Convention on the Rights of the Child. The aim of the present study is to determine the criterion-related validity of the BIC-Q using internalizing behavioural problems as criteria. In the case of good predictive validity, this instrument might be a suitable tool in judicial decision-making with respect to a possible change in an asylum-seeking child's place of residence. We investigated the criterion-related validity of the BIC-Q using logistical regression analysis and an ROC-curve to determine the relation between the quality of the childrearing environment and the child's internalizing behavioural problems. Logistic regression analysis showed that the current quality of the childrearing environment is negatively related to the risk of internalizing behavioural problems in children. The ROC shows that 81% of the children are correctly predicted whether they have internalizing behavioural problems or not. For seven conditions, the sum of the sensitivity and specificity was at a maximum (.75 and .71, respectively).


Assuntos
Defesa da Criança e do Adolescente/legislação & jurisprudência , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/psicologia , Educação Infantil/psicologia , Proteção da Criança/legislação & jurisprudência , Técnicas de Apoio para a Decisão , Emigrantes e Imigrantes/legislação & jurisprudência , Emigrantes e Imigrantes/psicologia , Controle Interno-Externo , Refugiados/legislação & jurisprudência , Refugiados/psicologia , Meio Social , Inquéritos e Questionários , Adolescente , Criança , Proteção da Criança/psicologia , Pré-Escolar , Estudos Transversais , Feminino , Cuidados no Lar de Adoção/legislação & jurisprudência , Cuidados no Lar de Adoção/psicologia , Humanos , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/psicologia , Países Baixos , Estudos Prospectivos , Psicometria , Reprodutibilidade dos Testes , Fatores de Risco , Adulto Jovem
13.
Behav Sci Law ; 30(6): 841-55, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22311710

RESUMO

The Best Interest of the Child Questionnaire (BIC-Q) has been designed as an instrument for screening the quality of the rearing situation of asylum-seeking or refugee children. It is intended to aid legal decisions in asylum procedures. The aim of this study was to determine the reliability and the construct validity of the BIC-Q. Based on a study sample of refugee or asylum-seeking children in the Netherlands (N = 74), the psychometric quality of the BIC-Q was investigated using Cohen's kappa for the inter- and intrarater reliability and a nonparametric item response model for the construct validity. The interrater and intrarater reliabilities of the BIC-Q were good (kappa = .65 and .74 respectively). The results of the item response model revealed that the 14 pedagogical environmental conditions formed a strong and valid measurement scale for the quality of the childrearing environment (H = .55; rho = .94). Preliminary results indicate that the BIC-Q may be applied to support decisions on where the asylum-seeking or refugee child has the best opportunities for development.


Assuntos
Defesa da Criança e do Adolescente , Educação Infantil , Refugiados , Inquéritos e Questionários/normas , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Humanos , Lactente , Países Baixos , Estudos Prospectivos , Psicometria , Adulto Jovem
14.
Z Gerontol Geriatr ; 43(4): 224-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20814797

RESUMO

Progressive supranuclear palsy (PSP) is a neurodegenerative disease with no sufficient treatment options to date. The most devastating symptom is the loss of balance with consecutive falls. Based on the observation that postural control improved in patients with vestibular dysfunction after audio-biofeedback training, we tested the effects of this training in PSP patients. Eight PSP patients were included into an uncontrolled 6-week intervention trial. The focus of the training was the improvement of posture and dynamic balance by using audio-biofeedback. The device was well accepted. No adverse events occurred. A significant improvement in the Berg Balance Scale was observed (T2 vs. T1, p=0.016), which remained significant at the 4-week follow-up (T3 vs. T1, p=0.008). Significant improvement of the Parkinson's disease questionnaire was demonstrated. No significant changes were found in the Timed Up-and-Go Test, the Five Chair Rise Test, and in specific clinical scales. To our knowledge, the present study is the first to demonstrate that audio-biofeedback training with PSP patients is associated with improvements of balance and psychosocial aspects.


Assuntos
Biorretroalimentação Psicológica/instrumentação , Computadores de Mão , Equilíbrio Postural/fisiologia , Transtornos de Sensação/reabilitação , Terapia Assistida por Computador/instrumentação , Estimulação Acústica , Idoso , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Limitação da Mobilidade , Exame Neurológico , Transtornos de Sensação/fisiopatologia , Paralisia Supranuclear Progressiva/fisiopatologia , Paralisia Supranuclear Progressiva/reabilitação , Inquéritos e Questionários
15.
Science ; 323(5912): 353-5, 2009 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-19150838

RESUMO

Interstellar dust plays a crucial role in the evolution of galaxies. It governs the chemistry and physics of the interstellar medium. In the local universe, dust forms primarily in the ejecta from stars, but its composition and origin in galaxies at very early times remain controversial. We report observational evidence of dust forming around a carbon star in a nearby galaxy with a low abundance of heavy elements, 25 times lower than the solar abundance. The production of dust by a carbon star in a galaxy with such primitive abundances raises the possibility that carbon stars contributed carbonaceous dust in the early universe.

16.
Gerontology ; 54(1): 40-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18460873

RESUMO

BACKGROUND: The Prevention of Falls Network Europe (ProFaNE) aims to bring together European researchers and clinicians to focus on the development of effective falls prevention programs for older people. One of the objectives is to identify suitable balance assessment tools. Assessment procedures that combine a balance task with a cognitive task may be relevant since part of all falls occurs during dual-task performance of walking or other balance activities. OBJECTIVE: To evaluate whether dual-task balance assessments are more sensitive than single balance tasks in predicting falls and detecting changes in balance performance after fall interventions. METHODS: A systematic literature search was performed in the databases PubMed, EMBASE, CINAHL, AMED, PsycINFO and Cochrane. Articles were selected according to the following inclusion criteria: (1) population: older adults (mean age > or =65 years), (2) assessment tool: dual task combining gait or other balance task with a cognitive task, (3) design: prospective or retrospective data collection of falls, or intervention study. Analysis of papers focused on measures of predictive ability or sensitivity-to-change for both tasks during dual-task performance as well as for the single balance and cognitive task. RESULTS: Out of 114 dual-task studies in older people, 19 articles matched the inclusion criteria. Fourteen studies had sample sizes of 60 subjects or less; the studied populations, task combinations as well as other methodological aspects varied. None of the articles reported the same statistical measures for both tasks during dual-task performance as well as single balance and cognitive task. In two studies with prospective data collection of falls, higher odds ratios were found for the dual compared to the single balance task. CONCLUSIONS: Upon the available literature, conclusions for an added value of dual balance tasks for fall prediction or assessing fall intervention effects cannot be made due to incomplete comparisons of single and dual balance tasks. Nevertheless, two studies do provide an indication that dual balance tasks may have added value for fall prediction.


Assuntos
Acidentes por Quedas/prevenção & controle , Equilíbrio Postural , Análise e Desempenho de Tarefas , Idoso , Idoso de 80 Anos ou mais , Atenção , Avaliação Geriátrica , Humanos , Valor Preditivo dos Testes , Caminhada
17.
Eur J Dent Educ ; 11(1): 2-9, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17227389

RESUMO

The Academic Centre for Dentistry Amsterdam introduced a fully renewed 5-year dental curriculum in September 2003. In this article, the educational principles and didactic choices that form the basis of the curriculum development are presented and attention is given to the process of development and the implementation strategy that constitute such an important part of the success of introducing a new curriculum. Special characteristics of the new curriculum are the clinical training practice, professional conduct, the elective profiles and academic education. In clinical practice, groups of students from different levels run a group practice in which they learn to work together, delegate tasks, solve clinical problems and apply evidence-based dentistry. In the new curriculum students learn to conduct themselves as professionals. In the third and in the fifth year, students choose an elective profile oriented, respectively, on research and on clinical knowledge and skills. Academic education is an important spearhead in this curriculum in which students not only learn why research is important to dentistry but also how dentists can use research to their own benefit. In development and implementation, a stepwise approach was used in which as many people as logistically possible were involved.


Assuntos
Currículo , Educação em Odontologia/métodos , Faculdades de Odontologia , Educação Baseada em Competências , Humanos , Países Baixos , Inovação Organizacional , Aprendizagem Baseada em Problemas , Desenvolvimento de Programas
18.
J Immunol ; 176(8): 4543-52, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16585544

RESUMO

Bruton's tyrosine kinase (Btk) and the adapter protein SLP-65 (Src homology 2 domain-containing leukocyte-specific phosphoprotein of 65 kDa) transmit precursor BCR (pre-BCR) signals that are essential for efficient developmental progression of large cycling into small resting pre-B cells. We show that Btk- and SLP-65-deficient pre-B cells have a specific defect in Ig lambda L chain germline transcription. In Btk/SLP-65 double-deficient pre-B cells, both kappa and lambda germline transcripts are severely reduced. Although these observations point to an important role for Btk and SLP-65 in the initiation of L chain gene rearrangement, the possibility remained that these signaling molecules are only required for termination of pre-B cell proliferation or for pre-B cell survival, whereby differentiation and L chain rearrangement is subsequently initiated in a Btk/SLP-65-independent fashion. Because transgenic expression of the antiapoptotic protein Bcl-2 did not rescue the developmental arrest of Btk/SLP-65 double-deficient pre-B cells, we conclude that defective L chain opening in Btk/SLP-65-deficient small resting pre-B cells is not due to their reduced survival. Next, we analyzed transgenic mice expressing the constitutively active Btk mutant E41K. The expression of E41K-Btk in Ig H chain-negative pro-B cells induced 1) surface marker changes that signify cellular differentiation, including down-regulation of surrogate L chain and up-regulation of CD2, CD25, and MHC class II; and 2) premature rearrangement and expression of kappa and lambda light chains. These findings demonstrate that Btk and SLP-65 transmit signals that induce cellular maturation and Ig L chain rearrangement independently of their role in termination of pre-B cell expansion.


Assuntos
Linfócitos B/imunologia , Proteínas de Transporte/imunologia , Rearranjo Gênico de Cadeia Leve de Linfócito B , Fosfoproteínas/imunologia , Proteínas Tirosina Quinases/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Tirosina Quinase da Agamaglobulinemia , Animais , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Sequência de Bases , Proteínas de Transporte/genética , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , DNA Complementar/genética , Interleucina-7/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Proteínas Tirosina Quinases/deficiência , Proteínas Tirosina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica
19.
Blood ; 105(1): 259-65, 2005 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-15331445

RESUMO

During B-cell development in the mouse, Bruton tyrosine kinase (Btk) and the adaptor protein SLP-65 (Src homology 2 [SH2] domain-containing leukocyte protein of 65 kDa) limit the expansion and promote the differentiation of pre-B cells. Btk is thought to mainly function by phosphorylating phospholipase Cgamma2, which is brought into close proximity of Btk by SLP-65. However, this model was recently challenged by the identification of a role for Btk as a tumor suppressor in the absence of SLP-65 and by the finding that Btk function is partially independent of its kinase activity. To investigate if enzymatic activity is critical for the tumor suppressor function of Btk, we crossed transgenic mice expressing the kinase-inactive K430R-Btk mutant onto a Btk/SLP-65 double-deficient background. We found that K430R-Btk expression rescued the severe developmental arrest at the pre-B-cell stage in Btk/SLP-65 double-deficient mice. Moreover, K430R-Btk could functionally replace wild-type Btk as a tumor suppressor in SLP-65- mice: at 6 months of age, the observed pre-B-cell lymphoma frequencies were approximately 15% for SLP-65- mice, 44% for Btk/SLP-65-deficient mice, and 14% for K430R-Btk transgenic mice on the Btk/SLP-65-deficient background. Therefore, we conclude that Btk exerts its tumor suppressor function in pre-B cells as an adaptor protein, independent of its catalytic activity.


Assuntos
Linfoma de Células B/enzimologia , Linfoma de Células B/patologia , Proteínas Tirosina Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Tirosina Quinase da Agamaglobulinemia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Cálcio/metabolismo , Sinalização do Cálcio , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Catálise , Diferenciação Celular , Células Cultivadas , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Lisina/genética , Lisina/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosfotirosina/metabolismo , Proteínas Tirosina Quinases/deficiência , Proteínas Tirosina Quinases/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Taxa de Sobrevida
20.
Prenat Diagn ; 22(11): 966-72, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12424757

RESUMO

OBJECTIVES: This study concerns the possible effect of practice of prenatal screening of congenital anomalies followed by termination of pregnancy on the perinatal mortality between European countries. METHODS: Data of nine region-specific EUROCAT registries from five European countries were used to compare the pregnancy termination rate and perinatal mortality due to congenital anomalies between the registries. The impact of pregnancy terminations on the perinatal mortality rate was estimated using a calculated lethality for each congenital anomaly in the hypothetical case that no pregnancy terminations had been performed and was expressed in the 'natural' perinatal mortality rate. RESULTS: There are large differences between the EUROCAT registries in the number of pregnancy terminations for congenital anomalies. The difference between the 'natural' and regular perinatal mortality rate vary between 3.7 and 14.1 per 10 000 live births and stillbirths. The difference is greater in regions where prenatal screening is more common than in regions where this is not common. CONCLUSION: Differences in practice of prenatal screening and termination of pregnancy of congenital anomalies contribute to the variations in the overall perinatal mortality rate between European regions and countries.


Assuntos
Aborto Eugênico/estatística & dados numéricos , Anormalidades Congênitas/mortalidade , Mortalidade Infantil/tendências , Diagnóstico Pré-Natal , Aborto Eugênico/tendências , Adulto , Anormalidades Congênitas/diagnóstico , Feminino , Humanos , Recém-Nascido , Programas de Rastreamento , Países Baixos/epidemiologia , Gravidez , Sistema de Registros , Fatores de Risco , Taxa de Sobrevida
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