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1.
Genet Med ; 23(11): 2087-2095, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34262154

RESUMO

PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.


Assuntos
Ataxia Telangiectasia , Melanoma , Proteínas Mutadas de Ataxia Telangiectasia/genética , Austrália , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Melanoma/genética
2.
Handb Exp Pharmacol ; 220: 121-64, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24668472

RESUMO

The p75 neurotrophin receptor (p75(NTR)) regulates a wide range of cellular functions, including programmed cell death, axonal growth and degeneration, cell proliferation, myelination, and synaptic plasticity. The multiplicity of cellular functions governed by the receptor arises from the variety of ligands and co-receptors which associate with p75(NTR) and regulate its signaling. P75(NTR) promotes survival through interactions with Trk receptors, inhibits axonal regeneration via partnerships with Nogo receptor (Nogo-R) and Lingo-1, and promotes apoptosis through association with Sortilin. Signals downstream of these interactions are further modulated through regulated intramembrane proteolysis (RIP) of p75(NTR) and by interactions with numerous cytosolic partners. In this chapter, we discuss the intricate signaling mechanisms of p75(NTR), emphasizing how these signals are differentially regulated to mediate these diverse cellular functions.


Assuntos
Receptor de Fator de Crescimento Neural/fisiologia , Transdução de Sinais/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Animais , Apoptose , Ciclo Celular , Sobrevivência Celular , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Bainha de Mielina/fisiologia , NF-kappa B/fisiologia , Plasticidade Neuronal , Precursores de Proteínas/fisiologia , Receptor de Fator de Crescimento Neural/química , Receptor trkA/fisiologia
3.
Cell Death Differ ; 15(12): 1921-9, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18772898

RESUMO

NRAGE (also known as Maged1, Dlxin) is a member of the MAGE gene family that may play a role in the neuronal apoptosis that is regulated by the p75 neurotrophin receptor (p75NTR). To test this hypothesis in vivo, we generated NRAGE knockout mice and found that NRAGE deletion caused a defect in developmental apoptosis of sympathetic neurons of the superior cervical ganglia, similar to that observed in p75NTR knockout mice. Primary sympathetic neurons derived from NRAGE knockout mice were resistant to apoptosis induced by brain-derived neurotrophic factor (BDNF), a pro-apoptotic p75NTR ligand, and NRAGE-deficient sympathetic neurons show attenuated BDNF-dependent JNK activation. Hair follicle catagen is an apoptosis-like process that is dependent on p75NTR signaling; we show that NRAGE and p75NTR show regulated co-expression in the hair follicle and that identical defects in hair follicle catagen are present in NRAGE and p75NTR knockout mice. Interestingly, NRAGE knockout mice have severe defects in motoneuron apoptosis that are not observed in p75NTR knockout animals, raising the possibility that NRAGE may facilitate apoptosis induced by receptors other than p75NTR. Together, these studies demonstrate that NRAGE plays an important role in apoptotic-signaling in vivo.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Proteínas de Neoplasias/metabolismo , Receptor de Fator de Crescimento Neural/metabolismo , Animais , Fertilidade , Marcação de Genes , Folículo Piloso/crescimento & desenvolvimento , Folículo Piloso/patologia , Camundongos , Camundongos Knockout , Neurônios Motores/citologia , Mutação/genética , Proteínas de Neoplasias/deficiência , Sistema Nervoso Simpático/citologia , Gânglio Trigeminal/anormalidades
4.
J Cell Biol ; 158(3): 453-61, 2002 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-12163468

RESUMO

Sympathetic neurons depend on NGF binding to TrkA for their survival during vertebrate development. NGF deprivation initiates a transcription-dependent apoptotic response, which is suggested to require activation of the transcription factor c-Jun. Similarly, apoptosis can also be induced by selective activation of the p75 neurotrophin receptor. The transcriptional dependency of p75-mediated cell death has not been determined; however, c-Jun NH2-terminal kinase has been implicated as an essential component. Because the c-jun-null mutation is early embryonic lethal, thereby hindering a genetic analysis, we used the Cre-lox system to conditionally delete this gene. Sympathetic neurons isolated from postnatal day 1 c-jun-floxed mice were infected with an adenovirus expressing Cre recombinase or GFP and analyzed for their dependence on NGF for survival. Cre immunopositive neurons survived NGF withdrawal, whereas those expressing GFP or those uninfected underwent apoptosis within 48 h, as determined by DAPI staining. In contrast, brain-derived neurotrophic factor (BDNF) binding to p75 resulted in an equivalent level of apoptosis in neurons expressing Cre, GFP, and uninfected cells. Nevertheless, cycloheximide treatment prevented BDNF-mediated apoptosis. These results indicate that whereas c-jun is required for apoptosis in sympathetic neurons on NGF withdrawal, an alternate signaling pathway must be induced on p75 activation.


Assuntos
Apoptose/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Fator de Crescimento Neural/deficiência , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-jun/deficiência , Receptor de Fator de Crescimento Neural/metabolismo , Gânglio Cervical Superior/embriologia , Animais , Apoptose/efeitos dos fármacos , Sequência de Bases/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Células Cultivadas , Cicloeximida/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Vetores Genéticos/genética , Proteínas de Fluorescência Verde , Imuno-Histoquímica , Indicadores e Reagentes , Integrases/genética , Proteínas Luminescentes , Camundongos , Camundongos Knockout , Mutação/efeitos dos fármacos , Mutação/fisiologia , Fator de Crescimento Neural/genética , Neurônios/citologia , Neurônios/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Proteínas Proto-Oncogênicas c-jun/genética , Receptor de Fator de Crescimento Neural/efeitos dos fármacos , Gânglio Cervical Superior/citologia , Gânglio Cervical Superior/crescimento & desenvolvimento , Transfecção , Proteínas Virais/genética
5.
J Biol Chem ; 275(11): 7558-65, 2000 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-10713062

RESUMO

Recent evidence indicates that nerve growth factor (NGF) produces its effects through signaling contributions from both TrkA and the p75 receptor. In contrast to its trophic actions through TrkA, NGF binding to p75 has been shown to activate programmed cell death through a mechanism involving the stress kinase JNK. However, this receptor also activates nuclear factor kappaB (NF-kappaB), the role of which has yet to be determined. We investigated the function of p75-mediated NF-kappaB stimulation in regulating cell survival in the rat schwannoma cell line RN22, which expresses p75, but not TrkA. Gel shift assays demonstrated activation of NF-kappaB in response to NGF within 30 min and lasting at least 4 h. NGF also stimulated JNK in the cells (detected by in vitro kinase assays) with a similar time course. Preventing activation of NF-kappaB with the specific inhibitor SN50 resulted in NGF-induced cell loss. Similarly, transfection of the cells with a mutant form of the endogenous NF-kappaB inhibitor (IkappaBalphaDeltaN), which cannot be degraded and therefore remains bound to NF-kappaB, preventing its activation, resulted in a significant increase in the number of apoptotic cells following NGF treatment. These results suggest that NGF activation of NF-kappaB through the p75 receptor promotes survival, counterbalancing the pro-apoptotic signal.


Assuntos
Apoptose/fisiologia , NF-kappa B/metabolismo , Fator de Crescimento Neural/metabolismo , Neurilemoma/metabolismo , Receptor de Fator de Crescimento Neural/metabolismo , Animais , Transporte Biológico , Núcleo Celular/metabolismo , Ativação Enzimática , Proteínas Quinases JNK Ativadas por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , Peptídeos/farmacologia , Ratos , Transdução de Sinais , Células Tumorais Cultivadas
6.
Pediatrics ; 103(5 Pt 1): 975-9, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10224175

RESUMO

OBJECTIVE: To determine if psychological morbidity in youth with chronic fatigue is caused by the stress of coping with a chronic illness. STUDY DESIGN: Case-control study comparing pediatric patients with debilitating chronic fatigue and matched subjects with juvenile rheumatoid arthritis, a chronic medical illness with similar functional sequelae. SETTING: Pediatric Infectious Diseases Clinic and Juvenile Rheumatoid Arthritis Clinic of Kosair Children's Hospital. PARTICIPANTS: Nineteen children and adolescents with debilitating chronic fatigue and 19 age- and sex-matched peers with juvenile rheumatoid arthritis. Outcome. Structured Interview, Kaufman Brief Intelligence Test, Child Behavior Checklist, and Youth Self-Report. RESULTS: Intellectual functioning on the Kaufman Brief Intelligence Test Composite was average (103, standard score) for both groups. Pediatric patients with chronic fatigue had higher levels of internalizing psychological distress than patients suffering from juvenile rheumatoid arthritis, despite the fact that both groups had a similar pattern of decline in social and physical activities. Duration of illness did not explain the difference in psychological symptoms. CONCLUSIONS: Psychological factors may play a more active role in debilitating chronic fatigue in pediatric patients than can be explained by the stress of coping with a similar chronic, non-life-threatening illness.


Assuntos
Artrite Juvenil/psicologia , Síndrome de Fadiga Crônica/psicologia , Adaptação Psicológica , Adolescente , Estudos de Casos e Controles , Criança , Feminino , Humanos , Testes de Inteligência , Masculino , Testes Psicológicos , Estresse Psicológico
7.
J Pediatr Health Care ; 12(4): 196-202, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9832734

RESUMO

INTRODUCTION: Marital adjustment, family characteristics, and parent-child stress and compliance with treatment were investigated in 41 families with a preadolescent child (age 3 to 11 years) who had cystic fibrosis (CF). METHOD: Mothers completed the Dyadic Adjustment Scale, the Family Adaptability and Cohesion Evolution Scale, and the short form of the Parenting Stress Index. Parents and medical staff completed questionnaires assessing the child's compliance with diet/nutritional intake, vitamins, pancreatic enzymes, other medications (such as oral antibiotics), and chest physiotherapy. RESULTS: Preadolescents with CF were viewed as generally cooperative with most aspects of treatment. Parental ratings of compliance with dietary and nutritional intake were associated with increased marital consensus and decreased parenting stress. Medical staff ratings of dietary compliance, medication compliance, and chest physiotherapy compliance were associated with lower parenting stress. DISCUSSION: Parent-child stress and lack of agreement between parents is associated with problems in compliance with treatment, which may have an adverse impact on the disease and health status of the child with CF.


Assuntos
Fibrose Cística/prevenção & controle , Fibrose Cística/psicologia , Relações Mãe-Filho , Cooperação do Paciente/psicologia , Adaptação Psicológica , Adulto , Criança , Pré-Escolar , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Nível de Saúde , Humanos , Estresse Psicológico/psicologia , Inquéritos e Questionários
8.
Nature ; 383(6602): 716-9, 1996 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-8878481

RESUMO

Members of the nerve growth factor (NGF) family promote the survival of neurons during development. NGF specifically activates the receptor trkA, initiating a signal transduction cascade which ultimately blocks cell death. Here we show that NGF can have the opposite effect, inducing the death of mature oligodendrocytes cultured from postnatal rat cerebral cortex. This effect was highly specific, because NGF had no effect on oligodendrocyte precursors and astrocytes. Other neurotrophins such as brain-derived neurotrophin factor (BDNF) and neurotrophin-3 (NT-3) did not induce cell death. NGF binding to mature oligodendrocytes expressing the p75 neurotrophin receptor, but not trkA, resulted in a sustained increase of intracellular ceramide and c-Jun amino-terminal kinase (JNK) activity, which are thought to participate in a signal transduction pathway leading to cell death. Taken together, these results indicate that NGF has the ability to promote cell death in specific cell types through a ligand-dependent signalling mechanism involving the p75 neurotrophin receptor.


Assuntos
Apoptose , Proteínas Quinases Ativadas por Mitógeno , Fatores de Crescimento Neural/metabolismo , Oligodendroglia/fisiologia , Receptores de Fator de Crescimento Neural/metabolismo , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Ceramidas/metabolismo , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Ativação Enzimática , Proteínas Quinases JNK Ativadas por Mitógeno , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Receptores Proteína Tirosina Quinases/metabolismo , Receptor de Fator de Crescimento Neural , Receptor trkA , Transdução de Sinais
9.
EMBO J ; 15(13): 3332-7, 1996 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-8670834

RESUMO

The trkB gene codes for a receptor tyrosine kinase, which is essential for the development of the peripheral nervous system. This receptor can be activated by three different neurotrophins: BDNF, NT-4/5 and NT-3. The extracellular domain of trkB was found to be encoded in 10 exons corresponding to receptor subdomains previously identified on the basis of protein sequence comparisons. Exon 9 was skipped in a novel tyrosine kinase transcript of the trkB gene, designated ctrkB-Short (ctrkB-S). While the previously described trkB receptor ctrkB-Long (ctrkB-L) and trkB-S receptors were activated similarly by BDNF, trkB-S interacted poorly with NT-4/5 and NT-3 as measured by ligand binding, ligand-induced autophosphorylation and ligand-dependent activation of p21ras. Efficient activation of ctrkB-S by NT-3 was restored by a single amino acid replacement in NT-3 (D15A). Both trkB-L and trkB-S transcripts were detected in embryonic neurons.


Assuntos
Processamento Alternativo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Animais , Sequência de Bases , Fator Neurotrófico Derivado do Encéfalo , Sistema Nervoso Central/metabolismo , Embrião de Galinha , DNA Complementar , Éxons , Ligantes , Camundongos , Dados de Sequência Molecular , Proteína Oncogênica p21(ras)/metabolismo , Sistema Nervoso Periférico , Fosforilação , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptor do Fator Neutrófico Ciliar , Especificidade por Substrato
10.
Science ; 272(5261): 542-5, 1996 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-8614802

RESUMO

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) selectively bind to distinct members of the Trk family of tyrosine kinase receptors, but all three bind with similar affinities to the neurotrophin receptor p75 (p75NTR). The biological significance of neurotrophin binding to p75NTR in cells that also express Trk receptors has been difficult to ascertain. In the absence of TrkA, NGF binding to p75NGR activated the transcription factor nuclear factor kappa B (NF-kappa B) in rat Schwann cells. This activation was not observed in Schwann cells isolated from mice that lacked p75NTR. The effect was selective for NGF; NF-kappa B was not activated by BDNF or NT-3.


Assuntos
NF-kappa B/metabolismo , Fatores de Crescimento Neural/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Células de Schwann/metabolismo , Transdução de Sinais/fisiologia , Animais , Sequência de Bases , Fator Neurotrófico Derivado do Encéfalo , Núcleo Celular/metabolismo , Células Cultivadas , DNA/metabolismo , Células L , Camundongos , Dados de Sequência Molecular , Fatores de Crescimento Neural/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Neurotrofina 3 , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Receptores Proteína Tirosina Quinases/metabolismo , Receptor de Fator de Crescimento Neural , Receptor trkA
11.
J Dev Behav Pediatr ; 17(1): 16-21, 1996 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8675709

RESUMO

A battery of self-report questionnaires and structured diagnostic interviews was administered to 20 children and adolescents who presented to a pediatric specialty clinic with chronic fatigue. Matched groups of healthy and depressed control subjects (aged 8 to 19 years) were also studied. Criteria were established to identify those items in the assessment battery that reliably differentiated among the three groups. Analysis of item content suggested several clusters of characteristics that discriminated among the subject groups, including life changes, cognitive difficulties, negative self-attributions, social relationship disruption, and somatic symptom presentation. The results suggest that certain psychological factors can discriminate chronic fatigue from depressive symptomatology, as well as normal functioning. Items discriminating among groups are presented in an organized questionnaire format to assist with the understanding and assessment of pediatric chronic fatigue cases.


Assuntos
Sintomas Afetivos/diagnóstico , Transtornos do Comportamento Infantil/diagnóstico , Síndrome de Fadiga Crônica/diagnóstico , Adolescente , Sintomas Afetivos/complicações , Sintomas Afetivos/psicologia , Criança , Transtornos do Comportamento Infantil/complicações , Transtornos do Comportamento Infantil/psicologia , Diagnóstico Diferencial , Síndrome de Fadiga Crônica/etiologia , Síndrome de Fadiga Crônica/psicologia , Feminino , Humanos , Acontecimentos que Mudam a Vida , Masculino , Equipe de Assistência ao Paciente , Determinação da Personalidade , Autoimagem , Papel do Doente , Transtornos Somatoformes/complicações , Transtornos Somatoformes/diagnóstico , Transtornos Somatoformes/psicologia
13.
J Biol Chem ; 270(37): 21751-7, 1995 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-7665594

RESUMO

Neurotrophins activate the Trk tyrosine kinase receptors, which subsequently initiate signaling pathways that have yet to be fully resolved, resulting in neuronal survival and differentiation. The ability of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) to activate GTP binding to p21ras was investigated using cultured embryonic chick neurons. In both sympathetic and sensory neurons, the addition of NGF markedly increased the formation of Ras-GTP. The magnitude of the effect was found to depend upon the developmental stage, peaking at embryonic day 11 in sympathetic neurons and at embryonic day 9 in sensory neurons, times when large numbers of neurons depend on NGF for survival. Surprisingly, following the addition of BDNF, no formation of Ras-GTP could be observed in neurons cultured with BDNF. When sensory neurons were cultured with NGF alone, both NGF and BDNF stimulated GTP binding to Ras. In rat cerebellar granule cells, while the acute exposure of these cells to BDNF resulted in the formation Ras-GTP, no response was observed following previous exposure of the cells to BDNF, as was observed with sensory neurons. However, this desensitization was not observed in a transformed cell line expressing TrkB. In neurons, the mechanism underlying the loss of the BDNF response appeared to involve a dramatic loss of binding to cell-surface receptors, as determined by cross-linking with radiolabeled BDNF. Receptor degradation could not account for the desensitization since cell lysates from neurons pretreated with BDNF revealed that the levels of TrkB were comparable to those in untreated cells. These results indicate that in neurons, the pathways activated by NGF and BDNF are differentially regulated and that prolonged exposure to BDNF results in the inability of TrkB to bind its ligand.


Assuntos
Guanosina Trifosfato/metabolismo , Fatores de Crescimento Neural/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Neurônios/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Animais , Sequência de Bases , Western Blotting , Fator Neurotrófico Derivado do Encéfalo , Células Cultivadas , Cerebelo/metabolismo , Embrião de Galinha , Primers do DNA , Gânglios Espinais/metabolismo , Gânglios Simpáticos/metabolismo , Cinética , Dados de Sequência Molecular , Neurônios/efeitos dos fármacos , Reação em Cadeia da Polimerase , Ligação Proteica , Ratos , Receptores Proteína Tirosina Quinases/biossíntese , Receptor do Fator Neutrófico Ciliar , Receptores de Fator de Crescimento Neural/análise , Receptores de Fator de Crescimento Neural/biossíntese , Proteínas Recombinantes/farmacologia
14.
Pediatrics ; 95(2): 179-86, 1995 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-7838632

RESUMO

OBJECTIVE: To determine the demographic characteristics, medical features, psychological profile, and natural history of children with chronic fatigue. DESIGN: Case control study. SETTING: Pediatric Infectious Diseases Clinic of Kosair Children's Hospital, 1990 to 1992. PARTICIPANTS: Forty-four patients referred for persistent fatigue were evaluated. Twenty patients participated in a psychological study; 20 healthy controls of similar age and gender were recruited from community pediatric practices and 20 matched depressed controls were recruited from university psychiatry services (subjects were treated as groups in the analyses). MEASURES: Demographic data were obtained for all referred patients. Those with fatigue for at least 2 months and no alternative diagnosis received a detailed history, physical, and battery of laboratory tests (complete blood count, sedimentation rate, chemistry panel, chest X-ray thyroid stimulating hormone, thyroxine, anti-nuclear antibodies, urinalysis, immunoglobulins, and Epstein-Barr virus (EBV), toxoplasma, and cytomegalovirus serologies). Psychological study participants completed the following: background structured interview; Kaufman Brief Intelligence Test; Children's Depression Inventory; Child Behavior Checklist; Youth Self Report; Diagnostic Interview for Children and Adolescents-Revised; mail-in follow-up survey. RESULTS: The median age of fatigue patients was 14.3 years; 60% were female, 96% white, and 87% from the mid/upper socioeconomic status (SES). Fatigue patients were demographically similar to 21 patients referred for infectious mononucleosis (IM) but were older than other clinic patients (P < .0001). White race (P = .0568) and mid/upper SES (P = .0403) were over-represented among fatigue patients compared to patients referred for other diagnoses. Of 36 patients meeting criteria for further study, 5 had an IM-like illness including evidence of recent EBV infection. For the remaining 31 patients, clinical and laboratory evaluations were unrevealing. Psychological study subjects reported marked declines in quality-of-life and scored high on measures of internalizing, withdrawal, and social isolation. Nine met diagnostic criteria for depression, although depressive symptoms were not as prominent as those reported by depressed controls. Fatigue subjects scored higher on somatization than both control groups. The follow-up survey indicated symptomatic improvement in most patients. CONCLUSIONS: Chronic fatigue was a common reason for referral, with over-representation of white children from mid/upper SES. After exclusion of EBV-associated IM, screening laboratory tests were not helpful in establishing specific organic diagnoses. Whereas the natural history was favorable, chronic fatigue resulted in major quality-of-life changes and was associated with significant levels of psychosocial distress. IMPLICATIONS: Psychological evaluation is warranted in these patients, as some may have treatable psychological conditions. Given the absence of proved medical therapies, psychosocial interventions to improve quality-of-life should be studied.


Assuntos
Síndrome de Fadiga Crônica/epidemiologia , Síndrome de Fadiga Crônica/psicologia , Adolescente , Estudos de Casos e Controles , Transtorno Depressivo/epidemiologia , Feminino , Seguimentos , Herpesvirus Humano 4/isolamento & purificação , Humanos , Mononucleose Infecciosa/epidemiologia , Entrevista Psicológica , Masculino , Testes Psicológicos , Qualidade de Vida , Encaminhamento e Consulta , Fatores Socioeconômicos , Fatores de Tempo
15.
Proc Natl Acad Sci U S A ; 90(9): 4062-6, 1993 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-8097884

RESUMO

In membranes from SH-SY5Y human neuroblastoma cells differentiated with retinoic acid, the mu-selective agonist Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) inhibited cAMP formation with an IC50 of 26 nM. Two separate antibodies raised against distinct regions of the Go alpha sequence attenuated the effect of DAMGO by 50-60%, whereas antibodies to Gi alpha 1,2 or Gi alpha 3 reduced the mu-opioid signal insignificantly or to a lesser extent. In contrast, inhibition of adenylyl cyclase by the delta-opioid agonist Tyr-D-Pen-Gly-Phe-D-Pen-OH (DPDPE; Pen = penicillamine) was very sensitive to the Gi alpha 1,2 antibody. In membranes from rat brain striatum, coupling of the mu opioid receptor to adenylyl cyclase was also maximally blocked by antibodies to Go alpha. After long-term treatment of the cells with DAMGO, the content of Go alpha was reduced by 26%, whereas the levels of Gi alpha 1,2, Gi alpha 3, and Gs alpha were unaltered. Addition of Go, purified from bovine brain, to membranes from pertussis toxin-treated SH-SY5Y cells restored the inhibition of adenylyl cyclase by DAMGO to 70% of that in toxin-untreated cells. To comparably restore the effect of DPDPE, much higher concentrations of Go were required. By demonstrating mediation of cAMP-dependent signal transduction by Go, these results describe (i) an additional role for this G protein present at a high concentration in brain, (ii) preferential, although not exclusive, interaction of mu and delta opioid receptors with different G protein subtypes in coupling to adenylyl cyclase, and (iii) reduced levels of Go following chronic opioid treatment of SH-SY5Y cells with mu opioids.


Assuntos
Adenilil Ciclases/metabolismo , Analgésicos/farmacologia , Corpo Estriado/metabolismo , Encefalinas/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Neuroblastoma/metabolismo , Receptores Opioides mu/metabolismo , Toxina Adenilato Ciclase , Animais , Anticorpos/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Membrana Celular/metabolismo , Células Clonais , AMP Cíclico/metabolismo , Ala(2)-MePhe(4)-Gly(5)-Encefalina , D-Penicilina (2,5)-Encefalina , Proteínas de Ligação ao GTP/imunologia , Humanos , Cinética , Proteínas de Membrana/isolamento & purificação , Proteínas de Membrana/metabolismo , Toxina Pertussis , Ratos , Somatostatina/análogos & derivados , Somatostatina/farmacologia , Células Tumorais Cultivadas , Fatores de Virulência de Bordetella/farmacologia
16.
Mol Pharmacol ; 43(3): 465-73, 1993 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8383804

RESUMO

In differentiated SH-SY5Y human neuroblastoma cells, various opioids exhibited a wide range of potencies (Ki) in acutely inhibiting adenylate cyclase to different extents (Imax). After exposure of the cells to opioids for 24 hr, the initially reduced cAMP content of the cells recovered toward pre-exposure levels. Withdrawal of agonist from, or addition of antagonist to, the tolerant cells rapidly increased the cAMP content to 1.5 times the basal value. Long term treatment of the cells with agonists of high acute potency, such as Tyr-D-Ala-Gly-(Me)Phe-Gly-ol and levorphanol, decreased the Bmax of the antagonist [3H]naltrexone by 80-95%, increased the Ks for GTPase stimulation 10-14-fold, and increased the Ki for adenylate cyclase inhibition 2-3-fold. On the other hand, these parameters were only marginally affected by agonists of lower acute potency, such as profadol and morphiceptin, regardless of their Imax in inhibiting adenylate cyclase. The reduction in the level of receptor binding was experimentally not dissociable from effector desensitization. Tyr-D-Ala-Gly-(Me)Phe-Gly-ol retained the characteristics of a potent agonist in inducing tolerance even under conditions of submaximal signal, produced by lower concentrations of the peptide or by pretreatment with pertussis toxin. Alkylation of receptors by beta-chlornaltrexamine, although it reduced [3H]naltrexone binding by 50%, did not significantly alter the rank order of opioid agonists based on their ability to acutely inhibit adenylate cyclase. These results show that in opioid-tolerant SH-SY5Y cells the concurrently occurring down-regulation of receptor and shifts in the concentration dependence of effector response correlate with the potency of a given opioid in producing its acute effect but not with the maximum extent of that effect.


Assuntos
Inibidores de Adenilil Ciclases , AMP Cíclico/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Entorpecentes/farmacologia , Receptores Opioides/efeitos dos fármacos , Sequência de Aminoácidos , Regulação para Baixo , Tolerância a Medicamentos , Ala(2)-MePhe(4)-Gly(5)-Encefalina , Encefalinas/farmacologia , Humanos , Levorfanol/farmacologia , Dados de Sequência Molecular , Naltrexona/metabolismo , Neuroblastoma/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores Opioides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
18.
J Neurochem ; 58(5): 1611-9, 1992 May.
Artigo em Inglês | MEDLINE | ID: mdl-1560222

RESUMO

Parameters of ligand binding, stimulation of low-Km GTPase, and inhibition of adenylate cyclase were determined in intact human neuroblastoma SH-SY5Y cells and in their isolated membranes, both suspended in identical physiological buffer medium. In cells, the mu-selective opioid agonist [3H]Tyr-D-Ala-Gly(Me)Phe-Gly-ol ([3H]DAMGO) bound to two populations of sites with KD values of 3.9 and 160 nM, with less than 10% of the sites in the high-affinity state. Both sites were also detected at 4 degrees C and were displaced by various opioids, including quaternary naltrexone. The opioid antagonist [3H]naltrexone bound to a single population of sites, and in cells treated with pertussis toxin the biphasic displacement of [3H]naltrexone by DAMGO became monophasic with only low-affinity binding present. The toxin specifically reduced high-affinity agonist binding but had no effect on the binding of [3H]naltrexone. In isolated membranes, both agonist and antagonist bound to a single population of receptor sites with affinities similar to that of the high-affinity binding component in cells. Addition of GTP to membranes reduced the Bmax for [3H]DAMGO by 87% and induced a linear ligand binding component; a low-affinity binding site, however, could not be saturated. Compared with results obtained with membranes suspended in Tris buffer, agonist binding, including both receptor density and affinity, in the physiological medium was attenuated. The results suggest that high-affinity opioid agonist binding represents the ligand-receptor-guanine nucleotide binding protein (G protein) complex present in cells at low density due to modulation by endogenous GTP.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Endorfinas/fisiologia , Neoplasias do Sistema Nervoso/fisiopatologia , Transdução de Sinais , Ala(2)-MePhe(4)-Gly(5)-Encefalina , Encefalinas/metabolismo , Guanosina Trifosfato/farmacologia , Humanos , Membranas Intracelulares/metabolismo , Ligantes , Neoplasias do Sistema Nervoso/patologia , Células Tumorais Cultivadas
19.
Psychosomatics ; 33(4): 397-403, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1461965

RESUMO

The authors take a developmental and family systems perspective in reviewing research on the family stressors inherent in caring for a child with a chronic disease. Cystic fibrosis, a genetically transmitted and life-shortening disorder, exemplifies a chronic disease that places demands on the family that are both unique and shared with other prolonged illnesses. The authors chronicle the interaction of the debilitating features of this disease and its demanding treatment regimen with family dynamics from the point of initial diagnosis to the terminal stages.


Assuntos
Proteção da Criança , Criança , Doença Crônica/psicologia , Fibrose Cística/genética , Família , Estresse Psicológico/psicologia , Pré-Escolar , Aberrações Cromossômicas/genética , Transtornos Cromossômicos , Fibrose Cística/diagnóstico , Fibrose Cística/etiologia , Feminino , Humanos , Acontecimentos que Mudam a Vida , Masculino
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