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1.
J Diabetes Res ; 2016: 3798729, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27088096

RESUMO

The Active Body Control (ABC) weight-reduction program is based on telemonitoring of physical activity and nutrition together with telecoaching by weekly counseling letters sent by post or by e-mail. The study presented here reports the results of a 1-year follow-up of 49 patients with the metabolic syndrome who had lost weight with the aid of the ABC program in the preceding year. The weight regain after the second year in patients not receiving any further care ("ABC discontinued" group; n = 24) and the potential benefit of continuing with the ABC program with monthly counseling letters ("ABC continued" group; n = 25) were investigated. The relative weight changes after the first year had been, respectively, -13.4% and -11.4% in the "ABC discontinued" and "ABC continued" groups, and after the second year they decreased by, respectively, 4.4 and 2.8%. However, this difference in weight regains between the two groups was not statistically significant. It is concluded that three-quarters of the weight loss after 1 year is maintained after the second year. The decision whether to continue with the ABC program after 1 year should be made individually.


Assuntos
Aconselhamento , Obesidade/terapia , Telemedicina/métodos , Redução de Peso , Programas de Redução de Peso , Adulto , Restrição Calórica , Correspondência como Assunto , Dieta , Correio Eletrônico , Exercício Físico , Feminino , Seguimentos , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Obesidade/diagnóstico , Obesidade/fisiopatologia , Recidiva , Fatores de Tempo , Resultado do Tratamento , Aumento de Peso
2.
J Am Coll Nutr ; 33(5): 363-74, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25105874

RESUMO

OBJECTIVE: Mobile technology can improve lifestyle programs, but the monitoring techniques and carer feedback need to be optimized. To this end, we investigated the efficacy of telemonitoring physical activity and nutrition over 12 months in patients with metabolic syndrome in a randomized, parallel-group, open trial. METHODS: Screening all over Germany yielded 184 patients with metabolic syndrome. All patients attended a single 2-hour instruction meeting in their region concerning a combination diet and the importance of physical activity. Thereafter they were randomized into a control group (controls, n = 62) or one of 2 different intervention groups. Both intervention groups were issued accelerometers, which measured physical activity, recorded daily weight and calorie intake, and transmitted these data to a central server for use by patient carers. In the Active Body Control Program of University of Magdeburg (ABC) intervention group (n = 60), information and motivation was ensured by weekly letters. In the 4sigma telephone coaching (4S) intervention group (n = 58), this was accomplished by monthly telephone calls from the carers. Clinical and biochemical data for all patients were collected at 0, 4, 8, and 12 months without any regular face-to-face meetings between patients and carers. The primary endpoint was weight loss and the secondary endpoint was the presence of metabolic syndrome. RESULTS: After 12 months the dropout rates in the control, 4S, and ABC groups were respectively 35%, 17%, and 18%. The adjusted relative weight losses after 12 months were respectively 3.7%, 8.6%, and 11.4% (all p < 0.000 versus baseline). ABC was more effective than 4S (p = 0.041); 43% of the patients completing the study in the ABC group lost more than 15% of their baseline weight. The diagnosis of metabolic syndrome was no longer applicable in 58% of the cases in the ABC group, in 41% of the 4S group, and in 33% of the controls. CONCLUSIONS: Telemonitoring of physical activity and nutrition markedly improves weight loss and markers of metabolic syndrome.


Assuntos
Ingestão de Energia , Exercício Físico , Síndrome Metabólica/terapia , Obesidade/terapia , Telemedicina/métodos , Redução de Peso , Programas de Redução de Peso , Acelerometria , Adulto , Comunicação , Dieta Redutora , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Pacientes Desistentes do Tratamento
3.
J Cell Sci ; 123(Pt 17): 2931-42, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20720151

RESUMO

In Notch signaling, cell-bound ligands activate Notch receptors on juxtaposed cells, but the relationship between ligand endocytosis, ubiquitylation and ligand-receptor interaction remains poorly understood. To study the specific role of ligand-receptor interaction, we identified a missense mutant of the Notch ligand Jagged1 (Nodder, Ndr) that failed to interact with Notch receptors, but retained a cellular distribution that was similar to wild-type Jagged1 (Jagged1(WT)) in the absence of active Notch signaling. Both Jagged1(WT) and Jagged1(Ndr) interacted with the E3 ubiquitin ligase Mind bomb, but only Jagged1(WT) showed enhanced ubiquitylation after co-culture with cells expressing Notch receptor. Cells expressing Jagged1(WT), but not Jagged1(Ndr), trans-endocytosed the Notch extracellular domain (NECD) into the ligand-expressing cell, and NECD colocalized with Jagged1(WT) in early endosomes, multivesicular bodies and lysosomes, suggesting that NECD is routed through the endocytic degradation pathway. When coexpressed in the same cell, Jagged1(Ndr) did not exert a dominant-negative effect over Jagged1(WT) in terms of receptor activation. Finally, in Jag1(Ndr/Ndr) mice, the ligand was largely accumulated at the cell surface, indicating that engagement of the Notch receptor is important for ligand internalization in vivo. In conclusion, the interaction-dead Jagged1(Ndr) ligand provides new insights into the specific role of receptor-ligand interaction in the intracellular trafficking of Notch ligands.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Receptores Notch/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Endocitose , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Jagged-1 , Ligantes , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Proteínas Serrate-Jagged , Transdução de Sinais , Transfecção , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
4.
Acta Neuropathol ; 112(3): 267-76, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16791600

RESUMO

Disturbance of intracellular trafficking plays a major role in several neurodegenerative disorders including Alzheimer or Parkinson's disease. The Chediak-Higashi syndrome (CHS), a life-threatening autosomal recessive disease with frequent mutations in the LYST gene, and its animal model, the beige mouse, are both characterized by lysosomal defects with accumulation of giant lysosomes. Clinically they manifest as hypopigmentation, abnormal bleeding and increased susceptibility to infection with various degrees of involvement of the nervous system. In the course of a recessive N-ethyl-N-nitrosurea (ENU) mutagenesis screen, we identified the first murine missense mutation in the lysosomal trafficking regulator gene (Lyst(Ing3618)) located at a highly conserved position in the WD40 protein domain. Nearly all described human Lyst alleles lead to protein truncation and fatal childhood CHS. Only four different missense mutations have been reported in patients with adolescent or adult forms of CHS involving the nervous system. Interestingly, the Lyst(Ing3618) model presents with a predominant neurodegenerative phenotype with progressive degeneration and loss of Purkinje cells and lacks severe impairment of the immune system. Therefore, the Lyst(Ing3618 )allele could represent a new model for adult CHS with neurological impairment. It could also provide an important tool to elucidate the role of neuronal lysosomal trafficking in the pathophysiology of neurodegeneration.


Assuntos
Proteínas dos Microfilamentos/genética , Mutação de Sentido Incorreto/fisiologia , Degeneração Neural/genética , Proteínas/genética , Células de Purkinje/patologia , Sequência de Aminoácidos , Animais , Calbindinas , Mapeamento Cromossômico , Clonagem Molecular , DNA/genética , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Dados de Sequência Molecular , Degeneração Neural/patologia , Reação do Ácido Periódico de Schiff , Fenótipo , Proteína G de Ligação ao Cálcio S100/metabolismo , Proteínas de Transporte Vesicular
5.
Blood ; 107(8): 3350-8, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16397132

RESUMO

Macrophage actin-associated tyrosine phosphorylated protein (MAYP)/PSTPIP2, a PCH protein, is involved in the regulation of macrophage motility. Mutations in a closely related gene, PSTPIP1/CD2BP1, cause a dominantly inherited autoinflammatory disorder known as PAPA syndrome. A mutant mouse obtained by chemical mutagenesis exhibited an autoinflammatory disorder characterized by macrophage infiltration and inflammation, leading to osteolysis and necrosis in paws and necrosis of ears. Positional cloning of this recessive mutation, termed Lupo, identified a T to A nucleotide exchange leading to an amino acid substitution (I282N) in the sequence of MAYP. Mayp(Lp/Lp) disease was transferable by bone marrow transplantation and developed in the absence of lymphocytes. Consistent with the involvement of macrophages, lesion development could be prevented by the administration of clodronate liposomes. MAYP is expressed in monocytes/macrophages and in a Mac1+ subfraction of granulocytes. LPS stimulation increases its expression in macrophages. Because of the instability of the mutant protein, MAYP expression is reduced 3-fold in Mayp(Lp/Lp) macrophages and, on LPS stimulation, does not rise above the level of unstimulated wild-type (WT) cells. Mayp(Lp/Lp) mice expressed elevated circulating levels of several cytokines, including MCP-1; their macrophages exhibited altered cytokine production in vitro. These studies suggest that MAYP plays an anti-inflammatory role in macrophages.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Substituição de Aminoácidos , Doenças Autoimunes/genética , Movimento Celular/genética , Proteínas do Citoesqueleto/genética , Macrófagos/metabolismo , Mutação Puntual , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Conservadores da Densidade Óssea/administração & dosagem , Transplante de Medula Óssea/métodos , Células Cultivadas , Ácido Clodrônico/administração & dosagem , Citocinas/metabolismo , Proteínas do Citoesqueleto/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Genes Recessivos/genética , Granulócitos/metabolismo , Granulócitos/patologia , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Linfócitos/metabolismo , Linfócitos/patologia , Antígeno de Macrófago 1/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Mutantes , Mutagênese , Osteólise/genética , Osteólise/metabolismo , Osteólise/patologia , Síndrome
6.
Ann Neurol ; 58(5): 777-80, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16240349

RESUMO

A heterozygous R1101K mutation of the p150 subunit of dynactin (DCTN1) is reported in a family with amyotrophic lateral sclerosis (ALS) and co-occurrence of frontotemporal dementia (FTD). Two members of our kindred were affected with motor neuron disease and two with dementia in an autosomal dominant pattern of inheritance. We excluded the involvement of the ALS and FTD-linked genes for copper/zinc superoxide dismutase (SOD1) and tau. The R1101K sequence alteration of the DCTN1 gene may predispose subjects to ALS and FTD.


Assuntos
Esclerose Lateral Amiotrófica/genética , Arginina/genética , Demência/genética , Lisina/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/patologia , Análise Mutacional de DNA/métodos , Demência/complicações , Demência/patologia , Complexo Dinactina , Saúde da Família , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade
7.
Genes Dev ; 18(5): 486-91, 2004 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15014044

RESUMO

The vestibular system of the inner ear is responsible for the perception of motion and gravity. Key elements of this organ are otoconia, tiny biomineral particles in the utricle and the saccule. In response to gravity or linear acceleration, otoconia deflect the stereocilia of the hair cells, thus transducing kinetic movements into sensorineural action potentials. Here, we present an allelic series of mutations at the otoconia-deficient head tilt (het) locus, affecting the gene for NADPH oxidase 3 (Nox3). This series of mutations identifies for the first time a protein with a clear enzymatic function as indispensable for otoconia morphogenesis.


Assuntos
Mutação , NADPH Oxidases/genética , Doenças Vestibulares/genética , Vestíbulo do Labirinto/anormalidades , Vestíbulo do Labirinto/enzimologia , Animais , Mapeamento Cromossômico , Genes Recessivos , Sensação Gravitacional , Camundongos , Camundongos Mutantes , Morfogênese/genética , NADPH Oxidases/fisiologia , Propriocepção , Doenças Vestibulares/enzimologia , Vestíbulo do Labirinto/anatomia & histologia
8.
Science ; 300(5620): 808-12, 2003 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-12730604

RESUMO

Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.


Assuntos
Transporte Axonal , Dineínas/genética , Dineínas/fisiologia , Doença dos Neurônios Motores/genética , Neurônios Motores/fisiologia , Degeneração Neural , Animais , Células do Corno Anterior/patologia , Apoptose , Diferenciação Celular , Movimento Celular , Sistema Nervoso Central/embriologia , Mapeamento Cromossômico , Dimerização , Dineínas/química , Feminino , Gânglios Espinais/patologia , Complexo de Golgi/metabolismo , Complexo de Golgi/ultraestrutura , Heterozigoto , Homozigoto , Corpos de Lewy/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Doença dos Neurônios Motores/patologia , Doença dos Neurônios Motores/fisiopatologia , Neurônios Motores/ultraestrutura , Mutação , Mutação de Sentido Incorreto , Fragmentos de Peptídeos/metabolismo , Fenótipo , Mutação Puntual , Nervos Espinhais/crescimento & desenvolvimento , Toxina Tetânica/metabolismo
9.
Am J Pharmacogenomics ; 2(4): 263-71, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12421097

RESUMO

The sequencing of the human genome has generated a drug discovery process that is based on sequence analysis and hypothesis-driven (inductive) prediction of gene function. This approach, which we term inductive genomics, is currently dominating the efforts of the pharmaceutical industry to identify new drug targets. According to recent studies, this sequence-driven discovery process is paradoxically increasing the average cost of drug development, thus falling short of the promise of the Human Genome Project to simplify the creation of much needed novel therapeutics. In the early stages of discovery, the flurry of new gene sequences makes it difficult to pick and prioritize the most promising product candidates for product development, as with existing technologies important decisions have to be based on circumstantial evidence that does not strongly predict therapeutic potential. This is because the physiological function of a potential target cannot be predicted by gene sequence analysis and in vitro technologies alone. In contrast, deductive genomics, or large-scale forward genetics, bridges the gap between sequence and function by providing a function-driven in vivo screen of a highly orthologous mammalian model genome for medically relevant physiological functions and drug targets. This approach allows drug discovery to move beyond the focus on sequence-driven identification of new members of classical drug-able protein families towards the biology-driven identification of innovative targets and biological pathways.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Genoma Humano , Genômica/métodos , Animais , Sistemas de Liberação de Medicamentos/tendências , Genoma , Genômica/tendências , Humanos
10.
Drug Discov Today ; 7(23): 1175-83, 2002 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-12547018

RESUMO

The flood of raw information generated by large-scale data acquisition technologies in genomics, microarrays and proteomics is changing the early stages of the drug discovery process. Although many more potential drug targets are now available compared with the pre-genomics era, knowledge about the physiological context in which these targets act--information crucial to both discovery and development--is scarce. Random mutagenesis strategies in the mouse provide scalable approaches for both the gene-driven validation of candidate targets in vivo and the discovery of new physiological pathways by phenotype-driven screens.


Assuntos
Indústria Farmacêutica/métodos , Camundongos/genética , Mutagênese , Tecnologia Farmacêutica/métodos , Sequência de Aminoácidos , Animais , Dados de Sequência Molecular , Mutagênese/efeitos dos fármacos , Mutagênese/genética , Reprodutibilidade dos Testes
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