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1.
Transl Behav Med ; 12(7): 800-809, 2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35429393

RESUMO

Motivating at-risk relatives to undergo cascade testing for familial hypercholesterolemia (FH) is critical for diagnosis and lifesaving treatment. As credible sources of information, clinicians can assist in family communication about FH and motivate cascade testing uptake. However, there are no guidelines regarding how clinicians should effectively communicate with probands (the first person diagnosed in the family) and at-risk relatives. Individuals and families with FH can inform our understanding of the most effective communications to promote cascade testing. Guided by the extended parallel process model (EPPM), we analyzed the perspectives of individuals and families with FH for effective messaging clinicians can use to promote cascade testing uptake. We analyzed narrative data from interviews and surveys collected as part of a larger mixed-methods study. The EPPM was used to identify message features recommended by individuals and families with FH that focus on four key constructs (severity, susceptibility, response efficacy, self-efficacy) to promote cascade testing. Participants included 22 individuals from 11 dyadic interviews and 98 survey respondents. Participants described prioritizing multiple messages that address each EPPM construct to alert relatives about their risk. They illustrated strategies clinicians could use within each EPPM construct to communicate to at-risk relatives about the importance of pursuing diagnosis via cascade testing and subsequent treatment for high cholesterol due to FH. Findings provide guidance on effective messaging to motivate cascade testing uptake for FH and demonstrates how the EPPM may guide communication with at-risk relatives about genetic risk and motivate cascade testing broadly.


Assuntos
Testes Genéticos , Hiperlipoproteinemia Tipo II , Comunicação , Testes Genéticos/métodos , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , Fatores de Risco
2.
J Pers Med ; 11(6)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205662

RESUMO

Guided by the Conceptual Model of Implementation Research, we explored the acceptability, appropriateness, and feasibility of: (1) automated screening approaches utilizing existing health data to identify those who require subsequent diagnostic evaluation for familial hypercholesterolemia (FH) and (2) family communication methods including chatbots and direct contact to communicate information about inherited risk for FH. Focus groups were conducted with 22 individuals with FH (2 groups) and 20 clinicians (3 groups). These were recorded, transcribed, and analyzed using deductive (coded to implementation outcomes) and inductive (themes based on focus group discussions) methods. All stakeholders described these initiatives as: (1) acceptable and appropriate to identify individuals with FH and communicate risk with at-risk relatives; and (2) feasible to implement in current practice. Stakeholders cited current initiatives, outside of FH (e.g., pneumonia protocols, colon cancer and breast cancer screenings), that gave them confidence for successful implementation. Stakeholders described perceived obstacles, such as nonfamiliarity with FH, that could hinder implementation and potential solutions to improve systematic uptake of these initiatives. Automated health data screening, chatbots, and direct contact approaches may be useful for patients and clinicians to improve FH diagnosis and cascade screening.

3.
Circ Genom Precis Med ; 14(1): e003120, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33480803

RESUMO

BACKGROUND: Familial hypercholesterolemia (FH) is the most common cardiovascular genetic disorder and, if left untreated, is associated with increased risk of premature atherosclerotic cardiovascular disease, the leading cause of preventable death in the United States. Although FH is common, fatal, and treatable, it is underdiagnosed and undertreated due to a lack of systematic methods to identify individuals with FH and limited uptake of cascade testing. METHODS AND RESULTS: This mixed-method, multi-stage study will optimize, test, and implement innovative approaches for both FH identification and cascade testing in 3 aims. To improve identification of individuals with FH, in Aim 1, we will compare and refine automated phenotype-based and genomic approaches to identify individuals likely to have FH. To improve cascade testing uptake for at-risk individuals, in Aim 2, we will use a patient-centered design thinking process to optimize and develop novel, active family communication methods. Using a prospective, observational pragmatic trial, we will assess uptake and effectiveness of each family communication method on cascade testing. Guided by an implementation science framework, in Aim 3, we will develop a comprehensive guide to identify individuals with FH. Using the Conceptual Model for Implementation Research, we will evaluate implementation outcomes including feasibility, acceptability, and perceived sustainability as well as health outcomes related to the optimized methods and tools developed in Aims 1 and 2. CONCLUSIONS: Data generated from this study will address barriers and gaps in care related to underdiagnosis of FH by developing and optimizing tools to improve FH identification and cascade testing.


Assuntos
Testes Genéticos/métodos , Hiperlipoproteinemia Tipo II/diagnóstico , Apolipoproteína B-100/genética , Bases de Dados Genéticas , Humanos , Hiperlipoproteinemia Tipo II/genética , Assistência Centrada no Paciente , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética
4.
J Clin Lipidol ; 14(2): 218-223.e2, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32143996

RESUMO

BACKGROUND: Barriers to genetic testing and subsequent family cascade screening for familial hypercholesterolemia (FH) include cost, patient and provider awareness, privacy and discrimination concerns, need for a physician order, underutilization of genetic counselors, and family concerns about the implications of genetic testing for care. OBJECTIVES: The objective of the study was to determine the uptake of genetic testing with cost and privacy removed. METHODS: The FH Foundation offered free genetic testing and counseling to patients in the patient portal of the CASCADE FH Registry, who had not previously undergone genetic testing for 3 genes associated with FH (LDLR, APOB, and PCSK9). The free testing offer was extended to first-degree relatives of participants who had a positive genetic test result for cascade screening. RESULTS: Of 435 eligible patients, 147 opted in to participate, 122 consented, and 110 (68.2% female, median age: 52 years) received genetic testing. Of the participants, 64 had a positive genetic test result for a pathogenic variant in LDLR (59) or APOB (5); 11 had a variant of uncertain significance. Only 3 first-degrees relatives underwent genetic testing. CONCLUSIONS: Although there was substantial interest in genetic testing, uptake of family cascade screening was poor. Innovative approaches to increase family cascade screening should be explored.


Assuntos
Testes Genéticos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Sistema de Registros , Adulto , Idoso , Confidencialidade , Custos e Análise de Custo , Feminino , Testes Genéticos/economia , Testes Genéticos/legislação & jurisprudência , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
Neurochem Int ; 53(6-8): 296-308, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18805448

RESUMO

Sodium-dependent glutamate uptake is essential for limiting excitotoxicity, and dysregulation of this process has been implicated in a wide array of neurological disorders. The majority of forebrain glutamate uptake is mediated by the astroglial glutamate transporter, GLT-1. We and others have shown that this transporter undergoes endocytosis and degradation in response to activation of protein kinase C (PKC), however, the mechanisms involved remain unclear. In the current study, transfected C6 glioma cells or primary cortical cultures were used to show that PKC activation results in incorporation of ubiquitin into GLT-1 immunoprecipitates. Mutation of all 11 lysine residues in the amino and carboxyl-terminal domains to arginine (11R) abolished this signal. Selective mutation of the seven lysine residues in the carboxyl terminus (C7K-R) did not eliminate ubiquitination, but it completely blocked PKC-dependent internalization and degradation. Two families of variants of GLT-1 were prepared with various lysine residues mutated to arginine. Analyses of these constructs indicated that redundant lysine residues in the carboxyl terminus were sufficient for the appearance of ubiquitinated product and degradation of GLT-1. Together these data define a novel mechanism by which the predominant forebrain glutamate transporter can be rapidly targeted for degradation.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Ubiquitina/metabolismo , Ubiquitinação/fisiologia , Sequência de Aminoácidos/genética , Animais , Linhagem Celular Tumoral , Córtex Cerebral/metabolismo , Regulação para Baixo/genética , Endocitose/fisiologia , Transportador 2 de Aminoácido Excitatório/química , Transportador 2 de Aminoácido Excitatório/genética , Lisina/metabolismo , Mutação/genética , Proteína Quinase C/metabolismo , Estrutura Terciária de Proteína/genética , Transporte Proteico/fisiologia , Ratos
6.
J Neurochem ; 103(5): 1917-31, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17868307

RESUMO

The neuronal glutamate transporter, excitatory amino acid carrier 1 (EAAC1), has a diverse array of physiologic and metabolic functions. There is evidence that there is a relatively large intracellular pool of EAAC1 both in vivo and in vitro, that EAAC1 cycles on and off the plasma membrane, and that EAAC1 cell surface expression can be rapidly regulated by intracellular signals. Despite the possible relevance of EAAC1 trafficking to both physiologic and pathologic processes, the cellular machinery involved has not been defined. In the present study, we found that agents that disrupt clathrin-dependent endocytosis or plasma membrane cholesterol increased steady-state levels of biotinylated EAAC1 in C6 glioma cells and primary neuronal cultures. Acute depletion of cholesterol increased the V(max) for EAAC1-mediated activity and had no effect on Na(+)-dependent glycine transport in the same system. These agents also impaired endocytosis as measured using a reversible biotinylating reagent. Co-expression with dominant-negative variants of dynamin or the clathrin adaptor, epidermal growth factor receptor pathway substrate clone 15, increased the steady-state levels of biotinylated myc-EAAC1. EAAC1 immunoreactivity was found in a subcellular fraction enriched in early endosome antigen 1 (EEA1) isolated by differential centrifugation and partially co-localized with EEA1. Co-expression of a dominant-negative variant of Rab11 (Rab11 S25N) reduced steady-state levels of biotinylated myc-EAAC1 and slowed constitutive delivery of myc-EAAC1 to the plasma membrane. Together, these observations suggest that EAAC1 is constitutively internalized via a clathrin- and dynamin-dependent pathway into early endosomes and that EAAC1 is trafficked back to the cell surface via the endocytic recycling compartment in a Rab11-dependent mechanism. As one defines the machinery required for constitutive trafficking of EAAC1, it may be possible to determine how intracellular signals regulate EAAC1 cell surface expression.


Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Endocitose/fisiologia , Transportador 3 de Aminoácido Excitatório/metabolismo , Neurônios/metabolismo , Animais , Biotinilação/métodos , Células Cultivadas , Embrião de Mamíferos , Endocitose/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Glicina/metabolismo , Hipocampo , Soluções Hipertônicas/farmacologia , Camundongos , Neurônios/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sódio/metabolismo , Sinaptossomos/efeitos dos fármacos , Transfecção/métodos , beta-Ciclodextrinas/farmacologia
7.
Neurochem Int ; 51(6-7): 333-55, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17517448

RESUMO

Extracellular concentrations of the predominant excitatory neurotransmitter, glutamate, and related excitatory amino acids are maintained at relatively low levels to ensure an appropriate signal-to-noise ratio and to prevent excessive activation of glutamate receptors that can result in cell death. The latter phenomenon is known as 'excitotoxicity' and has been associated with a wide range of acute and chronic neurodegenerative disorders, as well as disorders that result in the loss of non-neural cells such as oligodendroglia in multiple sclerosis. Unfortunately clinical trials with glutamate receptor antagonists that would logically seem to prevent the effects of excessive receptor activation have been associated with untoward side effects or little clinical benefit. In the mammalian CNS, the extracellular concentrations of glutamate are controlled by two types of transporters; these include a family of Na(+)-dependent transporters and a cystine-glutamate exchange process, referred to as system X(c)(-). In this review, we will focus primarily on the Na(+)-dependent transporters. A brief introduction to glutamate as a neurotransmitter will be followed by an overview of the properties of these transporters, including a summary of the presumed physiologic mechanisms that regulate these transporters. Many studies have provided compelling evidence that impairing the function of these transporters can increase the sensitivity of tissue to deleterious effects of aberrant activation of glutamate receptors. Over the last decade, it has become clear that many neurodegenerative disorders are associated with a change in localization and/or expression of some of the subtypes of these transporters. This would suggest that therapies directed toward enhancing transporter expression might be beneficial. However, there is also evidence that glutamate transporters might increase the susceptibility of tissue to the consequences of insults that result in a collapse of the electrochemical gradients required for normal function such as stroke. In spite of the potential adverse effects of upregulation of glutamate transporters, there is recent evidence that upregulation of one of the glutamate transporters, GLT-1 (also called EAAT2), with beta-lactam antibiotics attenuates the damage observed in models of both acute and chronic neurodegenerative disorders. While it seems somewhat unlikely that antibiotics specifically target GLT-1 expression, these studies identify a potential strategy to limit excitotoxicity. If successful, this type of approach could have widespread utility given the large number of neurodegenerative diseases associated with decreases in transporter expression and excitotoxicity. However, given the massive effort directed at developing glutamate receptor agents during the 1990s and the relatively modest advances to date, one wonders if we will maintain the patience needed to carefully understand the glutamatergic system so that it will be successfully targeted in the future.


Assuntos
Química Encefálica/fisiologia , Encéfalo/metabolismo , Ácido Glutâmico/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas Vesiculares de Transporte de Glutamato/metabolismo , Animais , Encéfalo/fisiopatologia , Transportador 2 de Aminoácido Excitatório/antagonistas & inibidores , Transportador 2 de Aminoácido Excitatório/metabolismo , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Neurotoxinas/antagonistas & inibidores , Neurotoxinas/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
8.
J Biol Chem ; 281(8): 4876-86, 2006 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-16368696

RESUMO

The neuronal glutamate transporter, EAAC1 (excitatory amino acid carrier 1), undergoes rapid regulation after treatment with platelet-derived growth factor (PDGF) or phorbol ester in C6 glioma cells and neurons. A large intracellular pool of EAAC1 exists, from which transporters are redistributed to the cell surface in response to these signals. Here we show that PDGF had no effect on subcellular localization of the glial glutamate transporter, GLT-1, after transfection into C6 glioma cells. Chimeras consisting of domains from EAAC1 or GLT-1 were used to investigate structural motifs involved in PDGF-dependent redistribution of EAAC1. PDGF did not induce trafficking of an EAAC1 chimera containing the carboxyl-terminal domain of GLT-1; however, it did induce trafficking of a GLT-1 chimera containing the carboxyl-terminal domain of EAAC1. A truncated mutant of EAAC1 lacking 10 carboxyl-terminal amino acids was responsive to PDGF, whereas a mutant lacking 20 residues was not. Alanine substitution mutagenesis in this region revealed a short motif, (502)YVN(504), necessary for regulated trafficking. This motif was also involved in protein kinase C-dependent trafficking, as mutant transporters exhibited an attenuated response to phorbol ester. Interestingly, the presence of YVN in the homologous region of a nonresponsive chimera was not sufficient to confer regulated trafficking; however, the presence of a 12-amino acid motif starting at this Tyr residue was sufficient to confer responsiveness to PDGF. These studies identify a novel motif within the carboxyl terminus of EAAC1 which is required for regulated trafficking. The possibility that this motif targets EAAC1 to an intracellular, "regulated pool" is discussed.


Assuntos
Transportador 3 de Aminoácido Excitatório/fisiologia , Ácido Glutâmico/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Alanina/química , Motivos de Aminoácidos , Animais , Transporte Biológico , Biotinilação , Western Blotting , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Clonagem Molecular , DNA Complementar/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Imunoprecipitação , Mutagênese , Mutação , Fosforilação , Estrutura Terciária de Proteína , Ratos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes/química , Sódio/química , Fatores de Tempo , Transfecção , Tirosina/química
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