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1.
Prev Med Rep ; 32: 102138, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36865395

RESUMO

The likelihood of clinicians prescribing direct-acting antiviral (DAA) therapy for patients with chronic hepatitis C virus (HCV) and substance use disorder (SUD) was assessed via a survey emailed throughout the United States to clinicians (physicians and advanced practice providers) in gastroenterology, hepatology, and infectious disease specialties. Clinicians' perceived barriers and preparedness and actions associated with current and future DAA prescribing practices of HCV-infected patients with SUD were assessed. Of 846 clinicians presumably receiving the survey, 96 completed and returned it. Exploratory factor analyses of perceived barriers indicated a highly reliable (Cronbach alpha = 0.89) model with five factors: HCV stigma and knowledge, prior authorization requirements, and patient- clinician-, and system-related barriers. In multivariable analyses, after controlling for covariates, patient-related barriers (P < 0.01) and prior authorization requirements (P < 0.01) were negatively associated with the likelihood of prescribing DAAs. Exploratory factor analyses of clinician preparedness and actions indicated a highly reliable (Cronbach alpha = 0.75) model with three factors: beliefs and comfort level; action; and perceived limitations. Clinician beliefs and comfort levels were negatively associated with the likelihood of prescribing DAAs (P = 0.01). Composite scores of barriers (P < 0.01) and clinician preparedness and actions (P < 0.05) were also negatively associated with the intent to prescribe DAAs. Conclusion: These findings underscore the importance of addressing patient-related barriers and prior authorization requirements-significant problematic barriers-and improving clinicians' beliefs (e.g., medication-assisted therapy should be prescribed before DAAs) and comfort levels for treating patients with HCV and SUD to enhance treatment access for patients with both HCV and SUD.

2.
Hepatology ; 74(6): 2952-2964, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34255381

RESUMO

BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.


Assuntos
Antivirais/administração & dosagem , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , 2-Naftilamina/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/administração & dosagem , Benzimidazóis/administração & dosagem , Benzofuranos/administração & dosagem , Ciclopropanos/administração & dosagem , Combinação de Medicamentos , Quimioterapia Combinada/métodos , Feminino , Fluorenos/administração & dosagem , Seguimentos , Técnicas de Genotipagem , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/virologia , Humanos , Imidazóis/administração & dosagem , Lactamas Macrocíclicas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Prolina/administração & dosagem , Prolina/análogos & derivados , Quinoxalinas/administração & dosagem , RNA Viral/sangue , Ribavirina/administração & dosagem , Sofosbuvir/administração & dosagem , Sulfonamidas/administração & dosagem , Resposta Viral Sustentada , Resultado do Tratamento , Uracila/administração & dosagem , Uracila/análogos & derivados , Valina/administração & dosagem , Adulto Jovem
3.
Clin Liver Dis (Hoboken) ; 13(6): 162-164, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31391926
4.
Contemp Clin Trials Commun ; 8: 62-66, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29503877

RESUMO

INTRODUCTION: Although registries can rapidly identify clinical study participants, it is unknown which follow up methods for recruiting are most effective. Our goal is to examine the efficacy of three communication strategies for recruiting and enrolling patients who were identified via a contact registry (i.e., registry linked to a consent to re-contact program). METHODS: Patients who met the study criteria were identified via the contact registry and targeted for recruitment. In condition 1, patients established in the university hepatology specialty clinics were contacted one time via phone call by the study coordinator and asked to participate (C1). In condition 2, non-established specialty clinic patients were mailed an IRB-approved letter with study information and instructions for calling the study coordinator to participate (C2). Condition 2A included patients who called within two weeks of receiving the letter (C2A); condition 2B included patients who did not call after receiving the letter but were subsequently contacted via phone call. RESULTS: A registry identified 1,060 patients, of which 661were eligible and targeted for recruiting. All 37 patients were reached in C1 and 17 (45.9%) were recruited. Nineteen of the 624 patients in C2A were reached and 10 were recruited whereas 120 of the 605 patients in C2B were reached and 53 (8.7%) were recruited. Seventy patients enrolled with C2B being the most effective (total, cost) recruitment strategy (n = 50) (p < .001). CONCLUSION: The efficacy of enrolling patients identified via a contact registry into clinical trials varies based on the communication strategies used for recruiting.

6.
Ann Neurol ; 66(1): 75-80, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19670443

RESUMO

OBJECTIVE: In familial amyotrophic lateral sclerosis (fALS) harboring superoxide dismutase (SOD1) mutations (fALS1), SOD1 toxicity has been linked to its propensity to misfold and aggregate. It has recently been proposed that misfolded SOD1 may be causative of all types of ALS, including sporadic cases (sALS). In the present study, we have used a specific antibody to test for the presence of monomer/misfolded SOD1 in sALS. METHODS: Sections from lumbar spinal cords of 5 fALS1 cases, 13 sALS cases, and 1 non-SOD1 fALS case were labeled immunocytochemically using SOD1-exposed-dimer-interface (SEDI) antibody, which we have previously validated as being specific for pathological monomer/misfolded forms of SOD1. RESULTS: Monomer/misfolded SOD1 was detected with SEDI antibody in all 5 of the fALS1 cases, localizing predominantly to hyaline conglomerate inclusions, a specific pathological feature of fALS1. In contrast, monomer/misfolded SOD1 was not detected in any of the 13 sALS cases or in the non-SOD1 fALS cases. These results were confirmed by immunoprecipitation. INTERPRETATION: Although SEDI antibody does not necessarily label all misfolded forms of SOD1, these findings show a distinct difference between fALS1 and sALS, and do not support that monomer/misfolded SOD1 is a common disease entity linking all types of ALS. This is important to our understanding of ALS disease pathogenesis and to considerations of the applicability of using therapeutics that target misfolded SOD1 to non-SOD1-related cases. Ann Neurol 2009;66:75-80.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Superóxido Dismutase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Dobramento de Proteína , Superóxido Dismutase/genética , Superóxido Dismutase-1
7.
J Neurosci ; 28(8): 1833-40, 2008 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-18287500

RESUMO

The neuronal intermediate filament protein peripherin is a component of ubiquitinated inclusions and of axonal spheroids in amyotrophic lateral sclerosis (ALS). Overexpression of peripherin causes motor neuron degeneration in transgenic mice and variations within the peripherin gene have been identified in ALS cases. We have shown previously the abnormal expression of a neurotoxic peripherin splice variant in transgenic mice expressing mutant superoxide dismutase-1. These findings indicated that abnormalities of peripherin splicing may occur in ALS. In the current study, peripherin splice variants were identified by reverse transcription-PCR of human neuronal RNA and comparisons in expression made between control and ALS spinal cord using Western blot analysis and immunocytochemistry. Using this approach we have identified a novel peripherin transcript retaining introns 3 and 4 that results in a 28 kDa splice isoform, designated Per 28. Using an antibody specific to Per 28, we show that this isoform is expressed at low stoichiometric levels from the peripherin gene, however causes peripherin aggregation when its expression is upregulated. Importantly we show an upregulation of Per 28 expression in ALS compared with controls, at both the mRNA and protein levels, and that Per 28 is associated with disease pathology, specifically round inclusions. These findings are the first to establish that peripherin splicing abnormalities occur in ALS, generating aggregation-prone splice isoforms.


Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Proteínas de Filamentos Intermediários/biossíntese , Proteínas de Filamentos Intermediários/genética , Íntrons/fisiologia , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Regulação para Cima/genética , Adolescente , Adulto , Idoso , Esclerose Lateral Amiotrófica/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Humanos , Proteínas de Filamentos Intermediários/fisiologia , Masculino , Glicoproteínas de Membrana/fisiologia , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/fisiologia , Periferinas , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia
8.
Mol Cell Proteomics ; 7(1): 15-34, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17934213

RESUMO

Despite intense research efforts, the physiological function and molecular environment of the amyloid precursor protein has remained enigmatic. Here we describe the application of time-controlled transcardiac perfusion cross-linking, a method for the in vivo mapping of protein interactions in intact tissue, to study the interactome of the amyloid precursor protein (APP). To gain insights into the specificity of reported protein interactions the study was extended to the mammalian amyloid precursor-like proteins (APLP1 and APLP2). To rule out sampling bias as an explanation for differences in the individual datasets, a small scale quantitative iTRAQ (isobaric tags for relative and absolute quantitation)-based comparison of APP, APLP1, and APLP2 interactomes was carried out. An interactome map was derived that confirmed eight previously reported interactions of APP and revealed the identity of more than 30 additional proteins that reside in spatial proximity to APP in the brain. Subsequent validation studies confirmed a physiological interaction between APP and leucine-rich repeat and Ig domain-containing protein 1, demonstrated a strong influence of Ig domain-containing protein 1 on the proteolytic processing of APP, and consolidated similarities in the biology of APP and p75.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Mapeamento de Interação de Proteínas/métodos , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/química , Animais , Anticorpos , Reagentes de Ligações Cruzadas/farmacologia , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Técnicas In Vitro , Espectrometria de Massas , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Camundongos , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Perfusão , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Reprodutibilidade dos Testes , Fatores de Tempo
9.
J Neuropathol Exp Neurol ; 66(12): 1147-53, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18090923

RESUMO

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the presence of various types of ubiquitinated inclusions in the cytoplasm of affected motor neurons. The identification of the ubiquitinated targets within these inclusions has represented a major challenge, as this may provide new gene candidates and/or clues to understanding the neurodegenerative mechanism(s) underlying the disease. As such, the nuclear factor TAR DNA-binding protein (TDP-43) was recently identified as a component of ubiquitinated skein-like inclusions and round inclusions in ALS. This identification combined with biochemical evidence led to the suggestion that TDP-43 is the key ubiquitinated target and major disease protein in ALS. Here, using 3-dimensional deconvolution imaging, we have obtained remarkable resolution of skein-like inclusions and round inclusions in ALS. Surprisingly we have found that in contrast to current thinking, TDP-43 is not the major ubiquitinated target within these types of inclusions. These findings raise the possibility that TDP-43 may not necessarily be the key disease protein in ALS and indicate that the major target(s) of ubiquitination remain to be identified.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a DNA/metabolismo , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Ubiquitina/metabolismo , Idoso , Feminino , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Periferinas
10.
EMBO J ; 26(17): 4038-50, 2007 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-17703189

RESUMO

The cellular prion protein, PrP(C), is neuroprotective in a number of settings and in particular prevents cerebellar degeneration mediated by CNS-expressed Doppel or internally deleted PrP ('DeltaPrP'). This paradigm has facilitated mapping of activity determinants in PrP(C) and implicated a cryptic PrP(C)-like protein, 'pi'. Shadoo (Sho) is a hypothetical GPI-anchored protein encoded by the Sprn gene, exhibiting homology and domain organization similar to the N-terminus of PrP. Here we demonstrate Sprn expression and Sho protein in the adult CNS. Sho expression overlaps PrP(C), but is low in cerebellar granular neurons (CGNs) containing PrP(C) and high in PrP(C)-deficient dendritic processes. In Prnp(0/0) CGNs, Sho transgenes were PrP(C)-like in their ability to counteract neurotoxic effects of either Doppel or DeltaPrP. Additionally, prion-infected mice exhibit a dramatic reduction in endogenous Sho protein. Sho is a candidate for pi, and since it engenders a PrP(C)-like neuroprotective activity, compromised neuroprotective activity resulting from reduced levels may exacerbate damage in prion infections. Sho may prove useful in deciphering several unresolved facets of prion biology.


Assuntos
Encéfalo/metabolismo , Glicoproteínas/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteínas PrPC/metabolismo , Doenças Priônicas/metabolismo , Príons/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Cerebelo/metabolismo , Proteínas Ligadas por GPI , Glicoproteínas/genética , Hipocampo/metabolismo , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Ligação Proteica
11.
Neurosci Lett ; 420(2): 128-32, 2007 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-17543992

RESUMO

Mislocalization of the TAR-DNA binding protein (TDP-43) from the nucleus to the cytoplasm of diseased motor neurons and association with intraneuronal ubiquitinated inclusions has recently been reported in amyotrophic lateral sclerosis (ALS). Here, we have investigated TDP-43 immunoreactivity in three lines of mutant SOD1 transgenic mice, G93A, G37R and G85R and compared with labeling in one sporadic ALS case and two familial ALS cases carrying mutations in SOD1, A4T and I113T. Our findings show that there is no mislocalization of TDP-43 to the cytoplasm in motor neurons of mutant SOD1 transgenic mice, nor association of TDP-43 with ubiquitinated inclusions. In contrast, mislocalization of TDP-43 to the cytoplasm and association with ubiquitinated inclusions was found in the ALS cases, including those carrying mutations in SOD1. Interestingly, there was no association of TDP-43 with ubiquitinated hyaline conglomerate inclusions, pathology closely associated with ALS cases carrying mutations in SOD1. Our findings indicate that the process of motor neuron degeneration in mutant SOD1 transgenic mice is unlikely to involve the abnormalities of TDP-43 described in the human disease.


Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Mutação/genética , Superóxido Dismutase/genética , Transporte Ativo do Núcleo Celular/genética , Adulto , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Citoplasma/metabolismo , Citoplasma/patologia , Modelos Animais de Doenças , Progressão da Doença , Humanos , Corpos de Inclusão/genética , Corpos de Inclusão/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Transporte Proteico/genética , Superóxido Dismutase-1
12.
Nat Med ; 13(6): 754-9, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17486090

RESUMO

Misfolding of Cu/Zn-superoxide dismutase (SOD1) is emerging as a mechanism underlying motor neuron degeneration in individuals with amyotrophic lateral sclerosis (ALS) who carry a mutant SOD1 gene (SOD1 ALS). Here we describe a structure-guided approach to developing an antibody that specifically recognizes monomer-misfolded forms of SOD1. We raised this antibody to an epitope that is normally buried in the SOD1 native homodimer interface. The SOD1 exposed dimer interface (SEDI) antibody recognizes only those SOD1 conformations in which the native dimer is disrupted or misfolded and thereby exposes the hydrophobic dimer interface. Using the SEDI antibody, we established the presence of monomer-misfolded SOD1 in three ALS mouse models, with G37R, G85R and G93A SOD1 mutations, and in a human individual with an A4V SOD1 mutation. Despite ubiquitous expression, misfolded SOD1 was found primarily within degenerating motor neurons. Misfolded SOD1 appeared before the onset of symptoms and decreased at the end stage of the disease, concomitant with motor neuron loss.


Assuntos
Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/imunologia , Epitopos/imunologia , Dobramento de Proteína , Superóxido Dismutase/imunologia , Sequência de Aminoácidos , Esclerose Lateral Amiotrófica/patologia , Animais , Anticorpos/metabolismo , Modelos Animais de Doenças , Epitopos/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Conformação Proteica , Coelhos , Ratos , Frações Subcelulares/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1
13.
Am J Pathol ; 169(4): 1365-75, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17003492

RESUMO

Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTauP301L) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTauP301L mice developed florid pathology including neuronal pretangles, numerous Gallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the cerebrum, in the brainstem, and to a lesser extent in the spinal cord. These features were accompanied by gliosis, neuronal loss, and cerebral atrophy. Accumulated tau was hyperphosphorylated, conformationally changed, ubiquitinated, and sarkosyl-insoluble, with electron microscopy demonstrating wavy filaments. Aged TgTauP301L mice exhibited impairment in hippocampally dependent and independent behavioral paradigms, with impairments closely related to the presence of tau pathologies and levels of insoluble tau protein. We conclude that TgTauP301L mice recreate the substantial phenotypic variation and spectrum of pathologies seen in FTDP-17 patients. Identification of genetic and/or environmental factors modifying the tau phenotype in these mice may shed light on factors modulating human tauopathies. These transgenic mice may aid therapeutic development for FTDP-17 and other diseases featuring accumulations of four-repeat tau, such as Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy.


Assuntos
Córtex Cerebral/patologia , Gliose/patologia , Transtornos da Memória/patologia , Doenças Neurodegenerativas/patologia , Neuroglia/patologia , Taurina/genética , Animais , Córtex Cerebral/química , Demência/genética , Demência/patologia , Modelos Animais de Doenças , Humanos , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Mutação , Doenças Neurodegenerativas/genética , Neurônios/patologia , Fenótipo , Taurina/análise
14.
Proc Natl Acad Sci U S A ; 102(25): 8972-7, 2005 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-15951428

RESUMO

Gamma-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-beta precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PS1 or PS2 genes shift APP cleavage from production of amyloid-beta (Abeta) 40 peptide to greater production of Abeta42. Although studies in PS1/PS2-deficient embryonic cells define overlapping activities for these proteins, in vivo complementation of PS1-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PS1 transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little Abeta40 or Abeta42 production, and FAD PS2 alleles support robust production of only Abeta42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a "gained" competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against gamma-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct gamma-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates.


Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Osso e Ossos/anormalidades , Osso e Ossos/patologia , Endopeptidases , Homozigoto , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mutação , Fragmentos de Peptídeos/metabolismo , Fenótipo , Presenilina-1 , Presenilina-2
15.
Proc Natl Acad Sci U S A ; 102(14): 5215-20, 2005 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-15784737

RESUMO

Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1-/- mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1-/-embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1-/- mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults.


Assuntos
Intoxicação por MPTP/metabolismo , Proteínas Oncogênicas/deficiência , Animais , Sequência de Bases , Morte Celular , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , DNA Complementar/genética , Denervação , Marcação de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Neurônios/citologia , Neurônios/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Estresse Oxidativo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Proteína Desglicase DJ-1
16.
Stud Health Technol Inform ; 111: 57-63, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15718699

RESUMO

This study examines the effectiveness of two virtual reality simulators when compared with traditional methods of teaching intravenous (IV) cannulation to third year medical students. Thirty-four third year medical students were divided into four groups and then trained to perform an IV cannulation using either CathSim, Virtual I.V., a plastic simulated arm or by practicing IV placement on each other. All subjects watched a five minute training video and completed a cannulation pretest and posttest on the simulated arm. The results showed significant improvement from pretest to posttest in each of the four groups. Students trained on the Virtual I.V. showed significantly greater improvement over baseline when compared with the simulated arm group (p<.026). Both simulators provided at least equal training to traditional methods of teaching, a finding with implications for future training of this procedure to novices.


Assuntos
Cateterismo , Simulação por Computador , Educação Médica/métodos , Estudantes de Medicina , Humanos , Infusões Intravenosas , Interface Usuário-Computador
17.
Proc Natl Acad Sci U S A ; 100(24): 14193-8, 2003 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-14617772

RESUMO

Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-beta (Abeta) peptide. To explore this relationship in vivo, toxic-milk (txJ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust Abeta deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive txJ mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma Abeta levels. In addition, homozygosity for txJ increased survival of young TgCRND8 mice and lowered endogenous CNS Abeta at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the txJ mutation on CNS Abeta burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Abeta peptide.


Assuntos
Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cobre/metabolismo , Secretases da Proteína Precursora do Amiloide , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases , Encéfalo/metabolismo , ATPases Transportadoras de Cobre , Endopeptidases/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Fenótipo , Processamento de Proteína Pós-Traducional
18.
Neurol Res ; 25(6): 590-600, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14503012

RESUMO

Alzheimer's disease (AD) is characterized by memory impairment leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid beta peptide, A beta, whereas NFTs contain hyperphosphorylated forms of the microtubule-associated protein tau (tau). Familial AD (FAD) mutations either elevate A beta synthesis by favoring 'secretase' of the Alzheimer beta-amyloid precursor protein (APP) or enhance the fibrillogenic properties of this peptide. Mutations in the tau gene cause a different disease denoted FTPD-17, but suggest that the aberrant forms of tau seen in AD are unlikely to be benign. These findings imply a complex pathogenic cascade in AD and important goals of transgenic modeling are to capture and stratify this pathogenic process. Several laboratories have created APP transgenic (Tg) mice that exhibit AD-like amyloid pathology and A beta burdens. These Tg lines also exhibit deficits in spatial reference and/or working memory, with immunization against A beta attenuating both AD-associated phenotypes. Tangle-like pathologies are observed in mice expressing FTPD-17 mutant forms of tau, but florid tau pathologies based upon the wild type (wt) tau isoforms present in AD have proven more elusive. Creation of animal models with robust amyloid and tau pathologies, yet free of irrelevant confounding pathologies, remains a major objective in this field.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Emaranhados Neurofibrilares/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/genética , Proteínas tau/genética
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