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1.
Alzheimers Dement ; 13(8): 841-849, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28734653

RESUMEN

INTRODUCTION: Cerebrospinal fluid analysis and other measurements of amyloidosis, such as amyloid-binding positron emission tomography studies, are limited by cost and availability. There is a need for a more practical amyloid ß (Aß) biomarker for central nervous system amyloid deposition. METHODS: We adapted our previously reported stable isotope labeling kinetics protocol to analyze the turnover kinetics and concentrations of Aß38, Aß40, and Aß42 in human plasma. RESULTS: Aß isoforms have a half-life of approximately 3 hours in plasma. Aß38 demonstrated faster turnover kinetics compared with Aß40 and Aß42. Faster fractional turnover of Aß42 relative to Aß40 and lower Aß42 and Aß42/Aß40 concentrations in amyloid-positive participants were observed. DISCUSSION: Blood plasma Aß42 shows similar amyloid-associated alterations as we have previously reported in cerebrospinal fluid, suggesting a blood-brain transportation mechanism of Aß. The stability and sensitivity of plasma Aß measurements suggest this may be a useful screening test for central nervous system amyloidosis.


Asunto(s)
Péptidos beta-Amiloides/sangre , Amiloidosis/sangre , Fragmentos de Péptidos/sangre , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Amiloidosis/líquido cefalorraquídeo , Amiloidosis/diagnóstico por imagen , Área Bajo la Curva , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Cromatografía Liquida , Humanos , Inmunoprecipitación , Marcaje Isotópico , Cinética , Espectrometría de Masas , Fragmentos de Péptidos/líquido cefalorraquídeo , Estudios Prospectivos , Curva ROC , Método Simple Ciego
2.
Am J Med Genet A ; 164A(8): 2036-42, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24719372

RESUMEN

There is limited information available related to the perinatal course of cardiofaciocutaneous syndrome (CFC) compared to other syndromes within the Ras-MAP kinase pathway (rasopathies) such as Noonan and Costello syndrome. Retrospective chart review revealed four cases of CFC with molecular confirmation between 2005 and 2012 at Hawaii's largest obstetric and pediatric referral center. We report on details of the prenatal, neonatal, and infancy course and long-term follow-up beyond infancy in two patients. This report includes novel features including systemic hypertension, hyponatremia, and chronic respiratory insufficiency, not previously reported in CFC. We provide pathologic diagnosis of loose anagen hair in one patient. Some of these findings have been reported in the other rasopathies, documenting further clinical overlap among these conditions. Molecular testing can be useful to differentiate CFC from other rasopathies and in counseling families about potential complications and prognosis. We recommend a full phenotypic evaluation including echocardiogram, renal ultrasound, brain imaging, and ophthalmology examination. We additionally recommend close follow-up of blood pressure, pulmonary function, and monitoring for electrolyte disturbance and extra-vascular fluid shifts.


Asunto(s)
Displasia Ectodérmica/diagnóstico , Insuficiencia de Crecimiento/diagnóstico , Cardiopatías Congénitas/diagnóstico , Fenotipo , Displasia Ectodérmica/genética , Displasia Ectodérmica/terapia , Facies , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/terapia , Femenino , Edad Gestacional , Cabello/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/terapia , Humanos , Lactante , Recién Nacido , MAP Quinasa Quinasa 2/genética , Masculino , Mutación , Piel/patología
3.
J Racial Ethn Health Disparities ; 10(6): 2663-2669, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-36357640

RESUMEN

BACKGROUND: Normative infant body composition data using air displacement plethysmography (ADP) are from primarily Caucasian populations. Racial differences may exist. OBJECTIVES: To describe body composition in Asian and Pacific Islander infants and compare them to previously published data on Caucasian infants. DESIGN: Body composition was measured using ADP with the PEA POD® Infant Body Composition System in 249 healthy full-term newborns in a predominately Asian and Pacific Islander population in Hawaii within the first 3 days of life and compared to published data on Caucasian infants with multiple t-tests adjusted for false discovery rate. RESULTS: There were no differences in percent body fat between Asian, Pacific Islander, or mixed race Asian Pacific Islander infants. Both Asian and Pacific Islander infants had significantly higher percent body fat than Caucasians from Italy in Europe (13.2% and 11.8% vs 8.9%, p < 0.01 among males, 15.3% and 15.6% vs 8.7%, p < 0.01 among females) but not when compared to Caucasians from New York. CONCLUSIONS: Racial and geographical differences in body composition exist at birth between Asian and Pacific Islanders and other Caucasian cohorts. Previously published ADP nomograms must be interpreted with caution. Future studies are needed to investigate the impact of environmental, perinatal, and genetic factors on infant body composition and its relationship to future cardiometabolic morbidity. Efforts to address racial disparities in cardiometabolic disease measures must also address pre-conceptual maternal health, which may have long-term implications on future body composition in offspring.


Asunto(s)
Composición Corporal , Nativos de Hawái y Otras Islas del Pacífico , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Tejido Adiposo , Asiático , Pueblos Isleños del Pacífico
4.
J Mol Biol ; 388(1): 144-58, 2009 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-19281821

RESUMEN

The direct induction of apoptosis has emerged as a powerful anticancer strategy, and small molecules that either inhibit or activate certain proteins in the apoptotic pathway have great potential as novel chemotherapeutic agents. Central to apoptosis is the activation of the zymogen procaspase-3 to caspase-3. Caspase-3 is the key "executioner" caspase, catalyzing the hydrolysis of a multitude of protein substrates within the cell. Interestingly, procaspase-3 levels are often elevated in cancer cells, suggesting a compound that directly stimulates the activation of procaspase-3 to caspase-3 could selectively induce apoptosis in cancer cells. We recently reported the discovery of a compound, PAC-1, which enhances procaspase-3 activity in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Described herein is the mechanism by which PAC-1 activates procaspase-3 in vitro. We show that zinc inhibits the enzymatic activity of procaspase-3 and that PAC-1 strongly activates procaspase-3 in buffers that contain zinc. PAC-1 and zinc form a tight complex with one another, with a dissociation constant of approximately 42 nM. The combined data indicate that PAC-1 activates procaspase-3 in vitro by sequestering inhibitory zinc ions, thus allowing procaspase-3 to autoactivate itself to caspase-3. The small-molecule-mediated activation of procaspases has great therapeutic potential and thus this discovery of the in vitro mechanism of action of PAC-1 is critical to the development and optimization of other procaspase-activating compounds.


Asunto(s)
Caspasa 3/metabolismo , Fosfatasa 2 de Especificidad Dual/metabolismo , Precursores Enzimáticos/metabolismo , Zinc/metabolismo , Caspasa 7/metabolismo , Inhibidores de Caspasas , Línea Celular Tumoral , Humanos
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