RESUMEN
BACKGROUND: Emerging research has shown that there may be a subset of patients who develop a first-break psychosis later in life when they are over 60 years of age. Very late-onset schizophrenia-like psychosis (VLOSLP) differs from early-onset schizophrenia in a few very important ways that lead us to believe that there may be a distinct pathologic process involved. METHODS: We present 4 cases of females with psychotic symptoms that first appeared after the patients were 60 years of age. We conducted a literature review and found that our older adult psychiatric unit is not alone in struggling with diagnoses for these individuals. RESULTS: Some of these patients have a disease that will progress to a neurocognitive disorder, but a large group of others will remain cognitively intact. Fortunately, the treatment for both processes is very similar, but studies have shown that patients with VLOSLP will need significantly lower doses of antipsychotics compared with those with early-onset schizophrenia. CONCLUSIONS: It remains unclear if VLOSLP is a unique disorder, a prodrome to dementia, or a different condition that is not yet understood. Further research is needed to develop comprehensive treatment for patients with VLOSLP.
Asunto(s)
Antipsicóticos , Demencia , Trastornos Psicóticos , Esquizofrenia , Anciano , Antipsicóticos/uso terapéutico , Demencia/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Trastornos Psicóticos/terapia , Esquizofrenia/tratamiento farmacológicoRESUMEN
AIMS: We previously reported that sodium-dependent glucose cotransporter 1 (SGLT1) is highly expressed in cardiomyocytes and is further up-regulated in ischaemia. This study aimed to determine the mechanisms by which SGLT1 contributes to ischaemia/reperfusion (I/R) injury. METHODS AND RESULTS: Mice with cardiomyocyte-specific knockdown of SGLT1 (TGSGLT1-DOWN) and wild-type controls were studied. In vivo, the left anterior descending coronary artery was ligated for 30 min and reperfused for 48 h. Ex vivo, isolated perfused hearts were exposed to 20 min no-flow and up to 2 h reperfusion. In vitro, HL-1 cells and isolated adult murine ventricular cardiomyocytes were exposed to 1 h hypoxia and 24 h reoxygenation (H/R). We found that TGSGLT1-DOWN hearts were protected from I/R injury in vivo and ex vivo, with decreased infarct size, necrosis, dysfunction, and oxidative stress. 5'-AMP-activated protein kinase (AMPK) activation increased SGLT1 expression, which was abolished by extracellular signal-related kinase (ERK) inhibition. Co-immunoprecipitation studies showed that ERK, but not AMPK, interacts directly with SGLT1. AMPK activation increased binding of the hepatocyte nuclear factor 1 and specificity protein 1 transcription factors to the SGLT1 gene, and HuR to SGLT1 mRNA. In cells, up-regulation of SGLT1 during H/R was abrogated by AMPK inhibition. Co-immunoprecipitation studies showed that SGLT1 interacts with epidermal growth factor receptor (EGFR), and EGFR interacts with protein kinase C (PKC). SGLT1 overexpression activated PKC and NADPH oxidase 2 (Nox2), which was attenuated by PKC inhibition, EGFR inhibition, and/or disruption of the interaction between EGFR and SGLT1. CONCLUSION: During ischaemia, AMPK up-regulates SGLT1 through ERK, and SGLT1 interacts with EGFR, which in turn increases PKC and Nox2 activity and oxidative stress. SGLT1 may represent a novel therapeutic target for mitigating I/R injury.
Asunto(s)
Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Transportador 1 de Sodio-Glucosa/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Proteína 1 Similar a ELAV/metabolismo , Receptores ErbB/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Factor Nuclear 1 del Hepatocito/metabolismo , Masculino , Ratones Noqueados , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/patología , NADPH Oxidasa 2/metabolismo , NADPH Oxidasas/metabolismo , Necrosis , Estrés Oxidativo , Proteína Quinasa C/metabolismo , Transducción de Señal , Transportador 1 de Sodio-Glucosa/deficiencia , Transportador 1 de Sodio-Glucosa/genéticaRESUMEN
Most studies of the mechanisms leading to hereditary dilated cardiomyopathy (DCM) have been performed in reconstituted in vitro systems. Genetically engineered murine models offer the opportunity to dissect these mechanisms in vivo. We generated a gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W) mutation in Tnnt2, which was first described in a human family with DCM. Mice heterozygous for the mutation (Tnnt2R141W/+) recapitulated the human phenotype, developing left ventricular dilation and reduced contractility. There was a gene dosage effect, so that the phenotype in Tnnt2R141W/+mice was attenuated by transgenic overexpression of wildtype Tnnt2 mRNA transcript. Male mice exhibited poorer survival than females. Biomechanical studies on skinned fibers from Tnnt2R141W/+ hearts showed a significant decrease in pCa50 (-log[Ca2+] required for generation of 50% of maximal force) relative to wildtype hearts, indicating Ca2+ desensitization. Optical mapping studies of Langendorff-perfused Tnnt2R141W/+ hearts showed marked increases in diastolic and peak systolic intracellular Ca2+ ([Ca2+]i), and prolonged systolic rise and diastolic fall of [Ca2+]i. Perfused Tnnt2R141W/+ hearts had slower intrinsic rates in sinus rhythm and reduced peak heart rates in response to isoproterenol. Tnnt2R141W/+ hearts exhibited a reduction in phosphorylated phospholamban relative to wildtype mice. However, crossing Tnnt2R141W/+ mice with phospholamban knockout (Pln-/-) mice, which exhibit increased Ca2+ transients and contractility, had no effect on the DCM phenotype. We conclude that the Tnnt2 R141W mutation causes a Ca2+ desensitization and mice adapt by increasing Ca2+-transient amplitudes, which impairs Ca2+ handling dynamics, metabolism and responses to ß-adrenergic activation.