RESUMEN
The gamma-secretase complex plays a role in Alzheimer's disease and cancer progression. The development of clinically useful inhibitors, however, is complicated by the role of the gamma-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different gamma-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B gamma-secretase in a mouse Alzheimer's disease model led to improvements of Alzheimer's disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total gamma-secretase activity in the human brain, and thus specific targeting of Aph1B-containing gamma-secretase complexes may help generate less toxic therapies for Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Endopeptidasas/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides/análisis , Péptidos beta-Amiloides/química , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Modelos Animales de Enfermedad , Endopeptidasas/química , Endopeptidasas/genética , Femenino , Humanos , Aprendizaje por Laberinto , Proteínas de la Membrana/metabolismo , Memoria , Ratones , Neuronas/metabolismo , Fragmentos de Péptidos/análisis , Fragmentos de Péptidos/metabolismo , Péptido Hidrolasas/metabolismo , Presenilina-1/química , Presenilina-1/genética , Presenilina-1/metabolismo , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Receptor Notch1/metabolismo , Transducción de SeñalRESUMEN
The practice of equine neurology has special challenges posed by the size of the animal being examined. Many diagnostic procedures routinely used in small animal practice are unsafe when applied to the equine patient or unavailable to the equine practitioner. Therefore, astute observation is the mainstay of making a neuroanatomic diagnosis, and detailed evidence on the deficits present may be difficult to obtain. Because clinical observation can sometimes be ambiguous and somewhat subjective, it is even more important to approach equine neurology from an evidence-based point of view. Here, such an approach is outlined for the diagnosis of cervical vertebral compressive myelopathy (CVCM), one of the most common noninfectious causes of equine neurologic disease. This article is an attempt to summarize all aspects of making a diagnosis of CVCM on the basis of signalment, clinical examination, ancillary diagnostic tests, and pathologic examination. Each of these considerations has inherent limitations regarding diagnostic accuracy, which are discussed.
Asunto(s)
Medicina Basada en la Evidencia , Enfermedades de los Caballos/diagnóstico , Neurología/métodos , Compresión de la Médula Espinal/veterinaria , Medicina Veterinaria/normas , Animales , Diagnóstico Diferencial , Caballos , Examen Neurológico/veterinaria , Compresión de la Médula Espinal/diagnóstico , Medicina Veterinaria/métodosRESUMEN
A 5-year-old Holstein cow, pregnant with a valuable calf, was presented with signs of heart failure (tachycardia, peripheral edema, and distended jugular veins) related to pericardial lymphoma and associated cardiac tamponade. In addition, pleural effusion was present in both hemithoraces. Medical treatment, which consisted of repeated pericardiocenteses, placement of indwelling pleural catheters, administration of intravenous fluid therapy, antibiotics and anti-inflammatory drugs, was ineffective in controlling recurrence of clinical signs despite a temporary improvement. A standing thoracoscopic pericardiotomy was performed in an attempt to reduce clinical signs of heart failure and to prolong life. Clinical signs of heart failure abated and no recurrence was seen. Standing thoracoscopic pericardiotomy along with possible corticosteroids can be recommended as palliative treatment in an effort to extend life for reproductive performance in genetically valuable animals.
