RESUMEN
Aicardi syndrome (AS) is defined by the triad of corpus callosum agenesis, chorioretinal "lacunae" and infantile spasms. Additional neuroimaging findings including migrational abnormalities are common. We report on serial neuroimaging findings of a female fetus with ventriculomegaly, corpus callosum agenesis and focal migrational abnormalities, suggestive of AS. Postnatal neuroimaging follow-up as well as ophthalmological evaluation and occurrence of infantile spasms confirmed the prenatally suspected diagnosis of AS. This case points out the key role of serial fetal magnetic resonance imaging (MRI) in detecting the full spectrum of pathologies associated with fetal ventriculomegaly. The associated neuroimaging findings may go undetected on prenatal ultrasound, but are important in terms of diagnosis and counseling of the parents. Additionally, this case emphasizes the importance of serial fetal MRI studies to more accurately delineate the progression of findings during brain development.
Asunto(s)
Síndrome de Aicardi/patología , Enfermedades Fetales/patología , Imagen por Resonancia Magnética/métodos , Diagnóstico Prenatal/métodos , Adulto , Ventrículos Cerebrales/anomalías , Ventrículos Cerebrales/patología , Cuerpo Calloso/patología , Femenino , Humanos , Embarazo , Tabique Pelúcido/anomalías , Tabique Pelúcido/patologíaRESUMEN
A major challenge in the inner ear research field is to restore hearing loss of both non-genetic and genetic origin. A large effort is being made to protect hair cells from cell death after exposure to noise or drugs that can cause hearing loss. Our research focused on protecting hair cells from cell death occurring in a genetic model for human deafness. POU4F3 is a transcription factor associated with human hearing impairment. Pou4f3 knockout mice (Pou4f3(-/-)) have no cochlear hair cells, resulting in complete deafness. Although the hair cells appear to form properly, they progressively degenerate via apoptosis. In order to rescue the hair cells in the knockout mice, we produced explant cultures from mouse cochleae at an early embryonic stage and treated the cells with z-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), a general caspase inhibitor. Hair cell numbers in the knockout mice treated with z-VAD-fmk were significantly higher than in the untreated mice. We found that the time window that z-VAD-fmk has a protective effect is between E14.5 (P=0.001) to E16.5 (P=0.03), but not after E18.5. The source of the surviving hair cells is not due to proliferation, as measured by 5-bromo-2-deoxyuridine (BrdU) labeling, or to supporting cell transdifferentiation to hair cells, since there was no change in supporting cell numbers. Instead, the survival appears to be a direct effect of the anti-apoptotic agent on the dying hair cells with an early developmental window. These results help towards providing a comprehensive understanding of the molecular mechanisms of hair cell death, which might lead to the development of new therapeutic anti-apoptotic agents to alleviate hereditary hearing loss (HL).
Asunto(s)
Clorometilcetonas de Aminoácidos/farmacología , Apoptosis/efectos de los fármacos , Cóclea/efectos de los fármacos , Sordera/patología , Células Ciliadas Auditivas Internas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Cóclea/patología , Modelos Animales de Enfermedad , Células Ciliadas Auditivas Internas/patología , Proteínas de Homeodominio/genética , Humanos , Ratones , Ratones Noqueados , Factor de Transcripción Brn-3C/genéticaRESUMEN
In streptozotocin (STZ)-induced diabetic rats, we previously showed an increased heparin-releasable (luminal) lipoprotein lipase (LPL) activity from perfused hearts. To study the effect of this enlarged LPL pool on triglyceride (TG)-rich lipoproteins, we examined the metabolism of very-low-density lipoprotein (VLDL) perfused through control and diabetic hearts. Diabetic rats had elevated TG levels compared with control. However, fasting for 16 h abolished this difference. When the plasma lipoprotein fraction of density <1.006 g/ml from fasted control and diabetic rats was incubated in vitro with purified bovine or rat LPL, VLDL from diabetic animals was hydrolyzed as proficiently as VLDL from control animals. Post-heparin plasma lipolytic activity was comparable in control and diabetic animals. However, perfusion of control and diabetic rats with heparinase indicated that diabetic hearts had larger amounts of LPL bound to heparan sulfate proteoglycan-binding sites. [(3)H]VLDL obtained from control rats, when recirculated through the isolated heart, disappeared at a significantly faster rate from diabetic than from control rat hearts. This increased VLDL-TG hydrolysis was essentially abolished by prior perfusion of the diabetic heart with heparin, implicating LPL in this process. These findings suggest that the enlarged LPL pool in the diabetic heart is present at a functionally relevant location (at the capillary lumen) and is capable of hydrolyzing VLDL. This could increase the delivery of free fatty acid to the heart, and the resultant metabolic changes could induce the subsequent cardiomyopathy that is observed in the chronic diabetic rat.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Lipoproteínas VLDL/metabolismo , Miocardio/metabolismo , Animales , Apolipoproteínas/sangre , Sangre/efectos de los fármacos , Sangre/metabolismo , Bovinos/sangre , Diabetes Mellitus Experimental/sangre , Heparina/farmacología , Liasa de Heparina/farmacología , Hidrólisis , Técnicas In Vitro , Lípidos/sangre , Lipólisis , Lipoproteína Lipasa/metabolismo , Masculino , Ratas , Ratas Wistar , Valores de ReferenciaRESUMEN
Vascular endothelium-bound lipoprotein lipase (LPL) is rate limiting for free fatty acid (FFA) transport into tissues. In streptozotocin (STZ)-diabetic rats, we have previously demonstrated an increased heparin-releasable LPL activity from perfused hearts. Because heparin can traverse the endothelial barrier, conventional Langendorff retrograde perfusion of the heart with heparin could release LPL from both the capillary luminal and abluminal surfaces. To determine the precise location of the augmented LPL, a modified Langendorff retrograde perfusion was used to isolate the enzyme at the coronary lumen from that in the interstitial effluent. In response to heparin, a 4-fold increase in LPL activity and protein mass was observed in the coronary perfusate after 2 weeks of STZ diabetes. Release of LPL activity into the interstitial fluid of control hearts was slow but progressive, whereas in diabetic hearts, peak enzyme activity was observed within 1 to 2 minutes after heparin, followed by a gradual decline. Immunohistochemical studies of myocardial sections confirmed that the augmented LPL in diabetic hearts was mainly localized at the capillary endothelium. To study the acute effects of insulin on endothelial LPL activity, we examined rat hearts at various times after the onset of hyperglycemia. An increased heparin-releasable LPL activity in diabetic rats was demonstrated shortly (6 to 24 hours) after STZ injection or after withdrawal from exogenous insulin. Heparin-releasable coronary LPL activity was also increased after an overnight fast. These studies indicate that the intravascular heparin-releasable fraction of cardiac LPL activity is acutely regulated by short-term changes in insulin rather than glucose. Thus, during short periods (hours) of hypoinsulinemia, increased LPL activity at the capillary endothelium can increase the delivery of FFAs to the heart. The resultant metabolic changes could induce the subsequent cardiomyopathy that is observed in the chronic diabetic rat.