Contemporary early results of late repair of tetralogy of Fallot in children: a single-centre case series.

AIMS: To describe the early results of complete repair of tetralogy of Fallot (TOF) in children older than one year of age. METHODS: We identified all patients older than one year of age who underwent TOF repair between 2007 and 2017. Data collected included type of surgical repair, survival at 30 days after surgery, reintervention within 30 days of surgery, length of stay in the intensive care unit (ICU), length of stay in hospital, and degree of residual right ventricular outflow tract (RVOT) stenosis and pulmonary insufficiency 30 days after surgery. RESULTS: 125 children (median age 4.4 years, interquartile range [IQR] 3–5.7) underwent complete repair of TOF, with pulmonary valve preservation in 66%, a transannular patch in 19%, and a valved right ventricular-to-pulmonary artery conduit in 15%. All patients survived. There were twelve (9.6%) reinterventions. Median ICU length of stay was 7 days and median hospital length of stay was 12 days. Significant residual RVOT stenosis was present in 7.2% and significant pulmonary insufficiency in 19.2%. Patients with a transannular patch had a significantly higher proportion of significant residual RVOT stenosis and significant pulmonary insufficiency compared with the other types of surgical repair. CONCLUSIONS: Compared with the existing literature on complete late repair of TOF in children, this study showed good early results with no mortality, similar rates of reintervention and valve-preserving surgery, higher ICU and hospital length of stay, higher incidence of significant residual RVOT stenosis, and lower incidence of significant pulmonary insufficiency. Repair with a transannular patch was a risk factor for significant residual RVOT stenosis and significant pulmonary insufficiency.

Postischemic treatment of neonatal cerebral ischemia should target autophagy.

OBJECTIVE: To evaluate the contributions of autophagic, necrotic, and apoptotic cell death mechanisms after neonatal cerebral ischemia and hence define the most appropriate neuroprotective approach for postischemic therapy. METHODS: Rats were exposed to transient focal cerebral ischemia on postnatal day 12. Some rats were treated by postischemic administration of pan-caspase or autophagy inhibitors. The ischemic brain tissue was studied histologically, biochemically, and ultrastructurally for autophagic, apoptotic, and necrotic markers. RESULTS: Lysosomal and autophagic activities were increased in neurons in the ischemic area from 6 to 24 hours postinjury, as shown by immunohistochemistry against lysosomal-associated membrane protein 1 and cathepsin D, by acid phosphatase histochemistry, by increased expression of autophagosome-specific LC3-II and by punctate LC3 staining. Electron microscopy confirmed the presence of large autolysosomes and putative autophagosomes in neurons. The increases in lysosomal activity and autophagosome formation together demonstrate increased autophagy, which occurred mainly in the border of the lesion, suggesting its involvement in delayed cell death. We also provide evidence for necrosis near the center of the lesion and apoptotic-like cell death in its border, but in nonautophagic cells. Postischemic intracerebroventricular injections of autophagy inhibitor 3-methyladenine strongly reduced the lesion volume (by 46%) even when given >4 hours after the beginning of the ischemia, whereas pan-caspase inhibitors, carbobenzoxy-valyl-alanyl-aspartyl(OMe)-fluoromethylketone and quinoline-val-asp(OMe)-Ch2-O-phenoxy, provided no protection. INTERPRETATION: The prominence of autophagic neuronal death in the ischemic penumbra and the neuroprotective efficacy of postischemic autophagy inhibition indicate that autophagy should be a primary target in the treatment of neonatal cerebral ischemia.

Ultrastructure of retinal ganglion cell death after axotomy in chick embryos.

Axotomy often leads to neuronal death, which occurs after a particularly short delay in immature animals. Tectal lesions were made in embryonic day (E) 12 chick embryos, thereby axotomizing the retinal ganglion cells of the contralateral eye, which then died within 3 days. We here describe the ultrastructural changes in the axotomized ganglion cells. The main changes were nuclear invagination and type 3B (cytoplasmic type) cell death characterized by dilation of the perinuclear space, endoplasmic reticulum, and Golgi apparatus. However, nuclear invagination was never seen in type 3B dying cells. All the axotomy-induced retinal ganglion cell death appears to have been of type 3B; apoptosis was not induced by axotomy, as was confirmed by additional light microscopic experiments showing that it did not increase the frequency of apoptotic markers revealed by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (the TUNEL method) labeling and immunoreactivity for activated caspase-3. However, the latter methods did show small numbers of apoptotic cells dying naturally even in control retinas. After the death of the axotomized ganglion cells, they were phagocytosed mainly in Müller processes. The present findings open up the chick tectal lesion model as a system for analyzing type 3B neuronal death in vivo.

Kainate-induced endocytosis in retinal amacrine cells.

Endocytosis is enhanced in some cases of neuronal death. We report for the first time that intraocular injections, in chick embryos, of excitotoxic doses of kainate induce strong endocytosis in retinal amacrine cells destined to die and that even subtoxic doses can induce some degree of endocytosis. That the uptake was due to endocytosis rather than passive diffusion through the plasma membrane was shown ultrastructurally. The endocytosis was demonstrated by using three unrelated tracers--horseradish peroxidase, microperoxidase, and 4.4-kDa fluorescein isothiocyanate (FITC)-labeled dextran--suggesting that it does not depend on the binding of the tracers to a particular receptor. However, it appears to be surprisingly sensitive to the size of the ligand, because a heavier (42-kDa) FITC-dextran was not endocytosed. The induction of endocytosis by kainate can occur even when protein synthesis is blocked. These results indicate that toxic or near-toxic doses of kainate induce endocytosis, raising the question of whether this is mechanistically implicated in causing or preventing excitotoxic neuronal death.