Chloride Channel-3 (ClC-3) Modifies the Trafficking of Leucine-Rich Repeat-Containing 8A (LRRC8A) Anion Channels.

Chloride channel-3 (ClC-3) Cl-/H+ antiporters and leucine-rich repeat-containing 8 (LRRC8) family anion channels have both been associated with volume-regulated anion currents (VRACs). VRACs are often altered in ClC-3 null cells but are absent in LRRC8A null cells. To explore the relationship between ClC-3, LRRC8A, and VRAC we localized tagged proteins in human epithelial kidney (HEK293) cells using multimodal microscopy. Expression of ClC-3-GFP induced large multivesicular bodies (MVBs) with ClC-3 in the delimiting membrane. LRRC8A-RFP localized to the plasma membrane and to small cytoplasmic vesicles. Co-expression demonstrated co-localization in small, highly mobile cytoplasmic vesicles that associated with the early endosomal marker Rab5A. However, most of the small LRRC8A-positive vesicles were constrained within large MVBs with abundant ClC-3 in the delimiting membrane. Dominant negative (S34A) Rab5A prevented ClC-3 overexpression from creating enlarged MVBs, while constitutively active (Q79L) Rab5A enhanced this phenotype. Thus, ClC-3 and LRRC8A are endocytosed together but independently sorted in Rab5A MVBs. Subsequently, LRRC8A-labeled vesicles were sorted to MVBs labeled by Rab27A and B exosomal compartment markers, but not to Rab11 recycling endosomes. VRAC currents were significantly larger in ClC-3 null HEK293 cells. This work demonstrates dependence of LRRC8A trafficking on ClC-3 which may explain the association between ClC-3 and VRACs.

Case series of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy during extracorporeal life support.

Therapeutic hypothermia initiated within 6 hours of birth is currently the standard of care for the management of neonates with hypoxic-ischemic encephalopathy. Neonates undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy are also at risk for severe respiratory failure and need for extracorporeal life support. The risks and benefits of therapeutic hypothermia for hypoxic-ischemic encephalopathy during extracorporeal life support are still not well defined. We report our experience of a case series of six neonates who underwent therapeutic hypothermia for hypoxic-ischemic encephalopathy during extracorporeal life support. We also report long-term neurodevelopmental follow-up from 6 to 24 months and add to the current body of evidence regarding feasibility, clinical experience, and short-term complications.

Extracorporeal Membrane Oxygenation (ECMO) Support in Special Patient Populations-The Bidirectional Glenn and Fontan Circulations.

Extracorporeal membrane oxygenation (ECMO) is a support modality used within the pediatric cardiac ICU population as a bridge to recovery or decision in the setting of acute myocardial decompensation, support for combined cardiopulmonary failure or in the setting of refractory cardiopulmonary arrest. Patients with univentricular physiology are at particular risk for decompensation requiring ECMO support. This review will focus upon current evidence and techniques for ECMO support of single ventricle patients who have undergone a stage II bidirectional Glenn procedure or the stage III Fontan procedure.

Hollow Fiber Oxygenator Composition Has a Significant Impact on Failure Rates in Neonates on Extracorporeal Membrane Oxygenation: A Retrospective Analysis.

In extracorporeal life support (ECLS), there are two main types of oxygenators in clinical use for neonates: polymethylpentene (PMP) hollow fiber and polypropylene (PP) hollow fiber. A retrospective study was performed on neonates ( n = 44) who had undergone ECLS for noncardiac indications from 2009 to 2015. Between the two groups (PMP n = 21, PP n = 23), the PP oxygenators failed 91% of the time, whereas the PMP oxygenators failed 43% of the time ( p < 0.05). Analysis suggests PMP oxygenators are less prone to failure than PP oxygenators, and they require fewer number of oxygenator changes during a neonatal ECLS.