Hypertonic Stress Causes Cytoplasmic Translocation of Neuronal, but Not Astrocytic, FUS due to Impaired Transportin Function.

The primarily nuclear RNA-binding protein FUS (fused in sarcoma) forms pathological cytoplasmic inclusions in a subset of early-onset amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. In response to cellular stress, FUS is recruited to cytoplasmic stress granules, which are hypothesized to act as precursors of pathological inclusions. We monitored the stress-induced nucleocytoplasmic shuttling of endogenous FUS in an ex vivo mouse CNS model and human neural networks. We found that hyperosmolar, but not oxidative, stress induced robust cytoplasmic translocation of neuronal FUS, with transient nuclear clearance and loss of function. Surprisingly, this reaction is independent of stress granule formation and the molecular pathways activated by hyperosmolarity. Instead, it represents a mechanism mediated by cytoplasmic redistribution of Transportin 1/2 and is potentiated by transcriptional inhibition. Importantly, astrocytes, which remain unaffected in ALS/FTD-FUS, are spared from this stress reaction that may signify the initial event in the development of FUS pathology.

Impact of therapeutic plasma exchange on cyclosporine kinetics during membrane-based lipid apheresis.

Cyclosporine is used widely as an immunosuppressant in transplant recipients and for various autoimmune diseases. In some cases, these patients require therapeutic plasma exchange (TPE). Cyclosporine is known to be highly bound to lipoproteins, and their removal by TPE would be expected to have an impact on drug dosing. We studied cyclosporine kinetics in a 54-year-old woman who is status post-cardiac transplant and has been receiving weekly TPE for familial hypercholesterolemia. We obtained serial measurements of cyclosporine, low-density lipoproteins, and high-density lipoproteins at scheduled times related to the dosing of the medication on days that she received TPE versus a day she did not. We also measured cyclosporine, low-density lipoprotein, and high-density lipoprotein levels in the fixed volume (3.5 L) of the discarded plasma. Our results show a similar rate of decline of serum cyclosporine levels on TPE days as compared with a day without TPE. Net cyclosporine in the discarded plasma was found to be approximately 1 mg per treatment or less, a relatively insignificant amount when compared with the ingested daily dose of 150 to 250 mg twice a day. Despite substantial removal of lipoproteins, there is minimal impact of TPE on serum levels of cyclosporine, and dosage adjustment is not needed for patients undergoing this procedure.

Scimitar syndrome: experience with 6 patients.

Scimitar syndrome is a rare congenital anomaly characterized by anomalous pulmonary venous drainage to the inferior vena cava, causing a left-to-right shunt. Six patients with scimitar syndrome were diagnosed in our hospital between 2002 and 2008. There were 4 girls and 2 boys; 4 < 5 kg in weight, 2 < 8 kg in weight. Scimitar syndrome was suspected in 5 cases because of dextroversion, and diagnosed by color Doppler echocardiography in all 6 when a scimitar vein was detected entering the inferior vena cava. Computed tomography confirmed the diagnosis in all patients. Two patients had horseshoe lung, 2 had a unilobar right lung, 1 had a hypoplastic right lung, and 1 had a hypoplastic right lower lobe. Three patients had severe pulmonary arterial hypertension, 2 had moderate pulmonary arterial hypertension, and one had normal pulmonary arterial pressure. All patients had lower respiratory tract infections, volume loss of the right lung, a normal or hyperinflated left lung, dextroversion of the heart, and scimitar arteries from the descending aorta. Pneumonectomy was performed in 3 patients, lobectomy in 1, ligation of anomalous vessels in 1, and 1 died before surgery.