Identification of an INa-dependent and Ito-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient

Brugada syndrome (BrS) is an inherited cardiac arrhythmia commonly associated with SCN5A mutations, yet its ionic mechanisms remain unclear due to a lack of cellular models. Here, we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a BrS patient (BrS1) to evaluate the roles of Na+ currents (INa) and transient outward K+ currents (Ito) in BrS induced action potential (AP) changes. To understand the role of these current changes in repolarization we employed dynamic clamp to "electronically express" IK1 and restore normal resting membrane potentials and allow normal recovery of the inactivating currents, INa, ICa and Ito. HiPSC-CMs were generated from BrS1 with a compound SCN5A mutation (p. A226V & p. R1629X) and a healthy sibling control (CON1). Genome edited hiPSC-CMs (BrS2) with a milder p. T1620M mutation and a commercial control (CON2) were also studied. CON1, CON2 and BrS2, had unaltered peak INa amplitudes, and normal APs whereas BrS1, with over 75% loss of INa, displayed a loss-of-INa basal AP morphology (at 1.0 Hz) manifested by a reduced maximum upstroke velocity (by ~80%, p < 0.001) and AP amplitude (p < 0.001), and an increased phase-1 repolarization pro-arrhythmic AP morphology (at 0.1 Hz) in ~25% of cells characterized by marked APD shortening (~65% shortening, p < 0.001). Moreover, Ito densities of BrS1 and CON1 were comparable and increased from 1.0 Hz to 0.1 Hz by ~ 100%. These data indicate that a repolarization deficit could be a mechanism underlying BrS

Alternating hemiplegia syndrome: Electroencephalogram, brain mapping, and brain perfusion SPECT scan study in a Chinese girl

A 3-year-old Chinese girl with alternating hemiplegia syndrome failed to respond to anticonvulsants, antimigrainous drugs, and calcium channel blockers. She made a complete remission with a 4-week course of steroid, and relapsed after steroid withdrawal. Electroencephalogram and brain mapping during the hemiplegic attack showed unilateral high-voltage sharp slow-wave discharges in the temporo-occipital region contralateral to the hemiplegic side and diffuse high-voltage slowing during attacks of quadriplegia or other clinical manifestation such as dullness, lethargy, or yawning. Brain perfusion single photon emission computed tomographic (SPECT) scan study during the attack showed decreased uptake in the temporoparietal region contralateral to the hemiplegic side and in the ipsilateral basal ganglia, whereas the perfusion was normal between attacks. Electroencephalogram background activity was improved while the child was in clinical remission with steroid treatment. Computed tomographic and magnetic resonance imaging scans of the brain were normal. Carotid angiogram failed to show any structural or dynamic changes of the carotid arteries. The possible mechanism underlying alternating hemiplegia syndrome might be transient and reversible cerebral ischemia with high-voltage slow-wave discharges shown in the electroencephalogram and decreased perfusion in SPECT scan.link_to_subscribed_fulltex

Capecitabine but not 5-FU worsened hepatosplenomegaly and liver function when used with oxaliplatin and cetuximab as first-line treatment in K-ras wild-type metastatic colorectal cancer

Theme: Building Bridges to Conquer CancerThis abstract will not be presented at the 2013 ASCO Annual Meeting but has been published in conjunction with the meeting - http://meetinglibrary.asco.org/content/113435-132BACKGROUND: MRC COIN study showed that OXA and CAP (CAPOX) have greater toxicities compared with OXA and 5-FU (FOLFOX) when cetuximab (C225) was added for mCRC. Meanwhile, OXA was associated with splenomegaly and hepatic sinusoidal injury. We investigated if CAPOX+C225 worsened hepatosplenomegaly and liver function compared with FOLFOX+C225 in K-rasWT mCRC. METHODS: 97 patients with K-ras WT mCRC received either FOLFOX or CAPOX ...link_to_OA_fulltex