One sentence summary: Bench to bedside translation using iPSC to characterise phenotype and pharmacology in primary erythromelalgia, an inherited chronic pain condition. ABSTRACTIn common with other chronic pain conditions, inherited erythromelalgia (IEM) represents a significant unmet medical need. The peripherally expressed SCN9A encoded sodium channel Nav1.7 plays a critical role in IEM with gain-of-function leading to aberrant sensory neuronal activity and extreme pain, particularly in response to heat. In five carefully phenotyped IEM patients, a novel highly potent and selective Nav1.7 blocker reduced heat-induced pain in the majority of subjects. In four of the five subjects we used induced pluripotent stem cell (iPSC) technology to create sensory neurons which uniquely emulated the clinical phenotype of hyperexcitability and aberrant responses to heat stimuli. When we compared the severity of the clinical phenotype with the iPSC-derived sensory neuron hyperexcitability we saw a trend towards a correlation for individual mutations. The in vitro IEM phenotype was sensitive to Nav1.7 blockers, including the clinical test agent. Given the importance of peripherally expressed sodium channels in many pain conditions, this translational approach is likely to have broader utility to a wide range of pain and sensory conditions. This emphasizes the use of iPSC approaches to bridge between clinical and preclinical studies, enabling greater understanding of a disease and the response to a therapeutic agent in defined patient populations.

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SUMMARY A 5-year-old boy with tetralogy of Fallot, near-atresia of the right ventricular outflow tract and large collateral arteries to the lungs underwent an infundibulectomy without closure of the ventricular septal defect. Further surgery required preliminary reduction of the collateral circulation. The collateral arteries were successfully occluded by metrizimide-filled balloons. There was no change in arterial oxygen saturation, nor were there any complications. This new technique has significant advantages over existing alternatives. LARGE SYSTEMIC arterial collaterals supplying the lungs in patients with tetralogy of Fallot may present severe problems at surgical closure of the ventricular septal defect. During cardiopulmonary bypass, they permit flow from aorta to lungs, which results in flooding of the surgical field and underperfusion of the patient. Postoperatively, such shunts may cause acute hypoperfusion and chronic cardiac failure. These large collateral flows may also cause pulmonary hemorrhages, resulting in marked difficulties in the postoperative period.In the presence of severe or complete pulmonic outflow obstruction or very small pulmonary vessels, these collaterals may be the only source of blood to the lungs. However, after correction of the pulmonary obstruction, these collaterals become a hazard. Surgical ligation may be difficult, and may require a lateral thoracotomy if the necessary exposure cannot be obtained through the median sternotomy performed for intracardiac repair.' Even with good preoperative angiography, the collaterals may be difficult to find. Some may arise from below the diaphragm.We successfully occluded such systemic collaterals by a transvascular method that has many advantages over the surgical approach.Case Report Soon after birth, the patient was moderately cyanotic. Continuous murmurs were heard throughout the chest. Cardiac catheterization demonstrated pulmonary atresia, ventricular septal defect, and pulmonary blood supply from numerous tortuous systemic arteries. At age 3 years, exploratory surgery revealed a diminutive but patent right ventricular outflow tract in continuity with a diminutive pulmonic valve orifice and small pulmonary trunk. Leaving the ventricular septal defect open, the surgeon resected the pulmonic valve, opened the infundibulum, and placed a pericardial graft across the outflow tract and pulmonary trunk.When first seen at Childrens Hospital of Los Angeles at the age of 4 years, the patient was in good health and taking no medications. He had mildly impaired exercise tolerance and mild cyanosis. Continuous murmurs were present bilaterally. There were no signs of congestive heart failure. The chest x-ray showed a dilated main pulmonary artery. Cardiac catheterization at age 5 years showed a bidirectional shunt through a large ventricular septal defect, an arterial oxygen saturation of 89% and pulmonary-tosystemic flow ratio of 1.5. The main pulmonary artery was markedly dilated, with no discernible valve tissue, and the pressure was equal ...

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