We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 ( D IV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype–phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM.

The THORN trial was a multicenter, randomized, double-blind, placebo-controlled clinical trial to test the hypothesis that administration of triiodothyronine (T 3 ) and hydrocortisone would decrease mortality and respiratory morbidity in preterm infants of less than 30 wk gestation. Two hundred fifty-three infants were randomized to receive either 6 μg·kg −1 ·d −1 of T 3 with 1 mg·kg −1 ·d −1 of hydrocortisone or 5% dextrose (placebo) as a continuous i.v. infusion for 7 d. The dose was halved on d 5. Our first primary outcome was death or ventilator dependence at 1 wk, and the second was death or oxygen dependence at 2 wk. The overall mortality rate for both groups was 11.4%. Relative risk of death or ventilator dependence at 1 wk, treated versus placebo, was 0.87, p = 0.2, and death or oxygen dependence at 2 wk, 1.00, p = 0.9. We examined the relationship between free T 3 (FT 3 ) and free thyroxine (FT 4 ) levels in the first 7 d and the primary outcome death or ventilator dependence at 1 wk in all 253 babies. We found significant positive correlations of p = 0.05 for FT 3 and p = 0.002 for FT 4 . Thus the higher the FT 3 and FT 4 levels, the better the outcome. No beneficial effects of T 3 and hydrocortisone were shown. In this study, although FT 3 levels were doubled by the treatment infusion, FT 4 levels were significantly suppressed. The lack of any beneficial effect of T 3 in our study may be explained by suppression of FT 4 in the treatment group.

A 2-day old baby girl, delivered at term in a hired birthing pool at home, was referred to hospital by her general practitioner (GP) because of slow feeding and floppiness. After an uneventful vaginal delivery into water maintained at around 36°C, the mother remained in the pool with her baby held at breast level whilst awaiting completion of the third stage of labour. The placenta had not delivered some 30 min later and the mother came out of the pool. After another 10 minutes, she agreed that the umbilical cord be clamped and syntocinon was given with rapid delivery of the placenta. Initial examination of the infant by the midwife was normal. Birth weight was 3700 g.

The case of a baby born with severe nonimmune hydrops fetalis in whom endocardial fibroelastosis was a late finding is reported. Left ventricular dimensions and systolic function were normal at presentation. After recovery from the hydrops, at 2 months of age, a dilated, poorly contracting left ventricle was documented and eventually led to the infant's death.

Background: This is the only study to date of Triiodothyronine(T3) and Hydrocortisone (HC) in preterm infants. The pilot study will determine the dose of T3 in the multicentre trial examining the incidence of lung disease in preterm infants.