Sodium channel slow inactivation as a therapeutic target for myotonia congenita.

OBJECTIVE: Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warmup phenomenon. Our goal was to identify the mechanism underlying warmup and to use this information to guide development of novel therapy. METHODS: To determine the mechanism underlying warmup, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warmup in a mouse model of myotonia congenita. RESULTS: Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warmup. These data suggested that enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are approved by the US Food and Drug Administration for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested that both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested that side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine's hypoexcitability side effects. INTERPRETATION: We conclude that ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita.

MR Imaging of Germ Cell and Sex Cord Stromal Tumors.

MR imaging is useful in the detection and characterization of adnexal lesions. This review discusses the clinical findings and MR imaging appearances of two types of ovarian neoplasms: germ cell and sex cord stromal tumors. The most common of these lesions, mature cystic teratomas, is characterized by the presence of bulk fat on MR imaging. Some of the other germ cell neoplasms and sex cord stromal tumors may have suggestive clinical, laboratory, or MR imaging features (eg, lipid and fibrosis) to establish a diagnosis. The ability to differentiate benign tumors from possible malignancy can aid in patient management.

Normal T1 relaxometry and extracellular volume of the pancreas in subjects with no pancreas disease: correlation with age and gender.

OBJECTIVE: Determine normal T1 and extracellular volume (ECV) of the pancreas in subjects with no pancreas disease and correlate with age and gender. SUBJECTS AND METHODS: We imaged 120 healthy subjects (age range 20-78 years) who are on annual screening with MRI/MRCP for the possibility of pancreatic cancer. Subjects had a predisposition to develop pancreatic cancer, but no history of pancreas disease or acute symptoms. Equal number (n = 60) of subjects were scanned on either 1.5 T or 3 T scanner using dual flip angle spoiled gradient echo technique incorporating fat suppression and correction for B1 field inhomogeneity. Optimization of imaging parameters was performed using a T1 phantom. ECV was calculated using pre- and post-contrast T1 of the pancreas and plasma. Regression analysis and Mann-Whitney tests were used for statistical analysis. RESULTS: Median T1 on 1.5 T was 654 ms (IQR 608-700); median T1 on 3 T was 717 ms (IQR 582-850); median ECV on 1.5 T was 0.28 (IQR 0.21-0.33), and median ECV on 3 T was 0.25 (IQR 0.19-0.28). Age had a mild positive correlation with T1 (r = 0.24, p = 0.009), but not with ECV (r = 0.06, p = 0.54). T1 and ECV were similar in both genders (p > 0.05). CONCLUSION: This study measured the median T1 and ECV of the pancreas in subjects with no pancreas disease. Pancreas shows longer T1 relaxation times in older population, whereas extracellular fraction remains unchanged. Median T1 values were different between two magnet strengths; however, no difference was seen between genders and ECV fractions.