A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy.

OBJECTIVE: Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We conducted a safety trial of a neutralizing antibody to myostatin, MYO-029, in adult muscular dystrophies (Becker muscular dystrophy, facioscapulohumeral dystrophy, and limb-girdle muscular dystrophy). METHODS: This double-blind, placebo-controlled, multinational, randomized study included 116 subjects divided into sequential dose-escalation cohorts, each receiving MYO-029 or placebo (Cohort 1 at 1 mg/kg; Cohort 2 at 3 mg/kg; Cohort 3 at 10 mg/kg; Cohort 4 at 30 mg/kg). Safety and adverse events were assessed by reported signs and symptoms, as well as by physical examinations, laboratory results, echocardiograms, electrocardiograms, and in subjects with facioscapulohumeral dystrophy, funduscopic and audiometry examinations. Biological activity of MYO-029 was assessed through manual muscle testing, quantitative muscle testing, timed function tests, subject-reported outcomes, magnetic resonance imaging studies, dual-energy radiographic absorptiometry studies, and muscle biopsy. RESULTS: MYO-029 had good safety and tolerability with the exception of cutaneous hypersensitivity at the 10 and 30 mg/kg doses. There were no improvements noted in exploratory end points of muscle strength or function, but the study was not powered to look for efficacy. Importantly, bioactivity of MYO-029 was supported by a trend in a limited number of subjects toward increased muscle size using dual-energy radiographic absorptiometry and muscle histology. INTERPRETATION: This trial supports the hypothesis that systemic administration of myostatin inhibitors provides an adequate safety margin for clinical studies. Further evaluation of more potent myostatin inhibitors for stimulating muscle growth in muscular dystrophy should be considered.

Cerebral infarction in eclampsia.

OBJECTIVE: This study was undertaken to characterize the neuroimaging findings of cerebral edema associated with eclamptic seizures by use of diffusion-weighted magnetic resonance imaging (MRI). STUDY DESIGN: During the 3-year period ending March 2002, 27 nulliparous women with eclampsia were evaluated with diffusion-weighted MRI and apparent diffusion coefficient mapping. Those with findings of restricted diffusion suggestive of cytotoxic edema underwent neuroimaging again 6 weeks post partum. RESULTS: All but 2 of these 27 women (93%) had reversible vasogenic edema. Six were also found to have areas of cytotoxic edema consistent with cerebral infarction. Five of these 6 women had persistent imaging findings of infarction when studied post partum, however, without clinical neurologic deficits. CONCLUSION: The spectrum of cerebral lesions in eclampsia as seen with MRI varies from initially reversible areas of vasogenic edema that may progress to cytotoxic edema and infarction in up to a fourth of women.

MR-guided catheter navigation of the intracranial subarachnoid space.

Percutaneous intraspinal navigation (PIN) is a new minimally invasive approach to the CNS. The authors studied the utility of MR-guided intracranial navigation following access to the subarachnoid compartment via PIN. The passive tracking technique was employed to visualize devices during intracranial navigation. Under steady-state free precession (SSFP) MR-guidance a microcatheter-microguidewire was successfully navigated to multiple brain foci in two cadavers. SSFP MR fluoroscopy possesses adequate contrast and temporal resolution to allow MR-guided intracranial navigation.

Second-opinion magnetic resonance imaging for suspected fetal central nervous system abnormalities.

OBJECTIVE: The purpose of this study was to evaluate the relationship of magnetic resonance imaging and gestational age in the setting of fetuses with suspected abnormalities of the central nervous system that were detected by ultrasound scanning. STUDY DESIGN: Multiplanar magnetic resonance studies were performed in fetuses with suspected central nervous system abnormalities on ultrasound scanning. Magnetic resonance imaging was evaluated for its ability to provide additional information, change the diagnosis, or impact obstetric treatment. Patients were grouped by gestational age at the time of magnetic resonance imaging. RESULTS: Magnetic resonance imaging provided additional information in 46 of 72 pregnancies (64%), changed the diagnosis in 20 of 72 pregnancies (28%), and potentially altered the timing or mode of delivery in 8 of 72 pregnancies (11%). Additional information increased with increasing gestational age groups (P =.03). CONCLUSION: Magnetic resonance imaging provided additional information in two thirds of the fetuses with central nervous system abnormalities, which was significantly increased with increasing gestation. Antenatal treatment was influenced by magnetic resonance imaging in 11% of the cases.

T2 mapping of muscle.

Muscle activation produces increases in magnetic resonance ( T(2)) signal intensity leading to recruitment images that demonstrate spatial patterns and intensity of muscle activation. These T(2) activation maps are useful for visualizing and quantifying various aspects of muscle function. Activity-dependent changes in T(2) result from an increase in the T(2) relaxation time of muscle water. The current state of investigation indicates that the mechanism of increased T(2) results from osmotically driven shifts of muscle water that increase the volume of the intracellular space and from intracellular acidification resulting from the end products of metabolism. Although the spatial resolution of magnetic resonance imaging is still insufficient to map territories of individual motor units, it is possible to demonstrate nonuniform activation between subregions or compartments of muscle. Taken together, the attributes of the T(2) mapping technique hold great potential for demonstrating aberrant muscle activation patterns in pathology and positive adaptation to exercise or rehabilitative intervention.