Multislice display of the fetal face using 3-dimensional ultrasonography.

OBJECTIVE: Multislice 3-dimensional ultrasonography (3DUS) allows ultrasonographic volume data to be presented in parallel slices. Our aim was to develop a technique using a multislice display to specifically differentiate the maxilla (primary palate) from the mandible and to display the orbits in a single image in fetuses with normal anatomy and cleft lip/palate. METHODS: Three-dimensional ultrasonographic volumes of the fetal face were acquired in 142 patients (49 prospective and 93 retrospective). Fifteen patients had a confirmed diagnosis of cleft lip with or without cleft palate. Three readers manipulated volumes in a standardized fashion to show the orbits, maxilla, and mandible. The best interslice distance was determined. Image quality was assessed. RESULTS: The mean gestational age of the fetuses was 23 weeks (range, 11-38 weeks). The mean interval distance used varied from 3 to 3.7 mm (range, 1-5.8 mm). The interval distance correlated with gestational age (Spearman rho = 0.66; P < .0001). Image quality obtained through multislice evaluation of the orbits, maxilla, and mandible was high and did not vary with gestational age, interval distance, retrospective versus prospective acquisition, or 3DUS versus 4-dimensional volumes. A higher image quality rating was associated with axial and sagittal planes of acquisition as opposed to coronal and oblique planes (Wilcoxon P < .002). All cases of cleft lip with or without cleft palate were correctly identified retrospectively. CONCLUSIONS: Multislice 3DUS evaluation of the fetal face can be performed successfully with high image quality. This technique can be used to consistently and accurately differentiate the fetal primary palate and mandible. Fetuses with cleft lip with or without cleft palate can be identified with confidence.

Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.

OBJECTIVE: To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN: Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING: Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES: Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS: Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS: LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.

Potential outcome measures and trial design issues for multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disorder exhibiting a combination of parkinsonism, cerebellar ataxia, and autonomic failure. A disease-specific scale, the Unified Multiple System Atrophy Rating Scale (UMSARS), has been developed and validated to measure progression of MSA, but its use as an outcome measure for therapeutic trials has not been evaluated. On the basis of twelve months of follow-up from an observational study of 67 patients with probable MSA, we evaluated three disease-specific scores: Activities of Daily Living, Motor Examination, and a combined score from the UMSARS and two general health scores, the Physical Health and Mental Health scores of the SF-36 health survey, for their use as outcome measures in a therapeutic trial. We discuss related design issues and provide sample size estimates. Scores based on the disease-specific UMSARS seemed to be equal or superior to scores based on the SF-36 health survey. They appeared to capture disease progression, were well correlated and required the smallest sample size. The UMSARS Motor Examination score exhibited the most favorable characteristics as an outcome measure for a therapeutic trial in MSA with 1 year of follow-up.