Abstract 8: Functional and societal limitation and disability outcomes in a randomized control trial of botulinum toxin type a for children with spastic diplegic cerebral palsy.

Objectives: To document the functional and societal limitation and disability level effects (National Center for Medical Rehabilitation Research framework) of gastrocnemius botulinum toxin type A (BTX) injections in children with spastic diplegic cerebral palsy (CP). Design: Randomized double-masked placebo controlled trial. Setting: Tertiary care children’s hospital. Participants: 33 children with spastic diplegic CP, (mean age, 5.5y; range, 3.0-11.9y), of whom 19 were boys (subjects’ Gross Motor Function Classification System levels: level I=12; level II=15; level III=6). Intervention: All participants were randomized to receive either 12U/kg BTX or placebo saline injections. Main Outcome Measures: Functional limitation and disability: Gross Motor Function Measure (GMFM-88, GMFM-66), energy cost index (ECI), and Canadian Occupational Performance Measure (COPM) performance scores were collected at selected weeks postinjection. Societal limitation: COPM satisfaction scores and Goal Attainment Scaling (GAS) were obtained at 12 and 24 weeks. Results: GMFM-88 total score (P=.00) and the GMFM-66 (P=.03) significantly increased for the treatment group compared with the placebo group at 24 weeks. No significant group differences were found for the ECI at any follow-up point. The COPM performance scores were significantly greater for the treatment group at 12 weeks (P=.04) and approached a significant difference at 24 weeks (P=.06). COPM satisfaction scores and GAS did not differ significantly by group at any follow-up point. Conclusions: The GMFM-88 and -66 scores and COPM performance scores demonstrated a significant difference at 12 weeks, with a diminishing effect noted at 24 weeks. In contrast, satisfaction with performance as measured by the COPM satisfaction scores and performance and importance of goals set as measured by the GAS did not differ significantly between treatment groups. These data documented consistent changes on the functional limitation and disability levels up to 6 months posttreatment, but not on the societal outcome level.     

Long-term safety and efficacy of continuous intrathecal baclofen

Long-term continuous intrathecal baclofen (CITB) infusion is a treatment option used to manage otherwise intractable spasticity and is delivered via an implantable pump. The purpose of this single-center multidisciplinary review was to report on the long-term safety and efficacy of CITB in the treatment of 21 children with intractable severe spasticity of cerebral origin. Nineteen recipients had spastic quadriplegia and two had spastic diplegia. Seven recipients had level IV severity on the Gross Motor Functional Classification System and 14 had level V. Median age at implantation was 12 years (range 4 to 20). Fifteen recipients were male, 6 were female. Seventeen recipients were alive at the end of the follow-up period (31 to 78 months; mean 53, SD 4). The Ashworth scale showed a substantial decrease in spasticity in the upper and lower extremities at 6 months and at the most recent follow-up. The Gross Motor Function Measure and Pediatric Evaluation of Disability Inventory showed no functional change. Most treatment goals were at least partly achieved. Caregivers reported a reduction in use of oral medication for spasticity, and improvements in comfort, function, and ease of care. Caregiver satisfaction was high. During 80 recipient-years of pump operation, 153 treatment-associated adverse events occurred: 27 of these were device-related. There were four deaths unrelated to CITE, including one from acute pancreatitis. Our findings might assist in establishing patient selection criteria and treatment goals, improving patient follow-up, and monitoring adverse events.     

Pregnancy after cryopreservation of donor oocytes and preimplantation genetic diagnosis of embryos in a patient with ovarian failure

OBJECTIVE: To describe the successful use of preimplantation genetic diagnosis to assess the prevalence of meiotic errors after oocyte cryopreservation in an oocyte donation cycle. DESIGN: Case report. SETTING: Private IVF center. PATIENT(S): A 42.6-year-old patient with ovarian failure. INTERVENTION(S): A donor oocyte IVF cycle with cryopreservation of oocytes followed by thaw, fertilization of oocytes, preimplantation genetic diagnosis for selective aneuploidy, and ET. MAIN OUTCOME MEASURE(S): Preimplantation genetic analysis of chromosomes 13,16,18, 21,22, X, and Y with fluorescence in-situ hybridization. RESULT(S): The recipient's initial serum beta-hCG level was 196 mIU/mL 15 days after oocyte retrieval. An initial ultrasound at the sixth week of gestation revealed two gestational sacs. A second ultrasound 1 week later showed a monochorionic twin in sac A and a singleton pregnancy in sac B. Fetal cardiac activity was visualized for all gestations. CONCLUSION(S): This case illustrates the feasibility of cryopreservation of donor oocytes combined with preimplantation genetic diagnosis for clinical use in those settings where there may be an increased risk of spindle-related abnormalities.     

Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG-PML/RARA transgenic mice

Therapy-related acute myelogenous leukemia (t-AML) is an important late adverse effect of alkylator chemotherapy. Susceptibility to t-AML has a genetic component, yet specific genetic variants that influence susceptibility are poorly understood. We analyzed an F(2) intercross (n = 282 mice) between mouse strains resistant or susceptible to t-AML induced by the alkylator ethyl-N-nitrosourea (ENU) to identify genes that regulate t-AML susceptibility. Each mouse carried the hCG-PML/RARA transgene, a well-characterized initiator of myeloid leukemia. In the absence of ENU treatment, transgenic F(2) mice developed leukemia with higher incidence (79.4% vs 12.5%) and at earlier time points (108 days vs 234 days) than mice in the resistant background. ENU treatment of F(2) mice further increased incidence (90.4%) and shortened median survival (171 vs 254 days). We genotyped F(2) mice at 384 informative single nucleotide polymorphisms across the genome and performed quantitative trait locus (QTL) analysis. Thirteen QTLs significantly associated with leukemia-free survival, spleen weight, or white blood cell count were identified on 8 chromosomes. These results suggest that susceptibility to ENU-induced leukemia in mice is a complex trait governed by genes at multiple loci. Improved understanding of genetic risk factors should lead to tailored treatment regimens that reduce risk for patients predisposed to t-AML.     

Vascular repair after menstruation involves regulation of vascular endothelial growth factor-receptor phosphorylation by sFLT-1

Regeneration of the endometrium after menstruation requires a rapid and highly organized vascular response. Potential regulators of this process include members of the vascular endothelial growth factor (VEGF) family of proteins and their receptors. Although VEGF expression has been detected in the endometrium, the relationship between VEGF production, receptor activation, and endothelial cell proliferation during the endometrial cycle is poorly understood. To better ascertain the relevance of VEGF family members during postmenstrual repair, we have evaluated ligands, receptors, and activity by receptor phosphorylation in human endometrium throughout the menstrual cycle. We found that VEGF is significantly increased at the onset of menstruation, a result of the additive effects of hypoxia, transforming growth factor-alpha, and interleukin-1beta. Both VEGF receptors, FLT-1 and KDR, followed a similar pattern. However, functional activity of KDR, as determined by phosphorylation studies, revealed activation in the late menstrual and early proliferative phases. The degree of KDR phosphorylation was inversely correlated with the presence of sFLT-1. Endothelial cell proliferation analysis in endometrium showed a peak during the late menstrual and early proliferative phases in concert with the presence of VEGF, VEGF receptor phosphorylation, and decrease of sFLT-1. Together, these results suggest that VEGF receptor activation and the subsequent modulation of sFLT-1 in the late menstrual phase likely contributes to the onset of angiogenesis and endothelial repair in the human endometrium.