Relative mortality in U.S. Medicare beneficiaries with Parkinson disease and hip and pelvic fractures

BACKGROUND: Parkinson disease is a neurodegenerative disease that affects gait and postural stability, resulting in an increased risk of falling. The purpose of this study was to estimate mortality associated with demographic factors after hip or pelvic (hip/pelvic) fracture in people with Parkinson disease. A secondary goal was to compare the mortality associated with Parkinson disease to that associated with other common medical conditions in patients with hip/pelvic fracture. METHODS: This was a retrospective observational cohort study of 1,980,401 elderly Medicare beneficiaries diagnosed with hip/pelvic fracture from 2000 to 2005 who were identified with use of the Beneficiary Annual Summary File. The race/ethnicity distribution of the sample was white (93.2%), black (3.8%), Hispanic (1.2%), and Asian (0.6%). Individuals with Parkinson disease (131,215) were identified with use of outpatient and carrier claims. Cox proportional hazards models were used to estimate the risk of death associated with demographic and clinical variables and to compare mortality after hip/pelvic fracture between patients with Parkinson disease and those with other medical conditions associated with high mortality after hip/pelvic fracture, after adjustment for race/ethnicity, sex, age, and modified Charlson comorbidity score. RESULTS: Among those with Parkinson disease, women had lower mortality after hip/pelvic fracture than men (adjusted hazard ratio [HR] = 0.63, 95% confidence interval [CI]) = 0.62 to 0.64), after adjustment for covariates. Compared with whites, blacks had a higher (HR = 1.12, 95% CI = 1.09 to 1.16) and Hispanics had a lower (HR = 0.87, 95% CI = 0.81 to 0.95) mortality, after adjustment for covariates. Overall, the adjusted mortality rate after hip/pelvic fracture in individuals with Parkinson disease (HR = 2.41, 95% CI = 2.37 to 2.46) was substantially elevated compared with those without the disease, a finding similar to the increased mortality associated with a diagnosis of dementia (HR = 2.73, 95% CI = 2.68 to 2.79), kidney disease (HR = 2.66, 95% CI = 2.60 to 2.72), and chronic obstructive pulmonary disease (HR = 2.48, 95% CI = 2.43 to 2.53). CONCLUSIONS: Mortality after hip/pelvic fracture in Parkinson disease varies according to demographic factors. Mortality after hip/pelvic fracture is substantially increased among those with Parkinson disease. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence

HDAC Regulates Transcription at the Outset of Axolotl Tail Regeneration

Tissue regeneration is associated with complex changes in gene expression and post-translational modifications of proteins, including transcription factors and histones that comprise chromatin. We tested 172 compounds designed to target epigenetic mechanisms in an axolotl (Ambystoma mexicanum) embryo tail regeneration assay. A relatively large number of compounds (N = 55) inhibited tail regeneration, including 18 histone deacetylase inhibitors (HDACi). In particular, romidepsin, an FDA-approved anticancer drug, potently inhibited tail regeneration when embryos were treated continuously for 7 days. Additional experiments revealed that romidepsin acted within a very narrow, post-injury window. Romidepsin treatment for only 1-minute post amputation inhibited regeneration through the first 7 days, however after this time, regeneration commenced with variable outgrowth of tailfin tissue and abnormal patterning. Microarray analysis showed that romidepsin altered early, transcriptional responses at 3 and 6-hour post-amputation, especially targeting genes that are implicated in tumor cell death, as well as genes that function in the regulation of transcription, cell differentiation, cell proliferation, pattern specification, and tissue morphogenesis. Our results show that HDAC activity is required at the time of tail amputation to regulate the initial transcriptional response to injury and regeneration

Attomolar Detection of Botulinum Toxin Type A in Complex Biological Matrices

BACKGROUND: A highly sensitive, rapid and cost efficient method that can detect active botulinum neurotoxin (BoNT) in complex biological samples such as foods or serum is desired in order to 1) counter the potential bioterrorist threat 2) enhance food safety 3) enable future pharmacokinetic studies in medical applications that utilize BoNTs. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe a botulinum neurotoxin serotype A assay with a large immuno-sorbent surface area (BoNT/A ALISSA) that captures a low number of toxin molecules and measures their intrinsic metalloprotease activity with a fluorogenic substrate. In direct comparison with the "gold standard" mouse bioassay, the ALISSA is four to five orders of magnitudes more sensitive and considerably faster. Our method reaches attomolar sensitivities in serum, milk, carrot juice, and in the diluent fluid used in the mouse assay. ALISSA has high specificity for the targeted type A toxin when tested against alternative proteases including other BoNT serotypes and trypsin, and it detects the holotoxin as well as the multi-protein complex form of BoNT/A. The assay was optimized for temperature, substrate concentration, size and volume proportions of the immuno-sorbent matrix, enrichment and reaction times. Finally, a kinetic model is presented that is consistent with the observed improvement in sensitivity. CONCLUSIONS/SIGNIFICANCE: The sensitivity, specificity, speed and simplicity of the BoNT ALISSA should make this method attractive for diagnostic, biodefense and pharmacological applications

High dose botulinum toxin A for the treatment of lower extremity hypertonicity in children with cerebral palsy

The aim of this study was to determine the safety profile of high dose (15-25 units/kg) of botulinum toxin A (BTX-A) in children with cerebral palsy (CP) and increased lower extremity muscle tone. We performed a retrospective review of 929 patient encounters at the Movement Disorders Center at Washington University. A total of 261 patients (105 females; 156 males) were treated during these visits, ages 6 months to 21 years (mean 8 y 4 mo [SD 4 y 8 mo]). Ambulatory ability at the time of BTX-A injection was independent ambulation (36.4%, n=95), ambulation with a walker (27.6%, n=72), and non-ambulatory (31.8%, n=83). A few patients (4.2%, n=11) were able to ambulate with a cane or crutch at the time of injection. Participants were characterized according to BTX-A dose, CP etiology, motor involvement pattern, muscles injected, ambulatory ability, and use of oral tone medications. Follow-up records were searched for reported adverse events (AEs), with a mean time to AE assessment of 6.5 weeks (SD 3.38). The AE occurrence was determined for doses of 0 to 4.9 units/kg, 5 to 9.9 units/kg, 10 to 14.9 units/kg, 15 to 19.9 units/kg, and 20 to 25 units/kg. The overall AE occurrence was 4.2%. Standard doses of BTX-A had side-effect occurrences of 3.9% for 5 to 10 units/kg and 7.6% for 10 to 15 units/kg. Among higher doses (15-20 units/kg and 20-25 units/kg) the AE occurrence was 3.5% and 8.6% respectively. No patient developed botulism. AEs were randomly distributed across dosing groups, CP etiologies, clinical phenotypes, ambulatory status, and treatment duration. All doses were associated with a significant increase in passive range of motion using the Tardieu scale. We conclude that higher dose BTX-A is safe in children with a spectrum of CP phenotypes and are well tolerated over time