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

Essential Content for Teaching Implementation Practice in Healthcare: A Mixed-Methods Study of Teams Offering Capacity-Building Initiatives

Background Applying the knowledge gained through implementation science can support the uptake of research evidence into practice; however, those doing and supporting implementation (implementation practitioners) may face barriers to applying implementation science in their work. One strategy to enhance individuals’ and teams’ ability to apply implementation science in practice is through training and professional development opportunities (capacity-building initiatives). Although there is an increasing demand for and offerings of implementation practice capacity-building initiatives, there is no universal agreement on what content should be included. In this study we aimed to explore what capacity-building developers and deliverers identify as essential training content for teaching implementation practice. Methods We conducted a convergent mixed-methods study with participants who had developed and/or delivered a capacity-building initiative focused on teaching implementation practice. Participants completed an online questionnaire to provide details on their capacity-building initiatives; took part in an interview or focus group to explore their questionnaire responses in depth; and offered course materials for review. We analyzed a subset of data that focused on the capacity-building initiatives’ content and curriculum. We used descriptive statistics for quantitative data and conventional content analysis for qualitative data, with the data sets merged during the analytic phase. We presented frequency counts for each category to highlight commonalities and differences across capacity-building initiatives. Results Thirty-three individuals representing 20 capacity-building initiatives participated. Study participants identified several core content areas included in their capacity-building initiatives: (1) taking a process approach to implementation; (2) identifying and applying implementation theories, models, frameworks, and approaches; (3) learning implementation steps and skills; (4) developing relational skills. In addition, study participants described offering applied and pragmatic content (e.g., tools and resources), and tailoring and evolving the capacity-building initiative content to address emerging trends in implementation science. Study participants highlighted some challenges learners face when acquiring and applying implementation practice knowledge and skills. Conclusions This study synthesized what experienced capacity-building initiative developers and deliverers identify as essential content for teaching implementation practice. These findings can inform the development, refinement, and delivery of capacity-building initiatives, as well as future research directions, to enhance the translation of implementation science into practice

Forced Notch Signaling Inhibits Commissural Axon Outgrowth in the Developing Chick Central Nerve System

BACKGROUND: A collection of in vitro evidence has demonstrated that Notch signaling plays a key role in the growth of neurites in differentiated neurons. However, the effects of Notch signaling on axon outgrowth in an in vivo condition remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the neural tubes of HH10-11 chick embryos were in ovo electroporated with various Notch transgenes of activating or inhibiting Notch signaling, and then their effects on commissural axon outgrowth across the floor plate midline in the chick developing central nerve system were investigated. Our results showed that forced expression of Notch intracellular domain, constitutively active form of RBPJ, or full-length Hes1 in the rostral hindbrain, diencephalon and spinal cord at stage HH10-11 significantly inhibited commissural axon outgrowth. On the other hand, inhibition of Notch signaling by ectopically expressing a dominant-negative form of RBPJ promoted commissural axonal growth along the circumferential axis. Further results revealed that these Notch signaling-mediated axon outgrowth defects may be not due to the alteration of axon guidance since commissural axon marker TAG1 was present in the axons in floor plate midline, and also not result from the changes in cell fate determination of commissural neurons since the expression of postmitotic neuron marker Tuj1 and specific commissural markers TAG1 and Pax7 was unchanged. CONCLUSIONS/SIGNIFICANCE: We first used an in vivo system to provide evidence that forced Notch signaling negatively regulates commissural axon outgrowth

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

Potent New Small-Molecule Inhibitor of Botulinum Neurotoxin Serotype A Endopeptidase Developed by Synthesis-Based Computer-Aided Molecular Design

Botulinum neurotoxin serotype A (BoNTA) causes a life-threatening neuroparalytic disease known as botulism. Current treatment for post exposure of BoNTA uses antibodies that are effective in neutralizing the extracellular toxin to prevent further intoxication but generally cannot rescue already intoxicated neurons. Effective small-molecule inhibitors of BoNTA endopeptidase (BoNTAe) are desirable because such inhibitors potentially can neutralize the intracellular BoNTA and offer complementary treatment for botulism. Previously we reported a serotype-selective, small-molecule BoNTAe inhibitor with a Kiapp value of 3.8±0.8 µM. This inhibitor was developed by lead identification using virtual screening followed by computer-aided optimization of a lead with an IC50 value of 100 µM. However, it was difficult to further improve the lead from micromolar to even high nanomolar potency due to the unusually large enzyme-substrate interface of BoNTAe. The enzyme-substrate interface area of 4,840 Å2 for BoNTAe is about four times larger than the typical protein-protein interface area of 750–1,500 Å2. Inhibitors must carry several functional groups to block the unusually large interface of BoNTAe, and syntheses of such inhibitors are therefore time-consuming and expensive. Herein we report the development of a serotype-selective, small-molecule, and competitive inhibitor of BoNTAe with a Ki value of 760±170 nM using synthesis-based computer-aided molecular design (SBCAMD). This new approach accounts the practicality and efficiency of inhibitor synthesis in addition to binding affinity and selectivity. We also report a three-dimensional model of BoNTAe in complex with the new inhibitor and the dynamics of the complex predicted by multiple molecular dynamics simulations, and discuss further structural optimization to achieve better in vivo efficacy in neutralizing BoNTA than those of our early micromolar leads. This work provides new insight into structural modification of known small-molecule BoNTAe inhibitors. It also demonstrates that SBCAMD is capable of improving potency of an inhibitor lead by nearly one order of magnitude, even for BoNTAe as one of the most challenging protein targets. The results are insightful for developing effective small-molecule inhibitors of protein targets with large active sites

Prospective study examining remote effects of botulinum toxin a in children with cerebral palsy

We examined the remote effects on muscle strength and functional decline of lower-extremity botulinum toxin A injections in children with cerebral palsy. This prospective study enrolled 34 children (19 boys, 15 girls; mean age, 7.7 years) diagnosed with spastic cerebral palsy. Patients were examined at baseline and 1 month to determine if they experienced a change in upper-extremity strength (handheld dynamometry) or function (Pediatric Outcomes Data Collection Instrument). Subjects were analyzed in aggregate and by dosing group (low dose, 0-10 U/kg body weight; high dose, 11-25 U/kg) to determine if injection dose was associated with a change in remote muscle strength or function. We measured baseline and 1-month postinjection strength in shoulder flexor, shoulder abductor, elbow flexor, elbow extensor, and finger flexor muscles. None of these remote muscle groups was significantly weaker at 1 month after injection. No correlation was evident between change in muscle strength and toxin dose. These findings indicate that doses of botulinum toxin A in the lower extremities, at up to 21 U/kg, do not affect upper-extremity strength. This information can help guide dosages of botulinum toxin A in the management of spasticity in children with cerebral palsy

The use of botulinum toxin therapy for lower-extremity spasticity in children with cerebral palsy

Hypertonicity is a leading cause of disability for children with cerebral palsy (CP). Botulinum toxin A (BTA) chemically denervates muscle tissue and is commonly used in the management of lower-extremity hypertonicity in children with CP because of its focal effects and wide safety margin. Randomized controlled trials have demonstrated that BTA injections in the ankle flexors, hamstrings, and adductors reduce spasticity and result in improved passive and active range of motion. In other studies, improvements in gait and measurements of functional outcome were found in appropriately selected children who had been injected with BTA. A multidisciplinary treatment approach that includes physical therapists, occupational therapists, orthotists, neurologists, physicians with expertise in performing botulinum toxin injections, orthopedic surgeons, and neurosurgeons is critical to optimize care in children with lower-extremity tone due to CP. In this paper, the authors propose treatment algorithms based on clinical presentation, detailed dosing, and technical information to optimize the treatment of these children. With a multidisciplinary approach, children with lower-extremity hypertonicity due to CP can experience improvements in muscle tone and function

Iatrogenic botulism due to therapeutic botulinum toxin a injection in a pediatric patient.

Botulinum toxin A is commonly used to reduce spasticity and dystonia in children with cerebral palsy. We report a pediatric patient who developed systemic botulism as a result of a severe overdose of the injected toxin (40 U/kg). This case highlights the importance of physicians having adequate knowledge of primate and human literature on the lethal dose, 50% of botulinum toxin A before injecting children

Iatrogenic botulism due to therapeutic botulinum toxin a injection in a pediatric patient

Botulinum toxin A is commonly used to reduce spasticity and dystonia in children with cerebral palsy. We report a pediatric patient who developed systemic botulism as a result of a severe overdose of the injected toxin (40 U/kg). This case highlights the importance of physicians having adequate knowledge of primate and human literature on the lethal dose, 50% of botulinum toxin A before injecting children