Targeted muscle reinnervation prevents and reverses rat pain behaviors after nerve transection.

ABSTRACT: Targeted muscle reinnervation (TMR) is a clinical intervention that is rapidly becoming common in major limb amputation to prevent or reduce amputation-related pain. However, TMR is much less effective when applied long after injury compared with acute TMR. Since the mechanisms governing pain relief in TMR of amputated nerves are unknown, we developed a preclinical model as a platform for mechanistic examination. Following spared nerve injury (SNI), rats underwent either TMR, simple neuroma excision, or a sham manipulation of the injury site. These interventions were performed immediately or delayed (3 or 12 weeks) after SNI. Pain behavior was measured as sensitivity to mechanical stimuli (pin, von Frey, and dynamic brush) and thermal stimuli (acetone and radiant heat). Spared nerve injury produced hypersensitivity to all mechanical stimuli and cold, which persisted after sham surgery. Targeted muscle reinnervation at the time of SNI prevented the development of pain behaviors and performing TMR 3 weeks after SNI reversed pain behaviors to baseline. By contrast, TMR performed at 12 weeks after SNI had no effect on pain behaviors. Neuroma excision resulted in significantly less reduction in hyperalgesia compared with TMR when performed 3 weeks after SNI but had no effect at 12 weeks after SNI. In this model, the pain phenotype induced by nerve transection is reduced by TMR when performed within 3 weeks after injury. However, TMR delayed 12 weeks after injury fails to reduce pain behaviors. This replicates clinical experience with limb amputation, supporting validity of this model for examining the mechanisms of TMR analgesia.

Student Leadership Development Initiative: Benefits of a Unique Medical Student Organization.

BACKGROUND: The Student Leadership Development Initiative was founded at the Medical College of Wisconsin to unite local physician leaders with Medical College of Wisconsin students to develop leadership skills and prepare for careers expanding beyond clinical practice. METHODS: An anonymous survey was distributed to 246 current and past Student Leadership Development Initiative participants, probing confidence in leadership skills, professional goals, and the perceived importance of leadership training. Feedback interviews were also conducted. RESULTS: Respondents reported improvement in areas such as compassion, leadership, and development of career goals. The perceived benefit for developing professional goals and compassion are positively related (P < 0.01) to the number of sessions attended. DISCUSSION: Survey results highlight the importance of leadership training in medical education and suggest an integration strategy for a successful leadership training platform.

Genetic variants in DGAT1 cause diverse clinical presentations of malnutrition through a specific molecular mechanism.

BACKGROUND: DGAT1, a gene encoding a protein involved in lipid metabolism, has been recently implicated in causing a rare nutritional and digestive disease presenting as Congenital Diarrheal Disorder (CDD). Genetic causes of malnutrition can be classified as metabolic disorders, caused by loss of a specific enzyme's function. However, disease driven by genetic variants in lipid metabolism genes is not well understood, and additional information is needed to better understand these effects. METHODS: We gathered a multi-institutional cohort of undiagnosed patients with a constellation of phenotypes presenting as malnutrition and metal ion dysregulation. Clinical Whole Exome Sequencing (WES) was performed on four patients and their unaffected parents. We prioritized genetic variants based on multiple criteria including population allele frequency and presumed inheritance pattern, and identified a candidate gene. Computational modeling was used to investigate if the altered amino acids are likely to result in a dysfunctional enzyme. RESULTS: We identified a multi-institutional cohort of patients presenting with malnutrition-like symptoms and likely pathogenic genomic variants within DGAT1. Multiple approaches were used to profile the effect these variants have on protein structure and function. Laboratory and nutritional intervention studies showed rapid and robust patient responses. CONCLUSIONS: This report adds on to the database for existing mutations known within DGAT1, a gene recently implicated with CDD, and also expands its clinical spectrum. Identification of these DGAT1 mutations by WES has allowed for changes in the patients' nutritional rehabilitation, reversed growth failure and enabled them to be weaned off of total parenteral nutrition (TPN).

Evaporative Cooling Hydrogel Packaging for Storing Biologics Outside of the Cold Chain.

Stabilizing thermolabile pharmaceuticals outside of the cold chain has the potential to alleviate some of the logistical and monetary burden of providing health care access in the developing world. Evaporative cooling hydrogel packaging is designed to extend the storage stability of existing pharmaceutical products without the need for reformulation. Hydrogels with high water content and reversible hydrophilicity offer a promising platform for reducing storage temperatures without refrigeration. As a model, poly(N-isopropylacrylamide) is selected as a basis for creating a potentially low cost and easy-to-fabricate hydrogels.

Fabrication of fillable microparticles and other complex 3D microstructures.

Three-dimensional (3D) microstructures created by microfabrication and additive manufacturing have demonstrated value across a number of fields, ranging from biomedicine to microelectronics. However, the techniques used to create these devices each have their own characteristic set of advantages and limitations with regards to resolution, material compatibility, and geometrical constraints that determine the types of microstructures that can be formed. We describe a microfabrication method, termed StampEd Assembly of polymer Layers (SEAL), and create injectable pulsatile drug-delivery microparticles, pH sensors, and 3D microfluidic devices that we could not produce using traditional 3D printing. SEAL allows us to generate microstructures with complex geometry at high resolution, produce fully enclosed internal cavities containing a solid or liquid, and use potentially any thermoplastic material without processing additives.

Impact of starch content on protein adsorption characteristics in amphiphilic hybrid graft copolymers.

Amphiphilic hybrid graft copolymers were synthesized using a graft-to methodology and their protein adsorption profiles studied. Three different hydrophilic side chains were studied: hydroxypropylated high amylose starch, maltodextrin, and polyethylene glycol (PEG). In the high amylose starch compositions, there was a pronounced decrease in protein adsorption with increasing polysaccharide content. As the starch content in the graft copolymers increased from 10 wt% to 53 wt%, BSA protein adsorption decreased by 83% whereas fibrinogen adsorption was reduced by 40%. Comparisons between the starch-containing hybrid polymers and their respective hydrophobic urethane-linked polyesters were also made. Hybrid 53, containing 53 wt% starch, showed a 85% reduction in BSA adsorption and 51% reduction in fibrinogen relative to their urethane-linked polyester backbone controls. Grafting branched high amylopectin-derived maltodextrin to the synthetic polymer backbones also conferred modest protein resistance to the hydrophobic backbone polymer. Lastly, it was found that a high amylose graft structure provided comparable, if not slightly more effective, protein resistance compared to a similarly constructed PEG-containing amphiphilic copolymer.