Managing Chronic Regional Pain Syndrome: The Potential Impact of the Food and Drug Omnibus Reform Act.

Complex regional pain syndrome (CRPS) is a neurological disorder characterized by persistent limb symptoms. With there being no definitive tests, diagnosis can be challenging. The Budapest criteria are the standard for diagnosis. The underlying mechanisms of CRPS involve changes in skin innervation, sensitization of the nervous system, inflammatory cytokines, and genetic and psychological factors. Treatment typically involves a multidisciplinary approach. We present a case of a 71-year-old male with CRPS involving the right upper extremity and a complex history of management including physical therapy, oxycodone, muscle relaxers, non-steroidal anti-inflammatory drugs, and multiple stellate ganglion blocks. The patient manages his pain with off-label medications, including methadone, duloxetine, and pregabalin. In the United States, the management of chronic pain may be affected by potential usage restrictions imposed by the Food and Drug Omnibus Reform Act (FDORA). Under this new act, physicians may face limitations in prescribing off-label medications for specific diagnoses. We aim to highlight the need for prioritizing patient care and individualized treatment in healthcare policy decision-making.

Differential Eye Expression of Xenopus Acyltransferase Gnpat and Its Biochemical Characterization Shed Light on Lipid-Associated Ocular Pathologies.

Purpose: Plasmalogens (Plgs) are highly abundant lipids in the retina, and their deficiency leads to severe abnormalities during eye development. The first acylation step in the synthesis of Plgs is catalyzed by the enzyme glyceronephosphate O-acyltransferase (GNPAT), which is also known as dihydroxyacetone phosphate-acyltransferase (EC 2.3.1.42). GNPAT deficiency produces rhizomelic chondrodysplasia punctata type 2, a genetic disorder associated with developmental ocular defects. Despite the relevance of retinal Plgs, our knowledge of the mechanisms that regulate their synthesis, and the role of GNPAT during eye development is limited. Methods: Using the Xenopus laevis model organism, we characterized by in situ hybridization the expression pattern of gnpat and compared it to glycerol 3-phosphate acyltransferase mitochondrial (gpam or gpat1) during eye neurogenesis, lamination, and morphogenesis. The Xenopus Gnpat was biochemically characterized in a heterologous expression system in yeast. Results: During development, gnpat is expressed in proliferative cells of the retina and lens, and post-embryogenesis in proliferative cells of the ciliary marginal zone and lens epithelium. In contrast, gpam expression is mainly restricted to photoreceptors. Xenopus Gnpat expressed in yeast is present in both soluble and membrane fractions, but only the membrane-bound enzyme displays activity. The amino terminal of Gnpat, conserved in humans, shows lipid binding capacity that is enhanced by phosphatidic acid. Conclusions: Enzymes involved in the Plgs and glycerophospholipid biosynthetic pathways are differentially expressed during eye morphogenesis. The gnpat expression pattern and the molecular determinants regulating Gnpat activity advance our knowledge of this enzyme, contributing to our understanding of the retinal pathophysiology associated with GNPAT deficiency.

Mechanisms of improved erythroid progenitor growth with removal of chronic stress after trauma.

BACKGROUND: Erythropoietic dysfunction after trauma and critical illness is associated with anemia, persistent inflammation, increased hematopoietic progenitor cell mobilization from the bone marrow, and reduced erythroid progenitor growth. Yet the duration and reversibility of these postinjury bone marrow changes remain unknown. This study sought to determine whether removal of chronic postinjury stress could induce improvements in erythroid progenitor growth. METHODS: Sprague-Dawley rats (n = 8-11/group) were assigned to the following: naïve, lung contusion and hemorrhagic shock, lung contusion and hemorrhagic shock plus daily chronic stress for 7 days followed by 7 days of routine handling to allow recovery (lung contusion and hemorrhagic shock + chronic stress 7), or lung contusion and hemorrhagic shock plus chronic stress for 14 days (lung contusion and hemorrhagic shock + chronic stress 14). Circulating CD117+CD71+ erythroid progenitors were detected by flow cytometry. Rodents were killed on day 14, and bone marrow erythroid progenitor growth and erythroid transcription factors were assessed. Differences were assessed by analysis of variance (P < .05). RESULTS: Compared to lung contusion and hemorrhagic shock + chronic stress 14, lung contusion and hemorrhagic shock + chronic stress 7 rodents had improved hemoglobin (8% ± 10% increase vs 6% ± 10% decrease) with fewer mobilized erythroid progenitors (898 × vs 1,524 cells), lower granulocyte-colony stimulating factor levels (3.1 ± 1.1 × pg/mL vs 5.9 ± 1.8 pg/mL), and improved erythroid progenitor growth. Cessation of stress had no impact on erythroid transcription factors GATA-1, GATA-2, LMO2, or KLF1. CONCLUSION: Improvements in erythroid progenitor growth and reduced hematopoietic progenitor cell mobilization were seen 7 days after cessation of chronic stress and were associated with an improvement in hemoglobin. Early bone marrow erythropoietic functional recovery may result from resolution of hematopoietic progenitor mobilization rather than upregulation of pro-erythroid transcription factors. This study suggests that postinjury anemia is reversible and has the potential to improve with the cessation of stress.

Prolonged Chronic Stress and Persistent Iron Dysregulation Prevent Anemia Recovery Following Trauma.

Introduction Following major trauma, persistent injury-associated anemia is associated with organ failure, increased length of stay and mortality. We hypothesize that prolonged adrenergic stimulation following trauma is directly responsible for persistent iron dysfunction that impairs anemia recovery. Materials and Methods Naïve rodents, lung contusion and hemorrhagic shock followed by daily handling for 13 d (LCHS), LCHS followed by 6 d of restraint stress and 7 d of daily handling (LCHS/CS-7) and LCHS/CS followed by 13 d of restraint stress with day and/or night disruption (LCHS/CS-14) were sacrificed on day 14. Hemoglobin, plasma, urine, bone marrow/liver inflammatory and erythropoietic markers were analyzed. Results LCHS/CS-14 led to a significant decline in weight gain and persistently elevated plasma and urine inflammatory markers. Liver IL-6, IL-1ß and hepcidin expression were significantly increased following LCHS/CS-14. LCHS/CS-14 also had impaired anemia recovery with reduced plasma transferrin and erythropoietin receptor expression. Conclusion Prolonged chronic stress following trauma/hemorrhagic shock led to sustained inflammation with increased expression of IL-1ß, IL-6 and hepcidin with decreased iron availability for uptake into erythroid progenitor cells and a lack of anemia recovery.

Stress-related changes in the gut microbiome after trauma.

BACKGROUND: The gut microbiome protects the host from infection by promoting epithelial integrity and providing basal immunologic stimulation. Disruption of this delicate ecosystem is linked to morbidity and mortality among critically ill patients, but the impact of traumatic injury on the gut microbiome is poorly understood. This study sought to identify alterations in gut microbiota following trauma and persistent stress in rodents without confounding antibiotics. METHODS: Male Sprague-Dawley rats aged 9 weeks to 11 weeks were randomized to naive, lung contusion with hemorrhagic shock (LCHS), and LCHS plus either 7 (LCHS/CS 7/7) or 14 days (LCHS/CS 14) of restraint cylinder stress for 2 hours daily. Stool was collected on Days 0, 3, 7, and 14 for bacterial whole genome DNA isolation. Alpha diversity, or the number and relative abundance of unique bacterial species within each cohort, was assessed using Chao1 indices. Beta diversity, or the measure of differences in biodiversity across cohorts, was assessed by principle coordinate analysis. False discovery rate correction was applied to all statistical analyses and corrected for cohousing effects. RESULTS: Rodent groups subject to restraint stress demonstrated a progressive increase in alpha diversity over time. These microbiota changes resolved after cessation of stress (LCHS/CS 7/7) but continued to increase among rats subjected to ongoing stress (LCHS/CS 14). The LCHS/CS 7/7 also demonstrated reductions in class Actinobacteria and increased abundance of the genus Bacteroides by Day 7, which resolved by Day 14. Increased abundance of Bacteroides was also noted in the LCHS/CS 14 cohort, suggesting the role of chronic stress in its destabilization. CONCLUSION: This study points to persistent stress as a potential source of the destabilization of microbial diversity seen after trauma. This lack of microbiota stability could be associated with worse long-term outcomes in critically ill trauma patients. Further studies are warranted to elucidate mechanistic pathways and potential therapeutic modalities.

Engineering bio-inspired peptide-polyurea hybrids with thermo-responsive shape memory behaviour.

Inspired by Nature's tunability driven by the modulation of structural organization, we utilize peptide motifs as an approach to tailor not only hierarchical structure, but also thermo-responsive shape memory properties of conventional polymeric materials. Specifically, poly(ß-benzyl-L-aspartate)-b-poly(dimethylsiloxane)-b-poly(ß-benzyl-L-aspartate) was incorporated as the soft segment in peptide-polyurea hybrids to manipulate hierarchical ordering through peptide secondary structure and a balance of inter- and intra-molecular hydrogen bonding. Employing these bioinspired peptidic polyureas, we investigated the influence of secondary structure on microphase-separated morphology, and shape fixity and recovery via attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), small-angle X-ray scattering (SAXS) and dynamic mechanical analysis (DMA). The ß-sheet motifs promoted phase mixing through extensive inter-molecular hydrogen bonding between the hard block and peptide segments and provided an increased chain elasticity, resulting in decreased shape fixity compared to a non-peptidic control. In contrast, intra-molecular hydrogen bonding driven by the α-helical arrangements yielded a microphase-separated and hierarchically ordered morphology, leading to an increase in the shape fixing ratio. These results indicate that peptide secondary structure provides a convenient handle for tuning shape memory properties by regulating hydrogen bonding with the surrounding polyurea hard segment, wherein extent of hydrogen bonding and phase mixing between the peptidic block and hard segment dictate the resulting shape memory behaviour. Furthermore, the ability to shift secondary structure as a function of temperature was also demonstrated as a pathway to influence shape memory response. This research highlights that peptide secondary conformation influences the hierarchical ordering and modulates the shape memory response of peptide-polymer hybrids. We anticipate that these findings will enable the design of smart bio-inspired materials with responsive and tailored function via a balance of hydrogen bonding character, structural organization, and mechanics.

100th Anniversary of Macromolecular Science Viewpoint: Engineering Supramolecular Materials for Responsive Applications-Design and Functionality.

Supramolecular polymers allow access to dynamic materials, where noncovalent interactions can be used to offer both enhanced material toughness and stimuli-responsiveness. The versatility of self-assembly has enabled these supramolecular motifs to be incorporated into a wide array of glassy and elastomeric materials; moreover, the interaction of these noncovalent motifs with their environment has shown to be a convenient platform for controlling material properties. In this Viewpoint, supramolecular polymers are examined through their self-assembly chemistries, approaches that can be used to control their self-assembly (e.g., covalent cross-links, nanofillers, etc.), and how the strategic application of supramolecular polymers can be used as a platform for designing the next generation of smart materials. This Viewpoint provides an overview of the aspects that have garnered interest in supramolecular polymer chemistry, while also highlighting challenges faced and innovations developed by researchers in the field.

Effect of Beta-Blockade on the Expression of Regulatory MicroRNA after Severe Trauma and Chronic Stress.

BACKGROUND: Beta-blockade administration after lung contusion, hemorrhagic shock, and chronic stress has been shown to improve bone marrow function, decrease hypercatecholaminemia, and reduce inflammation. MicroRNAs (miR) are critical biologic regulators that can downregulate gene expression by causing messenger RNA degradation or inhibition of translation. This study sought to expand our understanding of the molecular mechanisms underlying the reduced inflammatory response after the administration of beta-blockade (BB) in our rodent trauma model. STUDY DESIGN: Male Sprague-Dawley rats aged 8 to 9 weeks were randomized to lung contusion, hemorrhagic shock with daily restraint stress (LCHS/CS) or LCHS/CS plus propranolol (LCHS/CS+BB). Restraint stress occurred 2 hours daily after LCHS. Propranolol (10 mg/kg) was given daily until day 7. Total RNA and miR were isolated from bone marrow and genome-wide miR expression patterns were assayed. Bone marrow cytokine expression was determined with quantitative polymerase chain reaction. RESULTS: LCHS/CS led to significantly increased bone marrow expression of interleukin (IL) 1ß, tumor necrosis factor-α, IL-6, nitric oxide, and plasma C-reactive protein. There were marked differences in expression of 45 miRs in the LCHS/CS+BB group compared with the LCHS/CS group when using a p value <0.001. Rno-miR-27a and miR-25 were upregulated 7- to 8-fold in the rodents who underwent LCHS/CS+BB compared with LCHS/CS alone, and this correlated with reduced bone marrow expression of IL-1ß, tumor necrosis factor-α, IL-6, nitric oxide, and reduced plasma C-reactive protein in the LCHS/CS+BB group. CONCLUSIONS: The genomic and miR expression patterns in bone marrow after LCHS/CS differed significantly compared with rodents that received propranolol after LCHS/CS. The use of BB after severe trauma can help mitigate persistent inflammation by upregulating Rno-miR-27a and miR-25 and reducing inflammatory cytokines in those who remain critically ill.

Secondary-Structure-Mediated Hierarchy and Mechanics in Polyurea-Peptide Hybrids.

Peptide-polymer hybrids combine the hierarchy of biological species with synthetic concepts to achieve control over molecular design and material properties. By further incorporating covalent cross-links, the enhancement of molecular complexity is achieved, allowing for both a physical and covalent network. In this work, the structure and function of poly(ethylene glycol) (PEG)-network hybrids are tuned by varying peptide block length and overall peptide content. Here the impact of poly(ε-carbobenzyloxy-l-lysine) (PZLY) units on block interactions and mechanics is explored by probing secondary structure, PEG crystallinity, and hierarchical organization. The incorporation of PZLY reveals a mixture of α-helices and ß-sheets at smaller repeat lengths ( n = 5) and selective α-helix formation at a higher peptide molecular weight ( n = 20). Secondary structure variations tailored the solid-state film hierarchy, whereby nanoscale fibers and microscale spherulites varied in size depending on the amount of α-helices and ß-sheets. This long-range ordering influenced mechanical properties, resulting in a decrease in elongation-at-break (from 400 to 20%) with increasing spherulite diameter. Furthermore, the reduction in soft segment crystallinity with the addition of PZLY resulted in a decrease in moduli. It was determined that, by controlling PZLY content, a balance of physical associations and self-assembly is obtained, leading to tunable PEG crystallinity, spherulite formation, and mechanics.

Harnessing Supramolecular and Peptidic Self-Assembly for the Construction of Reinforced Polymeric Tissue Scaffolds.

The repair and regeneration of the body's tissue using polymeric materials remains a main focus of biomaterials research. While hydrogels and elastomers have shown biocompatibility and high extensibility, they lack the required toughness to host proliferating cells. As the need for robust polymeric scaffolds grows, new technologies must emerge to meet the stringent physical and biological needs of proliferating cells. To this end, the utilization of self-assembling motifs allows for the construction of versatile networks in which cells can grow. In this review, we discuss emerging techniques that harness the assembling capabilities of synthetic supramolecular and natural peptide motifs to construct mechanically robust elastomers and hydrogel scaffolds. In particular, we focus on how the design and structure impact their mechanical properties and interaction with the cellular environment.