Complex regional pain syndrome of the foot and its management using spinal cord stimulation

Background: This article discusses neuropathic foot pain with particular reference to complex regional pain syndrome. It provides recommendations for the clinical evaluation of complex regional pain syndrome and highlights the value of spinal cord stimulation in its management. The aim is to review neuropathic foot pain in complex regional pain syndrome and outline its management using spinal cord stimulation. It is important for Podiatrists managing such patients to have an understanding of this treatment modality. Methods: A narrative literature review was undertaken using English language medical databases combining search strategies for complex regional pain syndrome and spinal cord stimulation. Results: Spinal cord stimulation improves the subjective symptoms of the neuropathic foot pain of complex regional pain syndrome, enables objective functional improvement and reduces analgesic consumption. Conclusion: Recent technical developments in spinal cord stimulation have led to improved stimulation patterns adapted to the patients’ needs. Careful preoperative diagnosis, robust patient selection and frequent follow-up are vital for the success of this method

Traceability

The importance of effective and timely traceability in both the recall of substances of human origin (blood, cells, tissues and organs) implicated in infectious transmission, and in the prevention of inappropriate use of substances of human origin is now well recognised. However, traceability remains poorly understood and inadequately controlled in many cases. In particular there is: a lack of appreciation of the complexity of the traceability pathway; a fragmented approach to traceability; and, an assumption that traceability data is static. The traceability path for a single tissue donor may involve dozens or even hundreds of different organizations, each responsible for one segment of the path. Whilst responsibility within each organization may be clearly defined, responsibility for maintaining the interfaces between organizations is often less clear. Traceability is seldom regarded in a holistic manner, the assumption being made that if each segment of the pathway is correctly maintained then the full path will be intact. End to end traceability audits are not routinely performed, and the only true test of the trail occurs when recall is required—often with inadequate results

Gender differences in coping strategies of undergraduate students and their impact on self-esteem and attainment

This study sought to investigate differences in the coping strategies adopted by male and female first year students in a higher education environment and the extent to which such strategies had an impact on self-esteem and attainment. Results revealed significant differences between males and females in terms of engagement in coping strategies and academic attainment. Specifically, males exhibited greater ability to detach themselves from the emotions of a situation, were more inclined to demonstrate emotional inhibition or ‘bottling up’ of emotions and reported higher self-esteem. In addition, it was observed that females attained at a significantly higher level than males. Practical implications and recommendations for future research are identified

Use of spinal cord stimulation in managing neuropathic foot pain: an observational pilot case series study

Objective: In cases of complex regional pain syndrome where conservative treatment is unsuccessful in controlling neuropathic foot pain spinal cord stimulation may be considered. To our knowledge there have been no such cases reported in the foot & ankle literature. The aim of the study was to establish useful information that may supplement our understanding of this complex multifactorial problem and help toinform future management of similar cases. Methods: A pilot observational case series study was undertaken to investigate the use of spinal cord stimulation in the management of neuropathic foot pain using five cases with complex regional pain syndrome (type I). Results: Reduced pain following spinal cord stimulation was reported. The interval between diagnosis and commencement of spinal cord stimulation was variable between cases and maybe responsible for differing levels and timing of pain relief experienced. Conclusion: Careful preoperative diagnosis, robust patient selection and close postoperative monitoring are vital for a successful outcome. The small sample size and potential for bias, limit the generalizability to a larger population. A larger study is therefore indicated to expand upon preliminary findings

Visualisation of variable binding pockets on protein surfaces by probabilistic analysis of related structure sets

Background: Protein structures provide a valuable resource for rational drug design. For a protein with no known ligand, computational tools can predict surface pockets that are of suitable size and shape to accommodate a complementary small-molecule drug. However, pocket prediction against single static structures may miss features of pockets that arise from proteins’ dynamic behaviour. In particular, ligand-binding conformations can be observed as transiently populated states of the apo protein, so it is possible to gain insight into ligand-bound forms by considering conformational variation in apo proteins. This variation can be explored by considering sets of related structures: computationally generated conformers, solution NMR ensembles, multiple crystal structures, homologues or homology models. It is non-trivial to compare pockets, either from different programs or across sets of structures. For a single structure, difficulties arise in defining particular pocket’s boundaries. For a set of conformationally distinct structures the challenge is how to make reasonable comparisons between them given that a perfect structural alignment is not possible. Results: We have developed a computational method, Provar, that provides a consistent representation of predicted binding pockets across sets of related protein structures. The outputs are probabilities that each atom or residue of the protein borders a predicted pocket. These probabilities can be readily visualised on a protein using existing molecular graphics software. We show how Provar simplifies comparison of the outputs of different pocket prediction algorithms, of pockets across multiple simulated conformations and between homologous structures. We demonstrate the benefits of use of multiple structures for protein-ligand and protein-protein interface analysis on a set of complexes and consider three case studies in detail: i) analysis of a kinase superfamily highlights the conserved occurrence of surface pockets at the active and regulatory sites ii) a simulated ensemble of unliganded Bcl2 structures reveals extensions of a known ligand-binding pocket not apparent in the apo crystal structure; iii) visualisations of interleukin-2 and its homologues highlight conserved pockets at the known receptor interfaces and regions whose conformation is known to change on inhibitor binding. Conclusions: Through post-processing of the output of a variety of pocket prediction software, Provar provides a flexible approach to the analysis and visualization of the persistence or variability of pockets in sets of related protein structures

Probing Matter Radii of Neutron-Rich Nuclei by Antiproton Scattering

We propose to use antiprotons to investigate the sizes of stable and neutron-rich exotic nuclei by measurements of the \pbar A absorption cross section along isotopic chains in inverse kinematics. The expected effects are studied theoretically in a microscopic model. The \pbar U optical potentials are obtained by folding free space \pbar N scattering amplitudes with HFB ground state densities and solving the scattering equations by direct integration. The mass dependence of absorption cross sections is found to follow closely the nuclear root-mean-square radii. The total absorption cross section is shown to be a superposition of cross sections describing partial absorption on neutrons and protons, respectively. Thus measuring the differential cross sections for absorption on neutrons and protons will give information on their respective distributions. In neutron-rich nuclei the outer neutron layer shields the absorption on the protons giving access to investigations of antiproton-neutron interactions in matter.Comment: 8 pages, 4 figure

High-global warming potential F-gas emissions in California: comparison of ambient-based versus inventory-based emission estimates, and implications of refined estimates.

To provide information for greenhouse gas reduction policies, the California Air Resources Board (CARB) inventories annual emissions of high-global-warming potential (GWP) fluorinated gases, the fastest growing sector of greenhouse gas (GHG) emissions globally. Baseline 2008 F-gas emissions estimates for selected chlorofluorocarbons (CFC-12), hydrochlorofluorocarbons (HCFC-22), and hydrofluorocarbons (HFC-134a) made with an inventory-based methodology were compared to emissions estimates made by ambient-based measurements. Significant discrepancies were found, with the inventory-based emissions methodology resulting in a systematic 42% under-estimation of CFC-12 emissions from older refrigeration equipment and older vehicles, and a systematic 114% overestimation of emissions for HFC-134a, a refrigerant substitute for phased-out CFCs. Initial, inventory-based estimates for all F-gas emissions had assumed that equipment is no longer in service once it reaches its average lifetime of use. Revised emission estimates using improved models for equipment age at end-of-life, inventories, and leak rates specific to California resulted in F-gas emissions estimates in closer agreement to ambient-based measurements. The discrepancies between inventory-based estimates and ambient-based measurements were reduced from -42% to -6% for CFC-12, and from +114% to +9% for HFC-134a

Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction

Diabetes, obesity and Alzheimer’s disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), APP and β-amyloid (Aβ) are linked with vascular disease development and raised BACE1 and Aβ accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, raised Aβ and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice raised plasma and vascular Aβ42 that correlated with decreased NO bioavailability, endothelial dysfunction and raised blood pressure. Genetic or pharmacological reduction of BACE1 activity and Aβ42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or Aβ42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation and raised blood pressure. In humans, raised plasma Aβ42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher Aβ42 reduced endothelial NO synthase (eNOS), cyclic GMP and protein kinase G (PKG) activity independently of diet whereas endothelin-1 was increased by diet and Aβ42. Lowering Aβ42 reversed the DIO deficit in the eNOS-cGMP-PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes

Behavioral and Enhanced Perinatal Intervention (B-EPIC): A Randomized Trial Targeting Tobacco Use among Opioid Dependent Pregnant Women

Background Opioid use during pregnancy is a significant public health issue. The standard of care for treating opioid use disorder during pregnancy includes medications for opioid disorder (MOUD). However, tobacco use often goes unaddressed among pregnant women on MOUD. In 2018, our team received a National Institute on Drug Abuse (NIDA) funded R34 to conduct a three year-randomized trial to test the feasibility of a novel tobacco intervention for pregnant women receiving MOUD. Aims The aims of this study are: (1) to determine the impact of the B-EPIC intervention on maternal tobacco use and stage of change; (2) to determine the impact of B-EPIC on tobacco-related maternal and infant health outcomes including gestational age at birth, birthweight, NAS diagnosis and severity, and number of ear and respiratory infections during the first six months; (3) to compare healthcare utilization and costs incurred by pregnant patients that receive the B-EPIC intervention versus TAU. Methods We plan to enroll 100 pregnant women on MOUD for this randomized controlled trial (B-EPIC intervention n = 50 and treatment as usual n = 50). A major strength of this study is its wide range of health and economic outcomes assessed on mother, neonate and the infant. Conclusions Despite the very high rates of smoking among pregnant women with OUD, there are few tobacco treatment interventions that have been tailored for this high - risk population. The overall goal of this study is to move towards a tobacco treatment standard for pregnant women receiving treatment for OUD

In silico assessment of potential druggable pockets on the surface of α1-Antitrypsin conformers

The search for druggable pockets on the surface of a protein is often performed on a single conformer, treated as a rigid body. Transient druggable pockets may be missed in this approach. Here, we describe a methodology for systematic in silico analysis of surface clefts across multiple conformers of the metastable protein α1-antitrypsin (A1AT). Pathological mutations disturb the conformational landscape of A1AT, triggering polymerisation that leads to emphysema and hepatic cirrhosis. Computational screens for small molecule inhibitors of polymerisation have generally focused on one major druggable site visible in all crystal structures of native A1AT. In an alternative approach, we scan all surface clefts observed in crystal structures of A1AT and in 100 computationally produced conformers, mimicking the native solution ensemble. We assess the persistence, variability and druggability of these pockets. Finally, we employ molecular docking using publicly available libraries of small molecules to explore scaffold preferences for each site. Our approach identifies a number of novel target sites for drug design. In particular one transient site shows favourable characteristics for druggability due to high enclosure and hydrophobicity. Hits against this and other druggable sites achieve docking scores corresponding to a Kd in the µM–nM range, comparing favourably with a recently identified promising lead. Preliminary ThermoFluor studies support the docking predictions. In conclusion, our strategy shows considerable promise compared with the conventional single pocket/single conformer approach to in silico screening. Our best-scoring ligands warrant further experimental investigation