39 results on '"Mikesh M"'
Search Results
2. The curious ability of polyethylene glycol fusion technologies to restore lost behaviors after nerve severance
- Author
-
Bittner, G.D., primary, Sengelaub, D.R., additional, Trevino, R.C., additional, Peduzzi, J.D., additional, Mikesh, M., additional, Ghergherehchi, C.L., additional, Schallert, T., additional, and Thayer, W.P., additional
- Published
- 2015
- Full Text
- View/download PDF
3. Robinson and madison have published no data on whether polyethylene glycol fusion repair prevents reinnervation accuracy in rat peripheral nerve.
- Author
-
Bittner, G.D., Sengelaub, D.R., Trevino, R.C., Ghergherehchi, C.L., and Mikesh, M.
- Published
- 2017
- Full Text
- View/download PDF
4. Polyethylene glycol-fused allografts produce rapid behavioral recovery after ablation of sciatic nerve segments
- Author
-
Riley, D.C., primary, Bittner, G.D., additional, Mikesh, M., additional, Cardwell, N.L., additional, Pollins, A.C., additional, Ghergherehchi, C.L., additional, Bhupanapadu Sunkesula, S.R., additional, Ha, T.N., additional, Hall, B.T.D., additional, Poon, A.D., additional, Pyarali, M., additional, Boyer, R.B., additional, Mazal, A.T., additional, Munoz, N., additional, Trevino, R.C., additional, Schallert, T., additional, and Thayer, W.P., additional
- Published
- 2014
- Full Text
- View/download PDF
5. Terminal Schwann Cells Participate in the Competition Underlying Neuromuscular Synapse Elimination
- Author
-
Smith, I. W., primary, Mikesh, M., additional, Lee, Y. i., additional, and Thompson, W. J., additional
- Published
- 2013
- Full Text
- View/download PDF
6. The curious ability of polyethylene glycol fusion technologies to restore lost behaviors after nerve severance.
- Author
-
Bittner, G.D., Sengelaub, D.R., Trevino, R.C., Peduzzi, J.D., Mikesh, M., Ghergherehchi, C.L., Schallert, T., and Thayer, W.P.
- Published
- 2016
- Full Text
- View/download PDF
7. Polyethylene glycol-fused allografts produce rapid behavioral recovery after ablation of sciatic nerve segments.
- Author
-
Riley, D.C., Bittner, G.D., Mikesh, M., Cardwell, N.L., Pollins, A.C., Ghergherehchi, C.L., Bhupanapadu Sunkesula, S.R., Ha, T.N., Hall, B.T.D., Poon, A.D., Pyarali, M., Boyer, R.B., Mazal, A.T., Munoz, N., Trevino, R.C., Schallert, T., and Thayer, W.P.
- Published
- 2015
- Full Text
- View/download PDF
8. The Nitrile Bis-Thiol Bioconjugation Reaction.
- Author
-
Patel M, Forte N, Bishop CR, Porter MJ, Dagwell M, Karu K, Chudasama V, and Baker JR
- Subjects
- Cysteine chemistry, Indicators and Reagents, Antibodies, Disulfides chemistry, Sulfhydryl Compounds chemistry, Nitriles chemistry
- Abstract
Electron-poor aryl nitriles are promising reagents for bioconjugation due to their high electrophilicity and selectivity for reaction with thiols, albeit generally in a reversible manner. A transient species has previously been observed in such reactions, involving the addition of two thiols to the nitrile functional group, forming a tetrahedral amino dithioacetal (ADTA). In this work, the reaction of heteroaryl nitriles with bis-thiols is explored in an attempt to generate stable ADTAs, which could facilitate new bioconjugation protocols. By use of a 1,2-dithiol, or the incorporation of an electrophilic trap into the aryl nitrile design, the formation of stable products is achieved. The resultant "nitrile bis-thiol" (NBT) reaction is then explored in the context of protein modification, specifically to carry out antibody conjugation. By addition of these nitriles to the reduced disulfide bond of an antibody fragment, it is shown that, depending on the reagent design, cysteine-to-lysine transfer or disulfide bridged NBT products can be generated. Both represent site-selective conjugates and are shown to be stable when challenged with glutathione under physiological conditions and upon incubation in serum. Furthermore, the NBT reaction is tested in the more challenging context of a full antibody, and all four disulfide bonds are effectively modified by these new one-carbon bridging reagents. Overall, this reaction of heteroaryl-nitriles with bis-thiols is shown to be highly efficient and versatile, of tunable reversibility, and offers enticing prospects as a new addition to the toolbox of biocompatible "click"-type reactions.
- Published
- 2024
- Full Text
- View/download PDF
9. Structure-preserving fixation allows scanning electron microscopy to reveal biofilm microstructure and interactions with immune cells.
- Author
-
Wells M, Mikesh M, and Gordon V
- Subjects
- Microscopy, Electron, Scanning, Biofilms, Neutrophils
- Abstract
Pseudomonas aeruginosa is a pathogen that forms robust biofilms which are commonly associated with chronic infections and cannot be successfully cleared by the immune system. Neutrophils, the most common white blood cells, target infections with pathogen-killing mechanisms that are rendered largely ineffective by the protective physicochemical structure of a biofilm. Visualisation of the complex interactions between immune cells and biofilms will advance understanding of how biofilms evade the immune system and could aid in developing treatment methods that promote immune clearance with minimal harm to the host. Scanning electron microscopy (SEM) distinguishes itself as a powerful, high-resolution tool for obtaining strikingly clear and detailed topographical images. However, taking full advantage of SEM's potential for high-resolution imaging requires that the fixation process simultaneously preserve both intricate biofilm architecture and the morphologies and structural signatures characterising neutrophils responses at an infection site. Standard aldehyde-based fixation techniques result in significant loss of biofilm matrix material and morphologies of responding immune cells, thereby obscuring the details of immune interactions with the biofilm matrix. Here we show an improved fixation technique using the cationic dye alcian blue to preserve and visualise neutrophil interactions with the three-dimensional architecture of P. aeruginosa biofilms. We also demonstrate that this technique better preserves structures of biofilms grown from two other bacterial species, Klebsiella pneumoniae and Burkholderia thailandensis., (© 2023 Royal Microscopical Society.)
- Published
- 2024
- Full Text
- View/download PDF
10. Polyethylene glycol has immunoprotective effects on sciatic allografts, but behavioral recovery and graft tolerance require neurorrhaphy and axonal fusion.
- Author
-
Smith TA, Zhou L, Ghergherehchi CL, Mikesh M, Yang CZ, Tucker HO, Allgood J, Bushman JS, and Bittner GD
- Abstract
JOURNAL/nrgr/04.03/01300535-202504000-00033/figure1/v/2024-07-06T104127Z/r/image-tiff Behavioral recovery using (viable) peripheral nerve allografts to repair ablation-type (segmental-loss) peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration. Furthermore, such peripheral nerve allografts undergo immunological rejection by the host immune system. In contrast, peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks, reduced immune responses, and many axons do not undergo Wallerian degeneration. The relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this study. We hypothesized that polyethylene glycol might have some immune-protective effects, but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral recovery. We examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal fusion. Ablation-type sciatic nerve injuries in outbred Sprague-Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts, but peripheral nerve allografts were loose-sutured (loose-sutured polyethylene glycol) with an intentional gap of 1-2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host axons. Similar to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts, animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days postoperatively. Other morphological signs of rejection, such as collapsed Schwann cell basal lamina tubes, were absent in polyethylene glycol-fused peripheral nerve allografts but commonly observed in negative control and loose-sutured polyethylene glycol peripheral nerve allografts at 21 days postoperatively. Loose-sutured polyethylene glycol peripheral nerve allografts had more pro-inflammatory and less anti-inflammatory macrophages than negative control peripheral nerve allografts. While T cell counts were similarly high in loose-sutured-polyethylene glycol and negative control peripheral nerve allografts, loose-sutured polyethylene glycol peripheral nerve allografts expressed some cytokines/chemokines important for T cell activation at much lower levels at 14 days postoperatively. MHCI expression was elevated in loose-sutured polyethylene glycol peripheral nerve allografts, but MHCII expression was modestly lower compared to negative control at 21 days postoperatively. We conclude that, while polyethylene glycol per se reduces some immune responses of peripheral nerve allografts, successful polyethylene glycol-fusion repair of some axons is necessary to prevent Wallerian degeneration of those axons and immune rejection of peripheral nerve allografts, and produce recovery of sensory/motor functions and voluntary behaviors. Translation of polyethylene glycol-fusion technologies would produce a paradigm shift from the current clinical practice of waiting days to months to repair ablation peripheral nerve injuries., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)
- Published
- 2025
- Full Text
- View/download PDF
11. Investigating Klebsiella pneumoniae biofilm preservation for scanning electron microscopy.
- Author
-
Fleeman RM, Mikesh M, and Davies BW
- Abstract
Klebsiella pneumoniae biofilm formation is associated with chronic and relapsing infections. Scanning electron microscopy (SEM) is a powerful tool for characterizing biofilm structure and studying their formation. Reliable visualization of biofilm structure requires careful sample preservation, otherwise there may be loss of non-covalent interactions that are susceptible to damage during the dehydration and washing preparation steps. However, no standard procedure has been adopted in the literature to fix K. pneumoniae biofilm for scanning electron microscopy studies. This lack of standardization makes it challenging to compare results between studies and determine the degree to which native structures have been preserved. To advance this critical area of study, we investigated different scanning electron microscopy fixation methods for K. pneumoniae biofilm preservation. Our study reveals the impact preparation steps can have on retaining in biofilm architecture observed using scanning electron microscopy. Using fixation methods developed through our studies, we show that although species that overproduce capsular extracellular polysaccharides produced more robust biofilms, K. pneumoniae can form a developed biofilm in the absence of capsular polysaccharides., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Authors.)
- Published
- 2023
- Full Text
- View/download PDF
12. Implementation of Passing Vehicle Search Algorithm for Optimization of WEDM Process of Nickel-Based Superalloy Waspaloy.
- Author
-
Chaudhari R, Ayesta I, Doshi M, Khanna S, Patel VK, Vora J, and López de Lacalle LN
- Abstract
Nickel-based superalloys find their main use in missile engines, atomic devices, investigational aircraft, aerospace engineering, industrial applications, and automotive gas turbines, spacecraft petrochemical tools, steam power, submarines, and broader heating applications. These superalloys impose certain difficulties during the process fabrication owing to their levels of higher hardness. In the current study, the precise machining of Waspaloy was attempted through the wire electrical discharge machining (WEDM) technique. A multi-objective optimization has been performed, and the influence of multi-walled carbon nanotubes (MWCNTs) has been assessed using the passing vehicle search (PVS) algorithm. The effects of machining variables like current, T
off , and Ton were studied using the output measures of material removal rate (MRR), recast layer thickness (RLT), and surface roughness (SR). The Box-Behnken design was applied to generate the experimental matrix. Empirical models were generated which show the interrelationship among the process variables and output measures. The analysis of variance (ANOVA) method was used to check the adequacy, and suitability of the models and to understand the significance of the parameters. The PVS technique was executed for the optimization of MRR, SR, and RLT. Pareto fronts were derived which gives a choice to the user to select any point on the front as per the requirement. To enhance the machining performance, MWCNTs mixed dielectric fluid was utilized, and the effect of these MWCNTs was also analyzed on the surface defects. The use of MWCNTs at 1 g/L enhanced the performance of MRR, SR, and RLT by 65.70%, 50.68%, and 40.96%, respectively. Also, the addition of MWCNTs has shown that the machined surface largely reduces the surface defects.- Published
- 2022
- Full Text
- View/download PDF
13. Polyethylene glycol-fusion repair of sciatic allografts in female rats achieves immunotolerance via attenuated innate and adaptive responses.
- Author
-
Smith TA, Ghergherehchi CL, Mikesh M, Shores JT, Tucker HO, and Bittner GD
- Subjects
- Adaptive Immunity drug effects, Allografts immunology, Allografts transplantation, Animals, Female, Immunity, Innate drug effects, Rats, Rats, Sprague-Dawley, Sciatic Neuropathy immunology, Transplantation, Homologous methods, Adaptive Immunity physiology, Immunity, Innate physiology, Polyethylene Glycols administration & dosage, Sciatic Nerve immunology, Sciatic Nerve transplantation, Sciatic Neuropathy therapy
- Abstract
Ablation/segmental loss peripheral nerve injuries (PNIs) exhibit poor functional recovery due to slow and inaccurate outgrowth of regenerating axons. Viable peripheral nerve allografts (PNAs) as growth-guide conduits are immunologically rejected and all anucleated donor/host axonal segments undergo Wallerian degeneration. In contrast, we report that ablation-type sciatic PNIs repaired by neurorrhaphy of viable sciatic PNAs and a polyethylene glycol (PEG)-fusion protocol using PEG immediately restored axonal continuity for many axons, reinnervated/maintained their neuromuscular junctions, and prevented much Wallerian degeneration. PEG-fused PNAs permanently restored many sciatic-mediated behaviors within 2-6 weeks. PEG-fused PNAs were not rejected even though host/donors were neither immunosuppressed nor tissue-matched in outbred female Sprague Dawley rats. Innate and adaptive immune responses to PEG-fused sciatic PNAs were analyzed using electron microscopy, immunohistochemistry, and quantitative reverse transcription polymerase chain reaction for morphological features, T cell and macrophage infiltration, major histocompatibility complex (MHC) expression, apoptosis, expression of cytokines, chemokines, and cytotoxic effectors. PEG-fused PNAs exhibited attenuated innate and adaptive immune responses by 14-21 days postoperatively, as evidenced by (a) many axons and cells remaining viable, (b) significantly reduced infiltration of cytotoxic and total T cells and macrophages, (c) significantly reduced expression of inflammatory cytokines, chemokines, and MHC proteins, (d) consistently low apoptotic response. Morphologically and/or biochemically, PEG-fused sciatic PNAs often resembled sciatic autografts or intact sciatic nerves. In brief, PEG-fused PNAs are an unstudied, perhaps unique, example of immune tolerance of viable allograft tissue in a nonimmune-privileged environment and could greatly improve the clinical outcomes for PNIs relative to current protocols., (© 2020 Wiley Periodicals LLC.)
- Published
- 2020
- Full Text
- View/download PDF
14. Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity.
- Author
-
Mahy W, Patel M, Steadman D, Woodward HL, Atkinson BN, Svensson F, Willis NJ, Flint A, Papatheodorou D, Zhao Y, Vecchia L, Ruza RR, Hillier J, Frew S, Monaghan A, Costa A, Bictash M, Walter MW, Jones EY, and Fish PV
- Subjects
- Carboxylic Ester Hydrolases chemistry, Drug Evaluation, Preclinical, Models, Molecular, Protein Conformation, Carboxylic Ester Hydrolases antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Pyrroles chemistry, Pyrroles pharmacology, Pyrrolidines chemistry, Pyrrolidines pharmacology
- Abstract
The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20 , guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26 . This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.
- Published
- 2020
- Full Text
- View/download PDF
15. Morphological remodeling during recovery of the neuromuscular junction from terminal Schwann cell ablation in adult mice.
- Author
-
Hastings RL, Mikesh M, Lee YI, and Thompson WJ
- Subjects
- Animals, Cell Differentiation physiology, Cell Proliferation physiology, Diphtheria Toxin pharmacology, Female, Male, Mice, Mice, Inbred C57BL, Microscopy, Electron, Schwann Cells drug effects, Synapses physiology, Tamoxifen pharmacology, Neuromuscular Junction physiology, Neuronal Plasticity physiology, Schwann Cells physiology
- Abstract
Schwann cells (SCs) are integral to the formation and function of the peripheral nervous system (PNS). Exemplifying their importance, the loss or dysfunction of SCs is a feature of a myriad of diseases and conditions that compromise the PNS. Thus, it remains essential to understand the rules that govern the proliferation, differentiation and reconnection of Schwann cells with peripheral axons. Here, we examined the consequences of locally and acutely ablating terminal Schwann cells (tSCs) at the adult mouse neuromuscular junction (NMJ) by using mice expressing diphtheria toxin receptor (DTR) preferentially in tSCs compared to myelinating SCs followed by local application of diphtheria toxin (DTX). After DTX application, tSCs died but, importantly and contrary to expectations, their associated motor axons did not fully degenerate. Within 3 weeks, tSCs returned and reestablished coverage of the synapse with increased numbers. Furthermore, the post-synaptic muscle fibers displayed increased distinct clusters of acetylcholine receptors and axon terminals exhibited numerous terminal varicosities. The lack of degeneration of bare motor axon terminals and the morphological remodeling that occurs upon the return of tSCs to the NMJ may have wider implications for the mechanisms governing tSC occupancy of the adult NMJ and for conditions that adversely affect tSCs.
- Published
- 2020
- Full Text
- View/download PDF
16. Terminal Schwann cell and vacant site mediated synapse elimination at developing neuromuscular junctions.
- Author
-
Jung JH, Smith I, and Mikesh M
- Subjects
- Animals, Computer Simulation, Female, Male, Mice, Mice, Inbred C57BL, Microscopy, Electron, Scanning, Motor Neurons physiology, Muscle Fibers, Skeletal physiology, Muscle, Skeletal innervation, Stochastic Processes, Axons physiology, Neuromuscular Junction physiopathology, Schwann Cells physiology, Synapses physiology
- Abstract
Synapses undergo transition from polyinnervation by multiple axons to single innervation a few weeks after birth. Synaptic activity of axons and interaxonal competition are thought to drive this developmental synapse elimination and tested as key parameters in quantitative models for further understanding. Recent studies of muscle synapses (endplates) show that there are also terminal Schwann cells (tSCs), glial cells associated with motor neurons and their functions, and vacant sites (or vacancies) devoid of tSCs and axons proposing tSCs as key effectors of synapse elimination. However, there is no quantitative model that considers roles of tSCs including vacancies. Here we develop a stochastic model of tSC and vacancy mediated synapse elimination. It employs their areas on individual endplates quantified by electron microscopy-based analyses assuming that vacancies form randomly and are taken over by adjacent axons or tSCs. The model reliably reproduced synapse elimination whereas equal or random probability models, similar to classical interaxonal competition models, did not. Furthermore, the model showed that synapse elimination is accelerated by enhanced synaptic activity of one axon and also by increased areas of vacancies and tSCs suggesting that the areas are important structural correlates of the rate of synapse elimination.
- Published
- 2019
- Full Text
- View/download PDF
17. Behavioral recovery and spinal motoneuron remodeling after polyethylene glycol fusion repair of singly cut and ablated sciatic nerves.
- Author
-
Ghergherehchi CL, Hibbard EA, Mikesh M, Bittner GD, and Sengelaub DR
- Subjects
- Action Potentials, Allografts, Animals, Cell Count, Dendrites metabolism, Disease Models, Animal, Electrophysiological Phenomena, Female, Immunohistochemistry, Motor Neurons cytology, Nerve Regeneration, Polyethylene Glycols, Rats, Recovery of Function, Sciatic Neuropathy rehabilitation, Motor Neurons metabolism, Neural Conduction, Sciatic Neuropathy etiology, Sciatic Neuropathy metabolism
- Abstract
Polyethylene glycol repair (PEG-fusion) of severed sciatic axons restores their axoplasmic and membrane continuity, prevents Wallerian degeneration, maintains muscle fiber innervation, and greatly improves recovery of voluntary behaviors. We examined alterations in spinal connectivity and motoneuron dendritic morphology as one potential mechanism for improved behavioral function after PEG-fusion. At 2-112 days after a single-cut or allograft PEG-fusion repair of transected or ablated sciatic nerves, the number, size, location, and morphology of motoneurons projecting to the tibialis anterior muscle were assessed by retrograde labeling. For both lesion types, labeled motoneurons were found in the appropriate original spinal segment, but also in inappropriate segments, indicating mis-pairings of proximal-distal segments of PEG-fused motor axons. Although the number and somal size of motoneurons was unaffected, dendritic distributions were altered, indicating that PEG-fusion preserves spinal motoneurons but reorganizes their connectivity. This spinal reorganization may contribute to the remarkable behavioral recovery seen after PEG-fusion repair., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
- Full Text
- View/download PDF
18. Salomone et al did not induce PEG-fusion repair of severed rat facial nerves.
- Author
-
Bittner G, Ghergherehchi C, Mikesh M, Sengelaub D, Trevino R, and Shores J
- Subjects
- Animals, Antioxidants, Facial Nerve, Nerve Regeneration, Polyethylene Glycols, Rats, Facial Nerve Injuries, Facial Paralysis
- Published
- 2019
- Full Text
- View/download PDF
19. Prevalence of Complications after Limberg Rhomboid Flap in Patients with Cutaneous Defects at A Tertiary Care Hospital.
- Author
-
Shrestha BB, Karmcharya M, Bogati L, and Ghimire P
- Subjects
- Adult, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Prevalence, Surgical Wound Infection epidemiology, Tertiary Care Centers, Young Adult, Postoperative Complications epidemiology, Skin Diseases surgery, Surgical Flaps
- Abstract
Introduction: Limberg rhomboid flap is an extremely useful and versatile technique to cover the cutaneous defects in various anatomical locations of different etiology and varied sizes. The main aim of the study is to find the prevalence of complications after limberg rhomboid flap in patients with cutaneous defects at a tertiary care hospital., Methods: This descriptive cross-sectional study was conducted at a tertiary care hospital from October 2015 to November 2018 after obtaining approval from the institutional review committee. Study population is patient admitted to ward and outpatient department of surgery. Convenience sampling was done. Data was entered and analyzed in statistical package for social sciences and point estimate at 95% confidence interval was calculated along with frequency and proportion for binary data., Results: Out of total patients, the complications were seen in total 8 (15.7%) patients. Prevalence of complications is 8 (15.7%) at 95% confidence interval (7.85-23.56). Among which, complications were seen in 5 (9.8%) bed sore, 2 (3.92%) in pilonidal sinus, 1 (1.96%) in traumatic ulcer and none in neoplastic lesion and types of complications seen were wound gaping in 3 (5.88%) cases, surgical site infection in 2 (3.92%) cases, recurrent pilonidal sinus in 1 (1.96%) case, flap necrosis in 1 (1.96%) case and epidermolysis in 1 (1.96%) case., Conclusions: The Limberg rhomboid flap can be used safely in patients with cutaneous defect with minimal complications and good surgical outcome however prevalence of complications after limberg rhomboid flap in patients with cutaneous defects at tertiary care center is high compared to the previous studies done.
- Published
- 2019
20. Polyethylene glycol (PEG) and other bioactive solutions with neurorrhaphy for rapid and dramatic repair of peripheral nerve lesions by PEG-fusion.
- Author
-
Ghergherehchi CL, Mikesh M, Sengelaub DR, Jackson DM, Smith T, Nguyen J, Shores JT, and Bittner GD
- Subjects
- Allografts, Animals, Axons drug effects, Axons pathology, Disease Models, Animal, Female, Male, Neuromuscular Junction pathology, Random Allocation, Rats, Sprague-Dawley, Sciatic Nerve pathology, Suture Techniques, Wallerian Degeneration prevention & control, Neuroprotective Agents pharmacology, Neurosurgical Procedures methods, Polyethylene Glycols pharmacology, Sciatic Nerve drug effects, Sciatic Nerve injuries
- Abstract
Background: Nervous system injuries in mammals often involve transection or segmental loss of peripheral nerves. Such injuries result in functional (behavioral) deficits poorly restored by naturally occurring 1-2 mm/d axonal outgrowths aided by primary repair or reconstruction. "Neurorrhaphy" or nerve repair joins severed connective tissues, but not severed cytoplasmic/plasmalemmal extensions (axons) within the tissue., New Method: PEG-fusion consists of neurorrhaphy combined with a well-defined sequence of four pharmaceutical agents in solution, one containing polyethylene glycol (PEG), applied directly to closely apposed viable ends of severed axons., Results: PEG-fusion of rat sciatic nerves: (1) restores axonal continuity across coaptation site(s) within minutes, (2) prevents Wallerian degeneration of many distal severed axons, (3) preserves neuromuscular junctions, (4) prevents target muscle atrophy, (5) produces rapid and improved recovery of voluntary behaviors compared with neurorrhaphy alone, and (6) PEG-fused allografts are not rejected, despite no tissue-matching nor immunosuppression., Comparison With Existing Methods: If PEG-fusion protocols are not correctly executed, the results are similar to that of neurorrhaphy alone: (1) axonal continuity across coaptation site(s) is not re-established, (2) Wallerian degeneration of all distal severed axons rapidly occurs, (3) neuromuscular junctions are non-functional, (4) target muscle atrophy begins within weeks, (5) recovery of voluntary behavior occurs, if ever, after months to levels well-below that observed in unoperated animals, and (6) allografts are either rejected or not well-accepted., Conclusion: PEG-fusion produces rapid and dramatic recovery of function following rat peripheral nerve injuries., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
21. Surgical Technique and Other Protocols Used Probably Did Not Induce Polyethylene Glycol Fusion of Rat Facial Nerves.
- Author
-
Bittner GD, Ghergherehchi CL, and Mikesh M
- Subjects
- Animals, Axons, Facial Nerve, Nerve Regeneration, Polyethylene Glycols, Rats, Facial Nerve Injuries
- Published
- 2019
- Full Text
- View/download PDF
22. Corrigendum to "Polyethylene glycol solutions rapidly restore and maintain axonal continuity, neuromuscular structures, and behaviors lost after sciatic nerve transections in female rats."
- Author
-
Mikesh M, Ghergherehchi CL, Louis Hastings R, Ali A, Rahesh S, Jagannath K, Sengelaub DR, Trevino RC, Jackson DM, and Bittner GD
- Published
- 2018
- Full Text
- View/download PDF
23. Corrigendum to "Polyethylene glycol treated allografts not tissue matched nor immunosuppressed rapidly repair sciatic nerve gaps, maintain neuromuscular functions, and restore voluntary behaviors in female rats".
- Author
-
Mikesh M, Ghergherehchi CL, Rahesh S, Jagannath K, Ali A, Sengelaub DR, Trevino RC, Jackson DM, Tucker HO, and Bittner GD
- Published
- 2018
- Full Text
- View/download PDF
24. Polyethylene glycol solutions rapidly restore and maintain axonal continuity, neuromuscular structures, and behaviors lost after sciatic nerve transections in female rats.
- Author
-
Mikesh M, Ghergherehchi CL, Hastings RL, Ali A, Rahesh S, Jagannath K, Sengelaub DR, Trevino RC, Jackson DM, and Bittner GD
- Subjects
- Animals, Axotomy, Disease Models, Animal, Female, Nerve Regeneration physiology, Neural Conduction drug effects, Rats, Recovery of Function, Sciatic Nerve physiology, Sciatic Nerve surgery, Sciatic Neuropathy chemically induced, Sciatic Neuropathy drug therapy, Sciatic Neuropathy pathology, Wallerian Degeneration drug therapy, Wallerian Degeneration pathology, Axons drug effects, Axons physiology, Nerve Regeneration drug effects, Neuromuscular Junction drug effects, Neuromuscular Junction physiology, Polyethylene Glycols pharmacology, Sciatic Nerve drug effects
- Abstract
Complete severance of major peripheral mixed sensory-motor nerve proximally in a mammalian limb produces immediate loss of action potential conduction and voluntary behaviors mediated by the severed distal axonal segments. These severed distal segments undergo Wallerian degeneration within days. Denervated muscles atrophy within weeks. Slowly regenerating (∼1 mm/day) outgrowths from surviving proximal stumps that often nonspecifically reinnervate denervated targets produce poor, if any, restoration of lost voluntary behaviors. In contrast, in this study using completely transected female rat sciatic axons as a model system, we provide extensive morphometric, immunohistochemical, electrophysiological, and behavioral data to show that these adverse outcomes are avoided by microsuturing closely apposed axonal cut ends (neurorrhaphy) and applying a sequence of well-specified solutions, one of which contains polyethylene glycol (PEG). This "PEG-fusion" procedure within minutes reestablishes axoplasmic and axolemmal continuity and signaling by nonspecifically fusing (connecting) closely apposed open ends of severed motor and/or sensory axons at the lesion site. These PEG-fused axons continue to conduct action potentials and generate muscle action potentials and muscle twitches for months and do not undergo Wallerian degeneration. Continuously innervated muscle fibers undergo much less atrophy compared with denervated muscle fibers. Dramatic behavioral recovery to near-unoperated levels occurs within days to weeks, almost certainly by activating many central nervous system and peripheral nervous system synaptic and other plasticities, some perhaps to a greater extent than most neuroscientists would expect. Negative control transections in which neurorrhaphy and all solutions except the PEG-containing solution are applied produce none of these remarkably fortuitous outcomes observed for PEG-fusion., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
- Full Text
- View/download PDF
25. Polyethylene glycol treated allografts not tissue matched nor immunosuppressed rapidly repair sciatic nerve gaps, maintain neuromuscular functions, and restore voluntary behaviors in female rats.
- Author
-
Mikesh M, Ghergherehchi CL, Rahesh S, Jagannath K, Ali A, Sengelaub DR, Trevino RC, Jackson DM, Tucker HO, and Bittner GD
- Subjects
- Allografts drug effects, Animals, Axons drug effects, Axons physiology, Axotomy, Disease Models, Animal, Female, Muscle, Skeletal, Nerve Fibers drug effects, Neural Conduction drug effects, Neuromuscular Junction drug effects, Peripheral Nerve Injuries pathology, Peripheral Nerve Injuries therapy, Random Allocation, Rats, Rats, Sprague-Dawley, Recovery of Function drug effects, Sciatic Nerve pathology, Sciatic Nerve physiology, Sciatic Nerve surgery, Sciatic Neuropathy chemically induced, Transplantation, Homologous, Wallerian Degeneration prevention & control, Nerve Regeneration drug effects, Peroneal Nerve drug effects, Peroneal Nerve transplantation, Polyethylene Glycols pharmacology, Sciatic Nerve drug effects, Sciatic Neuropathy therapy
- Abstract
Many publications report that ablations of segments of peripheral nerves produce the following unfortunate results: (1) Immediate loss of sensory signaling and motor control; (2) rapid Wallerian degeneration of severed distal axons within days; (3) muscle atrophy within weeks; (4) poor behavioral (functional) recovery after many months, if ever, by slowly-regenerating (∼1mm/d) axon outgrowths from surviving proximal nerve stumps; and (5) Nerve allografts to repair gap injuries are rejected, often even if tissue matched and immunosuppressed. In contrast, using a female rat sciatic nerve model system, we report that neurorrhaphy of allografts plus a well-specified-sequence of solutions (one containing polyethylene glycol: PEG) successfully addresses each of these problems by: (a) Reestablishing axonal continuity/signaling within minutes by nonspecific ally PEG-fusing (connecting) severed motor and sensory axons across each anastomosis; (b) preventing Wallerian degeneration by maintaining many distal segments of inappropriately-reconnected, PEG-fused axons that continuously activate nerve-muscle junctions; (c) maintaining innervation of muscle fibers that undergo much less atrophy than otherwise-denervated muscle fibers; (d) inducing remarkable behavioral recovery to near-unoperated levels within days to weeks, almost certainly by CNS and PNS plasticities well-beyond what most neuroscientists currently imagine; and (e) preventing rejection of PEG-fused donor nerve allografts with no tissue matching or immunosuppression. Similar behavioral results are produced by PEG-fused autografts. All results for Negative Control allografts agree with current neuroscience data 1-5 given above. Hence, PEG-fusion of allografts for repair of ablated peripheral nerve segments expand on previous observations in single-cut injuries, provoke reconsideration of some current neuroscience dogma, and further extend the potential of PEG-fusion in clinical practice., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
- Full Text
- View/download PDF
26. Corrigendum to "Sealing frequency of B104 cells declines exponentially with decreasing transection distance from the axon hillock" [Exp. Neurol. 279 (2016) 149-158].
- Author
-
McGill CH, Bhupanapadu Sunkesula SR, Poon AD, Mikesh M, and Bittner GD
- Published
- 2017
- Full Text
- View/download PDF
27. Mature brain tissue in the sacrococcygeal region.
- Author
-
Shrestha BB, Ghimire P, Ghartimagar D, Jwarchan B, Lalchan S, and Karmacharya M
- Abstract
Complete mature brain tissue in sacrococcygeal region is a rare congenital anomaly in a newborn, which usually is misdiagnosed for sacrococcygeal teratoma. Glial tumor-like ependymoma is also common in sacrococcygeal area but mostly appears later in life. We present a case of complete heterotopic brain tissue in the sacrococcygeal region. The patient underwent total excision of mass with coccygectomy. To our knowledge it is the second case being reported., (Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 2016.)
- Published
- 2016
- Full Text
- View/download PDF
28. Sealing frequency of B104 cells declines exponentially with decreasing transection distance from the axon hillock.
- Author
-
McGill CH, Bhupanapadu Sunkesula SR, Poon AD, Mikesh M, and Bittner GD
- Subjects
- Animals, Apoptosis, Axons ultrastructure, Axotomy, Calcium metabolism, Calcium Signaling, Cell Line, Tumor, Cell Membrane metabolism, Fluorescent Dyes, Models, Neurological, Neurites, Neurons ultrastructure, Rats, Axons pathology, Neurons pathology
- Abstract
Transection of nerve axons (axotomy) leads to rapid (Wallerian) degeneration of the distal portion of the severed axon whereas the proximal portion and the soma often survive. Clinicians and neuroscientists have known for decades that somal survival is less likely for cells transected nearer to the soma, compared to further from the soma. Calcium ion (Ca(2+)) influx at the cut axonal end increases somal Ca(2+) concentration, which subsequently activates apoptosis and other pathways that lead to cell death. The same Ca(2+) influx activates parallel pathways that seal the plasmalemma, reduce Ca(2+) influx, and thereby enable the soma to survive. In this study, we have examined the ability of transected B104 axons to seal, as measured by uptake or exclusion of fluorescent dye, and quantified the relationship between sealing frequency and transection distance from the axon hillock. We report that sealing frequency is maximal at about 150μm (μm) from the axon hillock and decreases exponentially with decreasing transection distance with a space constant of about 40μm. We also report that after Ca(2+) influx is initiated, the curve of sealing frequency versus time is well-fit by a one-phase, rising exponential model having a time constant of several milliseconds that is longer nearer to, versus further from, the axon hillock. These results could account for the increased frequency of cell death for axotomies nearer to, versus farther from, the soma of many types of neurons., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
29. Effects of extracellular calcium and surgical techniques on restoration of axonal continuity by polyethylene glycol fusion following complete cut or crush severance of rat sciatic nerves.
- Author
-
Ghergherehchi CL, Bittner GD, Hastings RL, Mikesh M, Riley DC, Trevino RC, Schallert T, Thayer WP, Bhupanapadu Sunkesula SR, Ha TA, Munoz N, Pyarali M, Bansal A, Poon AD, Mazal AT, Smith TA, Wong NS, and Dunne PJ
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Animals, Axons drug effects, Axons physiology, Calcium therapeutic use, Disease Models, Animal, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Female, Fluorescent Dyes pharmacokinetics, Male, Mental Disorders etiology, Mental Disorders therapy, Nerve Regeneration drug effects, Neural Conduction drug effects, Neuromuscular Junction drug effects, Neuromuscular Junction pathology, Rats, Rats, Sprague-Dawley, Sciatic Neuropathy complications, Time Factors, Calcium metabolism, Neurosurgery methods, Polyethylene Glycols therapeutic use, Recovery of Function drug effects, Sciatic Neuropathy drug therapy, Sciatic Neuropathy surgery
- Abstract
Complete crush or cut severance of sciatic nerve axons in rats and other mammals produces immediate loss of axonal continuity. Loss of locomotor functions subserved by those axons is restored only after months, if ever, by outgrowths regenerating at ∼1 mm/day from the proximal stumps of severed axonal segments. The distal stump of a severed axon typically begins to degenerate in 1-3 days. We recently developed a polyethylene glycol (PEG) fusion technology, consisting of sequential exposure of severed axonal ends to hypotonic Ca(2+) -free saline, methylene blue, PEG in distilled water, and finally Ca(2+) -containing isotonic saline. This study examines factors that affect the PEG fusion restoration of axonal continuity within minutes, as measured by conduction of action potentials and diffusion of an intracellular fluorescent dye across the lesion site of rat sciatic nerves completely cut or crush severed in the midthigh. Also examined are factors that affect the longer-term PEG fusion restoration of lost behavioral functions within days to weeks, as measured by the sciatic functional index. We report that exposure of cut-severed axonal ends to Ca(2+) -containing saline prior to PEG fusion and stretch/tension of proximal or distal axonal segments of cut-severed axons decrease PEG fusion success. Conversely, trimming cut-severed ends in Ca(2+) -free saline just prior to PEG fusion increases PEG fusion success. PEG fusion prevents or retards the Wallerian degeneration of cut-severed axons, as assessed by measures of axon diameter and G ratio. PEG fusion may produce a paradigm shift in the treatment of peripheral nerve injuries. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
30. Polyethylene glycol-fusion retards Wallerian degeneration and rapidly restores behaviors lost after nerve severance.
- Author
-
Bittner GD, Mikesh M, and Ghergherehchi CL
- Published
- 2016
- Full Text
- View/download PDF
31. Neuregulin1 displayed on motor axons regulates terminal Schwann cell-mediated synapse elimination at developing neuromuscular junctions.
- Author
-
Lee YI, Li Y, Mikesh M, Smith I, Nave KA, Schwab MH, and Thompson WJ
- Subjects
- Alternative Splicing, Amyloid Precursor Protein Secretases genetics, Animals, Animals, Newborn, Aspartic Acid Endopeptidases genetics, Axons chemistry, Axons physiology, Gene Dosage, Heterozygote, Membrane Proteins physiology, Mice, Mice, Knockout, Mice, Transgenic, Motor Neurons chemistry, Muscle, Skeletal growth & development, Muscle, Skeletal innervation, Neck Muscles growth & development, Neck Muscles innervation, Neuregulin-1 genetics, Neuromuscular Junction growth & development, Neuromuscular Junction metabolism, Phagocytosis genetics, Protein Isoforms genetics, Protein Isoforms physiology, Receptors, Cholinergic metabolism, Recombinant Fusion Proteins metabolism, Signal Transduction, Spinal Cord cytology, Spinal Cord growth & development, Synapses ultrastructure, Motor Neurons physiology, Neuregulin-1 physiology, Neuromuscular Junction ultrastructure, Neuronal Plasticity physiology, Schwann Cells physiology, Synapses physiology
- Abstract
Synaptic connections in the nervous system are rearranged during development and in adulthood as a feature of growth, plasticity, aging, and disease. Glia are implicated as active participants in these changes. Here we investigated a signal that controls the participation of peripheral glia, the terminal Schwann cells (SCs), at the neuromuscular junction (NMJ) in mice. Transgenic manipulation of the levels of membrane-tethered neuregulin1 (NRG1-III), a potent activator of SCs normally presented on motor axons, alters the rate of loss of motor inputs at NMJs during developmental synapse elimination. In addition, NMJs of adult transgenic mice that expressed excess axonal NRG1-III exhibited continued remodeling, in contrast to the more stable morphologies of controls. In fact, synaptic SCs of these adult mice with NRG1-III overexpression exhibited behaviors evident in wild type neonates during synapse elimination, including an affinity for the postsynaptic myofiber surface and phagocytosis of nerve terminals. Given that levels of NRG1-III expression normally peak during the period of synapse elimination, our findings identify axon-tethered NRG1 as a molecular determinant for SC-driven neuromuscular synaptic plasticity.
- Published
- 2016
- Full Text
- View/download PDF
32. Torsion of a lipoma of parietal peritoneum: a rare case mimicking acute appendicitis.
- Author
-
Shrestha BB and Karmacharya M
- Abstract
Lipomas are found most often on the torso, neck, upper thighs, upper arms and armpits; they can also occur almost anywhere in the body. Parietal peritoneum lipoma is a rare intraoperative finding during abdominal surgery. We present a case of a torted, pedunculated parietal wall lipoma in the right iliac fossa that gave rise to a clinical diagnosis of appendicitis. So far only one case has been reported., (Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 2014.)
- Published
- 2014
- Full Text
- View/download PDF
33. Terminal Schwann cells participate in neuromuscular synapse remodeling during reinnervation following nerve injury.
- Author
-
Kang H, Tian L, Mikesh M, Lichtman JW, and Thompson WJ
- Subjects
- Animals, Denervation, Disease Models, Animal, Female, Luminescent Proteins genetics, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Confocal, Microscopy, Electron, Transmission, Muscle, Skeletal pathology, Muscle, Skeletal ultrastructure, Neuromuscular Junction metabolism, Neuromuscular Junction ultrastructure, Receptors, Cholinergic metabolism, Recovery of Function, Schwann Cells ultrastructure, Time Factors, Gene Expression Regulation physiology, Nerve Regeneration physiology, Neuromuscular Junction physiopathology, Peripheral Nerve Injuries pathology, Peripheral Nerve Injuries physiopathology, Schwann Cells physiology
- Abstract
Schwann cells (SCs) at neuromuscular junctions (NMJs) play active roles in synaptic homeostasis and repair. We have studied how SCs contribute to reinnervation of NMJs using vital imaging of mice whose motor axons and SCs are transgenically labeled with different colors of fluorescent proteins. Motor axons most commonly regenerate to the original synaptic site by following SC-filled endoneurial tubes. During the period of denervation, SCs at the NMJ extend elaborate processes from the junction, as shown previously, but they also retract some processes from territory they previously occupied within the endplate. The degree of this retraction depends on the length of the period of denervation. We show that the topology of the remaining SC processes influences the branching pattern of regenerating axon terminals and the redistribution of acetylcholine receptors (AChRs). Upon arriving at the junction, regenerating axons follow existing SC processes within the old synaptic site. Some of the AChR loss that follows denervation is correlated with failure of portions of the old synaptic site that lack SC coverage to be reinnervated. New AChR clustering is also induced by axon terminals that follow SC processes extended during denervation. These observations show that SCs participate actively in the remodeling of neuromuscular synapses following nerve injury by their guidance of axonal reinnervation.
- Published
- 2014
- Full Text
- View/download PDF
34. Prognostic variables in patients with primary soft tissue sarcoma of the extremity and trunk treated with neoadjuvant radiotherapy or neoadjuvant sequential chemoradiotherapy.
- Author
-
Bedi M, King DM, Shivakoti M, Wang T, Zambrano EV, Charlson J, Hackbarth D, Neilson J, Whitfield R, and Wang D
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Prognosis, Radiotherapy, Adjuvant, Retrospective Studies, Sarcoma mortality, Young Adult, Chemoradiotherapy methods, Neoadjuvant Therapy methods, Sarcoma drug therapy, Sarcoma radiotherapy
- Abstract
Background: Neoadjuvant radiotherapy (NRT) is an effective strategy to treat soft tissue sarcomas (STS). However, the role of neoadjuvant chemoradiotherapy (NCRT) remains to be determined., Methods: From May 1999 to July 2010, 112 patients with localized STS of the extremity and trunk who were treated with NRT or NCRT followed by surgery were retrospectively reviewed. Clinical outcomes including overall survival (OS), disease-free survival (DFS), and distant metastasis free survival (DMFS) were calculated using Kaplan-Meier survival analyses. Prognostic variables were determined by univariate (UVA) and multivariate analyses (MVA)., Results: Median follow-up was 37 months. Median RT dose was 50 Gy. Forty-nine patients received NCRT. Overall limb-preservation rate was 99% and local control was 97%. The estimated 3-year OS, DFS, and DMFS were 86%, 68%, and 72%, respectively. Age was the only variable to predict for OS, DFS and DMFS on UVA. Age ≥ 70 predicted for poor OS, stage III disease predicted for poor DFS and DMFS, and the addition of chemotherapy predicted for improved DMFS on MVA., Conclusions: Excellent rates of local control and limb-preservation were observed in patients with primary STS treated with neoadjuvant therapy followed by surgery. Neoadjuvant sequential chemotherapy followed by radiotherapy may be considered for young patients with stage III STS.
- Published
- 2013
- Full Text
- View/download PDF
35. Thirty-day readmissions after elective spine surgery for degenerative conditions among US Medicare beneficiaries.
- Author
-
Wang MC, Shivakoti M, Sparapani RA, Guo C, Laud PW, and Nattinger AB
- Subjects
- Aged, Aged, 80 and over, Cervical Vertebrae pathology, Cervical Vertebrae surgery, Female, Humans, Lumbar Vertebrae pathology, Lumbar Vertebrae surgery, Male, Middle Aged, Postoperative Complications epidemiology, Postoperative Complications etiology, Risk Factors, Spinal Diseases epidemiology, United States epidemiology, Elective Surgical Procedures adverse effects, Medicare Part A, Patient Readmission statistics & numerical data, Spinal Diseases surgery
- Abstract
Background Context: Readmissions within 30 days of hospital discharge are undesirable and costly. Little is known about reasons for and predictors of readmissions after elective spine surgery to help plan preventative strategies., Purpose: To examine readmissions within 30 days of hospital discharge, reasons for readmission, and predictors of readmission among patients undergoing elective cervical and lumbar spine surgery for degenerative conditions., Study Design: Retrospective cohort study., Patient Sample: Patient sample includes 343,068 Medicare beneficiaries who underwent cervical and lumbar spine surgery for degenerative conditions from 2003 to 2007., Outcome Measures: Readmissions within 30 days of discharge, excluding readmissions for rehabilitation., Methods: Patients were identified in Medicare claims data using validated algorithms. Reasons for readmission were classified into clinically meaningful categories using a standardized coding system (Clinical Classification Software)., Results: Thirty-day readmissions were 7.9% after cervical surgery and 7.3% after lumbar surgery. There was no dominant reason for readmissions. The most common reasons for readmissions were complications of surgery (26%-33%) and musculoskeletal conditions in the same area of the operation (15%). Significant predictors of readmission for both operations included older age, greater comorbidity, dual eligibility for Medicare/Medicaid, and greater number of fused levels. For cervical spine readmissions, additional risk factors were male sex, a diagnosis of myelopathy, and a posterior or combined anterior/posterior surgical approach; for lumbar spine readmissions, additional risk factors were black race, Middle Atlantic geographic region, fusion surgery, and an anterior surgical approach. Our model explained more than 60% of the variability in readmissions., Conclusions: Among Medicare beneficiaries, 30-day readmissions after elective spine surgery for degenerative conditions represent a target for improvement. Both patient factors and operative techniques are associated with readmissions. Interventions to minimize readmissions should be specific to surgical site and focus on high-risk subgroups where clinical trials of interventions may be of greatest benefit., (Published by Elsevier Inc.)
- Published
- 2012
- Full Text
- View/download PDF
36. Influence of fear-avoidance beliefs on functional status outcomes for people with musculoskeletal conditions of the shoulder.
- Author
-
Sindhu BS, Lehman LA, Tarima S, Bishop MD, Hart DL, Klein MR, Shivakoti M, and Wang YC
- Subjects
- Cohort Studies, Disability Evaluation, Female, Humans, Male, Musculoskeletal Diseases rehabilitation, Pain Measurement, Retrospective Studies, Shoulder, Surveys and Questionnaires, Fear psychology, Musculoskeletal Diseases psychology, Personality Disorders psychology
- Abstract
Background: The influence of elevated fear-avoidance beliefs on change in functional status is unclear., Objective: The purpose of this study was to determine the influence of fear-avoidance on recovery of functional status during rehabilitation for people with shoulder impairments., Design: A retrospective longitudinal cohort study was conducted., Methods: Data were collected from 3,362 people with musculoskeletal conditions of the shoulder receiving rehabilitation. At intake and discharge, upper-extremity function was measured using the shoulder Computerized Adaptive Test. Pain intensity was measured using an 11-point numerical rating scale. Completion rate at discharge was 57% for function and 47% for pain intensity. A single-item screen was used to classify patients into groups with low versus elevated fear-avoidance beliefs at intake. A general linear model (GLM) was used to describe how change in function is affected by fear avoidance in 8 disease categories. This study also accounted for within-clinic correlation and controlled for other important predictors of functional change in functional status, including various demographic and health-related variables. The parameters of the GLM and their standard errors were estimated with the weighted generalized estimating equations method., Results: Functional change was predicted by the interaction between fear and disease categories. On further examination of 8 disease categories using GLM adjusted for other confounders, improvement in function was greater for the low fear group than for the elevated fear group among people with muscle, tendon, and soft tissue disorders (Δ=1.37, P<.01) and those with osteopathies, chondropathies, and acquired musculoskeletal deformities (Δ=5.52, P<.02). These differences were below the minimal detectable change. Limitations Information was not available on whether therapists used information on level of fear to implement treatment plans., Conclusions: The influence of fear-avoidance beliefs on change in functional status varies among specific shoulder impairments.
- Published
- 2012
- Full Text
- View/download PDF
37. Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons.
- Author
-
Lee YI, Mikesh M, Smith I, Rimer M, and Thompson W
- Subjects
- Animals, Apoptosis, Mice, Microscopy, Electron, Models, Animal, Motor Neurons cytology, Motor Neurons physiology, Muscle Fibers, Skeletal physiology, Muscular Atrophy, Spinal pathology, Myosin Heavy Chains analysis, Neuromuscular Junction pathology, Neuromuscular Junction ultrastructure, Synapses pathology, Motor Neurons pathology, Muscular Atrophy, Spinal physiopathology, Neuromuscular Junction physiology, Synaptic Transmission
- Abstract
A mouse model of the devastating human disease "spinal muscular atrophy" (SMA) was used to investigate the severe muscle weakness and spasticity that precede the death of these animals near the end of the 2nd postnatal week. Counts of motor units to the soleus muscle as well as of axons in the soleus muscle nerve showed no loss of motor neurons. Similarly, neither immunostaining of neuromuscular junctions nor the measurement of the tension generated by nerve stimulation gave evidence of any significant impairment in neuromuscular transmission, even when animals were maintained up to 5days longer via a supplementary diet. However, the muscles were clearly weaker, generating less than half their normal tension. Weakness in 3 muscles examined in the study appears due to a severe but uniform reduction in muscle fiber size. The size reduction results from a failure of muscle fibers to grow during early postnatal development and, in soleus, to a reduction in number of fibers generated. Neuromuscular development is severely delayed in these mutant animals: expression of myosin heavy chain isoforms, the elimination of polyneuronal innervation, the maturation in the shape of the AChR plaque, the arrival of SCs at the junctions and their coverage of the nerve terminal, the development of junctional folds. Thus, if SMA in this particular mouse is a disease of motor neurons, it can act in a manner that does not result in their death or disconnection from their targets but nonetheless alters many aspects of neuromuscular development., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
38. Regulation of the intermediate filament protein nestin at rodent neuromuscular junctions by innervation and activity.
- Author
-
Kang H, Tian L, Son YJ, Zuo Y, Procaccino D, Love F, Hayworth C, Trachtenberg J, Mikesh M, Sutton L, Ponomareva O, Mignone J, Enikolopov G, Rimer M, and Thompson W
- Subjects
- Animals, Enhancer Elements, Genetic physiology, Mice, Mice, Transgenic, Muscle, Skeletal cytology, Nestin, Neuromuscular Junction cytology, Rats, Schwann Cells cytology, Schwann Cells physiology, Sciatic Neuropathy pathology, Intermediate Filament Proteins physiology, Muscle, Skeletal innervation, Muscle, Skeletal physiology, Nerve Tissue Proteins physiology, Neuromuscular Junction physiology
- Abstract
The intermediate filament nestin is localized postsynaptically at rodent neuromuscular junctions. The protein forms a filamentous network beneath and between the synaptic gutters, surrounds myofiber nuclei, and is associated with Z-discs adjacent to the junction. In situ hybridization shows that nestin mRNA is synthesized selectively by synaptic myonuclei. Although weak immunoreactivity is present in myelinating Schwann cells that wrap the preterminal axon, nestin is not detected in the terminal Schwann cells (tSCs) that cover the nerve terminal branches. However, after denervation of muscle, nestin is upregulated in tSCs and in SCs within the nerve distal to the lesion site. In contrast, immunoreactivity is strongly downregulated in the muscle fiber. Transgenic mice in which the nestin neural enhancer drives expression of a green fluorescent protein (GFP) reporter show that the regulation in SCs is transcriptional. However, the postsynaptic expression occurs through enhancer elements distinct from those responsible for regulation in SCs. Application of botulinum toxin shows that the upregulation in tSCs and the loss of immunoreactivity in muscle fibers occurs with blockade of transmitter release. Extrinsic stimulation of denervated muscle maintains the postsynaptic expression of nestin but does not affect the upregulation in SCs. Thus, a nestin-containing cytoskeleton is promoted in the postsynaptic muscle fiber by nerve-evoked muscle activity but suppressed in tSCs by transmitter release. Nestin antibodies and GFP driven by nestin promoter elements serve as excellent markers for the reactive state of SCs. Vital imaging of GFP shows that SCs grow a dynamic set of processes after denervation.
- Published
- 2007
- Full Text
- View/download PDF
39. Fluorescent proteins expressed in mouse transgenic lines mark subsets of glia, neurons, macrophages, and dendritic cells for vital examination.
- Author
-
Zuo Y, Lubischer JL, Kang H, Tian L, Mikesh M, Marks A, Scofield VL, Maika S, Newman C, Krieg P, and Thompson WJ
- Subjects
- Adipocytes cytology, Animals, Cell Line, Green Fluorescent Proteins biosynthesis, Humans, Langerhans Cells cytology, Lens, Crystalline cytology, Luminescent Proteins biosynthesis, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Fluorescence, Nerve Growth Factors, Neuroglia cytology, Neuromuscular Junction cytology, Receptors, Cholinergic analysis, S100 Calcium Binding Protein beta Subunit, S100 Proteins genetics, Schwann Cells chemistry, Schwann Cells ultrastructure, Transgenes, Dendritic Cells cytology, Macrophages cytology, Neurons cytology, Recombinant Fusion Proteins biosynthesis, S100 Proteins biosynthesis, Schwann Cells cytology
- Abstract
To enable vital observation of glia at the neuromuscular junction, transgenic mice were generated that express proteins of the green fluorescent protein family under control of transcriptional regulatory sequences of the human S100B gene. Terminal Schwann cells were imaged repetitively in living animals of one of the transgenic lines to show that, except for extension and retraction of short processes, the glial coverings of the adult neuromuscular synapse are stable. In other lines, subsets of Schwann cells were labeled. The distribution of label suggests that Schwann cells at individual synapses are clonally related, a finding with implications for how these cells might be sorted during postnatal development. Other labeling patterns, some present in unique lines, included astrocytes, microglia, and subsets of cerebellar Bergmann glia, spinal motor neurons, macrophages, and dendritic cells. We show that lines with labeled macrophages can be used to follow the accumulation of these cells at sites of injury.
- Published
- 2004
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.