Questioning rotary functionality in the bacterial flagellar system and proposing a murburn model for motility.

Bacterial flagellar system (BFS) was the primary example of a purported 'rotary-motor' functionality in a natural assembly. This mandates the translation of a circular motion of components inside into a linear displacement of the cell body outside, which is supposedly orchestrated with the following features of the BFS: (i) A chemical/electrical differential generates proton motive force (pmf, including a trans-membrane potential, TMP), which is electro-mechanically transduced by inward movement of protons via BFS. (ii) Membrane-bound proteins of BFS serve as stators and the slender filament acts as an external propeller, culminating into a hook-rod that pierces the membrane to connect to a 'broader assembly of deterministically movable rotor'. We had disclaimed the purported pmf/TMP-based respiratory/photosynthetic physiology involving Complex V, which was also perceived as a 'rotary machine' earlier. We pointed out that the murburn redox logic was operative therein. We pursue the following similar perspectives in BFS-context: (i) Low probability for the evolutionary attainment of an ordered/synchronized teaming of about two dozen types of proteins (assembled across five-seven distinct phases) towards the singular agendum of rotary motility. (ii) Vital redox activity (not the gambit of pmf/TMP!) powers the molecular and macroscopic activities of cells, including flagella. (iii) Flagellar movement is noted even in ambiances lacking/countering the directionality mandates sought by pmf/TMP. (iv) Structural features of BFS lack component(s) capable of harnessing/achieving pmf/TMP and functional rotation. A viable murburn model for conversion of molecular/biochemical activity into macroscopic/mechanical outcomes is proposed herein for understanding BFS-assisted motility. HIGHLIGHTSThe motor-like functionalism of bacterial flagellar system (BFS) is analyzedProton/Ion-differential based powering of BFS is unviable in bacteriaUncouplers-sponsored effects were misinterpreted, resulting in a detour in BFS researchThese findings mandate new explanation for nano-bio-mechanical movements in BFSA minimalist murburn model for the bacterial flagella-aided movement is proposedCommunicated by Ramaswamy H. Sarma.

Low-dose mesenchymal stem cell therapy for discogenic pain: safety and efficacy results from a 1-year feasibility study.

Aim: To evaluate safety and efficacy of low dose autologous adipose-derived mesenchymal stem cells (ADMSCs) for treatment of disc degeneration resulting in low back pain (LBP). Methods: Nine participants with chronic LBP originating from single-level lumbar disc disease underwent intradiscal injection of 10 million ADMSCs with optional repetition after 6 months. Results: No unexpected or serious adverse events were recorded. Seven (78%) of participants reported reductions in pain 12 months after treatment. Five (56%) reported increased work capacity. Three (33%) reduced analgesic medication. Improvements in EQ-5D and Oswestry disability index results were observed. MRI demonstrated no further disc degeneration and improvements to annular fissures and disc protrusions. Conclusion: This study provides initial evidence of safety and efficacy of ADMSCs for discogenic LBP.

Structure-function correlations and system dynamics in oxygenic photosynthesis: classical perspectives and murburn precepts.

HIGHLIGHTS: Contemporary beliefs on oxygenic photosynthesis are critiqued.Murburn model is suggested as an alternative explanation.In the new model, diffusible reactive species are the main protagonists.All pigments are deemed photo-redox active in the new stochastic mechanism.NADPH synthesis occurs via simple electron transfers, not via elaborate ETC.Oxygenesis is delocalized and not just centered at Mn-Complex.Energetics of murburn proposal for photophosphorylation is provided.The proposal ushers in a paradigm shift in photosynthesis research.

Hemoglobin catalyzes ATP-synthesis in human erythrocytes: a murburn model.

Blood hemoglobin (Hb), known to transport oxygen, is the most abundant globular protein in humans. Erythrocytes have ∼10-3 M concentration of ATP in steady-state and we estimate that this high amounts cannot be formed from 10-4 - 10-7 M levels of precursors via substrate-level phosphorylation of glycolysis. To account for this discrepancy, we propose that Hb serves as a 'murzyme' (a redox enzyme working along the principles of murburn concept), catalyzing the synthesis of the major amounts of ATP found in erythrocytes. This proposal is along the lines of our earlier works demonstrating DROS (diffusible reactive oxygen species) mediated ATP-synthesis as a thermodynamically and kinetically viable mechanism for physiological oxidative phosphorylation. We support the new hypothesis for Hb with theoretical arguments, experimental findings of reputed peers and in silico explorations. Using in silico methods, we demonstrate that adenosine nucleotide and 2,3-bisphosphoglycerate (2,3-BPG) binding sites are located suitably on the monomer/tetramer, thereby availing facile access to the superoxide emanating from the heme center. Our proposal explains earlier reported in situ experimental findings/suggestions of 2,3-BPG and ADP binding at the same locus on Hb. The binding energy is in the order of 2,3-BPG > NADH > ATP > ADP > AMP and agrees with earlier reports, potentially explaining the bioenergetic physiology of erythrocytes. Also, the newly discovered site for 2,3-BPG shows lower affinity in fetal Hb (as compared to adults) explaining oxygen transfer from mother to embryo. The findings pose significant implications in routine physiology and pathologies like sickle cell anemia and thalassemia.Communicated by Ramaswamy H. Sarma.

Validating the predictions of murburn model for oxygenic photosynthesis: Analyses of ligand-binding to protein complexes and cross-system comparisons.

In this second half of our treatise on oxygenic photosynthesis, we provide support for the murburn model of the light reaction of photosynthesis and ratify key predictions made in the first part. Molecular docking and visualization of various ligands of quinones/quinols (and their derivatives) with PS II/Cytochrome b6f complexes did not support chartered 2e-transport role of quinols. A broad variety of herbicides did not show any affinity/binding-based rationales for inhibition of photosynthesis. We substantiate the proposal that disubstituted phenolics (perceived as protonophores/uncouplers or affinity-based inhibitors in the classical purview) serve as interfacial modulators of diffusible reactive (oxygen) species or DR(O)S. The DRS-based murburn model is evidenced by the identification of multiple ADP-binding sites on the extra-membraneous projection of protein complexes and structure/distribution of the photo/redox catalysts. With a panoramic comparison of the redox metabolic machinery across diverse organellar/cellular systems, we highlight the ubiquitous one-electron murburn facets (cofactors of porphyrin, flavin, FeS, other metal centers and photo/redox active pigments) that enable a facile harnessing of the utility of DRS. In the summative analyses, it is demonstrated that the murburn model of light reaction explains the structures of membrane supercomplexes recently observed in thylakoids and also accounts for several photodynamic experimental observations and evolutionary considerations. In toto, the work provides a new orientation and impetus to photosynthesis research. Communicated by Ramaswamy H. Sarma.

Acute toxicity of cyanide in aerobic respiration: Theoretical and experimental support for murburn explanation.

The inefficiency of cyanide/HCN (CN) binding with heme proteins (under physiological regimes) is demonstrated with an assessment of thermodynamics, kinetics, and inhibition constants. The acute onset of toxicity and CN's mg/Kg LD50 (µM lethal concentration) suggests that the classical hemeFe binding-based inhibition rationale is untenable to account for the toxicity of CN. In vitro mechanistic probing of CN-mediated inhibition of hemeFe reductionist systems was explored as a murburn model for mitochondrial oxidative phosphorylation (mOxPhos). The effect of CN in haloperoxidase catalyzed chlorine moiety transfer to small organics was considered as an analogous probe for phosphate group transfer in mOxPhos. Similarly, inclusion of CN in peroxidase-catalase mediated one-electron oxidation of small organics was used to explore electron transfer outcomes in mOxPhos, leading to water formation. The free energy correlations from a Hammett study and IC50/Hill slopes analyses and comparison with ligands ( CO/ H 2 S/ N 3 - ) $\left( {\text{CO}}/{{{{\text{H}}_{2}}\text{S}}/{\text{N}_{3}^{\text{-}}}\;}\; \right)$ provide insights into the involvement of diffusible radicals and proton-equilibriums, explaining analogous outcomes in mOxPhos chemistry. Further, we demonstrate that superoxide (diffusible reactive oxygen species, DROS) enables in vitro ATP synthesis from ADP+phosphate, and show that this reaction is inhibited by CN. Therefore, practically instantaneous CN ion-radical interactions with DROS in matrix catalytically disrupt mOxPhos, explaining the acute lethal effect of CN.

Dorsal Root Ganglion Stimulation Is Paresthesia-Independent: A Retrospective Study.

INTRODUCTION: Neuromodulation is an important tool for achieving pain relief in otherwise-intractable neuropathic pain conditions. Dorsal root ganglion (DRG) stimulation, in which primary sensory neurons are stimulated prior to their entry into the spinal canal, provides treatment with high levels of dermatomal specificity and can provide advantages compared to conventional spinal cord stimulation. Although DRG stimulation can produce perceptible paresthesias, many patients operate their systems at subthreshold amplitudes that do not elicit this sensation. Pain relief both with and without paresthesia was investigated in this retrospective analysis. MATERIALS AND METHODS: A retrospective review of all qualifying permanent DRG stimulation systems at a single center over more than a three-year period was completed. Pain (0-10 numeric rating scale) was assessed at baseline, at the end of the trial, and after three, six, and twelve months of treatment. Patients were categorized based on their usage of the stimulator at amplitudes that either did or did not produce paresthesias. RESULTS: Of the 39 patients, 34 (87%) reported having no-paresthesias at any of the follow-up visits. Average pain relief was 73.9% after the trial period and 63.1% after 12 months of treatment. The responder rate (50% or better pain relief) after three months of treatment was more than 80%. Exploratory subgroup analyses showed that similar degrees of pain relief were achieved in numerous body regions and with various pain etiologies. The five patients who reported paresthesias during treatment had pain relief similar to those of the group that did not experience paresthesias. DISCUSSION: Clinically significant and sustained pain relief over more than a period of 12 months was achieved with DRG stimulation programmed at amplitudes below the perceptual level. Thus, the reported analgesia was paresthesia-independent. That good clinical outcomes were observed independent of the generation of paresthesia in DRG stimulation suggests several mechanisms of action, including the inhibition of supraspinal regions involved in somatic paresthesia sensation. The retrospective results presented here posit that future prospective study of DRG stimulation delivered at below the threshold of perceptible paresthesias is warranted.

New Therapy for Refractory Chronic Mechanical Low Back Pain-Restorative Neurostimulation to Activate the Lumbar Multifidus: One Year Results of a Prospective Multicenter Clinical Trial.

OBJECTIVES: The purpose of the international multicenter prospective single arm clinical trial was to evaluate restorative neurostimulation eliciting episodic contraction of the lumbar multifidus for treatment of chronic mechanical low back pain (CMLBP) in patients who have failed conventional therapy and are not candidates for surgery or spinal cord stimulation (SCS). MATERIALS AND METHODS: Fifty-three subjects were implanted with a neurostimulator (ReActiv8, Mainstay Medical Limited, Dublin, Ireland). Leads were positioned bilaterally with electrodes close to the medial branch of the L2 dorsal ramus nerve. The primary outcome measure was low back pain evaluated on a 10-Point Numerical Rating Scale (NRS). Responders were defined as subjects with an improvement of at least the Minimal Clinically Important Difference (MCID) of ≥2-point in low back pain NRS without a clinically meaningful increase in LBP medications at 90 days. Secondary outcome measures included Oswestry Disability Index (ODI) and Quality of Life (QoL; EQ-5D). RESULTS: For 53 subjects with an average duration of CLBP of 14 years and average NRS of 7 and for whom no other therapies had provided satisfactory pain relief, the responder rate was 58%. The percentage of subjects at 90 days, six months, and one year with ≥MCID improvement in single day NRS was 63%, 61%, and 57%, respectively. Percentage of subjects with ≥MCID improvement in ODI was 52%, 57%, and 60% while those with ≥MCID improvement in EQ-5D was 88%, 82%, and 81%. There were no unanticipated adverse events (AEs) or serious AEs related to the device, procedure, or therapy. The initial surgical approach led to a risk of lead fracture, which was mitigated by a modification to the surgical approach. CONCLUSIONS: Electrical stimulation to elicit episodic lumbar multifidus contraction is a new treatment option for CMLBP. Results demonstrate clinically important, statistically significant, and lasting improvement in pain, disability, and QoL.

Peripheral Nerve Field Stimulation Therapy for Patients With Thoracic Pain: A Prospective Study.

OBJECTIVE: Relative to the number of patients suffering chronic lumbar and cervical pain, fewer patients suffer persistent thoracic pain. Consequently there is less literature, with smaller sample sizes, reporting treatment of this cohort. Here, we assess peripheral nerve field stimulation (PNfS) as a potential treatment for chronic thoracic pain. MATERIALS AND METHODS: This study included 20 consecutive chronic thoracic pain sufferers that responded successfully to PNfS trial. The patients were subsequently implanted with permanent eight-contact electrode linear percutaneous leads within their major area of pain. Patients were followed up at 12 months for outcome reporting. All 20 patients were considered in the statistical analysis, despite removal of three devices prior to follow up. RESULTS: The average baseline pre-treatment Numerical Pain Rating Scale (NPRS) score was 7.75 ± 1.4. Following PNfS, the mean NPRS score was 2.25 ±2.14, reflecting a significant average improvement of 5.5 ± 3.31. Three patients were explanted prior to follow up: the first gained excellent thoracic pain relief but pain at the Implantable Pulse Generator (IPG) site could not be overcome, the second achieved excellent pain relief but the PNfS was removed due to recurrent infection and in the final instance, the intervention offered only poor relief and the device removed. CONCLUSION: PNfS is an effective intervention for intractable disabling thoracic pain, offering sustained and worthwhile pain relief, for the overwhelming majority of the cohort. This may be especially true when considering a combined treatment approach of PNfS and analgesic use to manage remnant pain.

Peripheral nerve field stimulation for chronic headache: 60 cases and long-term follow-up.

OBJECTIVE: The objective of this study is to evaluate the efficacy of peripheral nerve field stimulation (PNFS) for the treatment of chronic headache conditions. MATERIALS AND METHODS: For more than a four-year period, 83 patients underwent a trial of a PNFS system targeting the nerve regions including occipital and supraorbital and infraorbital nerves, which best corresponded with their area of head pain. Sixty patients reported a successful trial and underwent a subsequent implant of the PNFS system. Questionnaires, along with patients' charts, were used to assess outcomes as follows: pain (11-point numerical pain rating scale), analgesic use, depression (Zung Depression Scale), disability (Neck Disability Index), patient satisfaction, and surgical complications. Patients were followed up for an average of 12.9 ± 9.4 months (range 3-42 months). RESULTS: An average pain reduction of 4.8 ± 2.3 pain scale points was observed (preimplant 7.4 ± 1.6; follow-up 2.6 ± 2.1 [p ≤ 0.001]). Of the 60 patients implanted, 41 reported >50% pain relief. Medication use was reduced in 83% of patients who were previously taking analgesics or prophylactic medications. Similarly, reductions in degree of disability and depression also were observed. Of the 60 cases, ten surgical revisions were required; however, no long-term complications were reported. CONCLUSIONS: PNFS for chronic headache is an evolving therapy. This study demonstrates that this reversible and effective treatment can be a promising pain relief strategy for this often intractable condition.

Peripheral nerve field stimulation for chronic pain: 100 cases and review of the literature.

OBJECTIVE: To evaluate the clinical outcomes of 100 consecutive patients receiving peripheral nerve field stimulation (PNFS) for the treatment of chronic intractable pain. DESIGN: Prospective, observational study. SETTING: A private interventional pain specialty referral practice. PATIENTS: One hundred consecutive private practice patients receiving PNFS for the treatment of chronic craniofacial, thorax, lumbosacral, abdominal, pelvic, and groin pain conditions. OUTCOME MEASURES: Pain (11-point numerical rating scale), complications, changes to analgesic use and employment status, disability (Oswestry or Neck Disability Indexes), depression (Zung Depression Index), and patient satisfaction. RESULTS: We demonstrate an average pain reduction of 4.2 ± 2.5 pain scale points on an 11-point scale following PNFS (preimplant pain score of 7.4 ± 1.7 to a follow-up average of 3.2 ± 2.3 pain scale points) (P≤0.00). At a follow-up period of 8.1 ± 4.7 months (range 1-23 months), an overall 72% of patients reduced their analgesic use following PNFS. Patients receiving a lumbosacral PNFS for chronic low back pain reported a significant reduction in disability following treatment, as determined by the Oswestry Disability Index. Of the 100 cases, no long-term complications were reported. CONCLUSIONS: This prospective 100 consecutive PNFS patient outcome study demonstrates that PNFS can be a safe and effective treatment option for, otherwise, intractable chronic pain conditions. PNFS has the potential to fundamentally change the way we think about pain management.

Peripheral nerve field stimulation: is age an indicator of outcome?

Objective. This study aims to assess peripheral nerve field stimulation as a treatment option for chronic pain and test for indicators of outcome. Materials and Methods. We reviewed all patients permanently implanted with peripheral nerve field stimulators over the past 24 months. A questionnaire was used to assess outcomes. Results. Twenty-seven questionnaires were sent out and 23/27 responded. A significant average decrease of 4.02 visual analog scale points was observed. The average pain decrease for the low back was 3.77 points and 5.9 for occipital implants. An age effect was detected; younger patients (<60 years) reported an average pain relief of 4.79 points while older patients (>61 years) reported an average pain relief decrement of only 2.83 points. Most patients reported decreases in analgesic use after treatment. Pain relief was significantly and highly correlated with reduced analgesic intake and patient satisfaction. Conclusion. Peripheral nerve field stimulation is a safe, reversible, and effective treatment option for patients with chronic pain, particularly those under 60 years.

Peripheral nerve stimulation: a treatment for chronic low back pain and failed back surgery syndrome?

Objective. This study aims to evaluate the usefulness of peripheral nerve stimulation as a treatment option for patients with chronic low back pain. Materials and Methods. More than 12 months, we collected data on consecutive patients who had successful trials and were subsequently implanted with octrode percutaneous leads placed subcutaneously within the major area of pain. Eleven patients met diagnostic criteria for failed back surgery syndrome. A questionnaire assessed outcomes including: pain, analgesic use, and patient satisfaction. The response rate was 93% (13/14): average follow-up time was seven months. Results. There was a significant decrease in pain levels: an average reduction of 3.77 visual analog scale points. Eleven patients (85%) reported successful outcomes and an average pain reduction of 4.18 points but two reported a poor response. Pain relief was highly correlated with reduced analgesia and patient satisfaction. No complications were reported. Conclusion. This study demonstrates a treatment option that is safe, nonpharmacologic, reversible, and effective for patients with chronic low back pain that have exhausted other treatment options.

The incidence of intravascular penetration in medial branch blocks: cervical, thoracic, and lumbar spines.

STUDY DESIGN: Clinical observational study. OBJECTIVE: To quantify the incidence of inadvertent intravascular injections in spinal medial branch blocks in a clinical setting. SUMMARY OF BACKGROUND DATA: Previous research established the rate of inadvertent intravascular injection in lumbar medial branch blocks at 8%. The incidence of intravascular injection in cervical and thoracic medial branch blocks has not been reported previously. This study establishes the rate of inadvertent intravascular injection in patients receiving medial branch blocks of the cervical and thoracic spines. Further, this study reports a significantly lower rate of inadvertent intravascular injection for lumbar medial branch blocks than previously reported. METHODS: Patients were originally referred to the clinic, for diagnosis and treatment of chronic spinal origin somatic pain. Medial branch blocks were then performed as diagnostic procedures to confirm the zygapophysial joint(s) as the suspected source of pain. Blocks were performed by experienced practitioners on nonidentified patients over a 3-year period. Clinical observations were recorded for 14,312 separate medial branch block levels. The level of the spine and the incidence of inadvertent intravascular injections were recorded. RESULTS: This study demonstrates that the overall incidence of intravascular penetration in medial branch blocks is rare, with an overall rate of 3.5%. This study also establishes the rate of intravascular injection for levels within the spine: the cervical spine is likely to be intravascular 3.9% of the time and the lumbar spine 3.7%, whereas the thoracic spine is significantly lower, with just 0.7% injections reported as intravascular. Significant differences were also observed between individual vertebral levels. CONCLUSION: The false-negative rate for medial branch blocks is likely to be lower than previously reported. The rate of inadvertent intravascular injection for thoracic medial branch blocks is 0.7%. Cervical and lumbar medial branch blocks are associated with an overall rate of 3.9% and 3.7%, respectively. Although these rates are lower than previously reported, the incidence of false-negative blocks still justifies the use of contrast to confirm nonvascular injection.

Interventions in chronic low back pain.

BACKGROUND: Chronic low back pain presents a major challenge for general practitioners and is a significant drain on community resources. Patients often feel frustrated by modern medicine's apparent failure to validate their symptoms with a specific diagnosis and management plan. OBJECTIVE: This article presents an evidence based guide to current interventions, including an algorithm for the interventional diagnostic workup of low back pain that has persisted beyond 3 months. DISCUSSION: Modern imaging techniques rarely determine the cause of pain. The GP must look for 'red flag' clues in the history. Management of low back pain includes NSAIDs, simple injections of plain local anaesthetic without adrenalin or cortisone, referral to a masseuse, cortisone, physiotherapist and/or a musculoskeletal pain physician. Specific management includes medial branch and sacroiliac joint blocks, and radiofrequency neurotomy. Patients with long term pain may be referred to a psychologist for cognitive behavioural therapy.