Targeted Redox Balancing through Pulmonary Nanomedicine Delivery Reverses Oxidative Stress Induced Lung Inflammation.

Non-invasive delivery of drugs is important for the reversal of respiratory diseases essentially by-passing metabolic pathways and targeting large surface area of drug absorption. Here, we study the inhalation of a redox nano medicine namely citrate functionalized Mn3O4 (C-Mn3O4) duly encapsulated in droplet evaporated aerosols for the balancing of oxidative stress generated by the exposure of Chromium (VI) ion, a potential lung carcinogenic agent. Our optical spectroscopic in-vitro experiments demonstrates the efficacy of redox balancing of the encapsulated nanoparticles (NP) for the maintenance of a homeostatic condition. The formation of Cr-NP complex as an excretion of the heavy metal is also demonstrated through optical spectroscopic and high resolution transmission optical microscopy (HRTEM). Our studies confirm the oxidative stress mitigation activity of the Cr-NP complex. A detailed immunological assay followed by histopathological studies and assessment of mitochondrial parameters in pre-clinical mice model with chromium (Cr) induced lung inflammation establishes the mechanism of drug action to be redox-buffering. Thus, localised delivery of C-Mn3O4 NPs in the respiratory tract via aerosols can act as an effective nanotherapeutic agent against oxidative stress induced lung inflammation.

Posterior cervical foraminotomy versus anterior cervical discectomy for Cervical Brachialgia: the FORVAD RCT.

Background: Posterior cervical foraminotomy and anterior cervical discectomy are routinely used operations to treat cervical brachialgia, although definitive evidence supporting superiority of either is lacking. Objective: The primary objective was to investigate whether or not posterior cervical foraminotomy is superior to anterior cervical discectomy in improving clinical outcome. Design: This was a Phase III, unblinded, prospective, United Kingdom multicentre, parallel-group, individually randomised controlled superiority trial comparing posterior cervical foraminotomy with anterior cervical discectomy. A rapid qualitative study was conducted during the close-down phase, involving remote semistructured interviews with trial participants and health-care professionals. Setting: National Health Service trusts. Participants: Patients with symptomatic unilateral cervical brachialgia for at least 6 weeks. Interventions: Participants were randomised to receive posterior cervical foraminotomy or anterior cervical discectomy. Allocation was not blinded to participants, medical staff or trial staff. Health-care use from providing the initial surgical intervention to hospital discharge was measured and valued using national cost data. Main outcome measures: The primary outcome measure was clinical outcome, as measured by patient-reported Neck Disability Index score 52 weeks post operation. Secondary outcome measures included complications, reoperations and restricted American Spinal Injury Association score over 6 weeks post operation, and patient-reported Eating Assessment Tool-10 items, Glasgow-Edinburgh Throat Scale, Voice Handicap Index-10 items, PainDETECT and Numerical Rating Scales for neck and upper-limb pain over 52 weeks post operation. Results: The target recruitment was 252 participants. Owing to slow accrual, the trial closed after randomising 23 participants from 11 hospitals. The qualitative substudy found that there was support and enthusiasm for the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial and randomised clinical trials in this area. However, clinical equipoise appears to have been an issue for sites and individual surgeons. Randomisation on the day of surgery and processes for screening and approaching participants were also crucial factors in some centres. The median Neck Disability Index scores at baseline (pre surgery) and at 52 weeks was 44.0 (interquartile range 36.0-62.0 weeks) and 25.3 weeks (interquartile range 20.0-42.0 weeks), respectively, in the posterior cervical foraminotomy group (n = 14), and 35.6 weeks (interquartile range 34.0-44.0 weeks) and 45.0 weeks (interquartile range 20.0-57.0 weeks), respectively, in the anterior cervical discectomy group (n = 9). Scores appeared to reduce (i.e. improve) in the posterior cervical foraminotomy group, but not in the anterior cervical discectomy group. The median Eating Assessment Tool-10 items score for swallowing was higher (worse) after anterior cervical discectomy (13.5) than after posterior cervical foraminotomy (0) on day 1, but not at other time points, whereas the median Glasgow-Edinburgh Throat Scale score for globus was higher (worse) after anterior cervical discectomy (15, 7, 6, 6, 2, 2.5) than after posterior cervical foraminotomy (3, 0, 0, 0.5, 0, 0) at all postoperative time points. Five postoperative complications occurred within 6 weeks of surgery, all after anterior cervical discectomy. Neck pain was more severe on day 1 following posterior cervical foraminotomy (Numerical Rating Scale - Neck Pain score 8.5) than at the same time point after anterior cervical discectomy (Numerical Rating Scale - Neck Pain score 7.0). The median health-care costs of providing initial surgical intervention were £2610 for posterior cervical foraminotomy and £4411 for anterior cervical discectomy. Conclusions: The data suggest that posterior cervical foraminotomy is associated with better outcomes, fewer complications and lower costs, but the trial recruited slowly and closed early. Consequently, the trial is underpowered and definitive conclusions cannot be drawn. Recruitment was impaired by lack of individual equipoise and by concern about randomising on the day of surgery. A large prospective multicentre trial comparing anterior cervical discectomy and posterior cervical foraminotomy in the treatment of cervical brachialgia is still required. Trial registration: This trial is registered as ISRCTN10133661. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 21. See the NIHR Journals Library website for further project information.

Cervical brachialgia is pain that starts in the neck and passes down into the arm. Although most people with cervical brachialgia recover quickly, in some patients pain persists, and in 15% of patients pain is so severe that they are unable to work. In the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial, we investigated two neck surgeries used to treat this problem: posterior cervical foraminotomy (surgery from the back of the neck) and anterior cervical discectomy (surgery from the front of the neck). This trial aimed to find out if one of them is better than the other at relieving pain and more cost-effective for the National Health Service. We assessed patients' quality of life 1 year after their surgery and how their pain changed over the course of the year. We also measured the number of complications patients had in the first 6 weeks after their operation. Recruitment was slow and so the trial was stopped early, after only 23 patients from 11 hospitals had been randomly allocated to the two surgery groups. We had planned to recruit 252 participants to the trial; the number of participants we were able to recruit in practice was too small to enable us to determine which surgery is better at relieving pain. To find out why the trial had struggled to recruit, we asked hospital staff and participants about their experiences. We found that hospital staff sometimes struggled to organise everything needed to randomise patients on the day of surgery. Some staff also found it difficult to randomise patients as they had an opinion on which surgery they thought the patient should receive. The data collected in the trial will still be useful to help design future research. Finding out which surgery is better at relieving pain remains important, and the data we have collected will support answering this question in future.

Chemoprevention of bilirubin encephalopathy with a nanoceutical agent.

BACKGROUND: Targeted rapid degradation of bilirubin has the potential to thwart incipient bilirubin encephalopathy. We investigated a novel spinel-structured citrate-functionalized trimanganese tetroxide nanoparticle (C-Mn3O4 NP, the nanodrug) to degrade both systemic and neural bilirubin loads. METHOD: Severe neonatal unconjugated hyperbilirubinemia (SNH) was induced in neonatal C57BL/6j mice model with phenylhydrazine (PHz) intoxication. Efficiency of the nanodrug on both in vivo bilirubin degradation and amelioration of bilirubin encephalopathy and associated neurobehavioral sequelae were evaluated. RESULTS: Single oral dose (0.25 mg kg-1 bodyweight) of the nanodrug reduced both total serum bilirubin (TSB) and unconjugated bilirubin (UCB) in SNH rodents. Significant (p < 0.0001) UCB and TSB-degradation rates were reported within 4-8 h at 1.84 ± 0.26 and 2.19 ± 0.31 mg dL-1 h-1, respectively. Neural bilirubin load was decreased by 5.6 nmol g-1 (p = 0.0002) along with improved measures of neurobehavior, neuromotor movements, learning, and memory. Histopathological studies confirm that the nanodrug prevented neural cell reduction in Purkinje and substantia nigra regions, eosinophilic neurons, spongiosis, and cell shrinkage in SNH brain parenchyma. Brain oxidative status was maintained in nanodrug-treated SNH cohort. Pharmacokinetic data corroborated the bilirubin degradation rate with plasma nanodrug concentrations. CONCLUSION: This study demonstrates the in vivo capacity of this novel nanodrug to reduce systemic and neural bilirubin load and reverse bilirubin-induced neurotoxicity. Further compilation of a drug-safety-dossier is warranted to translate this novel therapeutic chemopreventive approach to clinical settings. IMPACT: None of the current pharmacotherapeutics treat severe neonatal hyperbilirubinemia (SNH) to prevent risks of neurotoxicity. In this preclinical study, a newly investigated nano-formulation, citrate-functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), exhibits bilirubin reduction properties in rodents. Chemopreventive properties of this nano-formulation demonstrate an efficacious, efficient agent that appears to be safe in these early studies. Translation of C-Mn3O4 NPs to prospective preclinical and clinical trials in appropriate in vivo models should be explored as a potential novel pharmacotherapy for SNH.

A national survey on the management of foot drop secondary to lumbar degenerative disease in the United Kingdom.

PURPOSE: There is considerable variation in the management of foot drop secondary to lumbar degenerative disease (LDD) that occurs between centres and surgeons (spinal surgeons and neurosurgeons). The lack of standardised practice reflects the paucity in evidence base for management of this condition. In this survey, we aimed to assess current practice in the UK and identify the areas of variation. METHODS: A case-based survey was distributed to members of the Society of British Neurological Surgeons and British Association of Spine Surgeons through an online questionnaire. The survey consisted of 10 questions designed to determine the management of foot drop secondary to LDD. RESULTS: A total of 163 responses were collected among UK neurosurgeons and spinal surgeons with good geographical representation. 92% were Consultants. 86% of the respondents would offer surgery. The indication for offering surgery varied but 54% of respondents would offer surgery to patients who present with a painful foot drop. There was a huge variation in offering surgery dependent on the grade of weakness. The strongest prognostic indicator predicted was duration of weakness (92%). The timing of intervention was wide-ranging in the responses received. Almost all responded that they would be willing to participate in a prospective study in the future to determine best practice. CONCLUSIONS: This survey highlights the significant variability in management of foot drop secondary to LDD amongst consultant surgeons within the UK. It is also suggestive of a weak evidence base and indicates an urgent need for a high quality national prospective study.

Prognostic indicators of surgical outcome in painful foot drop: a systematic review and meta-analysis.

PURPOSE: Foot drop is a relatively uncommon presentation of lumbar degenerative disease and there is currently a paucity of evidence on management and outcomes which is reflective of the lack of standardised treatment provided to patients. The purpose of this systematic review and meta-analysis is to determine the effectiveness of surgical management and the factors that predict surgical outcome. METHODS: A systematic database search of Cochrane Library, Ovid Medline, Pubmed, Embase and Google Scholar was undertaken from inception through August 2018. Only studies reporting on surgical outcome in adult patients who had a painful foot drop and underwent decompression were included. Case reports and studies with surgical fixation were excluded. Study quality was assessed using the Newcastle-Ottawa Scale. Data were pooled using a random-effects model. RESULTS: 797 studies were screened and 9 observational studies met the inclusion criteria. This resulted in a total of 431 patients who underwent decompression for foot drop. Pooled rates of outcome for improvement in foot drop MRC grade were 84.5% (range 67.9-96%). Sub-group meta-analyses of studies revealed a statistically significant association between duration of foot drop (pooled 4.95 [95% CI 1.13-21.74]), severity of preoperative weakness (pooled 0.38 [95% CI 0.15-0.93]) on post-operative outcome and age (pooled 6.28 [1.33-29.72]). CONCLUSION: This is the first systematic review and meta-analysis to explore the outcome and prognostic indicators of lumbar decompression for foot drop. Findings indicate that age, duration of foot drop weakness and MRC grade of foot drop prior to intervention were strong predictors of surgical outcome.

Intramedullary spinal cord tumours - a single Centre, 10-year review of clinical and pathological outcomes.

BACKGROUND: Intramedullary spinal cord tumours are relatively rare tumours of the central nervous system. Surgical outcomes are affected by many variables, including pre-operative neurological function, tumour histology and extent of resection. Emphasis remains on surgical treatment due to limited adjunctive therapeutic options and poor drug penetration. OBJECTIVE: To identify clinically relevant predictors of progression free survival by retrospectively analysing the extent of resection, pre- and post-operative neurological function and histology in intramedullary spinal cord tumours from a single neurosurgical centre over 10 years. METHODS: Forty-three adult cases were identified from a surgical database. Variables collected included pre-and post-operative Frankel Grade and Modified McCormick Scale assessments, tumour histology, extent of resection and length of follow up. Chi-Squared, Kaplan-Mier Survival and Mann-Whitney U-tests were completed. RESULTS: Ependymoma (41.9%) and haemangioblastoma (14.0%) were the commonest tumour histologies. In total, 17 different histological tumours were identified in the series. There was a statistically significant relationship between identification of the tumour plane and extent of resection (p < 0.01), along with the extent of resection and recurrence (p = 0.04). Compared to the other histological subtypes, ependymoma's demonstrated a significantly greater extent of resection (p = 0.01). There was a significant relationship between the grade of tumour and progression-free survival (p < 0.01). CONCLUSION: Tumour plane and the extent of tumour resection are significant determinants of progression-free survival. Ependymoma, whilst being the commonest histology in our series were also the most resectable. Whilst complete resection reduces the rate of recurrence, tumour grade is the most important predictor of outcome. Given the importance of the extent of resection, and following a similar trend to other low volume pathologies, these tumours should only be tackled by neurosurgeons with experience in their resection.

Direct Lateral Minimally Invasive Approach for Excision of a L1/L2 Neurofibroma-A Technical Note and Literature Review.

A case of resection of a large dumbbell-shaped nerve sheath tumor at L1/L2 via a direct lateral minimally invasive approach is described. The tumor was removed via a lateral, subdiaphragmatic, rib-sparing, retropleural, retroperitoneal approach. The thoracolumbar junction can be challenging via the lateral approach and to the best of our knowledge this is the first report of excision of a paravertebral tumor via this approach. We believe this provided the benefits of direct operative trajectory and exposure, excellent tumor access, and avoided the need for facetectomy and extended spinal instrumentation across the thoracolumbar junction. Complete tumor excision was achieved with preserved motor function and improvement in radicular pain and sensory neurological deficit.

Thoracic Intradural Extramedullary Ependymoma with Anaplastic Transformation: Case Report and Discussion.

BACKGROUND: Intradural extramedullary spinal ependymomas arising from outside the region of the conus medullaris are rare clinical entities, and anaplastic transformation of these lesions is even more exceptional. CASE DESCRIPTION: We report on a case of an intradural extramedullary T5-T6 ependymoma that underwent gross total resection. Histologic analysis of the initial tumor revealed a World Health Organization grade 2 ependymoma. Two years after initial surgical resection, there was radiologic recurrence and a re-do resection was performed with subsequent spinal stabilization. Histologic analysis of the recurrent tumor revealed a World Health Organization grade 3 ependymoma. After surgery the patient received radiotherapy, and he remains disease free at 2 years following his second surgery. In addition, we employed carbon fiber screws and rods for stabilization in his second operation to reduce artefact on follow-up imaging. CONCLUSIONS: We advocate that primary spinal ependymomas should be within the differential of intradural extramedullary lesions arising outside the region of the conus medullaris.

Novel one pot synthesis and spectroscopic characterization of a folate-Mn3O4 nanohybrid for potential photodynamic therapeutic application.

Treatment of cancer using nanoparticles made of inorganic and metallic compounds has been increasingly used, owing to their novel intrinsic physical properties and their potential to interact with specific cellular sites, thereby significantly reducing severe secondary effects. In this study, we report a facile strategy for synthesis of folate capped Mn3O4 nanoparticles (FA-Mn3O4 NPs) with high colloidal stability in aqueous media using a hydrothermal method for potential application in photodynamic therapy (PDT) of cancer. The capping of FA to Mn3O4 NPs was confirmed using various spectroscopic techniques. In adenocarcinomic human alveolar basal epithelial cells (A549), the nanohybrid synthesised with a combination of FA and Mn3O4 shows remarkable PDT activity via intracellular ROS generation (singlet oxygen). As established by a DNA fragmentation assay and fluorescence studies, the nanohybrid can cause significant nuclear DNA damage by light induced enhanced ROS generation. In the assessment of Bax, Bcl2 provides strong evidence of apoptotic cellular death. Cumulatively, the outcomes of this study suggest that these newly synthesized FA-Mn3O4 NPs can specifically destroy cells with overexpressed folate receptors, thereby providing a solution in the journey of cancer eradication.

Spectroscopic Studies on Dual Role of Natural Flavonoids in Detoxification of Lead Poisoning: Bench-to-Bedside Preclinical Trial.

Ubiquitousness in the target organs and associated oxidative stress are the most common manifestations of heavy-metal poisoning in living bodies. While chelation of toxic heavy metals is important as therapeutic strategy, scavenging of increased reactive oxygen species, reactive nitrogen species and free radicals are equally important. Here, we have studied the lead (Pb) chelating efficacy of a model flavonoid morin using steady-state and picosecond-resolved optical spectroscopy. The efficacy of morin in presence of other flavonoid (naringin) and polyphenol (ellagic acid) leading to synergistic combination has also been confirmed from the spectroscopic studies. Our studies further reveal that antioxidant activity (2,2-diphenyl-1-picrylhydrazyl assay) of the Pb-morin complex is sustainable compared to that of Pb-free morin. The metal-morin chelate is also found to be significantly soluble compared to that of morin in aqueous media. Heavy-metal chelation and sustainable antioxidant activity of the soluble chelate complex are found to accelerate the Pb-detoxification in the chemical bench (in vitro). Considering the synergistic effect of flavonoids in Pb-detoxification and their omnipresence in medicinal plants, we have prepared a mixture (SKP17LIV01) of flavonoids and polyphenols of plant origin. The mixture has been characterized using high-resolution liquid chromatography assisted mass spectrometry. The mixture (SKP17LIV01) containing 34 flavonoids and 76 other polyphenols have been used to investigate the Pb detoxification in mouse model. The biochemical and histopathological studies on the mouse model confirm the dual action in preclinical studies.

Spontaneous regression of retro-odontoid post traumatic cicatrix following occipitocervical fixation.

This case report describes a patient who presented with myelopathy secondary to a large retro-odontoid post traumatic cicatrix. The objective of this study was to discuss the clinical presentation, pathogenesis, imaging, and surgical management of pseudoarthrosis tissue mass associated with odontoid nonunion. Atlantoaxial subluxation (AAS) has been widely reported in patients with rheumatoid arthritis. AAS leads to repeated cycles of partial tear and repair of ligaments around the altantoaxial complex, resulting in the formation of periodontoid mass (pseudotumor). It is thought that formation of retro-odontoid post traumatic mass (cicatrix), in certain cases of odontoid fracture, is because of similar pathology. This is a retrospective review of case note. Here, the patient underwent posterior decompression through a C1-C2 laminectomy and occipitocervical (C0-C4) fusion with instrumentation, which resulted in dramatic improvement in his symptoms and spontaneous regression of retro-odontoid post traumatic cicatrix. We have described an interesting and a rare case of a large pseudoarthrosis tissue mass associated with odontoid nonunion, which regressed following stand-alone posterior instrumentation. To the best of our knowledge, only a handful of such cases of spontaneous regression of retro-odontoid post traumatic cicatrix following occipitocervical fixation have been described in literature, and our case adds to the growing list of such cases and may help in understanding the natural history of the disease process one day. Although rare, post traumatic cicatrix should be considered as a differential diagnosis of enhancing retro-odontoid mass, especially if there is any history of cervical spine trauma.

Spontaneous resolution of symptomatic lumbar synovial cyst.

Lumbar synovial cyst arises from the facet joint and can lead to back pain, radiculopathy, neurogenic claudication or even cauda equina syndrome. Although most surgeons would consider surgery to be the treatment of choice, the natural history of the disease process remains unknown and uncertainty still exists regarding optimal management of this controversial entity. We illustrate a case of large L5/S1 synovial cyst for which surgery was initially planned. However, it resolved spontaneously without any treatment. We also provide a brief literature review regarding conservative, surgical and minimally invasive management of symptomatic lumbar synovial cyst with special reference to patient outcome.

Surgical outcome for foot drop in lumbar degenerative disease.

Controversy exists regarding the timing and outcome of surgery for lumbar degenerative disease (LDD) associated with foot drop. In this work, we report the results of a retrospective observational study from our center. We had a sample size of 26 patients with a minimum follow-up of 6 months. Of the 26 patients, 88% improved, with complete recovery observed in 61%. Thus, our data support the view that there is good recovery from operative management of foot drop secondary to LDD. Adjusting for preoperative strength, preoperative duration of weakness was a significant predictor of extent of recovery (odds ratio = 0.93; 95% confidence interval 0.88 to 0.98; p = 0.019). The model explained 50% of the variance in outcome in this study.

Spinal Epidural Abscess Presenting with Paraplegia Following Delayed Presentation of Traumatic Esophageal Perforation without Spinal Fracture: Lessons to be Learnt.

We describe a case of esophageal perforation following blunt chest trauma with delayed presentation as paraplegia secondary to spinal epidural abscess formation. The case highlights the importance of the awareness of the possibility of esophageal injury in patients following road traffic collisions.

Glioblastoma multiforme fades on CT imaging after dexamethasone therapy.

We describe a patient in whom an enhancing lesion seen on CT scan faded following dexamethasone therapy. Subsequent biopsy revealed a glioblastoma multiforme. Various intrinsic cerebral lesions have been noted to disappear on CT imaging after the administration of corticosteroids, but it is less common for gliomas to exhibit this property.

Paediatric intramedullary spinal cord cavernous malformations: case report and review of the literature.

Cavernous malformations are vascular lesions which can occur throughout the entire neuraxis. This term is synonymous to cavernous angioma, cavernous haemangioma, and cavernoma. They comprise of closely packed, capillary-like vascular channels, without intervening neural tissue. MR imaging is currently the study of choice for the diagnosis of cavernous malformations as they are considered angiographically occult lesions. Intramedullary location represents only 3-5% of all central nervous system cavernous malformations, with the majority of them being supratentorial. Only 10% of the intramedullary cavernous malformations present in the paediatric population. As the natural history of these lesions is not well known, the debate on the optimal management of them is still ongoing. Here we describe the case of a 14-year-old male with progression of symptoms over an 18 months period, which necessitated microsurgical removal of a T9 intramedullary cavernous malformation.

Intradural extramedullary primary malignant melanoma radiographically mimicking a neurofibroma.

A case of intradural extramedullary primary malignant melanoma mimicking the presentation of a neurofibroma is described. We emphasise the fact that surgeons should be aware of unexpected malignant lesions involving spinal nerve roots.