High mobility group box-1 serves a pathogenic role in spinal cord injury via the promotion of pro-inflammatory cytokines.

Traumatic spinal cord injury (SCI) is a devastating condition marked by permanent motor, sensory, and autonomic dysfunction, in which the inflammatory response serves an important and preventable role. High mobility group box-1 (HMGB1) is a potent regulator of inflammation in numerous acute and chronic inflammatory conditions.; however, the role of HMGB1 in SCI remains unclear. The present study aimed to characterize the temporal dynamics of HMGB1 release after SCI, to investigate the role of spinal microglia activation in mediating the effects of HMGB1 on SCI, and to explore the therapeutic potential of intrathecal anti-HMGB1 polyclonal antibody on alleviating SCI. The present study demonstrated that HMGB1 expression was increased immediately after traumatic injury of a primary spinal neuron culture. It was found that neutralizing HMGB1 significantly ameliorated SCI pathogenesis and hind limb paralysis. Moreover, the levels of a number of pro-inflammatory cytokines in the SCI lesion were reduced when local HMGB1 was blocked by anti-HMGB1 antibody. In addition, the injured neuron-derived conditioned medium increased TNF-α secretion and the NF-κB pathway in the BV2 microglia cell line via HMGB1. Collectively, these results indicated that HMGB1 served an important role in SCI inflammation and suggested the therapeutic potential of an anti-HMGB1 antibody for SCI.

Albendazole and Corticosteroids for the Treatment of Solitary Cysticercus Granuloma: A Network Meta-analysis.

BACKGROUND: Solitary cysticercus granuloma (SCG) is the commonest form of neurocysticercosis in the Indian subcontinent and in travelers. Several different treatment options exist for SCG. We conducted a Bayesian network meta-analysis of randomized clinical trials (RCTs) to identify the best treatment option to prevent seizure recurrence and promote lesion resolution for patients with SCG. METHODS AND PRINCIPAL FINDINGS: PubMed, EMBASE and the Cochrane Library databases (up to June 1, 2015) were searched for RCTs that compared any anthelmintics or corticosteroids, alone or in combination, with placebo or head to head and reported on seizure recurrence and lesion resolution in patients with SCG. A total of 14 RCTs (1277 patients) were included in the quantitative analysis focusing on four different treatment options. A Bayesian network model computing odds ratios (OR) with 95% credible intervals (CrI) and probability of being best (Pbest) was used to compare all interventions simultaneously. Albendazole and corticosteroids combination therapy was the only regimen that significantly decreased the risk of seizure recurrence compared with conservative treatment (OR 0.32, 95% CrI 0.10-0.93, Pbest 73.3%). Albendazole and corticosteroids alone or in combination were all efficacious in hastening granuloma resolution, but the combined therapy remained the best option based on probability analysis (OR 3.05, 95% CrI 1.24-7.95, Pbest 53.9%). The superiority of the combination therapy changed little in RCTs with different follow-up durations and in sensitivity analyses. The limitations of this study include high risk of bias and short follow-up duration in most studies. CONCLUSIONS: Dual therapy of albendazole and corticosteroids was the most efficacious regimen that could prevent seizure recurrence and promote lesion resolution in a follow-up period of around one year. It should be recommended for the management of SCG until more high-quality evidence is available.

Pneumothorax as the initial manifestation of idiopathic hypereosinophilic syndrome.

We report a case of hypereosinophilic syndrome in a 47-year-old man who had acute pneumothorax as the initial presentation. Peripheral blood eosinophil count increased continuously over a period of 1 month and was associated with pulmonary changes and appearance of skin lesions on the right chest wall. Idiopathic hypereosinophilic syndrome was confirmed by bone marrow aspiration biopsy and skin lesion biopsy after exclusion of all possible secondary etiologies. The clinical status and chest radiographs showed marked improvement after treatment with corticosteroids.

Pathogen characteristics reveal novel antibacterial approaches for interstitial lung disease.

Interstitial lung disease (ILD) is a clinical disorder associated with changes of lung structure. Concurrent infection is a serious complication and one of the major factors that exacerbates ILD. Pathogen screening is a critical step in early diagnosis and proper treatment of ILD with secondary infection. Here we analyzed distribution and drug susceptibility of pathogens isolated from hospitalized ILD patients from January, 2007 to December, 2008 and compared them to bacterial drug resistance data in CHINET during the same period. The main specimens were from sputum culture, lavage fluid culture, lung biopsy tissue culture, and pleural effusion culture and bacterial or fungal cultures were performed on these specimens accordingly. Drug susceptibility was tested for positive bacterial cultures using disk diffusion (Kirby-Bauer method) and E Test strips in which results were determined based on the criteria of CLSI (2007). A total of 371 pathogen strains from ILD patients, including 306 bacterial strains and 65 fungal strains were isolated and cultured. Five main bacterial strains and their distribution were as follows: Klebsiella pneumoniae (31.7%), Pseudomonas aeruginosa (20.6%), Acinetobacter (12.7%), Enterobacter cloacae (8.2%), and Staphylococcus aureus (7.8%). The results showed that ILD patients who had anti-infection treatment tended to have Gram-negative bacteria, whether they acquired an infection in the hospital or elsewhere. Drug resistance screening indicated that aminoglycosides and carbapenems had lower antibiotic resistance rates. In addition, we found that the usage of immunosuppressants was associated with the increased infection rate and number of pathogens that were isolated. In conclusion, aminoglycosides and carbapenems may be selected as a priority for secondary infection to control ILD progression. Meanwhile, the use of anti-MRSA/MRCNS drugs may be considered for Staphylococcus infection.

Ossification process involving the human thoracic ligamentum flavum: role of transcription factors.

INTRODUCTION: Ossification of the ligamentum flavum (OLF) of the spine is associated with serious neurologic compromise, but the pathomechanism of this process remains unclear. The objective of this study was to investigate the pathomechanism of the ossification process, including the roles of various transcriptional factors in the ossification of human thoracic ligamentum flavum. METHODS: Sections of the thoracic ligamentum flavum were obtained from 31 patients with OLF who underwent posterior thoracic decompression, and from six control patients free of OLF. Cultured ligamentum flavum cells (n = 6, each) were examined with real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis for Sry-type high-mobility group box 9 (Sox9), runt-related transcription factor 2 (Runx2), muscle segment homeobox 2 (Msx2), Osterix, distal-less homeobox 5 (Dlx5), and AP-1. The harvested sections were examined with hematoxylin-eosin, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method, and immunohistochemistry for the transcriptional factors. RESULTS: Compared with the control, the OLF showed disorganization of the elastic fiber bundles and abundant hypertrophic chondrocytes in the ossification front. TUNEL-positive chondrocytes were found near the ossified plaques. The mRNA expression levels of Sox9, Runx2, Msx2, and AP-1 in cultured cells from the ligamentum flavum of OLF patients were significantly different from those of the control. OLF samples were strongly immunoreactive to Sox9, Runx2, and Msx2 at proliferating chondrocytes in the fibrocartilage area. Hypertrophic chondrocytes were positive for Runx2, Osterix, Dlx5, and AP-1. CONCLUSIONS: The ossification process in OLF seems to involve chondrocyte differentiation under the unique expression of transcriptional factors. Accumulation of hypertrophic chondrocytes was evident around the calcified area at the ossification front, and we suggest that the differentiation of these cells seems to be concerned with the ossification process.

High-mobility group box-1 and its receptors contribute to proinflammatory response in the acute phase of spinal cord injury in rats.

STUDY DESIGN: To examine the localization and expression of high-mobility group box-1 (HMGB-1) protein and its receptors after rat spinal cord injury. OBJECTIVE: To elucidate the contribution of HMGB-1 and its receptors as potential candidates in a specific upstream pathway to the proinflammatory response leading to a cascade of secondary tissue damage after spinal cord injury. SUMMARY OF BACKGROUND DATA: HMGB-1 was recently characterized as a key cytokine with a potential role in nucleosome formation and regulation of gene transcription. No studies have investigated the role of HMGB-1 in spinal cord injury. METHODS: Injured thoracic spinal cord from 62 rats aged 8 to 12 weeks and spinal cord from 20 control rats were examined. HMGB-1 was localized by immunofluorescence staining, costaining with cell markers, and by immunoelectron microscopy. The expression of HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)2, and TLR4 were also examined by immunohistochemistry. RESULTS: HMGB-1 expression appeared earlier than that of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in the spinal cord injury rats, with the HMGB-1 produced by both macrophages and neurons. HMGB-1 translocated from nucleus to cytoplasm in some neurons at an early stage after neural injury. Increased expression of HMGB-1, RAGE, and TLRs was observed after injury, and interaction of HMGB-1 with RAGE or TLRs, particularly in macrophage, was confirmed at 3 days after injury. CONCLUSION: Our results demonstrated an earlier onset in the expression of HMGB-1 than in tumor necrosis factor-α, IL-1ß, and IL-6 after spinal cord injury. The release of HMGB-1 from neurons and macrophages is mediated through the HMGB-1/RAGE or TLR pathways. HMGB-1 seems to play at least some roles in the proinflammatory cascade originating the secondary damage after the initial spinal cord injury.

Tumor necrosis factor-α antagonist reduces apoptosis of neurons and oligodendroglia in rat spinal cord injury.

STUDY DESIGN: To examine the effects of a tumor necrosis factor (TNF)-α antagonist (etanercept) on rat spinal cord injury and identify a possible mechanism for its action. OBJECTIVE: To elucidate the contribution of etanercept to the pathologic cascade in spinal cord injury and its possible suppression of neuronal and oligodendroglial apoptosis. SUMMARY OF BACKGROUND DATA: Etanercept has been recently used successfully for treatment of inflammatory disorders. However, only a few studies have examined its role in suppressing neuronal and oligodendroglial apoptosis in spinal cord injury. METHODS: Etanercept or saline (control) was administered by intraperitoneal injection 1 hour after thoracic spinal cord injury in rats. The expressions and localizations of TNF-α, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2) were examined by immunoblot and immunohistochemical analyses. Spinal cord tissue damage between saline- and etanercept-treated groups was also compared after hematoxylin-eosin and luxol fast blue (LFB) staining. The Basso-Beattie-Bresnahan (BBB) scale was used to evaluate rat locomotor function after etanercept administration. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells were counted and the immunoreactivity to active caspase-3 and caspase-8 was examined after etanercept administration. RESULTS: Immunoblot and double immunofluorescence staining revealed suppression of TNF-α, TNFR1, and TNFR2 expression after administration of etanercept in the acute phase of spinal cord injury. LFB staining demonstrated potential myelination in the etanercept-treated group from 2 week after spinal cord injury, together with an increased BBB locomotor score. Double immunofluorescence staining showed a significant decrease in TUNEL-positive neurons and oligodendroglia from 12 hour to 1 week in the gray and white matters after etanercept administration. Immunoblot analysis demonstrated overexpression of activated caspase-3 and caspase-8 after spinal cord injury, which was markedly inhibited by etanercept. CONCLUSION: Our results indicated that etanercept reduces the associated tissue damage of spinal cord injury, improves hindlimb locomotor function, and facilitates myelin regeneration. This positive effect of etanercept on spinal cord injury is probably attributable to the suppression of TNF-α, TNFR1, TNFR2, and activated caspase-3 and caspase-8 overexpressions, and the inhibition of neuronal and oligodendroglial apoptosis.

Microarray analysis of expression of cell death-associated genes in rat spinal cord cells exposed to cyclic tensile stresses in vitro.

BACKGROUND: The application of mechanical insults to the spinal cord results in profound cellular and molecular changes, including the induction of neuronal cell death and altered gene expression profiles. Previous studies have described alterations in gene expression following spinal cord injury, but the specificity of this response to mechanical stimuli is difficult to investigate in vivo. Therefore, we have investigated the effect of cyclic tensile stresses on cultured spinal cord cells from E15 Sprague-Dawley rats, using the FX3000 Flexercell Strain Unit. We examined cell morphology and viability over a 72 hour time course. Microarray analysis of gene expression was performed using the Affymetrix GeneChip System, where categorization of identified genes was performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) systems. Changes in expression of 12 genes were validated with quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The application of cyclic tensile stress reduced the viability of cultured spinal cord cells significantly in a dose- and time-dependent manner. Increasing either the strain or the strain rate independently was associated with significant decreases in spinal cord cell survival. There was no clear evidence of additive effects of strain level with strain rate. GO analysis identified 44 candidate genes which were significantly related to "apoptosis" and 17 genes related to "response to stimulus". KEGG analysis identified changes in the expression levels of 12 genes of the mitogen-activated protein kinase (MAPK) signaling pathway, which were confirmed to be upregulated by RT-PCR analysis. CONCLUSIONS: We have demonstrated that spinal cord cells undergo cell death in response to cyclic tensile stresses, which were dose- and time-dependent. In addition, we have identified the up regulation of various genes, in particular of the MAPK pathway, which may be involved in this cellular response. These data may prove useful, as the accurate knowledge of neuronal gene expression in response to cyclic tensile stress will help in the development of molecular-based therapies for spinal cord injury.

Transpedicular fixation in management of thoracolumbar burst fractures: monosegmental fixation versus short-segment instrumentation.

STUDY DESIGN: A prospective clinical trial was conducted. OBJECTIVE: To compare the clinical and radiologic late results of monosegmental transpedicular fixation versus short-segment pedicle instrumentation (SSPI) in management of thoracolumbar burst fractures and evaluate the efficacy of monosegmental transpedicular fixation. SUMMARY OF BACKGROUND DATA: SSPI (1 level above and 1 below the fracture level) are accepted by many surgeons as an accepted technique for the treatment of thoracolumbar burst fractures. To preserve more motion segments, some authors have advocated monosegmental pedicle instrumentation (MSPI). The recent developments showed that MSPI yielded good clinical results; however, there were no report about comparison of clinical outcome between monosegmental and biosegmental transpedicular fixation in management of thoracolumbar burst fractures. METHODS: Eighty-five patients with thoracolumbar burst fractures fulfilling the inclusion criteria were included in the study. The patients were randomized by a simple method into 2 groups. Group 1 were treated with monosegmental transpedicular fixation (n = 47), and group 2 were treated with biosegmental transpedicular fixation (n = 38). Clinical (Low Back Outcome Score and Oswestry Disability Index) and radiologic (load-sharing classification index, sagittal index, and percentage of anterior body height compression) outcomes were analyzed. RESULTS: The 2 groups were similar in age, follow-up period, and severity of the deformity and fracture. The postoperative and follow-up sagittal index, local kyphosis, percentage of anterior body height compression, and average correction loss in local kyphosis in both groups were not significantly different. The failure rate between the 2 surgical approaches was also not significantly different (group 1 = 6.38% and group 2 = 5.26%). Oswestry Disability Index improved in both groups by >25 points in a similar amount (P = 0.23). The average follow-up Low Back Outcome Score was 74.9 and 60.2 for group 1 and group 2, respectively (P = 0.033). CONCLUSION: In conclusion, radiologic parameters demonstrated that both MSPI and SSPI are the effective and reliable operative techniques for selected thoracolumbar burst fractures. MSPI shortened the operative time and decreased the amount of blood loss significantly and, thus, offered better clinical results. Nevertheless, long-term studies are supposed to be performed to support the outcomes.

Epidural abscess associated with pyogenic spondylodiscitis of the lumbar spine; evaluation of a new MRI staging classification and imaging findings as indicators of surgical management: a retrospective study of 37 patients.

INTRODUCTION: The aim of this study was to review the patients with lumbar epidural abscess in terms of neurological morbidity, therapeutic outcome, and prognosis, while assessing the usefulness of a new MRI staging classification and specific imaging findings as indicators for surgical management. MATERIALS AND METHODS: We reviewed 37 patients who sustained epidural abscess associated with pyogenic spondylodiscitis of the lumbar spine. Ten patients were treated conservatively, while 27 required urgent or elective surgical drainage. We studied patients with respect to symptomatology, Frankel-American Spinal Injury Association (ASIA) scale evaluation and a new proposed system of MRI staging of pyogenic spondylodiscitis (stages I­V). RESULTS: Of the 37 patients with stage IV and V MRI lesions, 13 (35%) had septicemia and 8 (22%) presented with Frankel-ASIA scale C-D neurological status. All cases with ringlike enhancement on gadolinium-enhanced MRI in the epidural abscess lesions were treated surgically. Progression of local kyphosis and loss of intervertebral disk height were significantly prevented in the surgical group (P < 0.05). Improvements of neurological status and laboratory data were better in the surgical group than the conservative group (P < 0.05), with significantly short hospital stay (P < 0.05). DISCUSSION: Epidural abscess associated with pyogenic spondylodiscitis presents with various neurological symptoms. In addition to assessment of progression by clinical symptomatology, modified neurological Frankel-ASIA scaling and the currently proposed MRI staging regimen may help to consider the timing of surgical intervention. In the acute, subacute or acute-on-chronic phase and the ringlike enhancement pattern of epidural abscess on gadolinium-enhanced MRI may be an indicator for surgery.