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Resume Introduction Avec l’augmentation du nombre d’internes en formation, la neurochirurgie francaise est en pleine mutation demographique. L’objectif de cette etude etait de dresser un etat des lieux des conditions de travail et des perspectives des jeunes neurochirurgiens francais. Methode Une enquete informatisee a ete adressee a une liste d’internes et jeunes seniors (219 adresses mail obtenue lors de reunions d’enseignement). Le questionnaire comportait des questions sur les perspectives de carriere, la quantite de travail, le salaire, l’ambiance, la qualite de vie, l’encadrement et le travail universitaire. Resultats Au total, 78 reponses ont ete obtenues entre janvier et mars 2014. Cinquante-six pour cent des jeunes seniors ont eu des difficultes a obtenir un post-internat mais en sont satisfaits a 78 %. Les seniors etaient plus nombreux a envisager une carriere liberale que les internes. Les jeunes neurochirurgiens semblaient inquiets vis-a-vis de leurs postes futurs et 33 % des sujets avaient un plan de carriere different de leurs aspirations initiales. Le temps de travail hebdomadaire moyen de 76,8 h etait juge excessif. Le repos de securite etait absent ou incomplet dans 91 % des cas. Par ailleurs, 81 % des sujets trouvaient leur salaire insuffisant. L’ambiance de travail etait globalement bien percue (3,7/5), de meme que la qualite de vie (3,2/5). L’encadrement theorique etait juge insatisfaisant (2,43/5) de meme que le temps de travail universitaire de 1,58 demi-journees mensuelle. En revanche, l’encadrement pratique etait tres bien percu (3,63/5). Conclusion Ce travail apporte des elements d’orientation pour les reformes futures, il devra etre reitere pour en evaluer l’efficacite.

Objective This article is protected by copyright. All rights reserved. Methods Synovial tissues from RA and osteoarthritis (OA) were stained for PTPN2. Synovial fibroblasts (SF), were stimulated with TNF and IL1β, LPS, TRAIL or thapsigargin. Expression of PTPN2 in SF or PBMCs was analyzed by Real-time PCR and Western blotting. Cell death, the release of IL-6 and IL-8 and the induction of autophagy were analyzed after PTPN2 silencing. MeDIP analysis was used to check DNA methylation-regulated gene expression of PTPN2. Results PTPN2 was significantly overexpressed in synovial tissues of RA compared to OA. Patients treated with anti-TNF therapy showed significantly reduced staining for PTPN2 compared with patients treated with non-biologics. In RASF, PTPN2 expression was higher compared to OASF. This differential expression is not regulated by DNA methylation. PTPN2 was further upregulated after stimulation with TNF, TNF combined with IL1β and LPS. There was no significant difference in basal PTPN2 expression in PBMCs from patients with RA, ankylosing spondylitis, systemic lupus erythematosus and healthy controls. Most interestingly, PTPN2 silencing in RASF significantly increased the production of the inflammatory cytokine IL-6 but did not affect levels of IL-8. Moreover, functional analysis showed that high PTPN2 levels contribute to the increased apoptosis resistance of RASF and increased autophagy. Conclusion This is the first study on PTPN2 in RASF showing that PTPN2 regulates IL-6 production, cell death and autophagy. This indicates that PTPN2 is linked to the pathogenesis of RA via synovial fibroblasts. This article is protected by copyright. All rights reserved.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells, SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study, we investigated the regulation, expression, and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNFα, but decreased upon treatment with cigarette smoke extract. Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1 modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can therefore promote progression of RA.SIRT1 is upregulated by TNFα but decreased upon CSE treatment of RASF. Upregulation of SIRT1 in RA smokers correlates with increased leukocytic infiltration. SIRT1 modulates expression of genes regulating cell adhesion and inflammation. SIRT1 regulates proliferation of RASF.

Extracellular vesicles (EV) can modulate the responses of cells to toll-like receptor (TLR) ligation; conversely, TLR ligands such as double-stranded RNA (dsRNA) can enhance the release of EV and influence of the composition and functions of EV cargos. Inflamed synovial joints in rheumatoid arthritis (RA) are rich in EV and extracellular RNA; besides, RNA released from necrotic synovial fluid cells can activate the TLR3 signaling in synovial fibroblasts (SFs) from patients with RA. Since EV occur prominently in synovial joints in RA and may contribute to the pathogenesis, we questioned whether EV can interact with dsRNA, a TLR3 ligand, and modify its actions in arthritis. We have used as model the effects on RA SFs, of EV released from monocyte U937 cells and peripheral blood mononuclear cells upon stimulation with Poly(I:C), a synthetic analog of dsRNA. We show that EV released from unstimulated cells and Poly(I:C)-stimulated U937 cells [Poly(I:C) EV] differ in size but bind similar amounts of Annexin V and express comparable levels of MAC-1, the receptor for dsRNA, on the vesicular membranes. Specifically, Poly(I:C) EV contain or associate with Poly(I:C) and at least partially protect Poly(I:C) from RNAse III degradation. Poly(I:C) EV shuttle Poly(I:C) to SFs and reproduce the proinflammatory and antiviral gene responses of SFs to direct stimulation with Poly(I:C). Poly(I:C) EV, however, halt the death receptor-induced apoptosis in SFs, thereby inverting the proapoptotic nature of Poly(I:C). These prosurvival effects sharply contrast with the high toxicity of cationic liposome-delivered Poly(I:C) and may reflect the route of Poly(I:C) delivery via EV or the fine-tuning of Poly(I:C) actions by molecular cargo in EV. The demonstration that EV may safeguard extracellular dsRNA and allow dsRNA to exert antiapoptotic effects on SFs highlights the potential of EV to amplify the pathogenicity of dsRNA in arthritis beyond inflammation (by concurrently enhancing the expansion of the invasive synovial stroma).

Objective Augmented soft tissue mobilization (ASTM) has been used to treat Achilles tendinopathy and is thought to promote collagen fiber realignment and hasten tendon regeneration. The objective of this study was to evaluate the biomechanical and histological effects of ASTM therapy on rabbit Achilles tendons after enzymatically induced injury. Methods This study was a non-human bench controlled research study using a rabbit model. Both Achilles tendons of 12 rabbits were injected with collagenase to produce tendon injury simulating Achilles tendinopathy. One side was then randomly allocated to receive ASTM, while the other received no treatment (control). ASTM was performed on the Achilles tendon on postoperative days 21, 24, 28, 31, 35, and 38. Tendons were harvested 10 days after treatment and examined with dynamic viscoelasticity and light microscopy. Results Cross-sectional area in the treated tendons was significantly greater than in controls. Storage modulus tended to be lower in the treated tendons but elasticity was not significantly increased. Loss modulus was significantly lower in the treated tendons. There was no significant difference found in tangent delta (loss modulus/storage modulus). Microscopy of control tendons showed that the tendon fibers were wavy and type III collagen was well stained. The tendon fibers of the augmented soft tissue mobilization treated tendons were not wavy and type III collagen was not prevalent. Conclusion Biomechanical and histological findings showed that the Achilles tendons treated with ASTM had better recovery of biomechanical function than did control tendons.

Study Design Case-control study. Objectives To explore self-reported responses for differentiating CAI(chronic ankle instability) and lateral ankle sprain(LAS)-Coper status. Background Self-reported instability and disability in conjunction with patient history have been used to differentiate CAI and LAS-Copers, but certain self-reported evaluation tools, such as the Identification of Functional Ankle Instability (IdFAI), may contain some redundancy. It remains unknown if other potential patient history items in concert with selected items from the IdFAI could create more efficient identification of CAI and LAS-Copers. Methods and Measures Data were extracted from 241 participants enrolled in previous laboratory studies that compared CAI(n=128) and LAS-Coper(n=113) groups classified by the guidelines of the International Ankle Consortium. Responses on each item of the IdFAI were examined, and patients responded if they had received formalised rehabilitation for their previous LAS(Y/N). Chi-square analyses were used to explore response distributions. Results Many of the items on the IdFAI resulted in statistically significant response distributions. Of note, 84% of CAI patients responded their ankle gives way(item#6) at least monthly, while 98.8% of LAS-Copers answered yearly or never(p Conclusions The frequency of giving-way and feeling unstable seems to differentiate CAI versus LAS-Copers effectively, which could be used to focus the categorization of patients with a history of LAS with the deficits that need addressing, while utilisation of crutches and initial rehabilitation was less definitive. Additional exploration on the severity of the previous LAS, and the interactions with utilisation of crutches and participation in rehabilitation is needed to shape future interventions for those with LAS history.

Introduction. Understanding the genetic architecture of scleroderma (SSc) susceptibility is vital both in gene discovery and in determining the influence of previously identified susceptibility variants. It is particularly important in understanding disease mechanism in a disease with few therapies and great morbidity and mortality. Methods. We selected 557 cases from the Australian Scleroderma Cohort Study (ASCS), for genotyping with the Immunochip, a custom Illumina Infinium genotyping array containing 196 524 rare and common variants shown to be important in a wide variety of autoimmune disorders. A total of 4537 controls were taken from the 1958 British Birth cohort. Genotype data were analysed with PLINK. Samples and SNPs with low call rates were excluded, as were SNPs in Hardy-Weinberg disequilibrium or with less than two occurrences of the minor allele. Eigenstrat was used to analyse population structure. The final data set consisted of 505 cases, 4491 controls and 146 867 SNPs. Allelic association analyses were conducted using Fisher's exact test. Genotype clusters were manually examined for all associations of P < 10−5 since calling is difficult for some rare variants. Results. Significant and suggestive associations were detected at seven loci. Several of these have been previously implicated in scleroderma susceptibility (HLA-DRB1 and STAT4) and several are novel associations, including SNPs near PXK (P = 4.4 × 10−6) and CFDP1(P = 2.6 × 10−6). The strongest associations were with SNPs in the Class II region of the MHC. One of the most strongly associated SNPs [rs4639334; P = 1.6 × 10−8; odds ratio (OR) = 1.8] is in linkage disequilibrium (r2 = 0.46) with the Class II allele HLA-DRB1*11:01. This allele has been associated with SSc. Another strongly associated SNP is rs2857130 (P = 1.6 × 10−8; OR = 0.67), which lies in the promoter region of HLA-DRB1, but is not in LD with any classical MHC alleles. Outside the MHC, there were six regions of association with P < 10−5,including the confirmed SSc locus at STAT4. Several SNPs implicate a locus at PXK, which has been previously associated with SLE but not with SSc. The remaining associations are novel for both SSc and SLE and require replication. Of particular interest is a rare variant located within a non-coding RNA on chromosome 6q21 which was ∼20 times more frequent in cases than controls. We are currently dissecting the potential biological implications of this locus. Conclusions. This pilot study has confirmed previously reported SSc associations, revealed further genetic overlap between SSc and SLE, and identified putative novel SSc susceptibility loci including a rare allele with major effect size

The draft genome of the Gram-positive spore-forming Anoxybacillus ayderensis strain MT-Cab (Firmicutes), isolated from an enrichment culture of Chloracidobacterium thermophilum, was sequenced and comprises 2,577,015 bp in 92 contigs. The draft genome is predicted to consist of 2,699 protein-coding genes, 73 tRNA-coding genes, and an estimated 8 rRNA operons.

Background The angiopoietin(Ang)/Tie2 system is a key regulator of vascular biology. The expression of membrane bound (mb) Tie2 and Ang-1 ensures vessel stability, whereas Ang-2, inducible by vascular endothelial growth factor (VEGF), hypoxia, and inflammation, acts as an antagonist. Tie2 signalling is also attenuated by soluble Tie2 (sTie2), the extracellular domain of the receptor, which is shed upon stimulation with VEGF. Herein, we investigate the role of Ang/Tie2 in the peripheral vasculopathy in systemic sclerosis (SSc) including animal models. Methods The expression of Ang-1/-2 and Tie2 in skin/serum of SSc patients was compared with healthy controls by immunohistochemistry (IHC)/ELISA. Expression of Ang/Tie2 was analysed in different animal models: VEGF transgenic (tg) mice, hypoxia model, bleomycin-induced skin fibrosis, and tight skin 1 (TSK1) mice. Results In SSc, dermal microvessels abundantly expressed Ang-2, but not Ang-1 compared with healthy controls. The percentage of mbTie2+ microvessels was profoundly decreased whereas the levels of sTie2 were increased already in early disease. Both in skin and sera of SSc patients, the Ang1/2 ratio was reduced, being lowest in patients with digital ulcers indicating vessel destabilizing conditions. We next studied potential influencing factors in animal models. The VEGF tg mouse model, the hypoxia, and the inflammation-dependent bleomycin model all showed a similar dysregulation of Ang/Tie2 as in SSc, which did not apply for the non-inflammatory TSK1 model. Conclusion Peripheral microvasculopathy in SSc results from a complex dysregulation of angiogenic signalling networks including the VEGF and the Ang/Tie2 system. The profoundly disturbed Ang-/Tie-2 balance might represent an important target for vascular therapeutic approaches in SSc. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1304-2) contains supplementary material, which is available to authorized users.

A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Here we show transcriptomic differences in synovial fibroblasts from different joint locations and that HOX gene signatures reflect the joint-specific origins of mouse and human synovial fibroblasts and synovial tissues. Alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns not only in arthritis but in any disease with a prominent stromal component., Nature Communications, 8, ISSN:2041-1723

International audience; This study addresses geographic variation of body size and shape and of allele frequencies at 21 microsatellite loci in southern African populations of the desert locust, Schistocercagregaria. These populations, which belong to the subspecies S. g. flaviventris, lack the capacity to change phase and to swarm relative to the northern populations of the nominate subspecies, S. g. gregaria. We reported overall genetic and morphological similarities among localities that cover most of the subspecies range. Of particular interest, the level of genetic diversity was moderately lower than in the swarming subspecies of the northern range. In addition, S. g. flaviventris populations were genetically homogeneous, such as observed in the northern range of the nominate subspecies. This result can be explained by north—southwest seasonal migration to follow rainfall.

Objective To investigate the effects of BET bromodomain protein inhibition on inflammatory activation and functional properties of rheumatoid arthritis synovial fibroblasts (RASF). Methods The expression of the BET bromodomain proteins BRD2, BRD3 and BRD4 was analysed in synovial tissue by immunohistochemistry. RASE were stimulated with tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and toll-like receptor (TLR) ligands (Pam3, pIC and lipopolysaccharide (LPS)) in the presence or absence of the BET inhibitor I-BET151, or siRNA targeting BRD2, BRD3 and BRD4. RASF expression of inflammatory mediators, including MMP1, MMP3, IL-6 and IL-8, was measured by q-PCR, q-PCR array and ELISA. Cellular viability, apoptosis, proliferation and chemoattractive properties of RASF were investigated using MTT, cell apoptosis ELISA, BrdU-based proliferation and transwell migration assays. Results BRD2, BRD3 and BRD4 proteins were detected in rheumatoid arthritis (RA) synovial tissue, expressed in both RASF and macrophages. I-BET151 suppressed cytokine and TLR ligand-induced secretion of MMP1, MMP3, IL-6 and IL-8, and mRNA expression of more than 70% of genes induced by TNF-alpha and IL-1 beta. Combined silencing of BRD2, BRD3 and BRD4 significantly reduced cytokine and TLR ligand-induced expression of a subset of gene products targeted by I-BET151, including MMP1, CXCL10 and CXCL11. I-BET151 treatment of RASF reduced RASF proliferation, and the chemotactic potential for peripheral blood leucocytes of RASF conditioned medium. Conclusions Inhibition of BET family proteins suppresses the inflammatory, matrix-degrading, proliferative and chemoattractive properties of RASF and suggests a therapeutic potential in the targeting of epigenetic reader proteins in RA

In this study, we analyzed the methylation status of human promoters in rheumatoid arthritis synovial fibroblasts (RASF). Differentially methylated genes between RASF and osteoarthritis synovial fibroblasts (OASF) were identified by methylated DNA immunoprecipitation and hybridization to human promoter tiling arrays. The methylation status was confirmed by pyrosequencing. Gene and protein expression of differentially methylated genes was evaluated with real-time PCR, Western blot, and immunohistochemistry. Chromatin immunoprecipitation was used to measure the gene promoter–associated acetylation and methylation of histones. Transcription factor–specific targets were identified with microarray and luciferase assays. We found that the transcription factor T-box transcription factor 5 (TBX5) was less methylated in rheumatoid arthritis (RA) synovium and RASF than in osteoarthritis (OA) samples. Demethylation of the TBX5 promoter in RASF and RA synovium was accompanied by higher TBX5 expression than in OASF and OA synovium. In RA synovium, TBX5 expression was primarily localized to the synovial lining. In addition, the TBX5 locus was enriched in activating chromatin marks, such as histone 4 lysine 4 trimethylation and histone acetylation, in RASF. In our functional studies, we observed that 790 genes were differentially expressed by 2–6-fold after overexpression of TBX5 in OASF. Bioinformatic analysis of these genes revealed that the chemokines IL-8, CXCL12, and CCL20 were common targets of TBX5 in OASF. Taken together, our data show that TBX5 is a novel inducer of important chemokines in RASF. Thus, we conclude that RASF contribute to the inflammatory processes operating in the pathogenesis of RA via epigenetic control of TBX5.

OBJECTIVE Changes in polyamine-modulated factor 1 (PMF-1) promoter methylation might favor the expression of spermidine/spermine N1-acetyltransferase 1 (SSAT-1), causing excessive consumption of S-adenosyl methionine (SAM). This study was undertaken to evaluate the effect of SSAT-1 activity inhibition, either alone or in combination with SAM. METHODS Synovial fibroblasts were isolated from patients with rheumatoid arthritis (RA) or osteoarthritis (OA). PMF-1 promoter methylation was determined by pyrosequencing. Small interfering RNAs (siRNAs) against SSAT-1 were transfected weekly in RA synovial fibroblasts (RASFs). In addition, synovial fibroblasts were treated with diminazene aceturate (DA), an inhibitor of SSAT-1. SSAT-1, 5-methylcytosine (5-MeC), adenosyl methionine decarboxylase (AMD), PMF-1, DNA methyltransferase 1 (DNMT-1), CXCL12, β1 integrin, and CD44 levels were measured by flow cytometry. Putrescine levels were determined by colorimetry. Levels of matrix metalloproteinases were measured by enzyme-linked immunosorbent assay. Cell adhesion was tested. The SCID mouse model of RA was used to monitor the invasiveness of RASFs. RESULTS RASFs showed elevated SSAT-1, AMD, and PMF-1 levels. However, PMF-1 promoter methylation was unchanged. Transfection of siRNA targeting SSAT-1 increased 5-MeC levels within 21 days. Similarly, DA increased 5-MeC levels in RASFs. In addition, DA increased the levels of DNMT-1, decreased the levels of AMD, putrescine, activation markers, and MMP-1, and altered the adhesion of RASFs. DA was more efficient in RASFs with higher levels of SSAT-1. Most interestingly, the combination of DA and SAM reduced the invasiveness of RASFs by 70%. CONCLUSION The use of DA alone or in combination with SAM/l-methionine might introduce a new therapeutic concept in RA. This is the first therapy that would directly target RASFs and thereby inhibit ongoing joint destruction.

Sebaceous carcinoma (SC) is an uncommon neoplasm manifesting itself either in the eyelid or extraocularly in the head and neck area. Surgery is the standard of care. Irradiation is rarely proposed as monotherapy but is frequently administered as an adjuvant regimen following surgical resection. There is no known strategy concerning chemotherapeutic treatment in highly aggressive recurrent - or metastatic - forms of the disease. Our patient presented with an aggressive SC of the scalp recurring after multiple excisions and local radiotherapy. Chemotherapy with 5-fluorouracil, cisplatin and docetaxel was then initiated; 4 cycles were administered, followed by capecitabine maintenance. Shortly after starting chemotherapy, dermal lesions had completely disappeared and radiological response could be seen. The patient experienced an extended period (>20 months) of complete remission. In this report, we show an excellent response of a highly aggressive SC after a combination of chemotherapy as for head and neck cancers.

The proportion of load transmitted through the lumbar neural arch increases with aging, spinal degeneration, and lordosis, effectively shielding the lumbar vertebral bodies from load. This stress shielding may contribute to bone loss in the vertebral body, leading to increased fracture risk. To test his hypothesis, we performed a study to determine if vertebral body fractures were associated with a higher neural arch/vertebral body volumetric bone mineral density (vBMD) ratio. Trabecular vBMD was calculated by quantitative CT in the L3 vertebral body and neural arch (pars interarticularis) of 36 women with vertebral compression fractures and 39 controls. Neural arch/vertebral body vBMD ratio was calculated, and its relationship to fracture status was determined using linear regression models adjusted for age and body mass index. Vertebral body trabecular vBMD was lower in fracture cases as compared to controls (mean ± SD, 49.0 ± 36.0 vs. 87.5 ± 36.8 mg/cm3, respectively; P

Objective To investigate the role of autophagy in the regulation of cell death in rheumatoid arthritis synovial fibroblasts (RASFs). Methods RASFs and osteoarthritis synovial fibroblasts (OASFs) were treated with thapsigargin (TG), an inducer of endoplasmic reticulum (ER) stress, and MG132, a proteasome inhibitor. Then, 3-methyladenine was used as an autophagy inhibitor and bafilomycin A1 as a lysosome inhibitor. Polyubiquitinated proteins, p62, and autophagy induction were evaluated by immunoblotting, immunofluorescence microscopy, and immunohistochemistry, respectively. OASFs were transfected with small interfering RNA targeting autophagy-linked FYVE protein (ALFY). Cell death was evaluated by flow cytometry and a caspase 3 activity assay. Results In RASFs, the induction of autophagy by TG and MG132 was increased compared to that in OASFs. Whereas autophagy promoted a caspase 3–independent induction of cell death under ER stress, autophagy had a protective role in apoptosis induced by proteasome inhibition. Treatment of RASFs with 3-methyladenine blocked TG-induced cell death. ER stress induced a strong accumulation of p62-positive polyubiquitinated protein aggregates, accompanied by the formation of large vacuoles in RASFs but not OASFs. Furthermore, TG-induced p62 protein expression was increased, whereas TG-induced ALFY expression was reduced, in RASFs compared to OASFs. ALFY knockdown promoted the accumulation of p62, the formation of polyubiquitinated protein aggregates, and cell death. Conclusion Our data provide the first evidence of a dual role of autophagy in the regulation of death pathways in RASFs. A reduced expression of ALFY and the formation of p62-positive polyubiquitinated protein aggregates promote cell death in RASFs under severe ER stress.

ObjectivesTo assess whether the discrepancy between the strong antifibrotic effects of tyrosine kinase inhibitors (TKIs) in animal models and the inconsistent results in clinical studies might be related to the activation levels of drug targets.MethodsSkin sections of bleomycin, TSK1, Fra-2 transgenic mice, SSc patients and controls were analysed by histology and immunohistochemistry. Subgroups of mice were treated with the TKIs nilotinib or imatinib. Differences in the activation levels of the TKI targets p-PDGFRβ (platelet derived growth factor β) and p-c-abl were assessed.ResultsIn bleomycin and TSK1 mice, expression of activated p-PDGFRβ (platelet derived growth factor receptor β) and p-c-abl was ubiquitous with strong upregulation compared with controls. Treatment with TKIs resulted in successful target inhibition and consequently reduced dermal fibrosis. In the Fra-2 model, the activation levels of p-PDGFRβ and p-c-abl were much lower than in the bleomycin and the TSK1 models. Accordingly, nilotinib did not prevent dermal fibrosis and target inhibition was unsuccessful. Notably, in skin biopsies of SSc patients, the mean activation levels of TKI targets were only moderate and in the majority of patients resembled those of the non-responsive Fra-2 model.ConclusionsAnimal models for proof-of-concept studies should be selected based on a similar activation level and expression pattern of drug targets as in human SSc.

Resume Nous rapportons une technique de reduction precoce suivie d’une fixation percutanee des fractures isolees du sacrum : traction manuelle forte associee a contre-traction manuelle du tronc afin de desimpacter le foyer de fracture, puis tractions transcondyliennes femorales bilaterales et vissage ilio-sacre (VISI) bilateral percutane par quatre vis ilio-sacrees. La reduction et fixation a ciel ouvert, associees a une laminectomie sacree en cas de signes neurologiques, restent le gold standard . La reduction precoce et la fixation percutanee permettent la restitution des parametres pelviens, en diminuant l’agression des parties molles et les risques d’infection. Elle est compatible avec les gestes de decompression, dans le meme temps operatoire avec deux installations ou bien differes de quelques jours. Ces patients complexes doivent etre orientes vers des centres de reference specialises.

A theoretical description is proposed for the formation of the extended fine structures of the secondary electrons in 3d-metals with allowance for the XAFS-like scattering of the secondary electrons in the final state through the first- and second-order processes, and an electron in the intermediate state through the second-order process. It is shown that considering the first- and second-order processes, as well as the nonmonotonic behavior of the intensity of the corresponding atomic electron transitions, we are able to describe anomalous thermal features of the extended fine structure in the secondary electron spectra.

Confirmatory factor analysis was used to determine the factor structure of the Wechsler Intelligence Scale for Children–Fourth Edition (WISC-IV) scores of 297 children referred to a children’s hospital in the Southwestern United States. Results support previous findings that indicate the WISC-IV is best represented by a direct hierarchical (bifactor) model including four first-order factors and one general intelligence factor. In this sample, the general intelligence factor accounted for 50% of the total variance and 76% of the common variance. Of the first-order factors, the Verbal Comprehension factor accounted for the most total (5.6%) and common (8.4%) variance. Furthermore, the general intelligence factor accounted for more variance in each subtest than did its respective first-order factor and it was the only factor that exhibited adequate measurement precision (ωh = .87). These findings support previous recommendations that WISC-IV interpretations should focus on the general intelligence factor over first-order factors.

Theoretical and empirical research suggests possible pathways between women's experiences of childhood emotional abuse (CEA) and later intimate partner violence victimization (IPV-V) and perpetration (IPV-P), including attachment style and early maladaptive schemas. This study tested a model examining the unique mediating effects of insecure attachment and early maladaptive schemas on the relationship between CEA and IPV-V (n = 396) or IPV-P (n = 409) in college women. Contrary to hypotheses that both attachment style and maladaptive schema endorsement would mediate the relationship between CEA and IPV-V and IPV-P, regression analyses indicated the disconnection/rejection schema domain was the only significant mediator between CEA and IPV-V (p = .01). This same relation held for childhood emotional abuse and IPV-P (p < .001). These findings provide preliminary clinical utility for examining schema endorsement, the use of schema therapy (Young, Klosko, & Weishar, 2003), or both with women who have emotiona...

Objective To elucidate whether the microRNA (miRNA) cluster miR-17–92 contributes to the activated phenotype of rheumatoid arthritis synovial fibroblasts (RASFs). Methods RASFs were stimulated with tumor necrosis factor α (TNFα), and the expression and regulation of the miR-17–92 cluster were studied using real-time quantitative PCR (PCR) and promoter activity assays. RASFs were transfected with single precursor molecules of miRNAs from miR-17–92 and the expression of matrix-degrading enzymes and cytokines was measured by quantitative PCR and enzyme-linked immunosorbent assay. Potential miRNA targets were identified by computational prediction and were validated using reporter gene assays and Western blotting. The activity of NF-κB signaling was determined by reporter gene assays. Results We found that TNFα induces the expression of miR-17–92 in RASFs in an NF-κB–dependent manner. Transfection of RASFs with precursor molecules of single members of miR-17–92 revealed significantly increased expression levels of matrix-degrading enzymes, proinflammatory cytokines, and chemokines in precursor miR-18a (pre-miR-18a)–transfected RASFs. Using reporter gene assays, we identified the NF-κB pathway inhibitor TNFα-induced protein 3 as a new target of miR-18a. In addition, pre-miR-18a–transfected RASFs showed stronger activation of NF-κB signaling, both constitutively and in response to TNFα stimulation. Conclusion Our data suggest that the miR-17–92–derived miR-18a contributes to cartilage destruction and chronic inflammation in the joint through a positive feedback loop in NF-κB signaling, with concomitant up-regulation of matrix-degrading enzymes and mediators of inflammation in RASFs.

Medical school admissions interviews are used to assess applicants’ nonacademic characteristics as advocated by the Association of American Medical Colleges’ Advancing Holistic Review Initiative. The objective of this study is to determine whether academic metrics continue to significantly influence interviewers’ scores in holistic processes by blinding interviewers to applicants’ undergraduate grade point averages (uGPA) and Medical College Admission Test (MCAT). This study examines academic and demographic predictors of interview scores for two applicant cohorts at the University of Michigan Medical School. In 2012, interviewers were provided applicants’ uGPA and MCAT scores; in 2013, these academic metrics were withheld from interviewers’ files. Hierarchical regression analysis was conducted to examine the influence of academic and demographic variables on overall cohort interview scores. When interviewers were provided uGPA and MCAT scores, academic metrics explained more variation in interview scores (7.9%) than when interviewers were blinded to these metrics (4.1%). Further analysis showed a statistically significant interaction between cohort and uGPA, indicating that the association between uGPA and interview scores was significantly stronger for the 2012 unblinded cohort compared to the 2013 blinded cohort (β = .573, P < .05). By contrast, MCAT scores had no interactive effects on interviewer scores. While MCAT scores accounted for some variation in interview scores for both cohorts, only access to uGPA significantly influenced interviewers’ scores when looking at interaction effects. Withholding academic metrics from interviewers’ files may promote assessment of nonacademic characteristics independently from academic metrics.

Objective Fibrin deposits are characteristic of the synovial tissues in rheumatoid arthritis (RA). Once citrullinated, fibrin becomes an autoantigen and is thought to contribute in this way to perpetuate the disease. Our study aimed to analyse the responses of RA synovial fibroblasts (RASF) to native and citrullinated fibrin. Methods The transcriptome induced by fibrin in RASF was approached with whole-genome-based gene expression arrays. The upregulation of selected pro-inflammatory genes by fibrin was confirmed in additional primary cell cultures using quantitative PCR and ELISA. Citrullination reactions were carried out with recombinant human peptidylarginine deiminases (PAD) 2 and 4. Results In the whole-genome array native fibrin was found to modulate the gene expression profile of RASF, particularly upregulating mRNA levels of several pro-inflammatory cytokines. The induction of interleukin (IL)-6 and IL-8 by fibrin was confirmed in additional samples at both the mRNA and the protein level. Blocking and knockdown experiments showed the participation of toll-like receptor (TLR)4 in the induction of both cytokines. As compared with the native macromolecule, PAD2-citrullinated fibrin induced significantly higher expression of the pro-inflammatory cytokines in these cells. Conclusions Our results suggest that fibrin mediates inflammatory responses in RASF via a TLR4 pathway. In this way, fibrin and particularly its citrullinated form may contribute to sustain the cytokine burst in RA.

Objective The PIWIL (P-element induced wimpy testis like protein) subfamily of argonaute proteins is essential for Piwi-interacting RNA (piRNA) biogenesis and their function to silence transposons during germ-line development. Here we explored their presence and regulation in rheumatoid arthritis (RA). Methods The expression of PIWIL genes in RA and osteoarthritis (OA) synovial tissues and synovial fibroblasts (SF) was analysed by Real-time PCR, immunofluorescence and Western blot. The expression of piRNAs was quantified by next generation small RNA sequencing (NGS). The regulation of PIWI/piRNAs, proliferation and methylation of LINE-1 after silencing of PIWIL genes were studied. Results PIWIL2 and 4 mRNA were similarly expressed in synovial tissues and SF from RA and OA patients. However, on the protein level only PIWIL4 was strongly expressed in SF. Using NGS up to 300 piRNAs were identified in all SF without significant differences in expression levels between RA and OASF. Of interest, the analysis of the co-expression of the detected piRNAs revealed a less tightly regulated pattern of piRNA-823, -4153 and -16659 expression in RASF. In RASF and OASF, stimulation with TNFα+IL1β/TLR-ligands further significantly increased the expression levels of PIWIL2 and 4 mRNA and piRNA-16659 was significantly (4-fold) induced upon Poly(I:C) stimulation. Silencing of PIWIL2/4 neither affect LINE-1 methylation/expression nor proliferation of RASF. Conclusion We detected a new class of small regulatory RNAs (piRNAs) and their specific binding partners (PIWIL2/4) in synovial fibroblasts. The differential regulation of co-expression of piRNAs in RASF and the induction of piRNA/Piwi-proteins by innate immune stimulators suggest a role in inflammatory processes.

Problem Most medical schools have either retained a traditional admissions interview or fully adopted an innovative, multisampling format (e.g., the multiple mini-interview) despite there being advantages and disadvantages associated with each format. Approach The University of Michigan Medical School (UMMS) sought to maximize the strengths associated with both interview formats after recognizing that combining the two approaches had the potential to capture additional, unique information about an applicant. In September 2014, the UMMS implemented a hybrid interview model with six, 6-minute short-form interviews-highly structured scenario-based encounters-and two, 30-minute semistructured long-form interviews. Five core skills were assessed across both interview formats. Outcomes Overall, applicants and admissions committee members reported favorable reactions to the hybrid model, supporting continued use of the model. The generalizability coefficients for the six-station short-form and the two-interview long-form formats were estimated to be 0.470 and 0.176, respectively. Different skills were more reliably assessed by different interview formats. Scores from each format seemed to be operating independently as evidenced through moderate to low correlations (r = 0.100-0.403) for the same skills measured across different interview formats; however, after correcting for attenuation, these correlations were much higher. Next steps This hybrid model will be revised and optimized to capture the skills most reliably assessed by each format. Future analysis will examine validity by determining whether short-form and long-form interview scores accurately measure the skills intended to be assessed. Additionally, data collected from both formats will be used to establish baselines for entering students' competencies.

The development of antimicrobial resistance has made it necessary to measure antimicrobial usage in animal production sectors. France is a major European producer of white veal calves, but few data were previously available for that sector, even though these young animals are particularly susceptible to infection and considered as a reservoir of antimicrobial resistance. A cross-sectional study was conducted on 186 batches of French calves to estimate the exposure of white veal calves to antimicrobials and identify the potential risk factors related to antimicrobial usage. An indicator of calf exposure was calculated as a count of the number of antimicrobial treatments per calf. The indicator was based on veterinary prescriptions (products, quantity dispensed and dosage prescribed) and the estimated weight of calves at treatment, using the dates of treatment collected from farm registers. The study showed that calves were exposed to an average of 8.55 antimicrobial treatments (SD: 2.21, range: 2.75–15.86) over the five to six months of the fattening process. Group treatments were predominant (95.8%) and administered by the oral route. The “starting treatments”, given during the first two weeks of the fattening period, were administered systematically (to all the calves in all the farms) and accounted for a third of all treatments. Tetracyclines, polypeptides and macrolides were the most widely used antimicrobials, with respectively 4.32, 1.59 and 1.01 treatments per calf. Only rare uses of 3rd and 4th generation cephalosporins and fluoroquinolones, considered as critically important in human medicine, were reported. Despite low variability of exposure between farms, a linear mixed-effects model highlighted a higher variability between farmers (ICC = 0.14) or veterinarians (ICC = 0.12), than between integrators (ICC = 0.06). The number of calves per pen, introduced as a fixed effect in the model, was also significant: calves housed in pens of 6–10 and fed in buckets had on average 2.55 more antimicrobial treatments per calf than calves housed in pairs with the same feeding system. The model also highlighted an increase of 1.48 treatments per calf for farms with more than five percent of mortality, versus those with two percent or less. The present study showed that antimicrobial treatments are numerous in veal calf fattening farms, particularly at the arrival of the animals. Taking into account the development of resistance to antimicrobials, the necessity and the effectiveness of some of these treatments should be re-evaluated.

Background The DNA of rheumatoid arthritis synovial fibroblasts (RASF) is globally hypomethylated; this contributes to an aggressive behaviour. In an attempt to remethylate these cells, we supplemented with methyl donors. We investigated the possible interference of microRNAs (miRs). Material and methods RASF were treated with L-methionine or betaine. Transcripts of de novo methyltransferases (DNMTs) and miRs were measured by real-time PCR, and a transcription PCR array was performed. Levels of homocysteine, matrix metalloproteinase-1 (MMP-1) and global DNA methylation were determined. Transfection with lipofectamine was performed with specific pre-miRs and anti-miRs, such as miR29 and let7f. Results L-methionine was more efficient to increase DNA methylation than betaine. This was associated with a reduced expression of DNMT3A mRNA in betaine-treated RASF. Betaine increases the expression of miR29 in RASF which targets DNMT3A, thereby limiting the remethylation process. Nevertheless, betaine inhibited the expression of multiple transcription factors, decreased the release of MMP-1, biosynthesis of homocysteine and cell migration. Conclusion Alterations in cellular miRs profiles, in particular the upregulation of miR29, which targets DNMT3A, may limit the efficiency of betaine if it is used as DNA remethylating agent. However, L-methionine also has similar impact on miR29 expression. On the other hand, betaine has multiple other beneficial effects on the activated phenotype of RASF; it is not excluded that the effect of betaine on DNMT3A is, at least in part, indirect. Clinical trials with betaine could be promising.

Spine intersegmental motion parameters and the resultant regional patterns may be useful for biomechanical classification of low back pain (LBP) as well as assessing the appropriate intervention strategy. Because of its availability and reasonable cost, two-dimensional (2D) fluoroscopy has great potential as a diagnostic and evaluative tool. However, the technique of quantifying intervertebral motion in the lumbar spine must be validated, and the sensitivity assessed. The purpose of this investigation was to (1) compare synchronous fluoroscopic and optoelectronic measures of intervertebral rotations during dynamic flexion–extension movements in vitro and (2) assess the effect of C-arm rotation to simulate off-axis patient alignment on intervertebral kinematics measures. Six cadaveric lumbar–sacrum specimens were dissected, and active marker optoelectronic sensors were rigidly attached to the bodies of L2–S1. Fluoroscopic sequences and optoelectronic kinematic data (0.15-mm linear, 0.17–0.20 deg rotational, accuracy) were obtained simultaneously. After images were obtained in a true sagittal plane, the image receptor was rotated in 5 deg increments (posterior oblique angulations) from 5 deg to 15 deg. Quantitative motion analysis (qma) software was used to determine the intersegmental rotations from the fluoroscopic images. The mean absolute rotation differences between optoelectronic values and dynamic fluoroscopic values were less than 0.5 deg for all the motion segments at each off-axis fluoroscopic rotation and were not significantly different (P > 0.05) for any of the off-axis rotations of the fluoroscope. Small misalignments of the lumbar spine relative to the fluoroscope did not introduce measurement variation in relative segmental rotations greater than that observed when the spine and fluoroscope were perpendicular to each other, suggesting that fluoroscopic measures of relative segmental rotation during flexion–extension are likely robust, even when patient alignment is not perfect.

Rheumatoid arthritis (RA) is a systemic, inflammatory, autoimmune disorder with progressive articular damage that may result in lifelong disability. Although major strides in understanding the disease have been made, the pathogenesis of RA has not yet been fully elucidated. Early treatment can prevent severe disability and lead to remarkable patient benefits, although a lack of therapeutic efficiency in a considerable number of patients remains problematic. MicroRNAs (miRNAs) are small, non-coding RNAs that, depending upon base pairing to messenger RNA (mRNA), mediate mRNA cleavage, translational repression or mRNA destabilization. As fine tuning regulators of gene expression, miRNAs are involved in crucial cellular processes and their dysregulation has been described in many cell types in different diseases. In body fluids, miRNAs are present in microvesicles or incorporated into complexes with Argonaute 2 (Ago2) or high-density lipoproteins and show high stability. Therefore, they are of interest as potential biomarkers of disease in daily diagnostic applications. Targeting miRNAs by gain or loss of function approaches have brought therapeutic effects in various animal models. Over the past several years it has become clear that alterations exist in the expression of miRNAs in patients with RA. Increasing numbers of studies have shown that dysregulation of miRNAs in peripheral blood mononuclear cells or isolated T lymphocytes, in synovial tissue and synovial fibroblasts that are considered key effector cells in joint destruction, contributes to inflammation, degradation of extracellular matrix and invasive behaviour of resident cells. Thereby, miRNAs maintain the pathophysiological process typical of RA. The aim of the current review is to discuss the available evidence linking the expression of miRNAs to inflammatory and immune response in RA and their potential as biomarkers and the novel targets for treatment in patients with RA.

Objective Pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain–containing protein 2 (NOD-2), have been shown to contribute to the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to analyze the expression, regulation, and function of the PRR NOD-1 in RA synovial fibroblasts (RASFs), and to examine its interaction with other PRRs. Methods Expression of NOD-1 was analyzed by immunohistochemistry in synovial tissue from RA patients, psoriatic arthritis patients, gout patients, and osteoarthritis (OA) patients. RASFs and human monocyte-derived macrophages (HMDMs) were stimulated with L-alanyl-γ-D-glutamyl-meso-diaminopimelic acid, palmitoyl-3-cysteine-serine-lysine-4, poly(I-C), lipopolysaccharide, heat-inactivated bacteria, tumor necrosis factor α (TNFα), or interleukin-1β (IL-1β). Expression levels of IL-6, CCL5, matrix metalloproteinases (MMPs), NODs, and TLRs were measured by real-time reverse transcription–polymerase chain reaction and/or enzyme-linked immunosorbent assay. NOD-1 and NOD-2 were silenced with target-specific small interfering RNA. Phosphorylation of IL-1 receptor–associated kinase 1 (IRAK-1) was measured by Western blotting. Results Expression of NOD-1 protein was significantly increased in RA synovium compared to OA synovium. The basal expression of NOD-1 was similar in RASFs, OASFs, healthy control peripheral blood mononuclear cells, and healthy control HMDMs. Stimulation of RASFs with TLR-3 up-regulated the expression of NOD-1. Expression of IL-6, CCL5, MMPs, TLR-2, and NOD-2 was significantly up-regulated in RASFs by stimulation with the NOD-1 ligand. A synergistic effect on IL-6 production was observed in cells stimulated with NOD-1 and TLR-2 ligands or NOD-1 and TLR-4 ligands. Silencing of NOD-1, but not NOD-2, decreased the levels of IL-6 in RASFs after stimulation with TLR-2 and IL-1β, and blocked the phosphorylation of IRAK-1. Conclusion NOD-1 is strongly expressed in different cell types in the synovial tissue of patients with RA. These results indicate that NOD-1, either alone or interacting with other inflammatory mediators, can play an important role in the chronic and destructive inflammation of the joints in RA.

Object The object of this study was to determine if the addition of transverse connectors (TCs) to a rod-screw construct leads to increased stabilization of the cervical spine. Methods Eleven human cadaveric cervical spines (C2–T1) were used to examine the effect of adding connectors to a C3–7 rod-screw construct in 3 models of instability: 1) C3–6 wide laminectomy, 2) wide laminectomy and 50% foraminotomy at C4–5 and C5–6, and 3) wide laminectomy with full medial to lateral foraminotomy. Following each destabilization procedure, specimens were tested with no TC, 1 TC between the C-5 screws, and 2 TCs between the C-4 and C-6 screws. Testing of the connectors was conducted in random order. Specimens were subjected to ± 2 Nm of torque in flexion and extension, lateral bending, and axial rotation. Range of motion was determined for each experimental condition. Statistical comparisons were made between the destabilized and intact conditions, and between the addition of TCs and the absence of TCs. Results The progressive destabilization procedures significantly increased motion. The addition of TCs did not significantly change motion in flexion and extension. Lateral bending was significantly decreased with 2 connectors, but not with 1 connector. The greatest effect was on axial rotation. In general, 2 TCs were more restrictive than 1 TC, and decreased motion 10% more than fixation alone. Conclusions Regardless of the degree of cervical destabilization, 1 or 2 TCs decreased motion compared with rods and screws alone. Axial rotation was most affected. Transverse connectors effectively increase the rigidity of rod-screw constructs in the cervical spine. Severe cervical instability can be overcome with the use of 2 TCs, but in cases in which 2 cannot be used, 1 should be adequate and superior to none.

SUMMARYThe purpose of this study was to develop a standardized tool for the assessment of surveillance systems on zoonoses and animal diseases. We reviewed three existing methods and combined them to develop a semi-quantitative assessment tool associating their strengths and providing a standardized way to display multilevel results. We developed a set of 78 assessment criteria divided into ten sections, representing the functional parts of a surveillance system. Each criterion was given a score according to the prescription of a scoring guide. Three graphical assessment outputs were generated using a specific combination of the scores. Output 1 is a general overview through a series of pie charts synthesizing the scores of each section. Output 2 is a histogram representing the quality of eight critical control points. Output 3 is a radar chart representing the level reached by ten system attributes. This tool was applied on five surveillance networks.

ObjectiveTo analyse the expression of SIRT1 in synovial tissues and cells of patients with rheumatoid arthritis (RA) and to study the function of SIRT1 in inflammation and apoptosis in RA.MethodsLevels of SIRT1 expression were analysed in synovial tissues and cells from patients with RA by real-time PCR and western blotting before and after stimulation with toll-like receptor ligands, tumour necrosis factor α (TNFα) and interleukin 1β (IL-1β). Immunohistochemistry was used to study the localisation of SIRT1. Fluorescence activated cell sorting analysis was performed to investigate the effect of SIRT1 on apoptosis. Peripheral blood monocytes and rheumatoid arthritis synovial fibroblasts (RASFs) were transfected with wild-type or enzymatically inactive SIRT1 expression vectors or with siRNA targeting SIRT1. Cytokine analysis of IL-6, IL-8 and TNFα were performed by ELISA to study the role of SIRT1 on proinflammatory mediators of RA.ResultsSIRT1 was found to be constitutively upregulated in synovial tissues and cells from patients with RA compared to osteoarthritis. TNFα stimulation of RASFs and monocytes resulted in further induced expression levels of SIRT1. Silencing of SIRT1 promoted apoptosis in RASFs, whereas SIRT1 overexpression protected cells from apoptosis. Inhibition of SIRT1 enzymatic activity by inhibitors, siRNA and overexpression of an enzymatically inactive form of SIRT1 reduced lipopolysaccharide-induced levels of TNFα in monocytes. Similarly, knockdown of SIRT1 resulted in a reduction of proinflammatory IL-6 and IL-8 in RASFs.ConclusionThe TNFα-induced overexpression of SIRT1 in RA synovial cells contributes to chronic inflammation by promoting proinflammatory cytokine production and inhibiting apoptosis.

The ability to temporarily maintain information in order to successfully perform a task is important in many daily activities. However, the ability to quickly and accurately update existing mental representations in distracting situations is also imperative in many of these same circumstances. In the current studies, individuals varying in working memory capacity (WMC) performed different varieties of go/no-go tasks that have been hypothesized to measure inhibitory ability. The results indicated that low-WMC individuals relative to high-WMC individuals showed worse performance specifically in certain conditions of the conditional go/no-go task. Further analyses showed that increasing the temporal lag/number of intervening items between the previous target and the current lure had a deleterious effect on the performance of the low-WMC group only. The results indicate a relationship between WMC and the ability to selectively update, maintain, and retrieve information, especially in interference-rich conditions.

Treatment of chronic low back pain due to degenerative lumbar spine conditions often involves fusion of the symptomatic level. A known risk of this procedure is accelerated adjacent level degeneration. Motion preservation devices have been designed to provide stabilization to the symptomatic motion segment while preserving some physiologic motion. The aim of this study was to compare the changes in relative range of motion caused as a result of application of two non-fusion, dynamic stabilization devices: the Universal Clamp (UC) and the Wallis device. Nine fresh, frozen human lumbar spines (L1–Sacrum) were tested in flexion–extension, lateral bending, and axial rotation with a custom spine simulator. Specimens were tested in four conditions: (1) intact, (2) the Universal Clamp implanted at L3–4 (UC), (3) the UC with a transverse rod added (UCTR), and (4) the Wallis device implanted at L3–4. Total range of motion at 7.5 N-m was determined for each device and compared to intact condition. The UC device (with or without a transverse rod) restricted motion in all planes more than the Wallis. The greatest restriction was observed in flexion. The neutral position of the L3–4 motion segment shifted toward extension with the UC and UCTR. Motion at the adjacent levels remained similar to that observed in the intact spine for all three constructs. These results suggest that the UC device may be an appropriate dynamic stabilization device for degenerative lumbar disorders.

Resume La survie des traumatises graves depend d’une chaine de soins structuree faisant intervenir le plus rapidement possible de nombreuses specialites medicales et chirurgicales. Les pays anglo-saxons sont organises en reseau au niveau regional (« Trauma system »), afin d’orienter les traumatises graves dans des centres specialises (« Trauma center »). En France, les patients sont orientes par des medecins urgentistes vers le centre hospitalier le plus proche disposant du plateau technique necessaire. Devant une technicite des soins aux traumatises de plus en plus importante, peu de centres hospitaliers disposent de toutes les ressources necessaires. Des transferts secondaires vers des centres plus specialises peuvent entrainer un delai de prise en charge influencant potentiellement la mortalite. La creation de reseau de soins en traumatologie a une echelle regionale est essentielle pour permettre une orientation initiale des blesses adaptee dans les meilleurs delais, ainsi que la mise en commun des competences et des plateaux techniques. Le Reseau Nord-Alpin des urgences (RENAU) a mis en place en 2008 un reseau de traumatologie comprenant les medecins de toutes les disciplines concernees et exercant dans les trois departements du nord des Alpes francaises. Son evaluation est assuree par un registre des traumatises graves. L’amelioration de la qualite se base sur la mise en commun des competences et sur une evaluation continue des actes de soins afin de proposer des prises en charge adaptees et efficaces. Temoins de l’accident, SAMU, urgentistes, anesthesistes-reanimateurs, radiologues et chirurgiens constituent une veritable chaine de survie que nous devons consolider.

Low back pain (LBP) continues to be a very prevalent, disabling, and costly spinal disorder. Numerous interventions are routinely used for symptoms of acute LBP. One of the most common approaches is spinal manipulation therapy (SMT).To assess the current scientific literature related to SMT for acute LBP.Not applicable.Not applicable.Systematic review (SR).Literature was identified by searching MEDLINE using indexed and free text terms. Studies were included if they were randomized controlled trials (RCTs) published in English, and SMT was administered to a group of patients with LBP of less than 3 months. RCTs included in two previous SRs were also screened, as were reference lists of included studies. Combined search results were screened for relevance by two reviewers. Data related to methods, risk of bias, harms, and results were abstracted independently by two reviewers.The MEDLINE search returned 699 studies, of which six were included; an additional eight studies were identified from two previous SRs. There were 2,027 participants in the 14 included RCTs, which combined SMT with education (n=5), mobilization (MOB) (n=4), exercise (n=3), modalities (n=3), or medication (n=2). The groups that received SMT were most commonly compared with those receiving physical modalities (n=7), education (n=6), medication (n=5), exercise (n=5), MOB (n=3), or sham SMT (n=2). The most common providers of SMT were chiropractors (n=5) and physical therapists (n=5). Most studies (n=6) administered 5 to 10 sessions of SMT over 2 to 4 weeks for acute LBP. Outcomes measured included pain (n=10), function (n=10), health-care utilization (n=6), and global effect (n=5). Studies had a follow-up of less than 1 month (n=7), 3 months (n=1), 6 months (n=3), 1 year (n=2), or 2 years (n=1). When compared with various control groups, results for improvement in pain in the SMT groups were superior in three RCTs and equivalent in three RCTs in the short term, equivalent in four RCTs in the intermediate term, and equivalent in two RCTs in the long term. For improvement in function, results from the SMT groups were superior in one RCT and equivalent in four RCTs in the short term, superior in one RCT and equivalent in one RCT in the intermediate term, and equivalent in one RCT and inferior in one RCT in the long term. No harms related to SMT were reported in these RCTs.Several RCTs have been conducted to assess the efficacy of SMT for acute LBP using various methods. Results from most studies suggest that 5 to 10 sessions of SMT administered over 2 to 4 weeks achieve equivalent or superior improvement in pain and function when compared with other commonly used interventions, such as physical modalities, medication, education, or exercise, for short, intermediate, and long-term follow-up. Spine care clinicians should discuss the role of SMT as a treatment option for patients with acute LBP who do not find adequate symptomatic relief with self-care and education alone.

Based on the concept that proteolytic enzymes, like cathepsins, are associated with tissue destruction, we investigated the expression of the matrix-degrading cysteine proteinase cathepsin B in synovial tissues from the joints of patients with rheumatoid arthritis. The data indicate an enhanced transcription of cathepsin B in synovial cells when compared with normal fibroblasts, cathepsin B-producing epithelial tumor cells (SW1116), or fibroblasts derived from inflamed tonsils. Immunolocalization of cathepsin B appeared to be restricted mainly to the synovial cells attached to cartilage and bone at sites of rheumatoid joint erosion.

In the event of a virulent influenza pandemic, certain resources including ventilators, antibiotics, vaccines, oxygen, hospital beds, and antiviral medications will need to be carefully allocated. It is essential that scarce resources are allocated in an ethical manner taking into account the patient’s individual right to competent care and a population’s right to the fair distribution of potentially life-saving treatments. This article summarizes the ethical basis for distributing scarce resources and the rationale for establishing a hospital-based Scarce Resource Allocation Committee, a system of multiple triage officers, and a Clinical Review Committee.

STUDY DESIGN A prospective, randomized, controlled, multicenter clinical study. OBJECTIVE To evaluate the safety and feasibility of osteogenic protein (OP)-1 in 1-level lumbar spine instrumented posterolateral fusions. SUMMARY OF BACKGROUND DATA Instrumented posterolateral fusion with the use of autograft is a commonly performed procedure for a variety of spinal disorders. However, harvesting of bone from the iliac crest is associated with complications. A promising alternative for autograft are bone morphogenetic proteins. METHODS As part of a larger prospective, randomized, multicenter study, 36 patients were included, who received a 1-level instrumented posterolateral fusion of the lumbar spine. All patients had a degenerative or isthmic spondylolisthesis with symptoms of neurologic compression. There were 2 treatment arms: OP-1 combined with locally available bone from laminectomy (OP-1 group) or iliac crest autograft (autograft group). The primary outcome was the fusion rate based on a computed tomography scan after 1-year follow-up. The clinical outcome was measured using the Oswestry Disability Index. Additionally, the safety of OP-1 was evaluated by comparing the number and severity of adverse events that occurred between both groups. RESULTS Using strict criteria, fusion rates of 63% were found in the OP-1 group and 67% in the control group (P = 0.95). There was a decrease in Oswestry scores at subsequent postoperative time points compared with preoperative values (P > 0.001). There were no significant differences in the mean Oswestry scores between the study group and control group at any time point (P = 0.56). No product-related adverse events occurred. CONCLUSION The results demonstrate that OP-1 combined with locally obtained autograft is a safe and effective alternative for iliac crest autograft in instrumented single-level posterolateral fusions of the lumbar spine. The main advantage of OP-1 is that it avoids morbidity associated with the harvesting of autogenous bone grafts from the iliac crest.

OBJECTIVE: To describe a successful case of dexrazoxane treatment after an extravasation of doxorubicin and share a creative solution for formulary cost management. CASE SUMMARY: A 42-year-old female diagnosed with breast cancer was receiving doxorubicin as adjuvant treatment. The patient recently underwent a right mastectomy for a 3-centimeter grade 3 invasive ductal carcinoma. Three of 20 lymph nodes were positive, and the patient was stage 2B at presentation, with an estrogen receptor/progesterone receptor-positive and HER-2/neu-negative tumor. At an outside hospital, the patient was receiving doxorubicin through an infusion port when extravasation was noted after approximately 15 mL had been infused. She was transferred to Riverside Methodist Hospital and dexrazoxane treatment was initiated within 6 hours after extravasation. She received a full 3-day course of dexrazoxane treatment without complication and was discharged home. Significant delays in chemotherapy administration were avoided, and the patient successfully completed her planned chemotherapy course. DISCUSSION: Dexrazoxane has the potential to minimize tissue damage and treatment delays after an anthracycline extravasation. Although dexrazoxane is commercially marketed for 2 separate treatment indications, Totect is the Food and Drug Administration-approved product for anthracycline extravasations. Facilities administering anthracyclines should proactively resolve how to obtain, process, prepare, and administer this antidote to a patient within 6 hours of an extravasation event. Developing a preprinted chemotherapy extravasation order may facilitate the incorporation of the most recent Oncology Nursing Society guidelines to utilize dexrazoxane for an anthracycline extravasation. Cost sharing with other institutions may offer a creative solution to lessen the financial impact of stocking dexrazoxane therapy. CONCLUSIONS: Ensuring expedient treatment and accessibility to dexrazoxane therapy after an anthracycline extravasation is critical to the success of the treatment. All facilities utilizing anthracycline chemotherapy should purchase dexrazoxane or secure agreements with other facilities to guarantee the administration of this medication should extravasation occur.

Resume Nous rapportons dans ce chapitre les resultats de l’activite d’un certain nombre de services de neurochirurgie, dediee a la prise en charge des tumeurs de l’orbite et la comparons a celle d’un service neurochirurgical parisien dont les liens et l’implication avec un service d’ophtalmologie etaient tres etroits. L’activite des differents centres interesses est relativement faible et est constituee principalement par le traitement des meningiomes spheno-orbitaires, les autres types tumoraux etant traites de facon inegale et sporadique.