Neurophysiological changes during shortening osteotomies of the spine.

BACKGROUND CONTEXT: Kyphotic deformities with sagittal imbalance of the spine can be treated with spinal osteotomies. Those procedures are known to have a high incidence of neurological complications, in particular at the thoracic level. Motor evoked potentials (MEPs) have been widely used in helping to avoid major neurological deficits postoperatively. Previous reports have shown that a significant proportion of such cases present with important transcranial MEP (Tc-MEP) changes during surgery with some of them being predictive of postoperative deficits. PURPOSE: Our aim was to study Tc-MEP changes in a consecutive series of patients and correlate them with clinical parameters and radiological changes. STUDY DESIGN/SETTING: Retrospective case notes study from a prospective patient register. PATIENT SAMPLE: Eighteen patients undergoing posterior shortening osteotomies (nine at thoracic and nine at lumbar levels) for kyphosis of congenital, degenerative, inflammatory, or post-traumatic origin were included. OUTCOME MEASURES: Loss of at least 80% of Tc-MEP signal expressed as the area under the curve percentual change, of at least one muscle. METHODS: We studied the relation between outcome measure (80% Tc-MEP loss in at least one muscle group) and amount of posterior vertebral body shortening as well as angular correction measured on computed tomography scans, occurrence of postoperative deficits, intraoperative blood pressure at the time of the osteotomy, and hemoglobin (Hb) change. RESULTS: All patients showed significant Tc-MEP changes. In particular, greater than 80% MEP loss in at least one muscle group was observed in five of nine patients in the thoracic group and four of nine patients in the lumbar group. No surgical maneuver was undertaken as a result of this loss in an effort to improve motor responses other than verifying the stability of the construct and the extent of the decompression. Four patients developed postoperative deficits of radicular origin, three of them recovering fully at 3 months. No relation was found between intraoperative blood pressure, Hb changes, and Tc-MEP changes. Severity of Tc-MEP loss did not correlate with postoperative deficits. Shortening of more than 10 mm was linked to more severe Tc-MEP changes in the thoracic group. CONCLUSIONS: Transcranial MEP changes during spinal shortening procedures are common and do not appear to predict severe postoperative deficits. Total loss of Tc-MEP (not witnessed in our series) might require a more drastic approach with possible reversal of the correction and wake-up test.

Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: modulation in the SNI model of neuropathic pain

La douleur neuropathique est une forme de douleur chronique apparaissant suite à des lésions du système nerveux somato-sensoriel. Caractérisée par une plasticité neuronale inadapté, elle est très souvent intense, invalidante, associe des symptômes comme l'allodynie ou l' hyperalgésie et reste difficile à traiter avec les agents thérapeutiques actuels. Le thème de mon travail de thèse se concentre sur des mécanismes moléculaires de modulation des canaux sodiques voltage-dépendants suite à une lésion du nerf périphérique. Dans l'article présenté en annexe, j'ai focalisé mon travail sur une protéine, Nedd4-2, qui est une ligase ubiquitine. Elle a pour rôle de réguler et d'internaliser dans la cellule des protéines membranaires dont les canaux sodiques. Suite aux lésions du système nerveux périphérique, il existe une hyperexcitabilité neuronale engendrée notamment par un surplus et une dysrégulation des canaux sodiques à la membrane cellulaire. Dans 1 'hypothèse que l'ubiquitine ligase Nedd4-2 soit présente dans les neurones sensitifs primaires et ait un rôle dans la régulation des canaux sodiques, nous avons identifié cette protéine dans les neurones nociceptifs primaires du rat. En utilisant des techniques de Western Blot et d'immunohistochimie, j'ai trouvé que Nedd4-2 est présente dans presque 50% des neurones du ganglion spinal et ces neurones sont principalement des neurones nociceptifs. Dans un modèle expérimental de douleur neuropathique (SN I, pour spared nerve injury), Nedd4-2 se retrouve significativement diminuée dans le tissu du ganglion spinal. J'ai également investigué 1' expression de 2 isoformes des canaux sodiques connues pour leur implication dans la douleur, Navl.7 et Navl.8, et ces 2 isoformes se retrouvent dans les mêmes neurones que Nedd4-2. La caractérisation détaillée est décrite dans le manuscrit: «Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: modulation in the SNI model of neuropathic pain; Cachemaille M, Laedermann CJ, Pertin M, Abriel H, Gasselin RD, Decosterd 1.» Les résultats obtenus indiquent que Nedd4-2, en étant downrégulé après une lésion nerveuse, pourrait ainsi contribuer à une augmentation des canaux sodiques fonctionnels à la membrane. Ainsi Nedd4-2 pourrait être proposée comme cible thérapeutique de manière alternative aux bloqueurs de canaux sodiques. Ce travail a permis l'initiation d'autres expériences. J'ai contribué activement à la construction de vecteurs viraux type adéno-associé recombinant (rAA V2/6) et surexprimé la protéine in vivo dans les ganglions spinaux. Cette partie de mon travail se trouve intégrée dans d'autres travaux de mon laboratoire d'accueil qui a pu démontrer les effets fonctionnels de cette approche sur les courants sodiques enregistrés par électrophysiologie et une diminution de la douleur neuropathique chez la souris. - Abstract-Neuronal hyperexcitability following peripheral nerve lesions may stem from altered activity of voltagegated sodium channels (VGSCs), which gives rise toallodynia or hyperalgesia. In vitro, the ubiquitin ligase Nedd4-2 is a negative regulator of VGSC a-subunits (Nav), in particular Nav1.7, a key actor in nociceptor excitability. We therefore studied Nedd4-2 in rat nociceptors, its co-expression with Nav1.7 and Nav1.8, and its regulation in pathology. Adult rats were submitted to the spared nerve injury (SNI) model of neuropathic pain or injected with complete Freund's adjuvant (CFA), a model of inflammatory pain. L4 dorsal root ganglia (DRG) were analyzed in shamoperated animals, seven days after SNI and 48 h after CFA with immunofluorescence and Western blot. We observed Nedd4-2 expression in almost 50% of DRG neurons, mostly small and medium-sized. A preponderant localization is found in the non-peptidergic sub-population. Additionally, 55.7± 2.7% and 55.0 ±3.6% of Nedd4-2-positive cells are co-labeled with Nav1.7 and Nav1.8 respectively. SNI significantly decreases the proportion of Nedd4-2-positive neurons from 45.9± 1.9% to 33.5± 0.7% (p < 0.01) and the total Nedd4-2 protein to 44%± 0.13% of its basal level (p <0.01, n = 4 animals in each group, mean± SEM). In contrast, no change in Nedd4-2 was found after peripheral inflammation induced by CFA. These results indicate that Nedd4-2 is present in nociceptive neurons, is downregulated after peripheral nerve injury, and might therefore contribute to the dysregulation of Navs involved in the hyperexcitability associated with peripheral nerve injuries.

The role of the inflammasome in nonmyeloid cells.

Inflammasomes are cytosolic multiprotein complexes that can proteolytically activate caspase-1. Activated caspase-1 is needed for the maturation and secretion of interleukin (IL)-1beta and IL-18. In the past decade, there has been tremendous progress in our knowledge of inflammasome function and IL-1 signaling, mainly in cells of the innate immune system, such as monocytes, macrophages, neutrophils, and dendritic cells. Because nonimmune cells, including keratinocytes, synovial cells, or astrocytes, can form an interface between the body and the environment or a defined compartment (brain, joint), they are important guardians for the detection of danger signals and the consecutive initiation of an inflammatory response. They are present in anatomical compartments that are less accessible to myeloid cells and thus can fulfill tasks usually performed by residential macrophages. This review focuses on recent progress in our understanding of the processing and functional role of IL-1 in epithelial, mesenchymal, and neuronal cells and in conditions such as tissue repair.

A Multi-SNP Locus-Association Method Reveals a Substantial Fraction of the Missing Heritability.

There are many known examples of multiple semi-independent associations at individual loci; such associations might arise either because of true allelic heterogeneity or because of imperfect tagging of an unobserved causal variant. This phenomenon is of great importance in monogenic traits but has not yet been systematically investigated and quantified in complex-trait genome-wide association studies (GWASs). Here, we describe a multi-SNP association method that estimates the effect of loci harboring multiple association signals by using GWAS summary statistics. Applying the method to a large anthropometric GWAS meta-analysis (from the Genetic Investigation of Anthropometric Traits consortium study), we show that for height, body mass index (BMI), and waist-to-hip ratio (WHR), 3%, 2%, and 1%, respectively, of additional phenotypic variance can be explained on top of the previously reported 10% (height), 1.5% (BMI), and 1% (WHR). The method also permitted a substantial increase (by up to 50%) in the number of loci that replicate in a discovery-validation design. Specifically, we identified 74 loci at which the multi-SNP, a linear combination of SNPs, explains significantly more variance than does the best individual SNP. A detailed analysis of multi-SNPs shows that most of the additional variability explained is derived from SNPs that are not in linkage disequilibrium with the lead SNP, suggesting a major contribution of allelic heterogeneity to the missing heritability.

Impact de la prophylaxie hormonale sur les fractures du fémur proximal des femmes postménopausiques: une étude de simulation. [Impact of hormonal prevention on fractures of the proximal femur in postmenopausal women: a simulation study].

A simulation model of the effects of hormone replacement therapy (HRT) on hip fractures and their consequences is based on a population of 100,000 post-menopausal women. This cohort is confronted with literature derived probabilities of cancers (endometrium or breast, which are contra-indications to HRT), hip fracture, disability requiring nursing home or home care, and death. Administration of HRT for life prevents 55,5% of hip fractures, 22,6% of years with home care and 4,4% of years in nursing homes. If HRT is administered for 15 years, these results are 15,5%, 10% and 2,2%, respectively. A slight gain in life expectancy is observed for both durations of HRT. The net financial loss in the simulated population is 222 million Swiss Francs (cost/benefit ratio 1.25) for lifelong administration of HRT, and 153 million Swiss Francs (cost/benefit ratio 1.42) if HRT is administered during 15 years.

Diagnosis of periprosthetic hip infection : review

Since its introduction, total hip arthroplasty has become one of the most successful orthopedic operations ever. However, periprosthetic infection, now reported with the prevalence of around 1-2% is the most challenging complication. It is associated with disasterous physiological, psychological and financial effects. Therefore, early firm diagnosis is essential to avoid further patient morbidity and mortality as well as overwhelming financial medical service costs. This article reviews our current understanding of periprosthetic infection with particular focus on the clinical usefulness of various tests which are used to help make the diagnosis.

Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension.

The 3-year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long-term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross-over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long-term; 2207 cross-over). Reductions in BTMs were maintained (long-term group) or occurred rapidly (cross-over group) following denosumab administration. In the long-term group, lumbar spine and total hip BMD increased further, resulting in 5-year gains of 13.7% and 7.0%, respectively. In the cross-over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2-year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a "virtual untreated twin" cohort. Adverse events did not increase with long-term denosumab administration. Two adverse events in the cross-over group were adjudicated as consistent with osteonecrosis of the jaw. Five-year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile.

The fixation of the cemented femoral component. Effects of stem stiffness, cement thickness and roughness of the cement-bone surface.

After cemented total hip arthroplasty (THA) there may be failure at either the cement-stem or the cement-bone interface. This results from the occurrence of abnormally high shear and compressive stresses within the cement and excessive relative micromovement. We therefore evaluated micromovement and stress at the cement-bone and cement-stem interfaces for a titanium and a chromium-cobalt stem. The behaviour of both implants was similar and no substantial differences were found in the size and distribution of micromovement on either interface with respect to the stiffness of the stem. Micromovement was minimal with a cement mantle 3 to 4 mm thick but then increased with greater thickness of the cement. Abnormally high micromovement occurred when the cement was thinner than 2 mm and the stem was made of titanium. The relative decrease in surface roughness augmented slipping but decreased debonding at the cement-bone interface. Shear stress at this site did not vary significantly for the different coefficients of cement-bone friction while compressive and hoop stresses within the cement increased slightly.

Novel method to estimate the phenotypic variation explained by genome-wide association studies reveals large fraction of the missing heritability.

Genome-wide association studies (GWAS) are conducted with the promise to discover novel genetic variants associated with diverse traits. For most traits, associated markers individually explain just a modest fraction of the phenotypic variation, but their number can well be in the hundreds. We developed a maximum likelihood method that allows us to infer the distribution of associated variants even when many of them were missed by chance. Compared to previous approaches, the novelty of our method is that it (a) does not require having an independent (unbiased) estimate of the effect sizes; (b) makes use of the complete distribution of P-values while allowing for the false discovery rate; (c) takes into account allelic heterogeneity and the SNP pruning strategy. We applied our method to the latest GWAS meta-analysis results of the GIANT consortium. It revealed that while the explained variance of genome-wide (GW) significant SNPs is around 1% for waist-hip ratio (WHR), the observed P-values provide evidence for the existence of variants explaining 10% (CI=[8.5-11.5%]) of the phenotypic variance in total. Similarly, the total explained variance likely to exist for height is estimated to be 29% (CI=[28-30%]), three times higher than what the observed GW significant SNPs give rise to. This methodology also enables us to predict the benefit of future GWA studies that aim to reveal more associated genetic markers via increased sample size.

Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis.

A chronic inflammatory microenvironment favors tumor progression through molecular mechanisms that are still incompletely defined. In inflammation-induced skin cancers, IL-1 receptor- or caspase-1-deficient mice, or mice specifically deficient for the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) in myeloid cells, had reduced tumor incidence, pointing to a role for IL-1 signaling and inflammasome activation in tumor development. However, mice fully deficient for ASC were not protected, and mice specifically deficient for ASC in keratinocytes developed more tumors than controls, suggesting that, in contrast to its proinflammatory role in myeloid cells, ASC acts as a tumor-suppressor in keratinocytes. Accordingly, ASC protein expression was lost in human cutaneous squamous cell carcinoma, but not in psoriatic skin lesions. Stimulation of primary mouse keratinocytes or the human keratinocyte cell line HaCaT with UVB induced an ASC-dependent phosphorylation of p53 and expression of p53 target genes. In HaCaT cells, ASC interacted with p53 at the endogenous level upon UVB irradiation. Thus, ASC in different tissues may influence tumor growth in opposite directions: it has a proinflammatory role in infiltrating cells that favors tumor development, but it also limits keratinocyte proliferation in response to noxious stimuli, possibly through p53 activation, which helps suppressing tumors.

Role of neutrophils in the early shaping of the Leishmania major specific immune response in experimental murine cutaneous Leishmaniasis

The development of a protective immune response to microorganisms involves complex interactions between the host and the pathogen. The murine model of infection with Leishmania major (L. major) allows the study of the factors leading to the development of a protective immune response. Following infection with the protozoan parasite L. major, most strains of mice heal their lesions, while a few fail to control infection, both processes linked to the development of specific T helper subsets. The early events occurring during the first days following parasite inoculation are thought to be critical in the development of the Leishmania-specific immune response. Neutrophils are the first cells arriving massively to the site of infection, and recent evidence points to their role as organizers of the immune response, yet their specific role in this process remains elusive. Through interactions with cells present at the parasite inoculation site, and possibly within the draining lymph nodes, neutrophils could have an impact not only on the recruitment of inflammatory cells but also on the activation of local as well as newly migrated cells that will be crucial in shaping the Leishmania-specific immune response.

Pro-inflammatory cytokines induce the transcription factors C/EBPbeta and C/EBPdelta in astrocytes.

The transcription factors CCAAT/enhancer binding protein (C/EBP)-beta and -delta are key regulators for the expression of the acute phase genes in the liver, such as complement component C3 and antichymotrypsin. In the brain, these acute phase proteins are produced in response to pro-inflammatory cytokines by the reactive astrocytes, in particular those surrounding the amyloid plaques of Alzheimer's disease brains. Here we show that lipopolysaccharides (LPS), IL-1beta, and TNFalpha induce the expression of the c/ebpbeta and -delta genes in mouse primary astrocytes. This induction precedes the expression of the acute phase genes coding for the complement component C3 and the mouse homologue of antichymotrypsin. The induction of these two acute phase genes by LPS is blocked by cycloheximide, whereas this protein synthesis inhibitor does not affect the expression of the c/ebp genes. Altogether, our data support a role as immediate-early genes for c/ebpbeta and -delta, whose expression is induced by pro-inflammatory cytokines in mouse cortical astrocytes. In the liver, these transcription factors are known to play an important role in inflammation and energy metabolism regulation. Therefore, C/EBPbeta and -delta could be pivotal transcription factors involved in brain inflammation, in addition to their previously demonstrated role in brain glycogen metabolism regulation (Cardinaux and Magistretti. J Neurosci 16:919-929, 1996).

Erythème borrélien de la face [Borrelial erythema of the face]

BACKGROUND: Borrelial infection is characterized by various skin manifestations that are usually classified into three main types: chronic migratory erythema, borrelial lymphocytoma and acrodermatitis chronica atrophicans. We report an unusual case of borrelial cutaneous infection presenting as a mediofacial erythema that cannot be included in any of these three categories. CASE REPORT: A 51-year-old woman presented with infiltrated erythema of the middle of the face extending to the neck and chin. Medical history and physical examination revealed no signs of rosaceae. Infection with Borrelia was suspected on skin biopsy examination, which showed an inflammatory dermal infiltrate containing numerous plasma cells. The diagnosis of B.afzelii infection was confirmed by serology and polymerase chain reaction on the skin biopsy, both of which were positive for B.afzelii. DISCUSSION: Borrelial erythema of the face may represent a special form of cutaneous borrelial infection, which must be considered in the differential diagnosis of facial erythema, especially in areas of endemic borreliosis.

A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease.

Macrophage migration inhibitory factor (MIF) is an abundantly expressed proinflammatory cytokine playing a critical role in innate immunity and sepsis and other inflammatory diseases. We examined whether functional MIF gene polymorphisms (-794 CATT(5-8) microsatellite and -173 G/C SNP) were associated with the occurrence and outcome of meningococcal disease in children. The CATT(5) allele was associated with the probability of death predicted by the Pediatric Index of Mortality 2 (P=0.001), which increased in correlation with the CATT(5) copy number (P=0.04). The CATT(5) allele, but not the -173 G/C alleles, was also associated with the actual mortality from meningoccal sepsis [OR 2.72 (1.2-6.4), P=0.02]. A family-based association test (i.e., transmission disequilibrium test) performed in 240 trios with 1 afflicted offspring indicated that CATT(5) was a protective allele (P=0.02) for the occurrence of meningococcal disease. At baseline and after stimulation with Neisseria meningitidis in THP-1 monocytic cells or in a whole-blood assay, CATT(5) was found to be a low-expression MIF allele (P=0.005 and P=0.04 for transcriptional activity; P=0.09 and P=0.09 for MIF production). Taken together, these data suggest that polymorphisms of the MIF gene affecting MIF expression are associated with the occurrence, severity, and outcome of meningococcal disease in children.

Quantitative Ultrasound of the Heel and Fracture Risk Assessment: an Updated Meta-Analysis

Objectives: Quantitative ultrasound (QUS) is an attractive method for assessing fracture risk because it is portable, inexpensive, without ionizing radiation, and available in areas of the world where DXA is not readily accessible or affordable. However, the diversity of QUS scanners and variability of fracture outcomes measured in different studies is an important obstacle to widespread utilisation of QUS for fracture risk assessment. We aimed in this review to assess the predictive power of heel QUS for fractures considering different characteristics of the association (QUS parameters and fracture outcomes measured, QUS devices, study populations, and independence from DXA-measured bone density).Materials/Methods : We conducted an inverse-variance randomeffects meta-analysis of prospective studies with heel QUS measures at baseline and fracture outcomes in their follow-up. Relative risks (RR) per standard deviation (SD) of different QUS parameters (broadband ultrasound attenuation [BUA], speed of sound &SOS;, stiffness index &SI;, and quantitative ultrasound index [QUI]) for various fracture outcomes (hip, vertebral, any clinical, any osteoporotic, and major osteoporotic fractures) were reported based on study questions.Results : 21 studies including 55,164 women and 13,742 men were included with a total follow-up of 279,124 person-years. All four QUS parameters were associated with risk of different fractures. For instance, RR of hip fracture for 1 SD decrease of BUA was 1.69 (95% CI 1.43-2.00), SOS was 1.96 (95% CI 1.64-2.34), SI was 2.26 (95%CI 1.71-2.99), and QUI was 1.99 (95% CI 1.49-2.67). Validated devices from different manufacturers predicted fracture risks with a similar performance (meta-regression p-values>0.05 for difference of devices). There was no sign of publication bias among the studies. QUS measures predicted fracture with a similar performance in men and women. Meta-analysis of studies with QUS measures adjusted for hip DXA showed a significant and independent association with fracture risk (RR/SD for BUA =1.34 [95%CI 1.22-1.49]).Conclusions : This study confirms that QUS of the heel using validated devices predicts risk of different fracture outcomes in elderly men and women. Further research and international collaborations are needed for standardisation of QUS parameters across various manufacturers and inclusion of QUS in fracture risk assessment tools. Disclosure of Interest : None declared.